EP1487414A2 - Antibiotic composition - Google Patents

Antibiotic composition

Info

Publication number
EP1487414A2
EP1487414A2 EP03714005A EP03714005A EP1487414A2 EP 1487414 A2 EP1487414 A2 EP 1487414A2 EP 03714005 A EP03714005 A EP 03714005A EP 03714005 A EP03714005 A EP 03714005A EP 1487414 A2 EP1487414 A2 EP 1487414A2
Authority
EP
European Patent Office
Prior art keywords
antibiotic
product
host
dosage form
dispersion
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP03714005A
Other languages
German (de)
French (fr)
Other versions
EP1487414A4 (en
Inventor
Edward M. Rudnic
James D. Isbister
Jr. Donald J. Treacy
Sandra E. Wassink
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MiddleBrook Pharmaceuticals Inc
Original Assignee
Advancis Pharmaceutical Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/092,854 external-priority patent/US6627222B2/en
Priority claimed from US10/092,811 external-priority patent/US6623758B2/en
Priority claimed from US10/093,321 external-priority patent/US6610328B2/en
Priority claimed from US10/093,214 external-priority patent/US6638532B2/en
Priority claimed from US10/092,858 external-priority patent/US6632453B2/en
Application filed by Advancis Pharmaceutical Corp filed Critical Advancis Pharmaceutical Corp
Publication of EP1487414A2 publication Critical patent/EP1487414A2/en
Publication of EP1487414A4 publication Critical patent/EP1487414A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose

Definitions

  • This invention relates to antibiotic compositions and the use thereof. More particularly, this invention relates to a composition for the delivery of two or more antibiotics, and the use thereof.
  • the present invention is directed to a new and improved product that delivers two antibiotics of specified antibiotic pairs, and the use thereof, with the antibiotic pairs being one of the following (1) a protein synthesis inhibiting antibiotic and a non- protein synthesis inhibiting antibiotic; (2) Tetracycline and Doxycycline; or (3) Ciprofoxacin and Metronidazole; or (4) Amoxicillin and Clarithromycin; or (5) Amoxicillin and Dicloxacillin; or (6) Cephalosporin and Metronidazole, with pair #4 being an example of pair #1.
  • an antibiotic product for delivering at least two different antibiotics that is comprised of at least three dosage forms each comprised of at least one antibiotic and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one antibiotic of the antibiotic pair and at least one dosage form including at least a second antibiotic of the antibiotic pair.
  • each of the dosage forms may include two antibiotics of the pair, or one or two of the dosage forms may include only one of the two antibiotics of the pair and each of the remaining dosage forms may include only one or two of the antibiotics of the pair.
  • an antibiotic product for delivering at least two of the antibiotics of the hereinabove described antibiotic pairs wherein the product includes at least three dosage forms wherein each of the antibiotics of the pair is present in at least one of the three dosage forms and each of the three dosage forms includes at least one of the two antibiotics.
  • each dosage form includes only one antibiotic.
  • an antibiotic product for delivering at least two different antibiotics that is comprised of at least three dosage forms each comprised of at least one antibiotic and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one of the at least two antibiotics and at least one dosage form including at least a second antibiotic of the at least two antibiotics, wherein one of the least two antibiotics is one of the antibiotics of the hereinabove described antibiotic pairs and the other of the at least two different antibiotics is the other antibiotic of such pair.
  • each dosage form includes at least one of such two antibiotics.
  • each dosage form includes only one of the two antibiotics with each of the two antibiotics being present in at least one of the three dosage forms.
  • each of the dosage forms of the product that contains the antibiotic pairs has a different release profile, with one of the dosage forms being an immediate release dosage form.
  • the present invention is directed to treating a bacterial infection by administering to a host in need thereof an antibiotic product as hereinabove and hereinafter described.
  • a single or unitary antibiotic product that has contained therein at least three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in each of the at least three dosage forms is released at different times, and wherein each of the dosage forms includes at least one of the antibiotics of the antibiotic pairs.
  • One or more of the dosage forms may include more than one antibiotic.
  • the antibiotic product may be comprised of at least four different dosage forms, each of which starts to release the antibiotic contained therein at different times after administration of the antibiotic product, with each of the dosage forms including at least one of the two antibiotic of an antibiotic pair and with each antibiotic of the pair being present in at least one of the dosage forms.
  • the antibiotic product generally does not include more than five dosage forms with different release times.
  • the antibiotic product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration of the total antibiotic released from the antibiotic product is achieved no earlier than four hours after administration.
  • one of the at least three dosage forms is an immediate release dosage form whereby initiation of release of antibiotic therefrom is not substantially delayed after administration of the antibiotic product.
  • the second and third of the at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antibiotic product), whereby antibiotic released therefrom is delayed until after initiation of release of antibiotic from the immediate release dosage form.
  • antibiotic release from the second of the at least two dosage forms achieves a C max (maximum serum concentration in the serum) at a time after antibiotic released from the first of the at least three dosage forms achieves a C ma ⁇ in the serum, and antibiotic released from the third dosage form achieves a C max in the serum after the C max of antibiotic released from the second dosage form.
  • C max maximum serum concentration in the serum
  • the second of the at least two dosage forms initiates release of antibiotic contained therein at least one hour after the first dosage form, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of antibiotic from the first dosage form of the at least three dosage forms.
  • the immediate release dosage form produces a C max for antibiotic released therefrom within from about 0.5 to about 2 hours, with the second dosage form of the at least three dosage forms producing a C max for antibiotic released therefrom in no more than about four hours.
  • the Cm ax for such second dosage form is achieved no earlier than two hours after administration of the antibiotic product; however, it is possible within the scope of the invention to achieve C max in a shorter period of time.
  • the antibiotic product may contain at least three or at least four or more different dosage forms.
  • the antibiotic released from the third dosage form reaches a C max at a time later than the C max is achieved for antibiotic released from each of the first and second dosage forms.
  • release of antibiotic from the third dosage form is started after initiation of release of antibiotic from both the first dosage form and the second dosage form.
  • Cmax for antibiotic release from the third dosage form is achieved within eight hours.
  • the antibiotic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby antibiotic released from each of the at least four different dosage forms achieves a C max at a different time.
  • C max for all the antibiotic released from the antibiotic product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.
  • the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period.
  • the preferred regimen is that the product is administered only once over a twenty-four hour period.
  • a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile with each of the dosage forms including at least one of the antibiotics of the hereinabove described antibiotic pairs and wherein each antibiotic of the pair is present in at least one of the dosage forms.
  • Each of the dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics.
  • the two different antibiotics comprise Tetracycline and Doxycycline. In another embodiment the two different antibiotics comprise Ciprofoxacin and Metronidazole. In another embodiment the two different antibiotics comprise Amoxicillin and Clarithromycin. In another embodiment the two different antibiotics comprise Amoxicillin and Dicloxacillin. In another embodiment the two different antibiotics comprise Cephalosporin and Metronidazole.
  • the first dosage form contains one of the first antibiotics of the antibiotic pair and is free of the other antibiotic of the antibiotic pair, and in a preferred embodiment contains only such one antibiotic;
  • the second dosage form contains the other antibiotic of the pair and is free of such one antibiotic of the pair and in a preferred embodiment contains only one antibiotic and
  • the third dosage form contains such one antibiotic of the pair and is free of the other antibiotic of the pair and in a preferred embodiment contains only one antibiotic and if a fourth dosage form is used, such fourth dosage form contains such other antibiotic and is free of such one antibiotic and in a preferred embodiment bacteria are exposed to alternating pulses of the two antibiotics of the hereinabove described antibiotic pairs.
  • the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though C max of the fourth dosage form of the at least four dosage forms is reached after the C ma ⁇ of each of the other dosage forms is reached, antibiotic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
  • one of the antibiotics of the antibiotic pairs as hereinabove and hereinafter described is a protein synthesis inhibiting antibiotic and the other antibiotic of the antibiotic pair is a non-protein synthesis inhibiting antibiotic.
  • protein synthesis inhibiting antibiotic means an agent that disrupts the bacterial ribosome cycle through which polypeptide chain initiation and elongation is normally effected. There are multiple points in the ribosome cycle at which this can occur.
  • non-protein synthesis inhibiting antibiotic means antibiotics other than protein synthesis inhibiting antibiotics.
  • protein synthesis inhibiting antibiotics there may be mentioned: the aminoglycosides such as streptomycin, amikacin, and tobramycin; the macrolides such as erythromycin, clarithromycin, and lincomycin; the tetracyclines such as tetracycline, doxycycline, chlortetracycline, and minocycline; the oxaxolidinones such as linezolid; fusidic acid; and chloramphenicol.
  • aminoglycosides such as streptomycin, amikacin, and tobramycin
  • macrolides such as erythromycin, clarithromycin, and lincomycin
  • the tetracyclines such as tetracycline, doxycycline, chlortetracycline, and minocycline
  • the oxaxolidinones such as linezolid
  • fusidic acid and chloramphenicol.
  • non-protein synthesis inhibiting antibiotics there may be mentioned: the beta-lactam penicillins such as penicillin, amoxicillin, dicloxacillin, and ampicillin; the beta lactam cephalsporins such as cefotaxime, cefuroxime, cefaclor, and ceftriaxone; the beta lactam carbapenems such as imipenem and meropenem; the quinolones such as ciprofloxacin, moxifloxacin, and levofloxacin; the sulfonamides such as sulfanilimide and sulfamethoxazole; metronidazole; rifampin; vancomycin; and nitrofurantoin.
  • the beta-lactam penicillins such as penicillin, amoxicillin, dicloxacillin, and ampicillin
  • the beta lactam cephalsporins such as cefotaxime, cefuroxime, cefaclor, and ceftri
  • an antibiotic composition that includes three different dosage forms: the first dosage form providing an initial dosage of a first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the first dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in one preferred embodiment contains only one antibiotic; the second dosage form providing an initial dosage of a second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the second dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics and in one preferred embodiment contains only one antibiotic; and the third dosage form providing an additional dosage of said first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the third dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in one preferred embodiment contains only one antibiotic.
  • the first dosage form is an immediate release dosage form; and the second and third dosage forms are delayed release dosage forms.
  • an antibiotic composition that includes four different dosage forms: the first dosage form providing an initial dosage of a first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the first dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic; the second dosage form providing an initial dosage of a second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the second dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic; the third dosage form providing an additional dosage of said first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the third dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic; and the fourth dosage form providing an additional dosage of said second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the fourth dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic.
  • the first dosage form is an immediate release dosage form
  • Particularly advantageous formulations of the immediately preceding embodiments of the present invention are those that comprise Clarithromycin, a protein synthesis inhibiting antibiotic as one of the antibiotics, and Amoxicillin, a non- protein synthesis inhibiting antibiotic as the other antibiotic.
  • a first, immediate release dosage form contains an initial dosage of Clarithromycin and is free of any non-protein synthesis inhibiting antibiotics
  • a second, delayed release dosage form contains an initial dosage of Amoxicillin and is free of any protein synthesis inhibiting antibiotics
  • a third, delayed release dosage form provides an additional dosage of Clarithromycin and is free of any non-protein synthesis inhibiting antibiotics.
  • An optional fourth, dosage form provides an additional dosage of Amoxicillin and is free of any protein synthesis inhibiting antibiotics.
  • This fourth dosage form is a delayed release or a sustained release dosage form, preferably a delayed release dosage form.
  • the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antibiotic to be delivered by the product, with such immediate release dosage form generally providing at least 25% of the total dosage of the antibiotic to be delivered by the product.
  • the immediate release dosage form provides from about 20% to about 30% of the total dosage of antibiotic to be delivered by the product; however, in some cases it may be desirable to have the immediate release dosage form provide for about 45% to about 50% of the total dosage of antibiotic to be delivered by the product.
  • each of the delayed release dosage forms may provide about equal amounts of antibiotic; however, they may also be formulated so as to provide different amounts.
  • the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, of the total antibiotic; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total antibiotic; and where there are four delayed release components, the immediate release component provides from 10% to 25%o, by weight, of the total antibiotic.
  • the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, of the total antibiotic provided by the two delayed release components with the second delayed release component providing the remainder of the antibiotic.
  • the earliest released component provides 20% to 35% by weight of the total antibiotic provided by the three delayed release components
  • the next in time delayed release component provides from 20% to 40%, by weight, of the antibiotic provided by the three delayed release components and the last in time providing the remainder of the antibiotic provided by the three delayed release components.
  • the earliest delayed release component provides from 15% to 30%, by weight
  • the next in time delayed release component provides from 15% to 30%
  • the next in time delayed release component provides from 20% to 35%, by weight
  • the last in time delayed release component provides from 20% to 35%, by weight, in each case of the total antibiotic provided by the four delayed release components.
  • an antibiotic composition that is a mixture of antibiotic compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first antibiotic and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first antibiotic and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second antibiotic different from the first antibiotic and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising the second antibiotic and a pharmaceutically acceptable carrier; wherein the second and third compositions each have a release profile that provides a maximum serum concentration of the first antibiotic released from the second composition and a maximum serum concentration for the second antibiotic released from the third composition at a time after the first antibiotic released from the first composition reaches a maximum serum concentration, and wherein the fourth composition has a release profile that provides for a maximum serum concentration of the second antibiotic released from the fourth composition at a time after the antibiotics released from the second and third compositions reach a maximum serum concentration.
  • the first antibiotic and second antibiotic are one of the antibiotics of the herein
  • the release profiles of the second and third dosage forms are such that the maximum serum concentration of the first antibiotic released from the second dosage form, and the maximum serum concentration of the second antibiotic released from the third dosage form are reached at approximately the same time, or where the first antibiotic reaches a maximum serum concentration before or after the second antibiotic reaches a maximum serum concentration.
  • a first pulse in which a first antibiotic reaches a maximum serum concentration
  • a second pulse wherein a further dosage of the first antibiotic, and an initial dosage of the second antibiotic reach a maximum serum concentration at a time after the first pulse of the first antibiotic reaches a maximum serum concentration
  • a third pulse wherein an additional dosage of the second antibiotic reaches a maximum serum concentration at a time after the maximum serum concentration is reached for each of the first and second antibiotic dosages provided in the second pulse.
  • the first dosage of the first antibiotic achieves a maximum serum concentration within four hours after administration of the antibiotic composition; the second dosage of the first antibiotic and the first dosage of the second antibiotic each reach a maximum serum concentration within four to eight hours after administration of the antibiotic composition; and the second dosage of the second antibiotic reaches a maximum serum concentration within twelve hours after administration of the antibiotic composition.
  • an antibiotic composition that includes four different dosage forms, with the first dosage form providing an initial dosage of a first antibiotic of the hereinabove described antibiotic pairs, the second dosage form providing a further dosage of the first antibiotic; the third dosage form providing an initial dosage of a second antibiotic of such pair; and the fourth dosage form providing an additional dosage of the second antibiotic, wherein the antibiotics released from the second and third dosage forms reach a maximum serum concentration at a time after the antibiotic released from the first dosage form reaches a maximum serum concentration, and the antibiotic released from the fourth dosage form reaching a maximum serum concentration at a time after the times at which the antibiotics released from each of the first, second, and third dosage forms reach a maximum serum concentration.
  • the first dosage form provides for immediate release
  • the second and third dosage forms provide for a delayed release (pH or non pH dependent, with the second dosage form preferably being a pH dependent release)
  • the fourth dosage form provides for pH dependent or non pH dependent release preferably non pH dependent release.
  • the first dosage form generally contains from about 30 percent to about 80 percent of the first antibiotic
  • the second dosage form contains from about 30 percent to about 80 percent of the first antibiotic
  • the third dosage form contains from about 30 percent to about 80 percent of the second antibiotic
  • the fourth antibiotic dosage form contains from about 30 percent to about 80 percent of the second antibiotic.
  • each unit or dosage form is present in an amount of at least 20 percent by weight, with each dosage form or unit being present in the overall composition in an amount that generally does not exceed 60 percent by weight.
  • Each of the first and second dosage forms include from 20% to 80% of the total dosage of the first antibiotic to be provided by the composition, and each of the first and second dosage forms may include the same or different dosages of the first antibiotic.
  • Each of the third and fourth dosage forms include from 20% to 80% of the total dosage of the second antibiotic to be delivered by the composition, and each of the third and fourth units may have the same or different dosages of the antibiotic.
  • the product as hereinabove described may also be formulated in a manner such that the product contains at least three dosage forms wherein each of the three dosage forms is a delayed release dosage form, with the product being free of an immediate release dosage form.
  • the product contains the antibiotic pairs as hereinabove described.
  • the overall Cmax is reached within 12 hours after initial release of antibiotic, i.e. Cmax is achieved in less than about twelve hours after initial release of antibiotic.
  • this product may optionally contain a fourth dosage form.
  • such fourth dosage form is preferably a delayed release dosage form, but may otherwise be a sustained release dosage form.
  • the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period.
  • the preferred regimen is that the product is administered only once over a twenty-four hour period.
  • the overall composition includes each of the antibiotics in a therapeutically effective amount.
  • the specific amount(s) is dependant on the antibiotic used, the disease or infection to be treated, and the number of times of day that the composition is to be administered.
  • the antibiotic composition of the present invention may be administered for example, by any one of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, oral, preferably by oral administration.
  • the antibiotic product of the present invention may be formulated for administration by a variety of routes of administration.
  • the antibiotic product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration.
  • the antibiotic product is formulated in a manner such that it is suitable for oral administration.
  • the at least two different dosage forms may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion.
  • the immediate release dosage form is in the continuous phase
  • the delayed release dosage form is in a discontinuous phase.
  • the formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described.
  • an oil-in-water-in-oil emulsion with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.
  • an antibiotic product in the form of a patch which includes antibiotic dosage forms having different release profiles, as hereinabove described.
  • the antibiotic product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion.
  • the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase of the emulsion.
  • the antibiotic product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration.
  • the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
  • the antibiotic product is formulated in a manner suitable for oral administration.
  • each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
  • each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product.
  • antibiotic products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release of the antibiotic, as hereinabove described, whereby the C max of the antibiotic released from each of the tablets is reached at different times, with the C ma ⁇ of the total antibiotic released from the antibiotic product being achieved in less than twelve hours.
  • an antibiotic product including at least three dosage forms with different release profiles for different routes of administration is deemed to be within the skill of the art from the teachings herein.
  • the time of release can be controlled by the concentration of antibiotics in the coating and/or the thickness of the coating.
  • the first and second antibiotics employed in the antibiotic composition may be a wide variety of products.
  • the combination of first and second antibiotics that are used in the composition may be, for example, a penicillin and an aminoglycoside, such as gentamycin, tobramicin, amikacin or vancomycin.
  • Another antibiotic composition that may be employed is a combination of a sulfonamide, such as sulfamethoxasol, which would be combined with trimethoporim.
  • the first and second, antibiotics are different antibiotics and each is from a different class of antibiotic.
  • the immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
  • the materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, ydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 dalton
  • ingredients in this system may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration.
  • These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Piuronic line of surfactants, or any other material with surface active properties, or any combination of the above.
  • surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic
  • These materials may be present in the rate of 0.05-15% (W/W).
  • compositions in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
  • Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.
  • PEG polyethylene glycol
  • Carbowax, Polyox polyethylene glycol
  • waxes such as white wax or bees wax
  • paraffin acrylic acid derivatives
  • acrylic acid derivatives Eudragit
  • propylene glycol and ethylcellulose
  • compositions in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
  • the kind of materials useful for this purpose can be, but are not limited to, cellulose acetate phthalate, Eudragit L, and other phthalate salts of cellulose derivatives.
  • These materials can be present in concentrations from 4-20% (W/W).
  • Example 4 Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
  • Polyethylene glycol 4000 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Clarithromycin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
  • Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Clarithromycin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
  • Ciprofoxacin 75% (W/W)
  • Ciprofoxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5
  • Polyethylene glycol 4000 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Example 20 Gentamicin 20% (W/W) Sodium lauryl sulfate 2 Sodium monoglycerides 10 Sodium diglycerides 20 Diethyleneglycolmethylether 5 Microcrystalline cellulose 43
  • Clarithromycin 70% (W/W) Hydroxypropylcellulose 15 phthalate 10
  • Ciprofoxacin 75% (W/W)
  • Microcrystalline cellulose 20 Cellulose acetate phthalate 10
  • Microcrystalline cellulose 25 Cellulose Acetate Phthalate 10 Hydroxypropylmethylcellulose 10
  • Example 36 Amoxicillin 65% (W/W)
  • composition of the antibiotic matrix pellets provided in Table 1.
  • composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 2.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 3.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%:
  • the capsule is filled with the three different pellets to achieve the desire dosage.
  • the immediate release matrix pellets include the first antibiotic, the L30 D-55 coated pellets are made by coating matrix pellets that contain the second antibiotic and the S100 coated pellets are made by coating matrix pellets that contain the first antibiotic.
  • composition of the Antibiotictrihydrate matrix pellets provided in Table 4.
  • composition of the aqueous Eudragit L30D-55 dispersion applied to the Antibiotic matrix pellets is provided below in Table 5.
  • the TEC/talc suspension is mixed using laboratory mixer.
  • composition of the aqueous Eudragit® S 100 dispersion applied to the Antibiotic matrix pellets is provided below in Table 6.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram per minute
  • ⁇ ydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
  • the fill weight should be adjusted to achieve the desired dosage.
  • composition of the antibiotic matrix pellets provided in Table 9.
  • composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 10.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 11.
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively.
  • the capsule is filled with the four different pellets to achieve the desired dosage.
  • the immediate release pellets contain the first antibiotic; the L30 D-55 12% weight gain coated pellets contain the second antibiotic; the L30 D-55 30% weight gain coated pellets contain the first antibiotic and the S100 coated pellets contain the second antibiotic.
  • composition of the aqueous Opadry solution applied to the Tetracycline pellets is provided below in Table 13.
  • composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated Tetracycline pellets is provided below in Table 14.
  • composition of the Doxycycline hyclate pellets provided in Table 15.
  • Blend Doxycycline hyclate, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator ⁇ Blend Doxycycline hyclate, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
  • composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Doxycycline hyclate pellets is provided below in Table 16.
  • Imwitor 900 Homogenize dispersion until temperature is less than
  • the TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
  • composition of the aqueous Eudragit® FS 30D dispersion applied to the Doxycycline hyclate pellets is provided below in Table 17.
  • Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
  • Granules between 20 and 40 Mesh are collected for further processing.
  • the fill weight should be adjusted to achieve a 350 mg total dose tablet.
  • composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Tetracycline pellets is provided below in Table 21.
  • Table 21 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
  • the TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
  • composition of the aqueous Opadry solution applied to the Tetracycline pellets is provided below in Table 22.
  • composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Tetracycline pellets is provided below in Table 23.
  • composition of the aqueous Eudragit® FS 30D dispersion applied to the Tetracycline pellets is provided below in Table 24.
  • Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
  • composition of the Doxycycline hyclate pellets provided in Table 25.
  • Blend Doxycycline hyclate, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator ⁇ Blend Doxycycline hyclate, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
  • composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the doxycycline hyclate pellets is provided below in Table 26.
  • Imwitor 900 Homogenize dispersion until temperature is less than
  • the TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
  • composition of the aqueous Opadry solution applied to the Doxycycline hyclate pellets is provided below in Table 27.
  • composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Doxycycline hyclate pellets is provided below in Table 28.
  • composition of the aqueous Eudragit® FS 30D dispersion applied to the doxycycline hyclate pellets is provided below in Table 29.
  • Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
  • Granules between 20 and 40 Mesh are collected for further processing.
  • Tetracycline coated pellets, Doxycycline hyclate coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender Tetracycline coated pellets, Doxycycline hyclate coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
  • the fill weight should be adjusted to achieve a 350 mg total dose tablet.
  • Tetracycline will be dosed in an alternate pulse to Doxycycline. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells.
  • the dosage forms as hereinabove described provide for improved treatment of infection.
  • composition of the metronidazole pellets provided in Table 32.
  • Blend metronidazole, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator Blend metronidazole, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
  • composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Metronidazole pellets is provided below in Table 33.
  • Imwitor 900 Homogenize dispersion until temperature is less than
  • the TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
  • composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 34.
  • composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 35.

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Abstract

Antibiotic products for delivering at least two different antibiotics, wherein the products are comprised of at least three or four dosage forms with different release profiles and the at least two different antibiotics are selected from specified antibiotic pairs.

Description

ANTIBIOTIC COMPOSITION
This invention relates to antibiotic compositions and the use thereof. More particularly, this invention relates to a composition for the delivery of two or more antibiotics, and the use thereof.
In many cases, it is desirable to employ two different antibiotics in the treatment of a bacterial infection, in that such antibiotics may have complementary mechanisms of action that facilitate treatment of the bacterial infection.
The present invention is directed to a new and improved product that delivers two antibiotics of specified antibiotic pairs, and the use thereof, with the antibiotic pairs being one of the following (1) a protein synthesis inhibiting antibiotic and a non- protein synthesis inhibiting antibiotic; (2) Tetracycline and Doxycycline; or (3) Ciprofoxacin and Metronidazole; or (4) Amoxicillin and Clarithromycin; or (5) Amoxicillin and Dicloxacillin; or (6) Cephalosporin and Metronidazole, with pair #4 being an example of pair #1. In accordance with an aspect of the present invention, there is provided an antibiotic product for delivering at least two different antibiotics that is comprised of at least three dosage forms each comprised of at least one antibiotic and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one antibiotic of the antibiotic pair and at least one dosage form including at least a second antibiotic of the antibiotic pair.
Thus, for example, each of the dosage forms may include two antibiotics of the pair, or one or two of the dosage forms may include only one of the two antibiotics of the pair and each of the remaining dosage forms may include only one or two of the antibiotics of the pair. Thus, in accordance with this aspect of the invention, there is provided an antibiotic product for delivering at least two of the antibiotics of the hereinabove described antibiotic pairs wherein the product includes at least three dosage forms wherein each of the antibiotics of the pair is present in at least one of the three dosage forms and each of the three dosage forms includes at least one of the two antibiotics. In one preferred embodiment each dosage form includes only one antibiotic.
In accordance with an embodiment of the present invention, there is provided an antibiotic product for delivering at least two different antibiotics that is comprised of at least three dosage forms each comprised of at least one antibiotic and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one of the at least two antibiotics and at least one dosage form including at least a second antibiotic of the at least two antibiotics, wherein one of the least two antibiotics is one of the antibiotics of the hereinabove described antibiotic pairs and the other of the at least two different antibiotics is the other antibiotic of such pair. In a preferred embodiment each dosage form includes at least one of such two antibiotics. In a particularly preferred embodiment, each dosage form includes only one of the two antibiotics with each of the two antibiotics being present in at least one of the three dosage forms. In a preferred embodiment each of the dosage forms of the product that contains the antibiotic pairs has a different release profile, with one of the dosage forms being an immediate release dosage form.
In another aspect, the present invention is directed to treating a bacterial infection by administering to a host in need thereof an antibiotic product as hereinabove and hereinafter described.
Thus, in accordance with an aspect of the present invention, there is provided a single or unitary antibiotic product that has contained therein at least three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in each of the at least three dosage forms is released at different times, and wherein each of the dosage forms includes at least one of the antibiotics of the antibiotic pairs. One or more of the dosage forms may include more than one antibiotic.
In accordance with a further aspect of the invention, the antibiotic product may be comprised of at least four different dosage forms, each of which starts to release the antibiotic contained therein at different times after administration of the antibiotic product, with each of the dosage forms including at least one of the two antibiotic of an antibiotic pair and with each antibiotic of the pair being present in at least one of the dosage forms.
The antibiotic product generally does not include more than five dosage forms with different release times.
In accordance with a preferred embodiment, the antibiotic product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration of the total antibiotic released from the antibiotic product is achieved no earlier than four hours after administration. In accordance with one preferred embodiment of the invention, one of the at least three dosage forms is an immediate release dosage form whereby initiation of release of antibiotic therefrom is not substantially delayed after administration of the antibiotic product. The second and third of the at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antibiotic product), whereby antibiotic released therefrom is delayed until after initiation of release of antibiotic from the immediate release dosage form. More particularly, antibiotic release from the second of the at least two dosage forms achieves a Cmax (maximum serum concentration in the serum) at a time after antibiotic released from the first of the at least three dosage forms achieves a Cmaχ in the serum, and antibiotic released from the third dosage form achieves a Cmax in the serum after the Cmax of antibiotic released from the second dosage form.
In one embodiment, the second of the at least two dosage forms initiates release of antibiotic contained therein at least one hour after the first dosage form, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of antibiotic from the first dosage form of the at least three dosage forms.
In general, the immediate release dosage form produces a Cmax for antibiotic released therefrom within from about 0.5 to about 2 hours, with the second dosage form of the at least three dosage forms producing a Cmax for antibiotic released therefrom in no more than about four hours. In general, the Cmax for such second dosage form is achieved no earlier than two hours after administration of the antibiotic product; however, it is possible within the scope of the invention to achieve Cmax in a shorter period of time.
As hereinabove indicated, the antibiotic product may contain at least three or at least four or more different dosage forms. For example, the antibiotic released from the third dosage form reaches a Cmax at a time later than the Cmax is achieved for antibiotic released from each of the first and second dosage forms. In a preferred embodiment, release of antibiotic from the third dosage form is started after initiation of release of antibiotic from both the first dosage form and the second dosage form. In one embodiment, Cmax for antibiotic release from the third dosage form is achieved within eight hours.
In another embodiment, the antibiotic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby antibiotic released from each of the at least four different dosage forms achieves a Cmax at a different time.
As hereinabove indicated, in a preferred embodiment, irrespective of whether the antibiotic contains at least three or at least four different dosage forms each with a different release profile, Cmax for all the antibiotic released from the antibiotic product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.
In a preferred embodiment, the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of an antibiotic product with the antibiotic being released in a manner such that overall antibiotic release is effected with different release profiles in a manner such that the overall Cmaχ for the antibiotic product is reached in less than twelve hours. The term single administration means that the total antibiotic administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are administered at essentially the same time.
Thus in accordance with an aspect of the invention, there is provided a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile with each of the dosage forms including at least one of the antibiotics of the hereinabove described antibiotic pairs and wherein each antibiotic of the pair is present in at least one of the dosage forms. Each of the dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics.
In one embodiment the two different antibiotics comprise Tetracycline and Doxycycline. In another embodiment the two different antibiotics comprise Ciprofoxacin and Metronidazole. In another embodiment the two different antibiotics comprise Amoxicillin and Clarithromycin. In another embodiment the two different antibiotics comprise Amoxicillin and Dicloxacillin. In another embodiment the two different antibiotics comprise Cephalosporin and Metronidazole.
In one embodiment, the first dosage form contains one of the first antibiotics of the antibiotic pair and is free of the other antibiotic of the antibiotic pair, and in a preferred embodiment contains only such one antibiotic; the second dosage form contains the other antibiotic of the pair and is free of such one antibiotic of the pair and in a preferred embodiment contains only one antibiotic and the third dosage form contains such one antibiotic of the pair and is free of the other antibiotic of the pair and in a preferred embodiment contains only one antibiotic and if a fourth dosage form is used, such fourth dosage form contains such other antibiotic and is free of such one antibiotic and in a preferred embodiment bacteria are exposed to alternating pulses of the two antibiotics of the hereinabove described antibiotic pairs.
It is to be understood that when it is disclosed herein that a dosage form initiates release after another dosage form, such terminology means that the dosage form is designed and is intended to produce such later initiated release. It is known in the art, however, notwithstanding such design and intent, some "leakage" of antibiotic may occur. Such "leakage" is not "release" as used herein.
If at least four dosage forms are used, the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though Cmax of the fourth dosage form of the at least four dosage forms is reached after the Cmaχ of each of the other dosage forms is reached, antibiotic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
In one embodiment of the invention, one of the antibiotics of the antibiotic pairs as hereinabove and hereinafter described is a protein synthesis inhibiting antibiotic and the other antibiotic of the antibiotic pair is a non-protein synthesis inhibiting antibiotic.
The terminology "protein synthesis inhibiting antibiotic" means an agent that disrupts the bacterial ribosome cycle through which polypeptide chain initiation and elongation is normally effected. There are multiple points in the ribosome cycle at which this can occur.
The terminology "non-protein synthesis inhibiting antibiotic" means antibiotics other than protein synthesis inhibiting antibiotics.
As non-limiting representative examples of "protein synthesis inhibiting antibiotics" there may be mentioned: the aminoglycosides such as streptomycin, amikacin, and tobramycin; the macrolides such as erythromycin, clarithromycin, and lincomycin; the tetracyclines such as tetracycline, doxycycline, chlortetracycline, and minocycline; the oxaxolidinones such as linezolid; fusidic acid; and chloramphenicol.
As non-limiting representative examples of "non-protein synthesis inhibiting antibiotics" there may be mentioned: the beta-lactam penicillins such as penicillin, amoxicillin, dicloxacillin, and ampicillin; the beta lactam cephalsporins such as cefotaxime, cefuroxime, cefaclor, and ceftriaxone; the beta lactam carbapenems such as imipenem and meropenem; the quinolones such as ciprofloxacin, moxifloxacin, and levofloxacin; the sulfonamides such as sulfanilimide and sulfamethoxazole; metronidazole; rifampin; vancomycin; and nitrofurantoin.
In a preferred embodiment such two antibiotics are delivered in alternating pulses. In a particularly preferred embodiment of the present invention, there is provided an antibiotic composition that includes three different dosage forms: the first dosage form providing an initial dosage of a first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the first dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in one preferred embodiment contains only one antibiotic; the second dosage form providing an initial dosage of a second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the second dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics and in one preferred embodiment contains only one antibiotic; and the third dosage form providing an additional dosage of said first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the third dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in one preferred embodiment contains only one antibiotic. The first dosage form is an immediate release dosage form; and the second and third dosage forms are delayed release dosage forms.
In another preferred embodiment of the present invention, there is provided an antibiotic composition that includes four different dosage forms: the first dosage form providing an initial dosage of a first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the first dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic; the second dosage form providing an initial dosage of a second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the second dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic; the third dosage form providing an additional dosage of said first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the third dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic; and the fourth dosage form providing an additional dosage of said second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the fourth dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics and in a preferred embodiment contains only one antibiotic. The first dosage form is an immediate release dosage form; the second and third dosage forms are delayed release dosage forms; and the fourth dosage form is optionally a delayed release dosage form or a sustained release dosage form, preferably a delayed release dosage form.
Particularly advantageous formulations of the immediately preceding embodiments of the present invention are those that comprise Clarithromycin, a protein synthesis inhibiting antibiotic as one of the antibiotics, and Amoxicillin, a non- protein synthesis inhibiting antibiotic as the other antibiotic. In these formulations a first, immediate release dosage form contains an initial dosage of Clarithromycin and is free of any non-protein synthesis inhibiting antibiotics; a second, delayed release dosage form contains an initial dosage of Amoxicillin and is free of any protein synthesis inhibiting antibiotics; and a third, delayed release dosage form provides an additional dosage of Clarithromycin and is free of any non-protein synthesis inhibiting antibiotics. An optional fourth, dosage form provides an additional dosage of Amoxicillin and is free of any protein synthesis inhibiting antibiotics. This fourth dosage form is a delayed release or a sustained release dosage form, preferably a delayed release dosage form.
In formulating an antibiotic product in accordance with the invention, in one embodiment, the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antibiotic to be delivered by the product, with such immediate release dosage form generally providing at least 25% of the total dosage of the antibiotic to be delivered by the product. In many cases, the immediate release dosage form provides from about 20% to about 30% of the total dosage of antibiotic to be delivered by the product; however, in some cases it may be desirable to have the immediate release dosage form provide for about 45% to about 50% of the total dosage of antibiotic to be delivered by the product.
The remaining dosage forms deliver the remainder of the antibiotic. If more than one delayed release dosage form is used, in one embodiment, each of the delayed release dosage forms may provide about equal amounts of antibiotic; however, they may also be formulated so as to provide different amounts. In one embodiment, where the composition contains one immediate release component and two delayed release components, the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, of the total antibiotic; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total antibiotic; and where there are four delayed release components, the immediate release component provides from 10% to 25%o, by weight, of the total antibiotic.
With respect to the delayed release components, where there are two delayed release components, the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, of the total antibiotic provided by the two delayed release components with the second delayed release component providing the remainder of the antibiotic.
Where there are three delayed release components, the earliest released component provides 20% to 35% by weight of the total antibiotic provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, of the antibiotic provided by the three delayed release components and the last in time providing the remainder of the antibiotic provided by the three delayed release components.
When there are four delayed release components, the earliest delayed release component provides from 15% to 30%, by weight, the next in time delayed release component provides from 15% to 30%, the next in time delayed release component provides from 20% to 35%, by weight, and the last in time delayed release component provides from 20% to 35%, by weight, in each case of the total antibiotic provided by the four delayed release components.
In accordance with another aspect of the present invention, there is provided an antibiotic composition that is a mixture of antibiotic compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first antibiotic and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first antibiotic and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second antibiotic different from the first antibiotic and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising the second antibiotic and a pharmaceutically acceptable carrier; wherein the second and third compositions each have a release profile that provides a maximum serum concentration of the first antibiotic released from the second composition and a maximum serum concentration for the second antibiotic released from the third composition at a time after the first antibiotic released from the first composition reaches a maximum serum concentration, and wherein the fourth composition has a release profile that provides for a maximum serum concentration of the second antibiotic released from the fourth composition at a time after the antibiotics released from the second and third compositions reach a maximum serum concentration. The first antibiotic and second antibiotic are one of the antibiotics of the hereinabove described antibiotic pairs.
In one embodiment, the release profiles of the second and third dosage forms are such that the maximum serum concentration of the first antibiotic released from the second dosage form, and the maximum serum concentration of the second antibiotic released from the third dosage form are reached at approximately the same time, or where the first antibiotic reaches a maximum serum concentration before or after the second antibiotic reaches a maximum serum concentration.
In effect, in accordance with a preferred embodiment of the present invention, there is provided a first pulse in which a first antibiotic reaches a maximum serum concentration, a second pulse wherein a further dosage of the first antibiotic, and an initial dosage of the second antibiotic reach a maximum serum concentration at a time after the first pulse of the first antibiotic reaches a maximum serum concentration, and a third pulse wherein an additional dosage of the second antibiotic reaches a maximum serum concentration at a time after the maximum serum concentration is reached for each of the first and second antibiotic dosages provided in the second pulse.
In a preferred embodiment of the present invention, the first dosage of the first antibiotic achieves a maximum serum concentration within four hours after administration of the antibiotic composition; the second dosage of the first antibiotic and the first dosage of the second antibiotic each reach a maximum serum concentration within four to eight hours after administration of the antibiotic composition; and the second dosage of the second antibiotic reaches a maximum serum concentration within twelve hours after administration of the antibiotic composition.
Thus, in accordance with an aspect of the present invention, there is provided an antibiotic composition that includes four different dosage forms, with the first dosage form providing an initial dosage of a first antibiotic of the hereinabove described antibiotic pairs, the second dosage form providing a further dosage of the first antibiotic; the third dosage form providing an initial dosage of a second antibiotic of such pair; and the fourth dosage form providing an additional dosage of the second antibiotic, wherein the antibiotics released from the second and third dosage forms reach a maximum serum concentration at a time after the antibiotic released from the first dosage form reaches a maximum serum concentration, and the antibiotic released from the fourth dosage form reaching a maximum serum concentration at a time after the times at which the antibiotics released from each of the first, second, and third dosage forms reach a maximum serum concentration.
In one embodiment of the invention, the first dosage form provides for immediate release, the second and third dosage forms provide for a delayed release (pH or non pH dependent, with the second dosage form preferably being a pH dependent release), and the fourth dosage form provides for pH dependent or non pH dependent release preferably non pH dependent release.
In formulating the antibiotic composition of the present invention, which contains four different dosage forms, as hereinabove described that contains the first antibiotic of the antibiotic pair in the first and second antibiotic dosage forms and the second antibiotic of the antibiotic pair in the third and fourth dosage forms, the first dosage form generally contains from about 30 percent to about 80 percent of the first antibiotic; the second dosage form contains from about 30 percent to about 80 percent of the first antibiotic; the third dosage form contains from about 30 percent to about 80 percent of the second antibiotic, and the fourth antibiotic dosage form contains from about 30 percent to about 80 percent of the second antibiotic. In formulating a composition comprised of such four dosage forms or units, each unit or dosage form is present in an amount of at least 20 percent by weight, with each dosage form or unit being present in the overall composition in an amount that generally does not exceed 60 percent by weight.
Each of the first and second dosage forms include from 20% to 80% of the total dosage of the first antibiotic to be provided by the composition, and each of the first and second dosage forms may include the same or different dosages of the first antibiotic.
Each of the third and fourth dosage forms include from 20% to 80% of the total dosage of the second antibiotic to be delivered by the composition, and each of the third and fourth units may have the same or different dosages of the antibiotic.
In another embodiment the product as hereinabove described may also be formulated in a manner such that the product contains at least three dosage forms wherein each of the three dosage forms is a delayed release dosage form, with the product being free of an immediate release dosage form. The product contains the antibiotic pairs as hereinabove described. In this embodiment the overall Cmax is reached within 12 hours after initial release of antibiotic, i.e. Cmax is achieved in less than about twelve hours after initial release of antibiotic. As hereinabove described this product may optionally contain a fourth dosage form. When such product contains a fourth dosage form, such fourth dosage form is preferably a delayed release dosage form, but may otherwise be a sustained release dosage form. As hereinabove described, in a preferred embodiment, the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of an antibiotic product with the antibiotic being released in a manner such that overall antibiotic release is effected with different release profiles in a manner such that the overall Cmax for the antibiotic product is reached in less than twelve hours from the initial release of antibiotic. The term single administration means that the total antibiotic administered over a twenty- four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are administered at essentially the same time.
The overall composition includes each of the antibiotics in a therapeutically effective amount. The specific amount(s) is dependant on the antibiotic used, the disease or infection to be treated, and the number of times of day that the composition is to be administered.
The antibiotic composition of the present invention may be administered for example, by any one of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, oral, preferably by oral administration.
The antibiotic product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the antibiotic product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration. In a preferred embodiment, the antibiotic product is formulated in a manner such that it is suitable for oral administration.
For example, in formulating the antibiotic product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an antibiotic, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in-oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.
It is also within the scope of the invention to provide an antibiotic product in the form of a patch, which includes antibiotic dosage forms having different release profiles, as hereinabove described.
In addition, the antibiotic product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion. For example, the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase of the emulsion.
Furthermore, the antibiotic product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration.
As a further embodiment, the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
In a preferred embodiment, the antibiotic product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
Alternatively, in formulating an oral delivery system, each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product. Thus, for example, antibiotic products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release of the antibiotic, as hereinabove described, whereby the Cmax of the antibiotic released from each of the tablets is reached at different times, with the Cmaχ of the total antibiotic released from the antibiotic product being achieved in less than twelve hours.
The formulation of an antibiotic product including at least three dosage forms with different release profiles for different routes of administration is deemed to be within the skill of the art from the teachings herein. As known in the art, with respect to delayed release, the time of release can be controlled by the concentration of antibiotics in the coating and/or the thickness of the coating.
As hereinabove indicated, the first and second antibiotics employed in the antibiotic composition may be a wide variety of products. In one embodiment, the combination of first and second antibiotics that are used in the composition may be, for example, a penicillin and an aminoglycoside, such as gentamycin, tobramicin, amikacin or vancomycin. Another antibiotic composition that may be employed is a combination of a sulfonamide, such as sulfamethoxasol, which would be combined with trimethoporim. In a preferred embodiment, the first and second, antibiotics are different antibiotics and each is from a different class of antibiotic.
The Immediate Release Component
The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
The materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, ydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
It may be useful to have these materials present in the range of 1.0 to 60% (W/W).
In addition, it may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration. These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Piuronic line of surfactants, or any other material with surface active properties, or any combination of the above.
These materials may be present in the rate of 0.05-15% (W/W).
The Delayed Release Component
The components in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this component. The Enteric Release Component
The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate phthalate, Eudragit L, and other phthalate salts of cellulose derivatives.
These materials can be present in concentrations from 4-20% (W/W).
The invention will be further described with respect to the following examples; however the scope of the invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified.
Examples
Immediate Release Component
Inqredient Cone. (% W/W)
Example 1 :
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5
Example 2:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10
Example 3:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 4:
Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
Example 5:
Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 6:
Clarithromycin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 7:
Clarithromycin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
Example 8:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
Example 9:
Clarithromycin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 10:
Ciprofoxacin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 11 :
Ciprofoxacin 75% (W/W)
Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
Example 12:
Ciprofoxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5
Example 13:
Cirpofoxacin 75% (W/W)
Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 14:
Ceftibuten 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
Example 15:
Ceftibuten 75% (W/W)
Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5
Delayed Release Component (non-pH dependant)
Ingredient Cone. (% W/W)
Example 16:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5
Example 17:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 18:
Amoxicillin 65% (W/W) Polyox 20
Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 19:
Clarithromycin 70% (W/W) Polyox 20
Hydroxypropylcellulose 5 Croscarmellose sodium 5
Example 20: Gentamicin 20% (W/W) Sodium lauryl sulfate 2 Sodium monoglycerides 10 Sodium diglycerides 20 Diethyleneglycolmethylether 5 Microcrystalline cellulose 43
Example 21 :
Gentamicin 10% (W/W) Glyvceryl behanate 30 Piuronic 10 Carbopol 94P 30 Microcrystalline cellulose 20
Example 22:
Gentamicin 25% (W/W) Carbopol 94P 35 Microcrystalline cellulose 20 Vitamin E TPGS 15 Sodium monoglycerate 5
Example 23:
Amikacin 25% (W/W) Carbopol 94P 10 Sodium monoglycerate 15 Sodium diglycerate 15 Piuronic 10 Lactose 25
Example 24:
Gentamicin 30% (W/W)
Triacetin 15
Capryol 90 5
Poloxamer Synperonic PE/F66 10
Cab-O-Sil 5
Microcrystalline cellulose 35
Enteric Release Component
Example 25:
Clarithromycin 70% (W/W) Hydroxypropylcellulose 15 phthalate 10 Croscarmellose sodium
Example 26:
Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15 Example 27:
Clarithromycin 40% (W/W) Lactose 50 Eudgragit E 30D 10
Example 28:
Ciprofoxacin 65% (W/W)
Microcrystalline Cellulose 20 Eudragit E 30D 10
Example 29:
Ciprofoxacin 75% (W/W)
Microcrystalline Cellulose 15 Hydroxypropylcellulose 10 phthalate
Example 30:
Ciprofoxacin 80% (W/W) Lactose 10 Eudragit E 30D 10
Example 31 :
Ciprofoxacin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate phthalate 10
Example 32:
Ceftibuten 60% (W/W)
Polyethylene glycol 2000 10 Lactose 20 Eudragit E 30D 10
Example 33:
Ceftibuten 70% (W/W)
Microcrystalline cellulose 20 Cellulose acetate phthalate 10
Example 34:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Cellulose Acetate Phthalate 15
Example 35:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25 Cellulose Acetate Phthalate 10 Hydroxypropylmethylcellulose 10
Example 36: Amoxicillin 65% (W/W)
Polyox 20
Hydroxypropylcellulose 10 phthalate 5
Eudragit E30D
Example 37:
Amoxicillin 40% (W/W)
Microcrystalline Cellulose 40 Cellulose Acetate Phthalate 10
Example 38:
Gentamicin 20% (W/W) Sodium lauryl sulfate 2 Sodium monoglycerides 10 Sodium diglycerides 20 Diethyleneglycolmethylether 5 Microcrystalline cellulose 30 Cellulose acetate phthalate 13
Example 39:
Gentamicin 10% (W/W) Glyceryl behanate 30 Piuronic 10 Carbopol 94P 10 Microcrystalline cellulose 20 Eudragit E30D 20
Example 40:
Gentamicin 25% (W/W) Carbopol 94P 15 Microcrystalline cellulose 20 Vitamin E TPGS 15 Sodium Monoglycerate 5 Eudragit E30D 20
Example 41 :
Amikacin 25% (W/W)
Carbopol 94P 10
Sodium monoglycerate 15
Sodium diglycerate 15
Piuronic 10
Lactose 15
Cellulose acetate phthalate 10
Example 42:
Gentamicin 30% (W/W) Triacetin 15 Capryol 90 5 Poloxamer SynperonicPE/F66 10
Cab-O-Sil 5
Microcrystalline cellulose 25
Eudragit E30D 10
Three Pulses
Example 43.
1. Antibiotic Matrix Pellet Formulation and Preparation Procedure (Immediate Release)
A. Pellet Formulation
The composition of the antibiotic matrix pellets provided in Table 1.
Table 1 Composition of Antibiotic Pellets
Component Percentage (%)
Antibiotic 50
Avicel PH 101 20
Lactose 20
PVP K29/32* 10
Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
B. Preparation Procedure for antibiotic Matrix Pellets
1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.
1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.
1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
1.2.5 Dry the spheronized pellets at 50°C overnight.
1.2.6 Pellets between 16 and 30 Mesh were collected for further processing. The above procedure is used to make pellets of a first antibiotic and pellets of a second different antibiotic.
1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
1.3.1 Suspend triethyl citrate and talc in deionized water.
1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the antibiotic matrix pellets.
1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
A. Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 3.
Table 3 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%) Part A
Eudragit® S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part i:
(i) Dispense Eudragit® S 100 powder in deionized water with stirring.
(ϋ) Add ammonium hydroxide solution drop-wise into the dispersion with stirring, (iii) Allow the partially neutralized dispersion to stir for 60 minutes. (iv) Add triethyl citrate drop-wise into the dispersion with stirring.
Stir for about 2 hours prior to the addition of Part B.
Part II:
(i) Disperse talc in the required amount of water
(ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.
(iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
1.5 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters are used to coat matrix pellets with each of the
Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar Pump Rate 2 gram per minute
(i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
(ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.
1.6 Encapsulation of the Antibiotic Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%:
Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S100 coated pellets respectively.
The capsule is filled with the three different pellets to achieve the desire dosage.
The immediate release matrix pellets include the first antibiotic, the L30 D-55 coated pellets are made by coating matrix pellets that contain the second antibiotic and the S100 coated pellets are made by coating matrix pellets that contain the first antibiotic.
Three Pulses
Example 44
Antibiotic Pellet Formulation and Preparation Procedure
44.1 Pellet Formulations for subsequent coating
The composition of the Antibiotictrihydrate matrix pellets provided in Table 4. Table 4 Composition of AntibioticMatrix Pellets
Component Percentage (%)
AntibioticTrihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
44.2 Preparation Procedure for Antibiotic Matrix Pellets
44.2.1 Blend Antibiotic and Avicel® PH 101 using a low shear blender.
44.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
44.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
44.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
44.2.5 Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
44.2.6 Pellets between 20 and 40 Mesh were collected for further processing.
44.2.7 The above procedure is used to produce pellets that contain a first antibiotic and pellets that contain a second and different antibiotic.
44.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
44.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antibiotic matrix pellets is provided below in Table 5.
Table 5 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 41.6
Triethyl Citrate 2.5
Talc 5.0
Purified Water 50.9
Solids Content 20.0
Polymer Content 12.5
44.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
44.4.1 Suspend triethyl citrate and talc in deionized water.
44.4.2 The TEC/talc suspension is mixed using laboratory mixer.
44.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
44.4.4 Allow the coating dispersion to stir for one hour prior to application onto the Antibiotic matrix pellets.
44.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 44.5.1 Dispersion Formulation
The composition of the aqueous Eudragit® S 100 dispersion applied to the Antibiotic matrix pellets is provided below in Table 6.
Table 6 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
44.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
44.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
44.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
44.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
44.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.
Part B:
44.6.5 Disperse talc in the required amount of water
44.6.6 Stir the dispersion using an overhead laboratory mixer.
44.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
44.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram per minute
44.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.
44.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.
44.8 Preparation of Antibiotic Granulation (Immediate Release Component) for tabletting
Table 7 Composition of Antibiotic Granulation
Component Percentage (%)
AntibioticTrihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
Ηydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
44.8.1 Blend Antibiotic and Avicel® PH 101 using a low shear blender.
44.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
44.8.3 Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
44.8.4 Granules between 20 and 40 Mesh are collected for further processing.
44.9 Tabletting of the Antibiotic Pellets Table 8 Composition of Antibiotic Tablets
Component Percentage (%)
First antibiotic granules
32.5
Avicel PH 200 5.0
Second antibioticL30D-55 coated pellets
30
First antibioticS100 coated pellets 30
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
44.9.1 Blend the Antibiotic granules, Avicel PH-200, Antibiotic pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
44.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
44.9.3 Compress the blend on a rotary tablet press.
44.9.4 The fill weight should be adjusted to achieve the desired dosage.
Four pulses Example 45. 1 Antibiotic Matrix Pellet Formulation and Preparation Procedure
45.1 Pellet Formulation
The composition of the antibiotic matrix pellets provided in Table 9.
Table 9 Composition of Antibiotic Pellets
Component Percentage (%)
Antibiotic 50
Avicel PH 101 20
Lactose 20
PVP K29/32* 10
Purified Water
Total 100
"PVP K29/32 was added as a 20% w/w aqueous solution during wet massing. 45.2 Preparation Procedure for Antibiotic Matrix Pellets
45.2.1 Blend antibiotic and Avicel® PH 101 using a Robot Coupe high shear granulator.
45.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.
45.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
45.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
45.2.5 Dry the spheronized pellets at 50°C overnight.
45.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
45.2.7 The above procedure is used to prepare pellets that contain a first antibiotic and pellets that contain a second antibiotic.
45.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
45.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 10.
Table 10 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
45.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
45.4.1 Suspend triethyl citrate and talc in deionized water.
45.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
45.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. 45.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antibiotic matrix pellets.
45.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
45.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 11.
Table 11 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
45.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
45.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
45.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
45.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
45.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.
Part B:
45.6.5 Disperse talc in the required amount of water
45.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer. 45.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
45.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters are used for coating with each of the Eudragit® L
30 D-55 and Eudragit® S 100 aqueous film coatings.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
45.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
45.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.
45.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets.
45.8 Encapsulation of the Antibiotic Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets respectively. The capsule is filled with the four different pellets to achieve the desired dosage.
The immediate release pellets contain the first antibiotic; the L30 D-55 12% weight gain coated pellets contain the second antibiotic; the L30 D-55 30% weight gain coated pellets contain the first antibiotic and the S100 coated pellets contain the second antibiotic.
Example 46
Tetracycline Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Tetracycline pellets provided in Table 12. Table 12 Composition of Tetracycline Pellets
Component Percentage (%)
Tetracycline 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing Preparation Procedure for Tetracycline Pellets
■ Blend Tetracycline, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Tetracycline Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Tetracycline pellets is provided below in Table 13.
Table 13 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated Tetracycline pellets is provided below in Table 14.
Table 14 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudragit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aqueous Dispersion
Disperse triethyl citrate in purified water with stirring.
Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour.
Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
Screen the dispersion through a No. 60 mesh sieve.
Continue to stir the screened coating dispersion throughout the coating process. Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D
Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Tetracycline pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated Tetracycline pellets with the AQOATAS- HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Doxycycline hyclate Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Doxycycline hyclate pellets provided in Table 15.
Table 15 Composition of Doxycycline hyclate Pellets
Component Percentage (%)
Doxycycline hyclate 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Doxycycline hyclate Pellets
■ Blend Doxycycline hyclate, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Doxycycline hyclate Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Doxycycline hyclate pellets is provided below in Table 16.
Table 16 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating. • Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Doxycycline hyclate pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Doxycycline hyclate Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the Doxycycline hyclate pellets is provided below in Table 17.
Table 17 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Tetracycline and Doxycycline hyclate Tablets
Preparation of Tetracycline Granulation for tableting
Table 18 Composition of Tetracycline Granulation (Immediate Release)
Component Percentage (%)
Tetracycline 40.0
Lactose monohydrate, spray dried 39.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Tetracycline, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Tetracycline and Doxycycline hyclate
Table 19 Composition of Tetracycline and Doxycycline hyclate Tablets
Component Percentage (%)
Tetracycline granules 45.0
Avicel PH 200 7.4
Eudragit L30D-55/NE 30D coated Doxycycline hyclate Pellets 9.2
AQOAT/Eudragit FS 30D coated Tetracycline Pellets 25.9
Eudragit FS 30D coated Doxycycline hyclate Pellets 10.0
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Tetracycline granules, Avicel PH-200, Tetracycline coated pellets, Doxycycline hyclate coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 350 mg total dose tablet.
Example 47.
Tetracycline Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Tetracycline pellets provided in Table 20.
Table 20 Composition of Tetracycline Pellets
Component Percentage (%)
Tetracycline 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
"Removed during processing Preparation Procedure for Tetracycline Pellets
■ Blend Tetracycline, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Tetracycline Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Tetracycline pellets is provided below in Table 21. Table 21 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Tetracycline pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Tetracycline Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Tetracycline pellets is provided below in Table 22.
Table 22 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Tetracycline pellets is provided below in Table 23.
Table 23 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudragit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Agueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add talc into the triethyl citrate dispersion with stirring.
■ Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.
■ Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.
■ Screen the dispersion through a No. 60 mesh sieve.
■ Continue to stir the screened coating dispersion throughout the coating process. Coating Conditions for the Application of Opadry and Eudragit FS 30D/ Eudragit L
30D-55 Agueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Tetracycline pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated Tetracycline pellets with the Eudragit FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 32% coat weight gain to the pellets.
Tetracycline Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the Tetracycline pellets is provided below in Table 24.
Table 24 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Doxycycline hyclate Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Doxycycline hyclate pellets provided in Table 25.
Table 25 Composition of Doxycycline hyclate Pellets
Component Percentage (%)
Doxycycline hyclate 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Doxycycline hyclate Pellets
■ Blend Doxycycline hyclate, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Doxycycline hyclate Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the doxycycline hyclate pellets is provided below in Table 26.
Table 26 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating.
Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat doxycycline hyclate pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Doxycycline hyclate Delayed Enteric-Release Pellet Formulation and
Preparation Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Doxycycline hyclate pellets is provided below in Table 27.
Table 27 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadn Clear Agueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Doxycycline hyclate pellets is provided below in Table 28.
Table 28 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Agueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add talc into the triethyl citrate dispersion with stirring.
■ Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.
■ Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.
■ Screen the dispersion through a No. 60 mesh sieve.
■ Continue to stir the screened coating dispersion throughout the coating process. Coating Conditions for the Application of Opadry and Eudragit FS 30D/ Eudragit L
30D-55 Agueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Doxycycline hyclate pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated Doxycycline hyclate pellets with the Eudragit FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 32% coat weight gain to the pellets.
Doxycycline hyclate Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the doxycycline hyclate pellets is provided below in Table 29.
Table 29 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Tetracycline and Doxycycline hyclate Tablets
Preparation of Tetracycline and Doxycycline hyclate Granulation for tableting
Table 30 Composition of Tetracycline and Doxycycline hyclate Granulation
(Immediate Release)
Component Percentage (%)
Tetracycline 15.6
Doxycycline hyclate 6.2
Lactose monohydrate, spray dried 57.2
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Tetracycline, Doxycycline hyclate, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Tetracycline and Doxycycline hyclate
Table 31 Composition of Tetracycline and Doxycycline hyclate Tablets
Component Percentage (%)
Tetracycline/Doxycycline hyclate granules
50.0
Avicel PH 200 2.5
Eudragit L30D-55/NE 30D coated Tetracycline Pellets 10.0
Eudragit L30D-55/NE 30D coated Doxycycline hyclate Pellets 4.0
Eudragit FS 30D/Eudragit L30D coated Tetracycline Pellets 11.3
Eudragit FS 30D/Eudragit L30D coated Doxycycline hyclate Pellets 4.5
Eudragit FS 30D coated Tetracycline Pellets
10.9
Eudragit FS 30D coated Doxycycline hyclate Pellets 4.3
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Tetracycline/Doxycycline hyclate granules, Avicel PH-200,
Tetracycline coated pellets, Doxycycline hyclate coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 350 mg total dose tablet.
In one embodiment, Tetracycline will be dosed in an alternate pulse to Doxycycline. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells. In addition, even when Tetracycline and Doxycycline are not delivered in alternate pulses, the dosage forms as hereinabove described provide for improved treatment of infection.
Example 48.
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the metronidazole pellets provided in Table 32.
Table 32 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Metronidazole Pellets
Blend metronidazole, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
Add the purified water slowly into the powder blend under continuous mixing.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50°C until moisture level is < 3%.
Pellets between 16 and 30 Mesh were collected for further processing. Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Metronidazole pellets is provided below in Table 33.
Table 33 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating.
Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
• Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 34.
Table 34 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1 -7006 to the water with continuous mixing.
Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 35.
Table 35 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Agueous Dispersion
Disperse triethyl citrate in purified water with stirring.
Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour.
Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
Screen the dispersion through a No. 60 mesh sieve.
Continue to stir the screened coating dispersion throughout the coating process.
Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D Aqueous Coating Dispersions The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated metronidazole pellets with the AQOATAS- HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the
Metronidazole pellets is provided below in Table 36.
Table 36 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous Coatinq
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Ciprofloxacin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Ciprofloxacin pellets provided in Table 37.
Table 37 Composition of Ciprofloxacin Pellets
Component Percentage (%)
Ciprofloxacin 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Ciprofloxacin Pellets
■ Blend Ciprofloxacin, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Ciprofloxacin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Ciprofloxacin pellets is provided below in Table 38.
Table 38 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating.
Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Ciprofloxacin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Ciprofloxacin Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Ciprofloxacin pellets is provided below in Table 39.
Table 39 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an Eudraqit® FS 30D/Eudraqit L 30D-55 Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Ciprofloxacin pellets is provided below in Table 40.
Table 40 Eudragit FS 30D/Eudragit L 30D-55 Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Aqueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add talc into the triethyl citrate dispersion with stirring.
■ Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.
■ Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.
■ Screen the dispersion through a No. 60 mesh sieve.
■ Continue to stir the screened coating dispersion throughout the coating process. Coating Conditions for the Application of Opadrv and Eudraqit FS 30D/ Eudraqit L
30D-55 Aqueous Coatinq Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Ciprofloxacin pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated Ciprofloxacin pellets with the Eudragit FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 32% coat weight gain to the pellets.
Ciprofloxacin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® FS 30D Aqueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the Ciprofloxacin pellets is provided below in Table 41.
Table 41 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Metronidazole and Ciprofloxacin Tablets
Preparation of Metronidazole and Ciprofloxacin Granulation for tableting
Table 42 Composition of Metronidazole and Ciprofloxacin Granulation
(Immediate Release)
Component Percentage (%)
Metronidazole Trihydrate powder 13.3
Ciprofloxacin 9.0
Lactose monohydrate, spray dried 56.7
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Metronidazole, Ciprofloxacin, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Metronidazole and Ciprofloxacin
Table 43 Composition of Metronidazole and Ciprofloxacin Tablets
Component Percentage (%)
Metronidazole/Ciprofloxacin granules
49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Metronidazole Pellets 8.4
Eudragit L30D-55/NE 30D coated Ciprofloxacin Pellets 5.6
AQOAT/ Eudragit FS 30D coated Metronidazole Pellets 9.5
Eudragit FS 30D / L30D coated Ciprofloxacin Pellets 6.3
Eudragit FS 30D coated Metronidazole Pellets
9.1
Eudragit FS 30D coated Ciprofloxacin Pellets
6.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Metronidazole/Ciprofloxacin granules, Avicel PH-200,
Metronidazole coated pellets, Ciprofloxacin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 625 mg total dose tablet.
Example 49.
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the metronidazole pellets provided in Table 44.
Table 44 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
"Removed during processing
Preparation Procedure for Metronidazole Pellets
■ Blend metronidazole, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing. Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® L 30 D-55/Eudraqit NE 30D Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Metronidazole pellets is provided below in Table 45.
Table 45 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® L 30D-55/Eudraqit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
• Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadrv Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 46.
Table 46 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadrv Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an AQOAT AS-HF/Eudraqit® FS30D Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 47.
Table 47 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudraqit FS30D Aqueous Dispersion
Disperse triethyl citrate in purified water with stirring.
Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour.
Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
Screen the dispersion through a No. 60 mesh sieve.
Continue to stir the screened coating dispersion throughout the coating process.
Coatinq Conditions for the Application of Opadrv and AQOAT/Eudragit FS30D Agueous Coating Dispersions The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated metronidazole pellets with the AQOATAS- HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the
Metronidazole pellets is provided below in Table 48.
Table 48 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudraqit FS30D Aqueous Coatinq
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Metronidazole and Ciprofloxacin Tablets
Preparation of Metronidazole and Ciprofloxacin Granulation for tabletinq
Table 49 Composition of Metronidazole and Ciprofloxacin Granulation
(Immediate Release)
Component Percentage (%)
Metronidazole 22.5
Ciprofloxacin 59.0
Lactose monohydrate, spray dried 10.0
Avicel PH 101 7.5
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Metronidazole, Ciprofloxacin, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Metronidazole and Ciprofloxacin
Table 50 Composition of Metronidazole and Ciprofloxacin Tablets
Component Percentage (%)
Metronidazole/Ciprofloxacin granules
49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Metronidazole Pellets 14.0
AQOAT/ Eudragit FS 30D coated Metronidazole Pellets 15.8
Eudragit FS 30D coated Metronidazole Pellets
15.2
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
• Blend the Metronidazole/Ciprofloxacin granules, Avicel PH-200, Metronidazole coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
• Add the magnesium stearate to the blender, and blend for 5 minutes.
• Compress the blend on a rotary tablet press.
• The fill weight should be adjusted to achieve a 625 mg total dose tablet.
In one embodiment, Ciprofoxacin will be dosed in an alternate pulse to Metronidazole. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells.
In addition, even when Ciprofoxacin and Metronidazole are not delivered in alternate pulses, the dosage forms as hereinabove described provide for improved treatment of infection. Example 50
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 51.
Table 51 Composition of Amoxicillin Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Cremaphor EL were added as a 2.9% w/w aqueous solution during wet massing. **Removed during processing
Preparation Procedure for Amoxicillin Pellets
• Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
• Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Pellets between 20 and 40 Mesh were collected for further processing. Amoxicillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® L 30 D-55/Eudraqit NE 30D Aqueous Coatinq
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 52.
Table 52 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® L 30D-55/Eudragit NE 30D Agueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Amoxicillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 53.
Table 53 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Agueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Amoxicillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® FS 30D Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the
Amoxicillin pellets is provided below in Table 54.
Table 54 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Clarithromycin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the clarithromycin pellets provided in Table 55.
Table 55 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water
Total 100
*Removed during processing Preparation Procedure for Clarithromycin Pellets
Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved. Blend clarithromycin, lactose monohydrate, and croscarmellose sodium using a Robot Coupe high shear granulator.
Add binder solution slowly into the powder blend under continuous mixing.
Granulate the powders in the high shear granulator with the binder solution.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50°C until the moisture level is > 3%.
Pellets between 16 and 30 Mesh were collected for further processing. Clarithromycin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® L 30 D-55/Eudraqit NE 30D Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the clarithromycin pellets is provided below in Table 56. Table 56 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® L 30D-55/Eudragit NE 30D Agueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating.
Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Clarithromycin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the clarithromycin pellets is provided below in Table 57.
Table 57 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Agueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Clarithromycin Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the clarithromycin pellets is provided below in Table 58.
Table 58 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Amoxicillin and Clarithromycin Tablets
Preparation of Amoxicillin and Clarithromycin Granulation for tableting
Table 59 Composition of Amoxicillin and Clarithromycin Granulation
(Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 22.0
Clarithromycin 22.0
Lactose monohydrate, spra f dried 45.0
Avicel PH 101 10.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Amoxicillin, Clarithromycin, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Amoxicillin and Clarithromycin
Table 60 Composition of Amoxicillin and Clarithromycin Tablets
Component Percentage (%)
Amoxicillin/Clarithromycin granules
45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Amoxicillin Pellets 6.4
Eudragit L30D-55/NE 30D coated Clarithromycin Pellets 7.6
AQOAT coated Amoxicillin Pellets 7.2
AQOAT coated Clarithromycin Pellets 8.6
Eudragit FS 30D coated Amoxicillin Pellets 6.9
Eudragit FS 30D coated Clarithromycin Pellets
8.3
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Amoxicillin/Clarithromycin granules, Avicel PH-200,
Amoxicillin coated pellets, Clarithromycin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg total dose tablet.
Example 51
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 61.
Table 61 Composition of Amoxicillin Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
Ηydroxypropyl methylcellulose and Cremaphor EL were added as a 2.9% w/w aqueous solution during wet massing. **Removed during processing
Preparation Procedure for Amoxicillin Pellets
• Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
• Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Pellets between 20 and 40 Mesh were collected for further processing. Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 62.
Table 62 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
I ll Coating Conditions for the Application of AQOAT AS-HF Aqueous Coatinq
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Clarithromycin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the clarithromycin pellets provided in Table 63.
Table 63 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water *
Total 100
*Removed during processing Preparation Procedure for Clarithromycin Pellets
Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved. Blend clarithromycin, lactose monohydrate, and croscarmellose sodium using a Robot Coupe high shear granulator.
Add binder solution slowly into the powder blend under continuous mixing.
Granulate the powders in the high shear granulator with the binder solution.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50°C until the moisture level is > 3%.
Pellets between 16 and 30 Mesh were collected for further processing. Clarithromycin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® L 30 D-55/Eudraqit NE 30D Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the clarithromycin pellets is provided below in Table 64. Table 64 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® L 30D-55/Eudraqit NE 30D Aqueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating.
Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudraqit L30D-55/Eudragit NE
30DAqueous Coatinq Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Clarithromycin Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudraqit® FS30D Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the clarithromycin pellets is provided below in Table 65.
Table 65 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Amoxicillin and Clarithromycin Tablets
Preparation of Amoxicillin Granulation for tabletinq
Table 66 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 22.0
Lactose monohydrate, spray dried 57.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Amoxicillin, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tabletinq of the Amoxicillin and Clarithromycin
Table 67 Composition of Amoxicillin and Clarithromycin Tablets
Component Percentage (%)
Amoxicillin granules 45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Clarithromycin Pellets 14.9
AQOAT coated Amoxicillin Pellets
14.0
Eudragit FS 30D coated Clarithromycin Pellets 16.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin coated pellets, Clarithromycin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg total dose tablet.
In one embodiment, Amoxicillin will be dosed in an alternate pulse to Clarithromycin. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells.
In addition, even when Amoxicillin and Clarithromycin are not delivered in alternate pulses, the dosage forms as hereinabove described provide for improved treatment of infection.
Clarithromycin and Amoxicillin Tablets Preparation of Clarithromycin Granulation for tabletinq
Table 68 Composition of Clarithromycin Granulation (Immediate Release)
Component Percentage (%)
Clarithromycin powder 22.0
Lactose monohydrate, spray dried 57.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Clarithromycin, lactose, and Avicel® PH 101 using a high shear mixer. Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C. Granules between 20 and 40 Mesh are collected for further processing. Tableting of the Amoxicillin and Clarithromycin
Table 69 Composition of Amoxicillin and Clarithromycin Tablets
Component Percentage (%)
Clarithromycin granules 45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Amoxicillin Pellets 14.9
AQOAT coated Clarithromycin Pellets
14.0
Eudragit FS 30D coated Amoxicillin Pellets
16.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Clarithromycin granules, Avicel PH-200, Amoxicillin coated pellets, Clarithromycin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender. Add the magnesium stearate to the blender, and blend for 5 minutes. • Compress the blend on a rotary tablet press. The fill weight should be adjusted to achieve a 500 mg total dose tablet.
Example 52
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 70.
Table 70 Composition of Amoxicillin Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Cremaphor EL were added as a 2.9% w/w aqueous solution during wet massing. **Removed during processing
Preparation Procedure for Amoxicillin Pellets
• Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
• Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
• Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Pellets between 20 and 40 Mesh were collected for further processing. Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 71.
Table 71 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Agueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Dicloxacillin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Dicloxacillin pellets provided in Table 72.
Table 72 Composition of Dicloxacillin Pellets
Component Percentage (%)
Dicloxacillin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water *
Total 100
*Removed during processing Preparation Procedure for Dicloxacillin Pellets
Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved. Blend Dicloxacillin, lactose monohydrate, and croscarmellose sodium using a Robot Coupe high shear granulator.
Add binder solution slowly into the powder blend under continuous mixing.
Granulate the powders in the high shear granulator with the binder solution.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50°C until the moisture level is > 3%.
Pellets between 16 and 30 Mesh were collected for further processing. Dicloxacillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Dicloxacillin pellets is provided below in Table 73. Table 73 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
Screen the dispersion through a No. 60 mesh sieve prior to coating.
Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Dicloxacillin Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the Dicloxacillin pellets is provided below in Table 74.
Table 74 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudraqit FS30D Aqueous Coatinq
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating, dispersion such that you apply 30% coat weight gain to the pellets.
Amoxicillin and Dicloxacillin Tablets
Preparation of Amoxicillin Granulation for tabletinq
Table 75 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 24.0
Lactose monohydrate, spray dried 55.0
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Amoxicillin, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tabletinq of the Amoxicillin and Dicloxacillin
Table 76 Composition of Amoxicillin and Dicloxacillin Tablets
Component Percentage (%)
Amoxicillin granules 45.0
Avicel PH 200 7.5
Eudragit L30D-55/NE 30D coated Dicloxacillin Pellets 14.0
AQOAT coated Amoxicillin Pellets
15.8
Eudragit FS 30D coated Dicloxacillin Pellets
15.2
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin coated pellets, Dicloxacillin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg total dose tablet.
Example 53
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Amoxicillin trihydrate pellets provided in Table 77.
Table 77 Composition of Amoxicillin Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
Ηydroxypropyl methylcellulose and Cremaphor EL were added as a 2.9% w/w aqueous solution during wet massing. **Removed during processing
Preparation Procedure for Amoxicillin Pellets
• Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Pellets between 20 and 40 Mesh were collected for further processing. Amoxicillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® L 30 D-55/Eudraqit NE 30D Aqueous Coatinq
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 78.
Table 78 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Amoxicillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 79.
Table 79 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Agueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Agueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Amoxicillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the
Amoxicillin pellets is provided below in Table 80.
Table 80 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Agueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Dicloxacillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Dicloxacillin trihydrate pellets provided in Table 81.
Table 81 Composition of Dicloxacillin Pellets
Component Percentage (%)
Dicloxacillin 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
Ηydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil were added as a 2.9% w/w aqueous solution during wet massing. **Removed during processing
Preparation Procedure for Dicloxacillin Pellets
• Blend Dicloxacillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
• Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
• Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
• Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
• Pellets between 20 and 40 Mesh were collected for further processing. Dicloxacillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coatinq
Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Dicloxacillin pellets is provided below in Table 82.
Table 82 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Dicloxacillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous AQOAT AS-HF aqueous coating dispersion applied to the Dicloxacillin pellets is provided below in Table 83.
Table 83 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Agueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Agueous Coating
Dispersion
The following coating parameters were used for coating of the AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Dicloxacillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the
Dicloxacillin pellets is provided below in Table 84.
Table 84 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudraqit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Amoxicillin and Dicloxacillin Tablets
Preparation of Amoxicillin and Dicloxacillin Granulation for tableting
Table 85 Composition of Amoxicillin and Dicloxacillin Granulation
(Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 22.0
Dicloxacillin 22.0
Lactose monohydrate, spray dried 45.0
Avicel PH 101 10.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Amoxicillin, Dicloxacillin, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Amoxicillin and Dicloxacillin
Table 86 Composition of Amoxicillin and Dicloxacillin Tablets
Component Percentage (%)
Amoxicillin/Dicloxacillin granules 49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Amoxicillin Pellets 7.0
Eudragit L30D-55/NE 30D coated Dicloxacillin Pellets 7.0
AQOAT coated Amoxicillin Pellets 7.9
AQOAT coated Dicloxacillin Pellets 7.9
Eudragit FS 30D coated Amoxicillin Pellets
7.6
Eudragit FS 30D coated Dicloxacillin Pellets
7.6
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Amoxicillin/Dicloxacillin granules, Avicel PH-200, Amoxicillin coated pellets, Dicloxacillin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg total dose tablet.
In one embodiment, Amoxicillin will be dosed in an alternate pulse to dicloxacillin. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells. In addition, even when Amoxicillin and dicloxacillin are not delivered in alternate pulses, the dosage forms as hereinabove described provide for improved treatment of infection. Example 54
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition of the Metronidazole pellets provided in Table 87.
Table 87 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
*Removed during processing Preparation Procedure for Metronidazole Pellets
■ Blend metronidazole, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing. Metronidazole Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an Opadrv Clear Coating Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 88.
Table 88 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadrv Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1 -7006 to the water with continuous mixing.
Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 89.
Table 89 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudragit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aqueous Dispersion
Disperse triethyl citrate in purified water with stirring.
Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour.
Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
Screen the dispersion through a No. 60 mesh sieve.
Continue to stir the screened coating dispersion throughout the coating process. Coating Conditions for the Application of Opadrv and AQOAT/Eudraqit FS30D
Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS- HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated metronidazole pellets with the AQOATAS- HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Cefuroxime axetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Cefuroxime axetil pellets provided in Table 90.
Table 90 Composition of Cefuroxime axetil Pellets
Component Percentage (%)
Cefuroxime axetil 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
"Removed during processing
Preparation Procedure for Cefuroxime axetil Pellets
■ Blend Cefuroxime axetil, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Cefuroxime axetil Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Cefuroxime axetil pellets is provided below in Table 91.
Table 91 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudraqit® L 30D-55/Eudragit NE 30D Agueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating. • Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAqueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Cefuroxime axetil Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the Cefuroxime axetil pellets is provided below in Table 92.
Table 92 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudraqit FS30D Aqueous Coatinq
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Metronidazole and Cefuroxime axetil Tablets
Preparation of Metronidazole Granulation for tabletinq
Table 93 Composition of Metronidazole Granulation (Immediate Release)
Component Percentage (%)
Metronidazole 42.5
Lactose monohydrate, spray dried 36.5
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
Ηydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Metronidazole, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tabletinq of the Metronidazole and Cefuroxime axetil
Table 94 Composition of Metronidazole and Cefuroxime axetil Tablets
Component Percentage (%)
Metronidazole granules 45.0
Avicel PH 200 7.6
Eudragit L30D-55/NE 30D coated Cefuroxime axetil Pellets 8.2
AQOAT/Eudragit FS 30D coated Metronidazole Pellets 27.8
Eudragit FS 30D coated Cefuroxime axetil Pellets 8.9
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Metronidazole granules, Avicel PH-200, Metronidazole coated pellets, Cefuroxime axetil coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg total dose tablet.
The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day administration of the antibiotic.
Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described. Example 55
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the metronidazole pellets provided in Table 95.
Table 95 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
"Removed during processing
Preparation Procedure for Metronidazole Pellets
Blend metronidazole, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
Add the purified water slowly into the powder blend under continuous mixing.
Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
Dry the spheronized pellets at 50°C until moisture level is < 3%.
Pellets between 16 and 30 Mesh were collected for further processing. Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudraqit® L 30 D-55/Eudraqit NE 30D Aqueous Coatinq Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Metronidazole pellets is provided below in Table 96.
Table 96 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of Eudraqit L30D-55/Eudraqit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
• Coat metronidazole pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadrv Clear Coatinq Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the metronidazole pellets is provided below in Table 97.
Table 97 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadrv Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an AQOAT AS-HF/Eudraqit® FS30D Aqueous Coatinq Dispersion Dispersion Formulation
The composition of the aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 98.
Table 98 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Agueous Dispersion
Disperse triethyl citrate in purified water with stirring.
Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
Slowly add the Eudragit FS30D dispersion to the AQOAT AS-HF dispersion and continue to stir for a minimum of 1 hour.
Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
Screen the dispersion through a No. 60 mesh sieve.
Continue to stir the screened coating dispersion throughout the coating process.
Coatinq Conditions for the Application of Opadrv and AQOAT/Eudraqit FS30D Aqueous Coating Dispersions The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the AQOATAS-
HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated metronidazole pellets with the AQOATAS- HF/Eudragit FS30D coating dispersion such that you apply 32% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the
Metronidazole pellets is provided below in Table 99.
Table 99 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudraqit FS30D Aqueous Coatinq
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Cefuroxime axetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition of the Cefuroxime axetil pellets provided in Table 100.
Table 100 Composition of Cefuroxime axetil Pellets
Component Percentage (%)
Cefuroxime axetil 93
Avicel PH 101 3
Methocel E5P LV 4
Purified Water *
Total 100
"Removed during processing
Preparation Procedure for Cefuroxime axetil Pellets
■ Blend Cefuroxime axetil, Avicel® PH 101 , and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Cefuroxime axetil Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Agueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Cefuroxime axetil pellets is provided below in Table 101.
Table 101 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating
Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Agueous
Dispersion
Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than
55°C.
The TEC/lmwitor 900 dispersion is then stirred until the temperature is less than 35°C.
Add the TEC/lmwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
Add Eudragit NE 30D to the Eudragit L30D/TEC/lmwitor 900 dispersion and stir for at least 10 minutes. • Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30DAgueous Coating Dispersion
The following coating parameters were used for coating of the Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Cefuroxime axetil Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadrv Clear Coatinq Solution
Dispersion Formulation
The composition of the aqueous Opadry solution applied to the Cefuroxime axetil pellets is provided below in Table 102.
Table 102 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadrv Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1 -7006 to the water with continuous mixing.
Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Cefuroxime axetil pellets is provided below in Table 103.
Table 103 Eudragit FS 30D/Eudragit L 30D-55 Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Agueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add talc into the triethyl citrate dispersion with stirring.
■ Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.
■ Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.
■ Screen the dispersion through a No. 60 mesh sieve.
■ Continue to stir the screened coating dispersion throughout the coating process. Coating Conditions for the Application of Opadrv and Eudragit FS 30D/ Eudragit L
30D-55 Agueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Cefuroxime axetil pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets.
The following coating parameters were used for coating with the Eudragit FS
30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
• Coat Opadry coated Cefuroxime axetil pellets with the Eudragit FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 32% coat weight gain to the pellets.
Cefuroxime axetil Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Agueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the Cefuroxime axetil pellets is provided below in Table 104.
Table 104 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Agueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each of the Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion such that you apply 30% coat weight gain to the pellets.
Metronidazole and Cefuroxime axetil Tablets
Preparation of Metronidazole and Cefuroxime axetil Granulation for tabletinq
Table 105 Composition of Metronidazole and Cefuroxime axetil Granulation
(Immediate Release)
Component Percentage (%)
Metronidazole Trihydrate powder 13.3
Cefuroxime axetil 9.0
Lactose monohydrate, spra . dried 56.7
Avicel PH 101 20.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
Blend Metronidazole, Cefuroxime axetil, lactose, and Avicel® PH 101 using a high shear mixer.
Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
Granules between 20 and 40 Mesh are collected for further processing.
Tableting of the Metronidazole and Cefuroxime axetil
Table 106 Composition of Metronidazole and Cefuroxime axetil Tablets
Component Percentage (%)
Metronidazole/Cefuroxime axetil granules
49.0
Avicel PH 200 3.5
Eudragit L30D-55/NE 30D coated Metronidazole Pellets 8.4
Eudragit L30D-55/NE 30D coated Cefuroxime axetil Pellets 5.6
AQOAT/ Eudragit FS 30D coated Metronidazole Pellets 9.5
Eudragit FS 30D / L30D coated Cefuroxime axetil Pellets 6.3
Eudragit FS 30D coated Metronidazole Pellets
9.1
Eudragit FS 30D coated Cefuroxime axetil Pellets 6.1
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
Blend the Metronidazole/Cefuroxime axetil granules, Avicel PH-200,
Metronidazole coated pellets, Cefuroxime axetil coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
Add the magnesium stearate to the blender, and blend for 5 minutes.
Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 625 mg total dose tablet.
In one embodiment, cephalosporin will be dosed in an alternate pulse to Metronidazole. This will alternate the exposure to the bacteria in such a way as to make both antibiotics more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial cell wall receptors, or sites within the bacterial cells. In addition, even when cephalosporin and Metronidazole are not delivered in alternate pulses, the dosage forms as hereinabove described provide for improved treatment of infection.
Numerous modifications and variations of the present invention are possible in light of the above teachings; therefore, within the scope of the appended claims, the invention may be practiced otherwise than as particularly described.

Claims

We claim:
1. A once-a-day antibiotic product comprising: first, second, and third dosage forms, wherein each of said dosage forms includes at least one antibiotic and a pharmaceutically acceptable carrier; one of said dosage forms includes at least a first antibiotic selected from the group consisting of: Tetracycline, Ciprofoxacin, Amoxicillin, and Cephalosporin; and at least one of said dosage forms includes at least a second antibiotic that is different from the first antibiotic such that: when said first antibiotic is Tetracycline said second antibiotic is Doxycycline; when said first antibiotic is Ciprofoxacin said second antibiotic is Metronidazole; when said first antibiotic is Amoxicilli/n said second antibiotic is either Clarithromycin or Dicloxacillin; and when said first antibiotic is Cephalosporin said second antibiotic is Metronidazole; and said third dosage form includes at least one of the first and second antibiotics; said first dosage form is an immediate release dosage form; said second and third dosage forms are delayed release dosage forms; each of said first, second, and third dosage forms initiates release of antibiotic at different times and Cmax in serum of the total antibiotic released from said antibiotic product is achieved in less than about 12 hours from administration; and said once-a-day antibiotic product contains the total dosage of said at least two different antibiotics for a twenty-four hour period.
2. The product of Claim 1 , wherein said first antibiotic is Tetracycline and said second antibiotic is Doxycycline.
3. The product of Claim 1 , wherein said first antibiotic is Doxycycline and said second antibiotic is Tetracycline.
4. The product of Claim 1 , wherein said first antibiotic is Ciprofoxacin and said second antibiotic is Metronidazole.
5. The product of Claim 1 , wherein said first antibiotic is Metronidazole and said second antibiotic is Ciprofoxacin.
6. The product of Claim 1 , wherein said first antibiotic is Amoxicillin and said second antibiotic is Clarithromycin.
7. The product of Claim 1 , wherein said first antibiotic is Clarithromycin and said second antibiotic is Amoxicillin.
8. The product of Claim 1 , wherein said first antibiotic is Amoxicillin and said second antibiotic is Dicloxacillin.
9. The product of Claim 1 , wherein said first antibiotic is Dicloxacillin and said second antibiotic is Amoxicillin.
10. The product of Claim 1 , wherein said first antibiotic is Cephalosporin and said second antibiotic is Metronidazole.
11. The product of Claim 1 , wherein said first antibiotic is Metronidazole and said second antibiotic is Cephalosporin.
12. The product of Claim 1 , wherein antibiotic released from the second dosage form reaches a Cmax in serum after antibiotic released from the first dosage reaches a Cmax in serum.
13. The product of Claim 12, wherein antibiotic released form the third dosage form reaches a Cmax in serum after antibiotic released from the second dosage form reaches Cmax in serum.
14. The product of Claim 1 , wherein the product includes a fourth dosage form that includes at least one of the first and second antibiotics and said fourth dosage form being a delayed release dosage form.
15. The product of Claim 1 , wherein the first dosage form includes the first antibiotic, the second dosage form includes the first and second antibiotics, and the third dosage form includes the second antibiotic.
16. The product of Claim 1, wherein the immediate release dosage form contains from 20% to 50% of the total dosage of antibiotic.
17. The product of Claim 1 , wherein said second dosage form initiates release of antibiotic before said third dosage form, wherein said second dosage form provides from 30% to 60% by weight of the total antibiotic released by said second and third dosage forms, and wherein said third dosage form provides the remainder of the total antibiotic released by said second and third dosage forms.
18. The product of Claim 1 , wherein antibiotic released from the second dosage form reaches a Cmax in serum in no more than about 4 hours after administration of the product.
19. The product of Claim 1 , wherein antibiotic released from the third dosage form reaches a Cmax in serum within 8 hours after administration of the product.
20. The product of Claim 1 , wherein the product is an oral dosage form.
21. The product of claim 1 further comprising: a fourth dosage form, and wherein said first dosage form contains said first antibiotic; said second dosage form contains said first antibiotic; said third dosage form contains said second antibiotic; said fourth dosage form includes said second antibiotic and a pharmaceutically acceptable carrier; and said second and third dosage forms have release profiles whereby Cmax in serum for the first antibiotic and Cmax in serum for the second antibiotic released from the second and third dosage forms respectively are reached later in time than Cmax in serum is reached for the first antibiotic released from the first dosage form, and whereby the Cmax in serum for the second antibiotic released from the fourth dosage form is reached at a time after Cmax in serum for antibiotic released from each of the first, second, and third dosage forms are reached.
22. The product of Claim 21 , wherein the first antibiotic released from the second dosage form, and the second antibiotic released from the third dosage form reach a Cmax in serum at about the same time.
23. The product of Claim 21 , wherein said fourth dosage form is a sustained release dosage form.
24. The product of Claim 21 , wherein said fourth dosage form is a delayed release dosage form.
25. The product of Claim 24, wherein the immediate release dosage form contains from 15% to 30% of the total dosage of antibiotic.
26. The product of Claim 24, wherein said second dosage form initiates release of antibiotic before said third dosage form; wherein said third dosage form initiates release of antibiotic before said fourth dosage form; wherein said second dosage form provides 20% to 35% by weight of the total antibiotic released by said second, third, and fourth dosage forms; wherein said third dosage form provides from 20% to 40% by weight of the total antibiotic released by said second, third, and fourth dosage forms; and wherein said fourth dosage form provides the remainder of the total antibiotic released by said second, third, and fourth dosage forms.
27. The product of Claim 21 , wherein antibiotic released from the second dosage form reaches a Cmax in serum in no more than about 4 hours after administration of the product.
28. The product of Claim 21 , wherein antibiotic released from the third dosage form reaches a Cmax in serum within 8 hours after administration of the product.
29. The product of Claim 21 , wherein the product is an oral dosage form.
30. The antibiotic product of claim 1 , wherein each of the first, second, and third dosage forms includes at least one of the first and second antibiotics.
31. The product of Claim 30, wherein antibiotic released from the second dosage form reaches a Cmax in serum after antibiotic released from the first dosage form reaches a Cmax in serum.
32. The product of Claim 30, wherein antibiotic released from the third dosage form reaches a Cmax in serum after antibiotic released from the second dosage form reaches a Cmax in serum.
33. The product of Claim 30, wherein the immediate release dosage form contains from 20% to 50% of the total dosage of antibiotic.
34. The product of Claim 30, wherein said second dosage form initiates release of antibiotic before said third dosage form, wherein said second dosage form provides from 30% to 60% by weight of the total antibiotic released by said second and third dosage forms, and wherein said third dosage form provides the remainder of the total antibiotic released by said second and third dosage forms.
35. The product of Claim 30, wherein antibiotic released from the second dosage form reaches a Cmax in serum in no more than about 4 hours after administration of the product.
36. The product of Claim 30, wherein antibiotic released from the third dosage form reaches a Cmax in serum within 8 hours after administration of the product.
37. The product of Claim 30, wherein the product is an oral dosage form.
38. The product of Claim 1 , wherein each of the first, second, and third dosage forms contains a single antibiotic selected from the group consisting of said first and second antibiotics.
39. The product of Claim 12, wherein antibiotic released from the third dosage form reaches a Cmax in serum after antibiotic released from the second dosage form reaches a Cmax in serum.
40. The product of Claim 38, wherein antibiotic released from the third dosage form reaches a Cmax in serum after antibiotic released from the second dosage form reaches a Cmax in serum, and wherein antibiotic released from the second dosage form reaches a Cmax in serum after antibiotic released from the first dosage form reaches a Cmax in serum.
41. The product of Claim 38, wherein antibiotic released from the second dosage form reaches a Cmax in serum after antibiotic released from the first dosage form reaches a Cmax in serum.
42. The product of Claim 38, wherein said third dosage form initiates release of antibiotic after antibiotic released from said second dosage form reaches a Cmax in serum and wherein said second dosage form initiates release of antibiotic after antibiotic released from said first dosage form reaches a Cmax in serum.
43. A once-a-day antibiotic product comprising: first, second, and third dosage forms, wherein each of said dosage forms includes at least one antibiotic and a pharmaceutically acceptable carrier; wherein the first dosage form contains an initial dosage of a first antibiotic that is a protein synthesis inhibiting antibiotic and wherein the first dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics; the second dosage form contains an initial dosage of a second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the second dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics; and the third dosage form contains an additional dosage of said first antibiotic that is a protein synthesis inhibiting antibioitic and wherein the third dosage form is free of antibiotics that are not protein synthesis inhibiting antibiotics; said first dosage form is an immediate release dosage form; said second and third dosage forms are delayed release dosage forms; each of said first, second, and third dosage forms initiates release of antibiotic at different times and Cmax in serum of the total antibiotic released from said antibiotic product is achieved in less than about 12 hours from administration; and said once-a-day antibiotic product contains the total dosage of said at least two different antibiotics for a twenty-four hour period.
44. The product of Claims 43 further comprising a fourth dosage form, said fourth dosage form comprising at least one antibiotic and a pharmaceutically acceptable carrier; and wherein said fourth dosage form is a delayed release dosage form contains an additional dosage of said second antibiotic that is not a protein synthesis inhibiting antibiotic and wherein the fourth dosage form is free of antibiotics that are protein synthesis inhibiting antibiotics.
45. The product of Claim 44 wherein said fourth dosage form is a delayed release dosage form.
46. The product of Claim 44 wherein said fourth dosage form is a sustained release dosage form.
47. The antibiotic product of Claim 44 wherein said first antibiotic is Clarithromycin.
48. The antibiotic product of Claim 44 wherein said second antibiotic is Amoxicillin.
49. The antibiotic product of Claim 44 wherein said first antibiotic is Clarithromycin and wherein said second antibiotic is Amoxicillin.
50. The antibiotic product of Claim 44 wherein said first antibiotic is selected from the group of protein synthesis inhibiting antibiotics consisting of the aminoglycosides, the macrolides, the tetracyclines, the oxaxolidinones, fusidic acid, and chloramphenicol.
51. The antibiotic product of Claim 44 wherein said second antibiotic is selected from the group of non-protein synthesis inhibiting antibiotics consisting of the beta- lactam penicillins, the beta lactam cephalsporins, the beta lactam carbapenems, the sulfonamides, metronidazole, rifampin, vancomycin, and nitrofurantoin.
52. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 1 once-a-day.
53. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 2 once-a-day.
54. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 3 once-a-day.
55. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 4 once-a-day.
56. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 5 once-a-day.
57. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 6 once-a-day.
58. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 7 once-a-day.
59. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 8 once-a-day.
60. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 9 once-a-day.
61. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 10 once-a-day.
62. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 11 once-a-day.
63. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 12 once-a-day.
64. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 13 once-a-day.
65. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 14 once-a-day.
66. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 15 once-a-day.
67. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 16 once-a-day.
68. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 17 once-a-day.
69. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 18 once-a-day.
70. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 19 once-a-day.
71. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 20 once-a-day.
72. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 21 once-a-day.
73. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 22 once-a-day.
74. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 23 once-a-day.
75. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 24 once-a-day.
76. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 25 once-a-day.
77. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 26 once-a-day.
78. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 27 once-a-day.
79. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 28 once-a-day.
80. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 29 once-a-day.
81. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 30 once-a-day.
82. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 31 once-a-day.
83. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 32 once-a-day.
84. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 33 once-a-day.
85. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 34 once-a-day.
86. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 35 once-a-day.
87. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 36 once-a-day.
88. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 37 once-a-day.
89. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 38 once-a-day.
90. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 39 once-a-day.
91. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 40 once-a-day.
92. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 41 once-a-day.
93. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 42 once-a-day.
94. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 43 once-a-day.
95. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 44 once-a-day.
96. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 45 once-a-day.
97. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 46 once-a-day.
98. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 47 once-a-day.
99. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 48 once-a-day.
100. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 49 once-a-day.
101. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 50 once-a-day.
102. A process for treating a bacterial infection in a host comprising: administering to the host the antibiotic product of Claim 51 once-a-day.
EP03714005A 2002-03-07 2003-03-07 Antibiotic composition Withdrawn EP1487414A4 (en)

Applications Claiming Priority (11)

Application Number Priority Date Filing Date Title
US93321 1979-11-13
US10/092,854 US6627222B2 (en) 2000-02-24 2002-03-07 Amoxicillin-dicloxacillin antibiotic composition
US92858 2002-03-07
US92854 2002-03-07
US10/092,811 US6623758B2 (en) 2000-02-24 2002-03-07 Cephalosporin-metronidazole antibiotic composition
US93214 2002-03-07
US10/093,321 US6610328B2 (en) 2000-02-24 2002-03-07 Amoxicillin-clarithromycin antibiotic composition
US92811 2002-03-07
US10/093,214 US6638532B2 (en) 2000-02-24 2002-03-07 Tetracycline—doxycycline antibiotic composition
US10/092,858 US6632453B2 (en) 2000-02-24 2002-03-07 Ciprofoxacin-metronidazole antibiotic composition
PCT/US2003/007118 WO2003075852A2 (en) 2002-03-07 2003-03-07 Antibiotic composition

Publications (2)

Publication Number Publication Date
EP1487414A2 true EP1487414A2 (en) 2004-12-22
EP1487414A4 EP1487414A4 (en) 2007-12-12

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EP03714005A Withdrawn EP1487414A4 (en) 2002-03-07 2003-03-07 Antibiotic composition

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JP (1) JP2005526059A (en)
CA (1) CA2478121A1 (en)
WO (1) WO2003075852A2 (en)

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WO2003075852A2 (en) 2003-09-18
CA2478121A1 (en) 2003-09-18
AU2003218024B2 (en) 2008-09-11
JP2005526059A (en) 2005-09-02
EP1487414A4 (en) 2007-12-12
AU2003218024A1 (en) 2003-09-22

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