US20020197314A1 - Anti-fungal composition - Google Patents

Anti-fungal composition Download PDF

Info

Publication number
US20020197314A1
US20020197314A1 US09/791,284 US79128401A US2002197314A1 US 20020197314 A1 US20020197314 A1 US 20020197314A1 US 79128401 A US79128401 A US 79128401A US 2002197314 A1 US2002197314 A1 US 2002197314A1
Authority
US
United States
Prior art keywords
fungal
product
dosage form
dosage forms
released
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.)
Abandoned
Application number
US09/791,284
Inventor
Edward Rudnic
James Isbister
Donald Treacy
Sandra 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.)
Advanced Pharma Inc
Original Assignee
Advanced Pharma Inc
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
Application filed by Advanced Pharma Inc filed Critical Advanced Pharma Inc
Priority to US09/791,284 priority Critical patent/US20020197314A1/en
Assigned to ADVANCED PHARMA, INC. reassignment ADVANCED PHARMA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: WASSINK, SANDRA E., TREACY, JR., DONALD J., ISBISTER, JAMES D., RUDNIC, EDWARD M.
Priority to US10/320,113 priority patent/US6929804B2/en
Publication of US20020197314A1 publication Critical patent/US20020197314A1/en
Assigned to HEALTHCARE VENTURES VI, L.P. reassignment HEALTHCARE VENTURES VI, L.P. SECURITY INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ADVANCIS PHARMACEUTICAL CORPORATION
Assigned to ADVANCIS PHARMACEUTICAL CORPORATION reassignment ADVANCIS PHARMACEUTICAL CORPORATION RELEASE BY SECURED PARTY (SEE DOCUMENT FOR DETAILS). Assignors: HEALTHCARE VENTURES VI, L.P.
Priority to US11/124,335 priority patent/US20050238714A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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

Definitions

  • This invention relates to anti-fungal compositions and the use thereof. More particularly, this invention relates to a composition for the delivery of two or more anti-fungals, and the use thereof.
  • the present invention is directed to a new and improved composition that delivers two or more anti-fungals, and the use thereof.
  • an anti-fungal product for delivering at least two different anti-fungals that is comprised of at least three dosage forms each comprised of at least one anti-fungal agent and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one of the at least two anti-fungals and at least one dosage form including at least a second anti-fungal of the at least two anti-fungals.
  • each of the dosage forms may include two or more anti-fungals, or one or two of the dosage forms may include only one of the two or more anti-fungals and each of the remaining dosage forms may include only one or more of the different anti-fungals or two or more of the anti-fungals.
  • an anti-fungal product for delivering at least two different anti-fungals wherein the product includes at least three dosage forms wherein each of the at least two anti-fungals is present in at least one of the three dosage forms.
  • each of the dosage forms 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 anti-fungal product as hereinabove and hereinafter described.
  • a single or unitary anti-fungal product that has contained therein at least three anti-fungal dosage forms, each of which has a different release profile, whereby the anti-fungal contained in each of the at least three dosage forms is released at different times, and wherein at least one of the dosage forms includes at least a first anti-fungal and at least one of the dosage forms includes at least a second anti-fungal different from the first anti-fungal.
  • the anti-fungal product may be comprised of at least four different dosage forms, each of which starts to release the anti-fungal contained therein at different times after administration of the anti-fungal product.
  • the anti-fungal product generally does not include more than five dosage forms with different release times.
  • the anti-fungal product has an overall release profile such that when administered the maximum serum concentration of the total anti-fungal 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 anti-fungal released from the anti-fungal 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 anti-fungal therefrom is not substantially delayed after administration of the anti-fungal 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 anti-fungal product), whereby anti-fungal released therefrom is delayed until after initiation of release of anti-fungal from the immediate release dosage form.
  • anti-fungal 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 anti-fungal released from the first of the at least three dosage forms achieves a C max in the serum, and anti-fungal released from the third dosage form achieves a C max in the serum after the C max of anti-fungal 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 anti-fungal 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 anti-fungal from the first dosage form of the at least three dosage forms.
  • the immediate release dosage form produces a C max for anti-fungal 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 anti-fungal released therefrom in no more than about four hours.
  • the C max for such second dosage form is achieved no earlier than two hours after administration of the anti-fungal product; however, it is possible within the scope of the invention to achieve C max in a shorter period of time.
  • the anti-fungal product may contain at least three or at least four or more different dosage forms.
  • the anti-fungal released from the third dosage form reaches a C max at a time later than the C max is achieved for anti-fungal released from each of the first and second dosage forms.
  • release of anti-fungal from the third dosage form is started after initiation of release of anti-fungal from both the first dosage form and the second dosage form.
  • C max for anti-fungal release from the third dosage form is achieved within eight hours.
  • the anti-fungal product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby anti-fungal released from each of the at least four different dosage forms achieves a C max at a different time.
  • C max for all the anti-fungal released from the anti-fungal product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.
  • the anti-fungal product is a once a day product, whereby after administration of the anti-fungal 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 term single administration means that the total anti-fungal 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.
  • a single dosage anti-fungal product comprised of at least three anti-fungal dosage forms each having a different release profile with each of the dosage forms including at least one of a first or second anti-fungal and at least one of the three dosage forms including at least the first anti-fungal and at least one of the dosage forms including at least the second anti-fungal.
  • Each of the dosage forms of anti-fungal in a pharmaceutically acceptable carrier may have one or more anti-fungals.
  • 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 max of each of the other dosage forms is reached, anti-fungal release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
  • an anti-fungal composition that is a mixture of anti-fungal compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first anti-fungal and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first anti-fungal and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second anti-fungal different from the first anti-fungal and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising the second anti-fungal 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 anti-fungal released from the second composition and a maximum serum concentration for the second anti-fungal released from the third composition at a time after the first anti-fungal 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 anti-fungal released from the fourth composition at
  • the release profiles of the second and third composition are such that the maximum serum concentration of the first anti-fungal released from the second composition, and the maximum serum concentration of the second anti-fungal released from the third composition are reached at approximately the same time, or where the first anti-fungal reaches a maximum serum concentration before or after the second anti-fungal reaches a maximum serum concentration.
  • a first pulse in which a first anti-fungal reaches a maximum serum concentration
  • a second pulse wherein a further dosage of the first anti-fungal, and an initial dosage of the second anti-fungal reach a maximum serum concentration at a time after the first pulse of the first anti-fungal reaches a maximum serum concentration
  • a third pulse wherein an additional dosage of the second anti-fungal reaches a maximum serum concentration at a time after the maximum serum concentration is reached for each of the first and second anti-fungal dosages provided in the second pulse.
  • the first dosage of the first anti-fungal achieves a maximum serum concentration within four hours after administration of the anti-fungal composition; the second dosage of the first anti-fungal and the first dosage of the second anti-fungal each reach a maximum serum concentration within four to eight hours after administration of the anti-fungal composition; and the second dosage of the second anti-fungal reaches a maximum serum concentration within twelve hours after administration of the anti-fungal composition.
  • an anti-fungal composition that includes four different dosage forms, with the first dosage form providing an initial dosage of a first anti-fungal, the second dosage form providing a further dosage of the first anti-fungal; the third dosage form providing an initial dosage of a second anti-fungal; and the fourth dosage form providing an additional dosage of the second anti-fungal, wherein the anti-fungals released from the second and third dosage forms reach a maximum serum concentration at a time after the anti-fungal released from the first dosage form reaches a maximum serum concentration, and the anti-fungal released from the fourth dosage form reaching a maximum serum concentration at a time after the times at which the anti-fungals 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 anti-fungal; the second dosage form contains from about 30 percent to about 80 percent of the first anti-fungal; the third dosage form contains from about 30 percent to about 80 percent of the second anti-fungal, and the fourth anti-fungal dosage form contains from about 30 percent to about 80 percent of the second anti-fungal.
  • 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 anti-fungal 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 anti-fungal.
  • Each of the third and fourth dosage forms include from 20% to 80% of the total dosage of the second anti-fungal to be delivered by the composition, and each of the third and fourth units may have the same or different dosages of the anti-fungal.
  • the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of anti-fungal to be delivered by the product, with such immediate release dosage form generally providing at least 25% of the total dosage of the anti-fungal to be delivered by the product.
  • the immediate release dosage form provides from about 20% to about 30% of the total dosage of anti-fungal 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 anti-fungal to be delivered by the product.
  • each of the delayed release dosage forms may provide about equal amounts of anti-fungal; 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 anti-fungal; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total anti-fungal; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, of the total anti-fungal.
  • the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, of the total anti-fungal provided by the two delayed release components with the second delayed release component providing the remainder of the anti-fungal.
  • the earliest released component provides 20% to 35% by weight of the total anti-fungal provided by the three delayed release components
  • the next in time delayed release component provides from 20% to 40%, by weight, of the anti-fungal provided by the three delayed release components and the last in time providing the remainder of the anti-fungal 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 anti-fungal provided by the four delayed release components.
  • the overall composition includes each of the anti-fungals in a therapeutically effective amount.
  • the specific amount(s) is dependant on the anti-fungal used, the disease or infection to be treated, and the number of times of day that the composition is to be administered.
  • the anti-fungal 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 anti-fungal product of the present invention may be formulated for administration by a variety of routes of administration.
  • the anti-fungal 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 anti-fungal 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 anti-fungal product in the form of a patch, which includes anti-fungal dosage forms having different release profiles, as hereinabove described.
  • the anti-fungal 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 anti-fungal 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 anti-fungal product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
  • the anti-fungal 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 anti-fungal product.
  • anti-fungal 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 anti-fungal, as hereinabove described, whereby the C max of the anti-fungal released from each of the tablets is reached at different times, with the C max of the total anti-fungal released from the anti-fungal product being achieved in less than twelve hours.
  • an anti-fungal 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 anti-finals in the coating and/or the thickness of the coating.
  • the immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the anti-fungal. 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 anti-finals 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
  • 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 Pluronic 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
  • these materials can be present in the range of 0.5-25% (W/W) of this component.
  • 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 pthalate, Eudragit L, and other pthalate salts of cellulose derivatives.
  • These materials can be present in concentrations from 4-20% (W/W).
  • amphotericin B flucytosine, fluconazole, griseofulvin, miconazole nitrate, terbinafine hydrochloride, ketoconazole, itraconazole, undecylenic acid and chloroxylenol, ciclopirox, clotrimazole, butenafine hydrochloride, nystatin, naftifine hydrochloride, oxiconazole nitrate, selenium sulfide, econazole nitrate, terconazole, butoconazole nitrate, carbol-fuchsin, clioquinol, methylrosaniline chloride, sodium thiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder
  • a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
  • the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • Example 1 Fluconazole 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5
  • Example 2 Fluconazole 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10
  • Example 3 Fluconazole 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
  • Example 4 Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Example 5 Fluconazole 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
  • Example 6 Ketoconazole 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
  • Example 7 Ketoconazole 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
  • Example 8 Ketoconazole 75% (W/W) Polyethylene glycol 4000 10
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
  • Example 16 Fluconazole 65% (W/W) Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5
  • Example 17 Fluconazole 55% (W/W) Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10
  • Example 18 Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
  • Example 19 Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5
  • Example 20 Fluconazole 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5
  • Example 21 Ketoconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5
  • Example 22 Ketoconazole 75% (W/W) Polyox 15 Hydroxypropylcellulose 5 Ethylcellulose 5
  • Example 23 Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10
  • Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
  • Example 31 Fluconazole 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15
  • Example 32 Fluconazole 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10
  • Example 33 Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5
  • Example 34 Fluconazole 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D 5
  • Example 35 Fluconazole 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10
  • Example 36 Ketoconazole 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10
  • Example 37 Ketoconazole 70% (W/W) Eudragit L 30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5
  • Example 38 Ketoconazole 75% (W/W) Polyethylene glycol
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical drier such as a vacuum oven or forced-air oven.
  • Example 46 Fluconazole 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5
  • Example 47 Fluconazole 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10
  • Example 48 Fluconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 10
  • Example 49 Ketoconazole 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5
  • Example 50 Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 Eudragit RL 30D 5
  • Example 51 Ketoconazole 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5
  • Example 52 Griseofulvin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5
  • Example 53 Griseofulvin 75% (W/W) Lac
  • composition of the antifungal matrix pellets provided in Table 1. TABLE 1 Composition of Antifungal Pellets Component Percentage (%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100
  • composition of the aqueous Eudragit L30D-55 dispersion applied to the antifungal 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
  • the composition of the aqueous Eudragit® S 100 dispersion applied to the antifungal 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
  • 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%: 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 a the desire dosage.
  • the immediate release matrix pellets include the first antifungal, the L30 D-55 coated pellets are made by coating matrix pellets that contain the second antifungal and the S100 coated pellets are made by coating matrix pellets that contain the first antifungal.
  • composition of the Antifungaltrihydrate matrix pellets provided in Table 4. TABLE 4 Composition of AntifungalMatrix Pellets Component Percentage (%) AntifungalTrihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100
  • 60.2.3 Extrude the wet mass using an LCI Bench Top Granulator.
  • the diameter of the screen of the Bench Top Granulator is 0.8 mm.
  • the composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungalmatrix 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
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • 60.9.3 Compress the blend on a rotary tablet press.
  • composition of the antifungal matrix pellets provided in Table 9. TABLE 9 Composition of Antifungal Pellets Component Percentage (%) Antifungal 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100
  • the composition of the aqueous Eudragit® S 100 dispersion applied to the antifungal 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
  • 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 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 antifungal; the L30 D-55 12% weight gain coated pellets containe the second antifungal; the L30 D-55 30% weight gain coated pellets contain the first antifungal and the S100 coated pellets contain the second antifungal.
  • the present invention is advantageous in that a synergistic anti-fungal will be dosed in an alternate pulse to another, synergistic anti-fungal. This will alternate the exposure to the fungus in such a way as to make both anti-fungals more effective than if they were co-administered.

Abstract

An anti-fungal product for delivering at least two different anti-fungals that is comprised of three dosage forms with different release profiles with each anti-fungal being present in at least one of the dosage forms.

Description

  • This invention relates to anti-fungal compositions and the use thereof. More particularly, this invention relates to a composition for the delivery of two or more anti-fungals, and the use thereof. [0001]
  • In many cases, it is desirable to employ two different anti-fungals in the treatment of a fungus infection, in that such anti-fungals may have complementary mechanisms of action that facilitate treatment of the fungus infection. [0002]
  • The present invention is directed to a new and improved composition that delivers two or more anti-fungals, and the use thereof. [0003]
  • In accordance with an aspect of the present invention, there is provided an anti-fungal product for delivering at least two different anti-fungals that is comprised of at least three dosage forms each comprised of at least one anti-fungal agent and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one of the at least two anti-fungals and at least one dosage form including at least a second anti-fungal of the at least two anti-fungals. [0004]
  • Thus, for example, each of the dosage forms may include two or more anti-fungals, or one or two of the dosage forms may include only one of the two or more anti-fungals and each of the remaining dosage forms may include only one or more of the different anti-fungals or two or more of the anti-fungals. Thus, in accordance with this aspect of the invention, there is an anti-fungal product for delivering at least two different anti-fungals wherein the product includes at least three dosage forms wherein each of the at least two anti-fungals is present in at least one of the three dosage forms. [0005]
  • In a preferred embodiment each of the dosage forms has a different release profile, with one of the dosage forms being an immediate release dosage form. [0006]
  • In another aspect, the present invention is directed to treating a bacterial infection by administering to a host in need thereof an anti-fungal product as hereinabove and hereinafter described. [0007]
  • Thus, in accordance with an aspect of the present invention, there is provided a single or unitary anti-fungal product that has contained therein at least three anti-fungal dosage forms, each of which has a different release profile, whereby the anti-fungal contained in each of the at least three dosage forms is released at different times, and wherein at least one of the dosage forms includes at least a first anti-fungal and at least one of the dosage forms includes at least a second anti-fungal different from the first anti-fungal. [0008]
  • In accordance with a further aspect of the invention, the anti-fungal product may be comprised of at least four different dosage forms, each of which starts to release the anti-fungal contained therein at different times after administration of the anti-fungal product. [0009]
  • The anti-fungal product generally does not include more than five dosage forms with different release times. [0010]
  • In accordance with a preferred embodiment, the anti-fungal product has an overall release profile such that when administered the maximum serum concentration of the total anti-fungal 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 anti-fungal released from the anti-fungal product is achieved no earlier than four hours after administration. [0011]
  • 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 anti-fungal therefrom is not substantially delayed after administration of the anti-fungal 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 anti-fungal product), whereby anti-fungal released therefrom is delayed until after initiation of release of anti-fungal from the immediate release dosage form. More particularly, anti-fungal release from the second of the at least two dosage forms achieves a C[0012] max (maximum serum concentration in the serum) at a time after anti-fungal released from the first of the at least three dosage forms achieves a Cmax in the serum, and anti-fungal released from the third dosage form achieves a Cmax in the serum after the Cmax of anti-fungal released from the second dosage form.
  • In one embodiment, the second of the at least two dosage forms initiates release of anti-fungal 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 anti-fungal from the first dosage form of the at least three dosage forms. [0013]
  • In general, the immediate release dosage form produces a C[0014] max for anti-fungal 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 anti-fungal 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 anti-fungal product; however, it is possible within the scope of the invention to achieve Cmax in a shorter period of time.
  • As hereinabove indicated, the anti-fungal product may contain at least three or at least four or more different dosage forms. For example, the anti-fungal released from the third dosage form reaches a C[0015] max at a time later than the Cmax is achieved for anti-fungal released from each of the first and second dosage forms. In a preferred embodiment, release of anti-fungal from the third dosage form is started after initiation of release of anti-fungal from both the first dosage form and the second dosage form. In one embodiment, Cmax for anti-fungal release from the third dosage form is achieved within eight hours.
  • In another embodiment, the anti-fungal product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby anti-fungal released from each of the at least four different dosage forms achieves a C[0016] max at a different time.
  • As hereinabove indicated, in a preferred embodiment, irrespective of whether the anti-fungal contains at least three or at least four different dosage forms each with a different release profile, C[0017] max for all the anti-fungal released from the anti-fungal product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.
  • In a preferred embodiment, the anti-fungal product is a once a day product, whereby after administration of the anti-fungal 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 anti-fungal product with the anti-fungal being released in a manner such that overall anti-fungal release is effected with different release profiles in a manner such that the overall C[0018] max for the anti-fungal product is reached in less than twelve hours. The term single administration means that the total anti-fungal 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 anti-fungal product comprised of at least three anti-fungal dosage forms each having a different release profile with each of the dosage forms including at least one of a first or second anti-fungal and at least one of the three dosage forms including at least the first anti-fungal and at least one of the dosage forms including at least the second anti-fungal. Each of the dosage forms of anti-fungal in a pharmaceutically acceptable carrier may have one or more anti-fungals. [0019]
  • 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 anti-fungal may occur. Such “leakage” is not “release” as used herein. [0020]
  • 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 C[0021] max of the fourth dosage form of the at least four dosage forms is reached after the Cmax of each of the other dosage forms is reached, anti-fungal release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
  • In accordance with an aspect of the present invention, there is provided an anti-fungal composition that is a mixture of anti-fungal compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first anti-fungal and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first anti-fungal and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second anti-fungal different from the first anti-fungal and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising the second anti-fungal 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 anti-fungal released from the second composition and a maximum serum concentration for the second anti-fungal released from the third composition at a time after the first anti-fungal 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 anti-fungal released from the fourth composition at a time after the anti-fungals released from the second and third compositions reach a maximum serum concentration. [0022]
  • In one embodiment, the release profiles of the second and third composition are such that the maximum serum concentration of the first anti-fungal released from the second composition, and the maximum serum concentration of the second anti-fungal released from the third composition are reached at approximately the same time, or where the first anti-fungal reaches a maximum serum concentration before or after the second anti-fungal reaches a maximum serum concentration. [0023]
  • In effect, in accordance with a preferred embodiment of the present invention, there is provided a first pulse in which a first anti-fungal reaches a maximum serum concentration, a second pulse wherein a further dosage of the first anti-fungal, and an initial dosage of the second anti-fungal reach a maximum serum concentration at a time after the first pulse of the first anti-fungal reaches a maximum serum concentration, and a third pulse wherein an additional dosage of the second anti-fungal reaches a maximum serum concentration at a time after the maximum serum concentration is reached for each of the first and second anti-fungal dosages provided in the second pulse. [0024]
  • In a preferred embodiment of the present invention, the first dosage of the first anti-fungal achieves a maximum serum concentration within four hours after administration of the anti-fungal composition; the second dosage of the first anti-fungal and the first dosage of the second anti-fungal each reach a maximum serum concentration within four to eight hours after administration of the anti-fungal composition; and the second dosage of the second anti-fungal reaches a maximum serum concentration within twelve hours after administration of the anti-fungal composition. [0025]
  • Thus, in accordance with an aspect of the present invention, there is provided an anti-fungal composition that includes four different dosage forms, with the first dosage form providing an initial dosage of a first anti-fungal, the second dosage form providing a further dosage of the first anti-fungal; the third dosage form providing an initial dosage of a second anti-fungal; and the fourth dosage form providing an additional dosage of the second anti-fungal, wherein the anti-fungals released from the second and third dosage forms reach a maximum serum concentration at a time after the anti-fungal released from the first dosage form reaches a maximum serum concentration, and the anti-fungal released from the fourth dosage form reaching a maximum serum concentration at a time after the times at which the anti-fungals released from each of the first, second, and third dosage forms reach a maximum serum concentration. [0026]
  • 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. [0027]
  • In formulating the anti-fungal composition of the present invention, which contains four different dosage forms, as hereinabove described, the first dosage form generally contains from about 30 percent to about 80 percent of the first anti-fungal; the second dosage form contains from about 30 percent to about 80 percent of the first anti-fungal; the third dosage form contains from about 30 percent to about 80 percent of the second anti-fungal, and the fourth anti-fungal dosage form contains from about 30 percent to about 80 percent of the second anti-fungal. 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. [0028]
  • Each of the first and second dosage forms include from 20% to 80% of the total dosage of the first anti-fungal 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 anti-fungal. [0029]
  • Each of the third and fourth dosage forms include from 20% to 80% of the total dosage of the second anti-fungal to be delivered by the composition, and each of the third and fourth units may have the same or different dosages of the anti-fungal. [0030]
  • In formulating an anti-fungal 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 anti-fungal to be delivered by the product, with such immediate release dosage form generally providing at least 25% of the total dosage of the anti-fungal 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 anti-fungal 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 anti-fungal to be delivered by the product. [0031]
  • The remaining dosage forms deliver the remainder of the anti-fungal. 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 anti-fungal; however, they may also be formulated so as to provide different amounts. [0032]
  • 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 anti-fungal; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total anti-fungal; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, of the total anti-fungal. [0033]
  • 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 anti-fungal provided by the two delayed release components with the second delayed release component providing the remainder of the anti-fungal. [0034]
  • Where there are three delayed release components, the earliest released component provides 20% to 35% by weight of the total anti-fungal provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, of the anti-fungal provided by the three delayed release components and the last in time providing the remainder of the anti-fungal provided by the three delayed release components. [0035]
  • 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 anti-fungal provided by the four delayed release components. [0036]
  • The overall composition includes each of the anti-fungals in a therapeutically effective amount. The specific amount(s) is dependant on the anti-fungal used, the disease or infection to be treated, and the number of times of day that the composition is to be administered. [0037]
  • The anti-fungal 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. [0038]
  • The anti-fungal product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the anti-fungal 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 anti-fungal product is formulated in a manner such that it is suitable for oral administration. [0039]
  • For example, in formulating the anti-fungal product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an anti-fungal, 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. [0040]
  • It is also within the scope of the invention to provide an anti-fungal product in the form of a patch, which includes anti-fungal dosage forms having different release profiles, as hereinabove described. [0041]
  • In addition, the anti-fungal 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. [0042]
  • Furthermore, the anti-fungal 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. [0043]
  • As a further embodiment, the anti-fungal product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation. [0044]
  • In a preferred embodiment, the anti-fungal 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. [0045]
  • 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 anti-fungal product. Thus, for example, anti-fungal 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 anti-fungal, as hereinabove described, whereby the C[0046] max of the anti-fungal released from each of the tablets is reached at different times, with the Cmax of the total anti-fungal released from the anti-fungal product being achieved in less than twelve hours.
  • The formulation of an anti-fungal 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 anti-finals in the coating and/or the thickness of the coating. [0047]
  • The Immediate Release Component [0048]
  • The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the anti-fungal. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components. [0049]
  • The materials to be added to the anti-finals 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. [0050]
  • It may be useful to have these materials present in the range of 1.0 to 60% (W/W). [0051]
  • 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 Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above. [0052]
  • These materials may be present in the rate of 0.05-15% (W/W). [0053]
  • The Delayed Release Component [0054]
  • 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. [0055]
  • 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. [0056]
  • Typically these materials can be present in the range of 0.5-25% (W/W) of this component. [0057]
  • The Enteric Release Component [0058]
  • 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. [0059]
  • The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives. [0060]
  • These materials can be present in concentrations from 4-20% (W/W). [0061]
  • The following are representative examples of some antifungals that can be employed in the composition of the invention: amphotericin B, flucytosine, fluconazole, griseofulvin, miconazole nitrate, terbinafine hydrochloride, ketoconazole, itraconazole, undecylenic acid and chloroxylenol, ciclopirox, clotrimazole, butenafine hydrochloride, nystatin, naftifine hydrochloride, oxiconazole nitrate, selenium sulfide, econazole nitrate, terconazole, butoconazole nitrate, carbol-fuchsin, clioquinol, methylrosaniline chloride, sodium thiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate salts (calcium undecylenate, copper undecylenate, zinc undecylenate)[0062]
  • The invention will be further described with respect to the following examples; however, the scope of the invention is not limited thereby. All percentages in this specification, unless otherwise specified, are by weight. [0063]
  • Immediate Release Component [0064]
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0065]
    Example 1:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Povidone 10
    Croscarmellose sodium  5
    Example 2:
    Fluconazole 55% (W/W)
    Microcrystalline cellulose 25
    Povidone 10
    Croscarmellose sodium 10
    Example 3:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium  5
    Example 4:
    Fluconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Hydroxypropylcellulose  5
    Example 5:
    Fluconazole 75% (W/W)
    Polyethylene glycol 8000 20
    Polyvinylpyrrolidone  5
    Example 6:
    Ketoconazole 65% (W/W)
    Microcrystalline cellulose 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium  5
    Example 7:
    Ketoconazole 75% (W/W)
    Microcrystalline cellulose 15
    Hydroxypropylcellulose  5
    Croscarmellose sodium  5
    Example 8:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Hydroxypropylcellulose  5
    Example 9:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 8000 20
    Polyvinylpyrrolidone  5
    Example 10:
    Griseofulvin 65% (W/W)
    Microcrystalline cellulose 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium  5
    Example 11:
    Griseofulvin 75% (W/W)
    Microcrystalline cellulose 15
    Hydroxypropylcellulose  5
    Croscarmellose sodium  5
    Example 12:
    Griseofulvin 75% (W/W)
    Polyethylene glycol 4000 10
    Polytheylene glycol 2000 10
    Hydroxypropylcellulose  5
    Example 13:
    Cirpofloxacin 75% (W/W)
    Polyethylene glycol 8000 20
    Polyvinylpyrrolidone  5
    Example 14:
    Terbinafine HCl 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Hydroxypropylcellulose  5
    Example 15:
    Terbinafine HCl 75% (W/W)
    Polyethylene Glycol 4000 20
    Polyvinylpyrrolidone  5
  • Non pH Sensitive Delayed Release Component [0066]
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0067]
    Ingredient Conc. (% W/W)
    Example 16:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Polyox 10
    Croscarmellose sodium  5
    Example 17:
    Fluconazole 55% (W/W)
    Microcrystalline cellulose 25
    Polyox 10
    Glyceryl monooleate 10
    Example 18:
    Fluconazole 65% (W/W)
    Polyox 20
    Hydroxypropylcellulose 10
    Croscarmellose sodium  5
    Example 19:
    Fluconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Eudragit RL 30D  5
    Example 20:
    Fluconazole 75% (W/W)
    Polyethylene glycol 8000 20
    Ethylcellulose  5
    Example 21:
    Ketoconazole 70% (W/W)
    Polyox 20
    Hydroxypropylcellulose  5
    Croscarmellose sodium  5
    Example 22:
    Ketoconazole 75% (W/W)
    Polyox 15
    Hydroxypropylcellulose  5
    Ethylcellulose  5
    Example 23:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Eudragit RL 30D  5
    Example 24:
    Ketoconazole 80% (W/W)
    Polyethylene glycol 8000 10
    Polyvinylpyrrolidone  5
    Eudgragit R 30D  5
    Example 25:
    Griseofulvin 65% (W/W)
    Polyethylene glycol 4000 20
    Hydroxypropylcellulose 10
    Eudragit RL 30D  5
    Example 26:
    Griseofulvin 75% (W/W)
    Microcrystalline cellulose 15
    Hydroxypropylcellulose  5
    Ethylcellulose  5
    Example 27:
    Griseofulvin 80% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000  5
    Eudgragit RL 30D  5
    Example 28:
    Griseofulvin 75% (W/W)
    Polyethylene glycol 8000 20
    Ethylcellulose  5
    Example 29:
    Terbinafine HCl 75% (W/W)
    Polyethylene glycol 4000 10
    Polyethylene glycol 2000 10
    Eudragit RL 30D  5
    Example 30:
    Terbinafine HCl 75% (W/W)
    Polyethylene glycol 8000 20
    Ethylcellulose  5
  • Enteric Release Component [0068]
  • Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0069]
    Ingredient Conc. (% W/W)
    Example 31:
    Fluconazole 65% (W/W)
    Microcrystalline cellulose 20
    Cellulose Acetate Pthalate 15
    Example 32:
    Fluconazole 55% (W/W)
    Microcrystalline cellulose 25
    Cellulose Acetate Pthalate 10
    Hydroxypropylmethylcellulose 10
    Example 33:
    Fluconazole 65% (W/W)
    Polyox 20
    Hydroxypropylcellulose pthalate 10
    Eudragit L30D  5
    Example 34:
    Fluconazole 75% (W/W)
    Polyethylene glycol 2000 10
    Eudragit L 30D 10
    Eudragit RL 30D  5
    Example 35:
    Fluconazole 40% (W/W)
    Microcrystalline Cellulose 40
    Cellulose Acetate Pthalate 10
    Example 36:
    Ketoconazole 70% (W/W)
    Hydroxypropylcellulose pthalate 15
    Croscarmellose sodium 10
    Example 37:
    Ketoconazole 70% (W/W)
    Eudragit L 30D 15
    Hydroxypropylcellulose 10
    Ethylcellulose  5
    Example 38:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 2000 10
    Eudragit L 30D 15
    Example 39:
    Ketoconazole 40% (W/W)
    Lactose 50
    Eudgragit L 30D 10
    Example 40:
    Griseofulvin 65% (W/W)
    Microcrystalline Cellulose 20
    Eudragit L 30D 10
    Example 41:
    Griseofulvin 75% (W/W)
    Microcrystalline Cellulose 15
    Hydroxypropylcellulose pthalate 10
    Example 42:
    Griseofulvin 80%(W/W)
    Lactose 10
    Eudragit L 30D 10
    Example 43:
    Griseofulvin 70% (W/W)
    Polyethylene glycol 4000 20
    Cellulose acetate pthalate 10
    Example 44:
    Terbinafine HCl 60% (W/W)
    Polyethylene glycol 2000 10
    Lactose 20
    Eudragit L 30D 10
    Example 45:
    Terbinafine HCl 70% (W/W)
    Microcrystalline cellulose 20
    Cellulose acetate pthalate 10
  • Sustained Release Component [0070]
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press. [0071]
    Ingredient Conc. % W/W)
    Example 46:
    Fluconazole 65% (W/W)
    Ethylcellulose 20
    Polyox 10
    Hydroxypropylmethylcellulose  5
    Example 47:
    Fluconazole 55% (W/W)
    Lactose 25
    Polyox 10
    Glyceryl monooleate 10
    Example 48:
    Fluconazole 70% (W/W)
    Polyox 20
    Hydroxypropylcellulose 10
    Example 49:
    Ketoconazole 75% (W/W)
    Lactose 15
    Hydroxypropylcellulose  5
    Ethylcellulose  5
    Example 50:
    Ketoconazole 75% (W/W)
    Polyethylene glycol 4000 10
    Lactose 10
    Eudragit RL 30D  5
    Example 51:
    Ketoconazole 80% (W/W)
    Polyethylene glycol 8000 10
    Hydroxypropylmethylcellulose  5
    Eudgragit RS 30D  5
    Example 52:
    Griseofulvin 75% (W/W)
    Hydroxyethylcellulose 10
    Polyethylene glycol 4000 10
    Hydroxypropylcellulose  5
    Example 53:
    Griseofulvin 75% (W/W)
    Lactose 10
    Povidone (PVP) 10
    Polyethylene glycol 2000  5
    Example 54:
    Terbinafine HCl 75% (W/W)
    Polyethylene glycol 4000 10
    Povidone (PVP) 10
    Hydroxypropylcellulose  5
    Example 55:
    Terbinafine HCl 75% (W/W)
    Lactose 15
    Polyethylene glycol 4000  5
    Polyvinylpyrrolidone  5
    Example 56:
    Ketoconazole 40% (W/W)
    Eudragit S100 50
    Triethyl Citrate 10
    Example 57:
    Ketoconazole 50% (W/W)
    Sureteric 50
    Example 58:
    Ketoconazole 50% (W/W)
    Eudragit S100 45
    Triethyl Citrate  5
  • Three Pulses [0072]
    • EXAMPLE 59
  • 1. Antifungal Matrix Pellet Formulation and Preparation Procedure (Immediate Release) [0073]
  • A. Pellet Formulation [0074]
  • The composition of the antifungal matrix pellets provided in Table 1. [0075]
    TABLE 1
    Composition of Antifungal Pellets
    Component Percentage (%)
    Antifungal 50
    Avicel PH 101 20
    Lactose 20
    PVP K29/32* 10
    Purified Water
    Total 100 
  • B. Preparation Procedure for antifungal Matrix Pellets [0076]
  • 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator. [0077]
  • 1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. [0078]
  • 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. [0079]
  • 1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer. [0080]
  • 1.2.5 Dry the spheronized pellets at 50° C. overnight. [0081]
  • 1.2.6 Pellets between 16 and 30 Mesh were collected for further processing. [0082]
  • The above procedure is used to make pellets of a first antifungal and pellets of a second different antifungal. [0083]
  • 1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion [0084]
  • A. Dispersion Formulation [0085]
  • The composition of the aqueous Eudragit L30D-55 dispersion applied to the antifungal matrix pellets is provided below in Table 2. [0086]
    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 [0087]
  • 1.3.1 Suspend triethyl citrate and talc in deionized water. [0088]
  • 1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer. [0089]
  • 1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. [0090]
  • 1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the antifungal matrix pellets. [0091]
  • 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion [0092]
  • A. Dispersion Formulation [0093]
  • The composition of the aqueous Eudragit® S 100 dispersion applied to the antifungal matrix pellets is provided below in Table 3. [0094]
    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 [0095]
  • Part I: [0096]
  • (i) Dispense Eudragit® S 100 powder in deionized water with stirring. [0097]
  • (ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring. [0098]
  • (iii) Allow the partially neutralized dispersion to stir for 60 minutes. [0099]
  • (iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. [0100]
  • Part II: [0101]
  • (i) Disperse talc in the required amount of water [0102]
  • (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer. [0103]
  • (iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. [0104]
  • 1.5 Coating Conditions for the Application of Aqueous Coating Dispersions [0105]
  • 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. [0106]
    STREA 1 ™ Table Top Laboratory
    Coating Equipment 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. [0107]
  • (ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets. [0108]
  • 1.6 Encapsulation of the Antifungal Pellets [0109]
  • 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 a the desire dosage. [0110]
  • The immediate release matrix pellets include the first antifungal, the L30 D-55 coated pellets are made by coating matrix pellets that contain the second antifungal and the S100 coated pellets are made by coating matrix pellets that contain the first antifungal. [0111]
  • Three Pulses [0112]
    • EXAMPLE 60.
  • Antifungal Pellet Formulation and Preparation Procedure [0113]
  • 60.1 Pellet Formulations for subsequent coating [0114]
  • The composition of the Antifungaltrihydrate matrix pellets provided in Table 4. [0115]
    TABLE 4
    Composition of AntifungalMatrix Pellets
    Component Percentage (%)
    AntifungalTrihydrate powder 92
    Avicel PH 101 7.0
    Hydroxypropyl methylcellulose, NF* 1.0
    Total 100
  • 60.2 Preparation Procedure for AntifingalMatrix Pellets [0116]
  • 60.2.1 Blend Antifungaland Avicel® PH 101 using a low shear blender. [0117]
  • 60.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. [0118]
  • 60.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm. [0119]
  • 60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate. [0120]
  • 60.2.5 Dry the spheronized pellets at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C. [0121]
  • 60.2.6 Pellets between 20 and 40 Mesh were collected for further processing. [0122]
  • 60.2.7 The above procedure is used to produce pellets that contain a first antifungal and pellets that contain a second and different antifungal. [0123]
  • 60.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion [0124]
  • 60.3.1 Dispersion Formulation [0125]
  • The composition of the aqueous Eudragit L30D-55 dispersion applied to the Antifulngalmatrix pellets is provided below in Table 5. [0126]
    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
  • [0127] 60.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
  • 60.4.1 Suspend triethyl citrate and talc in deionized water. [0128]
  • 60.4.2 The TEC/talc suspension is mixed using laboratory mixer. [0129]
  • 60.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. [0130]
  • 60.4.4 Allow the coating dispersion to stir for one hour prior to application onto the Antifingalmatrix pellets. [0131]
  • 60.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion [0132]
  • 60.5.1 Dispersion Formulation [0133]
  • The composition of the aqueous Eudragit® S 100 dispersion applied to the Antifungalmatrix pellets is provided below in Table 6. [0134]
    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
  • [0135] 60.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
  • Part A: [0136]
  • 60.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. [0137]
  • 60.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. [0138]
  • 60.6.3 Allow the partially neutralized dispersion to stir for 60 minutes. [0139]
  • 60.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B. [0140]
  • Part B: [0141]
  • 60.6.5 Disperse talc in the required amount of water [0142]
  • 60.6.6 Stir the dispersion using an overhead laboratory mixer. [0143]
  • 60.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. [0144]
  • 60.7 Coating Conditions for the Application of Aqueous Coating Dispersions [0145]
  • The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes. [0146]
    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
  • 60.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets. [0147]
  • 60.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets. [0148]
  • 60.8 Preparation of AntifungalGranulation (Immediate Release Component) for tabletting [0149]
    TABLE 7
    Composition of AntifungalGranulation
    Component Percentage (%)
    AntifungalTrihydrate powder 92
    Avicel PH 101 7.0
    Hydroxypropyl methylcellulose, NF* 1.0
    Total 100
  • 60.8.1 Blend Antifungaland Avicel® PH 101 using a low shear blender. [0150]
  • 60.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing. [0151]
  • 60.8.3 Dry the granulation at 60° C. using a fluid bed dryer until the exhaust temperature reaches 40° C. [0152]
  • 60.8.4 Granules between 20 and 40 Mesh are collected for further processing. [0153]
  • 60.9 Tabletting of the AntifungalPellets [0154]
    TABLE 8
    Composition of AntifungalTablets
    Component Percentage (%)
    First antifungalgranules 32.5
    Avicel PH 200 5.0
    Second antifungalL30D-55 coated pellets 30
    First antifungalS100 coated pellets 30
    Colloidal silicon dioxide 1.5
    Magnesium stearate 1.0
    Total 100
  • 60.9.1 Blend the Antifungalgranules, Avicel PH-200, Antifungalpellets and colloidal silicon dioxide for 15 minutes in a tumble blender. [0155]
  • 60.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes. [0156]
  • 60.9.3 Compress the blend on a rotary tablet press. [0157]
  • 60.9.4 The fill weight should be adjusted to achieve the desired dosage. [0158]
  • Four pulses [0159]
    • EXAMPLE 61
  • 1 Antifungal Matrix Pellet Formulation and Preparation Procedure [0160]
  • 61.1 Pellet Formulation [0161]
  • The composition of the antifungal matrix pellets provided in Table 9. [0162]
    TABLE 9
    Composition of Antifungal Pellets
    Component Percentage (%)
    Antifungal 50
    Avicel PH 101 20
    Lactose 20
    PVP K29/32* 10
    Purified Water
    Total 100 
  • 61.2 Preparation Procedure for Antifungal Matrix Pellets [0163]
  • 61.2.1 Blend antifingal and Avicel® PH 101 using a Robot Coupe high shear granulator. [0164]
  • 61.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. [0165]
  • 61.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm. [0166]
  • 61.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer. [0167]
  • 61.2.5 Dry the spheronized pellets at [0168] 50° C. overnight.
  • 61.2.6 Pellets between 16 and 30 Mesh were collected for further processing. [0169]
  • 61.2.7 The above procedure is used to prepare pellets that contain a first antifungal and pellets that contain a second antifungal. [0170]
  • 61.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion [0171]
  • 61.3.1 Dispersion Formulation [0172]
  • The composition of the aqueous Eudragit L30D-55 dispersion applied to the antifingal matrix pellets is provided below in Table 10. [0173]
    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
  • [0174] 61.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
  • 61.4.1 Suspend triethyl citrate and talc in deionized water. [0175]
  • 61.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer. [0176]
  • 61.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring. [0177]
  • 61.4.4 Allow the coating dispersion to stir for one hour prior to application onto the antifungal matrix pellets. [0178]
  • 61.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion [0179]
  • 61.5.1 Dispersion Formulation [0180]
  • The composition of the aqueous Eudragit® S 100 dispersion applied to the antifungal matrix pellets is provided below in Table 11. [0181]
    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
  • [0182] 61.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
  • Part A: [0183]
  • 61.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. [0184]
  • 61.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. [0185]
  • 61.6.3 Allow the partially neutralized dispersion to stir for 60 minutes. [0186]
  • 61.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. [0187]
  • Part B: [0188]
  • 61.6.5 Disperse talc in the required amount of water [0189]
  • 61.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer. [0190]
  • 61.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. [0191]
  • 61.7 Coating Conditions for the Application of Aqueous Coating Dispersions [0192]
  • The following coating parameters are used for coating with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings. [0193]
    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
  • 61.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets. [0194]
  • 61.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets. [0195]
  • 61.7.3 Coat matrix pellets with S 100 dispersion such that you apply 20% coat weight gain to the pellets. [0196]
  • 61.8 Encapsulation of the Antifungal Pellets [0197]
  • 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. [0198]
  • The capsule is filled with the four different pellets to achieve the desired dosage. [0199]
  • The immediate release pellets contain the first antifungal; the L30 D-55 12% weight gain coated pellets containe the second antifungal; the L30 D-55 30% weight gain coated pellets contain the first antifungal and the S100 coated pellets contain the second antifungal. [0200]
  • The present invention is advantageous in that a synergistic anti-fungal will be dosed in an alternate pulse to another, synergistic anti-fungal. This will alternate the exposure to the fungus in such a way as to make both anti-fungals more effective than if they were co-administered. [0201]
  • 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. [0202]

Claims (20)

What is claimed is:
1. An anti-fungal product comprising:
at least three dosage forms, each dosage form comprising an anti-fungal and a pharmaceutically acceptable carrier, one of said dosage forms including at least a first anti-fungal and a second of said dosage forms including at least a second anti-fungal that is different than the first anti-fungal.
2. The product of claim 1 wherein each of the dosage forms has a different release profile.
3. The product of claim 1 wherein the first dosage form is an immediate release dosage form.
4. The product of claim 3 wherein the second and third dosage forms are delayed release dosage forms.
5. The product of claim 4 wherein anti-fungal released from the second dosage form reaches a Cmax in serum after anti-fungal released from the first dosage form reaches Cmax in serum.
6. The product of claim 5 wherein anti-fungal released from the third dosage form reaches Cmax in serum after anti-fungal released from the second dosage form reaches Cmax in serum.
7. The product of claim 6 wherein total anti-fungal released from the product reaches Cmax in serum within twelve hours of administration.
8. The product of claim 7 wherein the product is a once a day product.
9. The product of claim 1 wherein each of the three dosage forms includes at least the first and second anti-fungal.
10. The product of claim 1 wherein the first dosage form includes the first anti-fungal, the second dosage form includes the first and second anti-fungal and the fourth dosage form includes the second anti-fungal.
11. An anti-fungal product comprising: a first, second, third and fourth dosage form, said first dosage form comprising a first anti-fungal and a pharmaceutically acceptable carrier; said second dosage form comprising said first anti-fungal and a pharmaceutically acceptable carrier; said third dosage form comprising a second anti-fungal different from the first anti-fungal and a pharmaceutically acceptable carrier; said fourth dosage form comprising said second anti-fungal and a pharmaceutically acceptable carrier, said second and third dosage forms having a release profile whereby the maximum serum concentration of the first anti-fungal and the second anti-fungal released from the second and third dosage forms is reached at a time later than the maximum serum concentration of the first anti-fungal released from the first dosage form, and wherein the maximum serum concentration of the second anti-fungal released from the fourth dosage form reaches a maximum serum concentration at a time after the maximum serum concentration for the anti-fungal released from each of the first, second and third dosage forms is reached.
12. The composition of claim 1 wherein the first anti-fungal released from the second dosage form, and the second anti-fungal released from the third dosage form reach a maximum serum concentration at about the same time.
13. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 1.
14. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 2.
15. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 3.
16. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 4.
17. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 5.
18. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 6.
19. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 7.
20. A process for treating a fungus infection in a host comprising:
administering to the host the anti-fungal product of claim 8.
US09/791,284 2001-02-23 2001-02-23 Anti-fungal composition Abandoned US20020197314A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US09/791,284 US20020197314A1 (en) 2001-02-23 2001-02-23 Anti-fungal composition
US10/320,113 US6929804B2 (en) 2001-02-23 2002-12-16 Anti-fungal composition
US11/124,335 US20050238714A1 (en) 2001-02-23 2005-05-06 Anti-fungal composition

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
US09/791,284 US20020197314A1 (en) 2001-02-23 2001-02-23 Anti-fungal composition

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US10/320,113 Continuation US6929804B2 (en) 2001-02-23 2002-12-16 Anti-fungal composition

Publications (1)

Publication Number Publication Date
US20020197314A1 true US20020197314A1 (en) 2002-12-26

Family

ID=25153224

Family Applications (3)

Application Number Title Priority Date Filing Date
US09/791,284 Abandoned US20020197314A1 (en) 2001-02-23 2001-02-23 Anti-fungal composition
US10/320,113 Expired - Lifetime US6929804B2 (en) 2001-02-23 2002-12-16 Anti-fungal composition
US11/124,335 Abandoned US20050238714A1 (en) 2001-02-23 2005-05-06 Anti-fungal composition

Family Applications After (2)

Application Number Title Priority Date Filing Date
US10/320,113 Expired - Lifetime US6929804B2 (en) 2001-02-23 2002-12-16 Anti-fungal composition
US11/124,335 Abandoned US20050238714A1 (en) 2001-02-23 2005-05-06 Anti-fungal composition

Country Status (1)

Country Link
US (3) US20020197314A1 (en)

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030099706A1 (en) * 2000-10-13 2003-05-29 Rudnic Edward M. Antiviral product, use and formulation thereof
US20040018234A1 (en) * 2000-02-24 2004-01-29 Rudnic Edward M. Antibiotic composition
US6713504B2 (en) * 2002-03-19 2004-03-30 Council Of Scientific & Industrial Research Antifungal molecule 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1-methylethyl pentanoate
US6723341B2 (en) 2000-02-24 2004-04-20 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
US20040114368A1 (en) * 2002-12-13 2004-06-17 Shyu Shing Jy Light device having rotatable or movable view
US20050095245A1 (en) * 2003-09-19 2005-05-05 Riley Thomas C. Pharmaceutical delivery system
US6929804B2 (en) 2001-02-23 2005-08-16 Advancis Pharmaceutical Corp. Anti-fungal composition
US20060140990A1 (en) * 2003-09-19 2006-06-29 Drugtech Corporation Composition for topical treatment of mixed vaginal infections
US20070110805A1 (en) * 2005-05-09 2007-05-17 Levinson R S Modified-release pharmaceutical compositions
US20070224226A1 (en) * 2006-01-05 2007-09-27 Drugtech Corporation Composition and method of use thereof
US20090170876A1 (en) * 2007-12-31 2009-07-02 Camargo Pharmaceutical Services, Llc Novel Topical Formulations of Flucytosine
US8062672B2 (en) 2003-08-12 2011-11-22 Shionogi Inc. Antibiotic product, use and formulation thereof
US8246996B2 (en) 2003-08-29 2012-08-21 Shionogi Inc. Antibiotic product, use and formulation thereof
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
US8313776B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8313775B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US8425936B2 (en) 2003-07-21 2013-04-23 Shionogi Inc. Antibiotic product, use and formulation thereof
US8460710B2 (en) 2003-09-15 2013-06-11 Shionogi, Inc. Antibiotic product, use and formulation thereof
US8715727B2 (en) 2004-07-02 2014-05-06 Shionogi Inc. Tablet for pulsed delivery
US8758820B2 (en) 2003-08-11 2014-06-24 Shionogi Inc. Robust pellet
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20020068078A1 (en) 2000-10-13 2002-06-06 Rudnic Edward M. Antifungal product, use and formulation thereof

Family Cites Families (135)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3870790A (en) * 1970-01-22 1975-03-11 Forest Laboratories Solid pharmaceutical formulations containing hydroxypropyl methyl cellulose
GB1472534A (en) * 1973-07-06 1977-05-04 Glaxo Lab Ltd 7beta-hydroxyiminoacylamido-cephalosporins
JPS5119765A (en) * 1974-08-09 1976-02-17 Takeda Chemical Industries Ltd Aminochiazoorujudotaino seizoho
US6218380B1 (en) * 1975-04-17 2001-04-17 Smithkline Beecham P.L.C. Pharmaceutical compositions
US6048977C1 (en) * 1975-04-17 2001-10-16 Smithkline Beecham Plc Clavulanic acid and salts thereof
US4018918A (en) * 1975-05-20 1977-04-19 The Upjohn Company Topical clindamycin preparations
US4250166A (en) * 1977-05-27 1981-02-10 Shionogi & Co., Ltd. Long acting preparation of cefalexin for effective treatments of bacterial infection sensitive to cefalexin
US4331803A (en) * 1980-06-04 1982-05-25 Taisho Pharmaceutical Co., Ltd. Novel erythromycin compounds
IL64009A (en) 1980-10-31 1984-09-30 Rech Applications Therap Crystalline 1,1-dioxopenicillanoyloxymethyl 6-(d-alpha-amino-alpha-phenylacetamido)penicillanate tosylate hydrates,their production and pharmaceutical compositions containing them
YU43006B (en) * 1981-03-06 1989-02-28 Pliva Pharm & Chem Works Process for preparing n-methyl-11-aza-10-deoxo-10-dihydro erythromycin and derivatives thereof
US4369172A (en) * 1981-12-18 1983-01-18 Forest Laboratories Inc. Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose
US4435173A (en) 1982-03-05 1984-03-06 Delta Medical Industries Variable rate syringe pump for insulin delivery
US4430495A (en) * 1982-09-17 1984-02-07 The Upjohn Company Process for preparing lincomycin and clindamycin ribonucleotides
AU575854B2 (en) * 1983-10-04 1988-08-11 Shionogi & Co., Ltd. 7beta-(carboxyalkenamido) cephalosporins
DE3405378A1 (en) * 1984-02-15 1985-08-22 Röhm GmbH, 6100 Darmstadt MEDICINE COVER
US4616008A (en) 1984-05-02 1986-10-07 Takeda Chemical Industries, Ltd. Antibacterial solid composition for oral administration
US4568741A (en) * 1984-05-15 1986-02-04 The Upjohn Company Synthesis of 7-halo-7-deoxylincomycins
US4894119A (en) * 1985-04-10 1990-01-16 Drew Chemical Corporation Retention and/or drainage and/or dewatering aid
DE3684446D1 (en) 1985-12-28 1992-04-23 Sumitomo Pharma MEDICINAL PRODUCTS WITH DELAYED RELEASED RELEASE.
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
US4904476A (en) 1986-03-04 1990-02-27 American Home Products Corporation Formulations providing three distinct releases
US4723958A (en) * 1986-05-23 1988-02-09 Merck & Co., Inc. Pulsatile drug delivery system
GB8613689D0 (en) * 1986-06-05 1986-07-09 Euro Celtique Sa Pharmaceutical composition
NZ220764A (en) * 1986-07-02 1989-09-27 Shionogi & Co Crystalline form of 7beta((z)-2-(2-aminothiazol-4-yl)-4- carboxybut-2-enoylamino)-3-cephem-4-carboxylic acid and pharmaceutical compositions
KR960000434B1 (en) * 1986-12-17 1996-01-06 다이쇼 세이야꾸 가부시끼가이샤 Eryhromycin a derivatives and process of method for the same
US5200193A (en) 1987-04-22 1993-04-06 Mcneilab, Inc. Pharmaceutical sustained release matrix and process
US4808411A (en) * 1987-06-05 1989-02-28 Abbott Laboratories Antibiotic-polymer compositions
US5110597A (en) 1987-06-25 1992-05-05 Alza Corporation Multi-unit delivery system
US4835140A (en) * 1987-08-20 1989-05-30 Indiana University Foundation Method for treating pneumocystis carinii pneumonia patients with clindamycin and primaquine
US4915953A (en) 1987-09-03 1990-04-10 Alza Corporation Dosage form for delivering acetaminophen or phenylpropanolamine
US4971805A (en) 1987-12-23 1990-11-20 Teysan Pharmaceuticals Co., Ltd. Slow-releasing granules and long acting mixed granules comprising the same
US4895934A (en) * 1988-08-22 1990-01-23 E. I. Du Pont De Nemours And Company Process for the preparation of clindamycin phosphate
US5133974A (en) 1989-05-05 1992-07-28 Kv Pharmaceutical Company Extended release pharmaceutical formulations
US5110598A (en) * 1989-06-30 1992-05-05 Smithkline Beecham Corp. Intermittent release dosage form
ES2064564T3 (en) 1989-09-21 1995-02-01 American Cyanamid Co PULSE PRESSURE RELEASE SYSTEM OF DAILY UNIT DOSE OF MINOCYCLINE.
DK469989D0 (en) 1989-09-22 1989-09-22 Bukh Meditec PHARMACEUTICAL PREPARATION
US5387380A (en) * 1989-12-08 1995-02-07 Massachusetts Institute Of Technology Three-dimensional printing techniques
US5204055A (en) * 1989-12-08 1993-04-20 Massachusetts Institute Of Technology Three-dimensional printing techniques
JPH0674206B2 (en) * 1989-12-28 1994-09-21 田辺製薬株式会社 Controlled release formulation and process for producing
US5229131A (en) 1990-02-05 1993-07-20 University Of Michigan Pulsatile drug delivery system
US5182374A (en) * 1990-03-21 1993-01-26 American Cyanamid Company Clindamycin phosphate synthesis
FI87539C (en) * 1990-11-19 1993-01-25 Outomec Oy Procedure for detaching filter cake
GEP19971086B (en) 1991-02-22 1997-12-02 Tillotts Pharma Ag Peroral Pharmaceutically Dispensed Form for Selective Introducing of the Medicine into the Intestine
GB9109862D0 (en) * 1991-05-08 1991-07-03 Beecham Lab Sa Pharmaceutical formulations
US5260066A (en) * 1992-01-16 1993-11-09 Srchem Incorporated Cryogel bandage containing therapeutic agent
TW203552B (en) * 1992-02-18 1993-04-11 J Baroody Lloyd Compositions of clindamycin and benzoyl peroxide for acne treatment
JP3265680B2 (en) * 1992-03-12 2002-03-11 大正製薬株式会社 Oral pharmaceutical composition
US5599557A (en) * 1992-04-30 1997-02-04 Schering Corporation Stable hydrated cephalosporin dry powder for oral suspension formulation
US5260068A (en) 1992-05-04 1993-11-09 Anda Sr Pharmaceuticals Inc. Multiparticulate pulsatile drug delivery system
MX9304638A (en) 1992-07-31 1994-05-31 Neose Pharm Inc COMPOSITION TO TREAT AND INHIBIT GASTRIC AND DUODENAL ULCERS.
US5260069A (en) 1992-11-27 1993-11-09 Anda Sr Pharmaceuticals Inc. Pulsatile particles drug delivery system
JP3319800B2 (en) * 1993-02-01 2002-09-03 辻本化学工業株式会社 Anti-resistant Staphylococcus aureus compounds
US5414014A (en) 1993-04-08 1995-05-09 Innova Biomed, Inc. Methods for efficacious removal of attached, sucking antropods from human dermis
IL109770A0 (en) 1993-05-29 1994-11-28 Smithkline Beecham Corp Thermal infusion process for preparing controlled release solid dosage forms of medicaments for oral administration and controlled release solid dosage forms of medicaments prepared thereby
WO1996010996A1 (en) * 1993-07-21 1996-04-18 The University Of Kentucky Research Foundation A multicompartment hard capsule with control release properties
CA2101241C (en) 1993-07-23 1998-12-22 Jonathan P. Wong Liposome-encapsulated ciprofloxacin
US5538954A (en) 1994-06-24 1996-07-23 A/S Dumex (Dumex Ltd.) Salts of tetracyclines
US6183778B1 (en) * 1993-09-21 2001-02-06 Jagotec Ag Pharmaceutical tablet capable of liberating one or more drugs at different release rates
US5490962A (en) * 1993-10-18 1996-02-13 Massachusetts Institute Of Technology Preparation of medical devices by solid free-form fabrication methods
US6280771B1 (en) * 1997-02-20 2001-08-28 Therics, Inc. Dosage forms exhibiting multi-phasic release kinetics and methods of manufacture thereof
US5393765A (en) * 1993-12-13 1995-02-28 Hoffmann-La Roche Inc. Pharmaceutical compositions with constant erosion volume for zero order controlled release
GB9402203D0 (en) 1994-02-04 1994-03-30 Smithkline Beecham Plc Pharmaceutical formulation
DE4404018A1 (en) * 1994-02-09 1995-08-10 Merck Patent Gmbh Protected release dosage forms containing clindamycin palmitate
US5395626A (en) 1994-03-23 1995-03-07 Ortho Pharmaceutical Corporation Multilayered controlled release pharmaceutical dosage form
GB9407386D0 (en) * 1994-04-14 1994-06-08 Smithkline Beecham Plc Pharmaceutical formulation
GB9408117D0 (en) * 1994-04-23 1994-06-15 Smithkline Beecham Corp Pharmaceutical formulations
SI9520049A (en) 1994-05-06 1997-12-31 Pfizer Controlled-release dosage forms of azithromycin
GB9416600D0 (en) 1994-08-17 1994-10-12 Smithkline Beecham Plc Pharmaceutical formulation
US5827531A (en) 1994-12-02 1998-10-27 The United States Of America As Represented By The Administrator Of The National Aeronautics And Space Administration Microcapsules and methods for making
US5872104A (en) * 1994-12-27 1999-02-16 Oridigm Corporation Combinations and methods for reducing antimicrobial resistance
US5567441A (en) 1995-03-24 1996-10-22 Andrx Pharmaceuticals Inc. Diltiazem controlled release formulation
US6013507A (en) * 1995-07-10 2000-01-11 The Rockefeller University Auxiliary genes and proteins of methicillin resistant bacteria and antagonists thereof
US6548084B2 (en) * 1995-07-20 2003-04-15 Smithkline Beecham Plc Controlled release compositions
US5872229A (en) * 1995-11-21 1999-02-16 Abbott Laboratories Process for 6-O-alkylation of erythromycin derivatives
US5705190A (en) * 1995-12-19 1998-01-06 Abbott Laboratories Controlled release formulation for poorly soluble basic drugs
SE9600072D0 (en) 1996-01-08 1996-01-08 Astra Ab New oral formulation of two active ingredients II
US5766220A (en) * 1996-02-29 1998-06-16 Moenning; Stephen P. Apparatus and method for protecting a port site opening in the wall of a body cavity
US5719272A (en) * 1996-04-02 1998-02-17 Abbott Laboratories 2'-protected 3'-dimethylamine, 9-etheroxime erythromycin A derivatives
US5719132A (en) 1996-06-27 1998-02-17 Bristol-Myers Squibb Company Compositions and methods of treating HIV with d4T, 5-fluorouracil/tegafur, and uracil
US5858986A (en) * 1996-07-29 1999-01-12 Abbott Laboratories Crystal form I of clarithromycin
GB9617780D0 (en) * 1996-08-24 1996-10-02 Smithkline Beecham Plc Method of treatment
IL119627A (en) 1996-11-17 2002-03-10 Yissum Res Dev Co PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED-RELEASE OF AN ACTIVE AGENT COMPRISING AT LEAST ONE β-LACTAM ANTIBIOTIC AGENT
IT1289160B1 (en) 1997-01-08 1998-09-29 Jagotec Ag FULLY COATED PHARMACEUTICAL TABLET FOR THE CONTROLLED RELEASE OF ACTIVE INGREDIENTS WHICH PRESENT PROBLEMS OF
US5864023A (en) * 1997-02-13 1999-01-26 Abbott Laboratories 3'-N'oxide, 3'-n-dimethylamine, 9-oxime erythromycin a derivatives
US6551616B1 (en) * 1997-04-11 2003-04-22 Abbott Laboratories Extended release formulations of erythromycin derivatives
US6010718A (en) * 1997-04-11 2000-01-04 Abbott Laboratories Extended release formulations of erythromycin derivatives
US6210710B1 (en) 1997-04-28 2001-04-03 Hercules Incorporated Sustained release polymer blend for pharmaceutical applications
US5877243A (en) 1997-05-05 1999-03-02 Icet, Inc. Encrustation and bacterial resistant coatings for medical applications
US5840329A (en) 1997-05-15 1998-11-24 Bioadvances Llc Pulsatile drug delivery system
ES2248908T7 (en) * 1997-06-06 2014-11-24 Depomed, Inc. Dosage forms of drugs orally and gastric retention for continued release of highly soluble drugs
US6503709B1 (en) * 1997-07-03 2003-01-07 Id Biomedical Corporation Methods for rapidly detecting methicillin resistant staphylococci
ES2234139T3 (en) 1997-08-11 2005-06-16 Alza Corporation DOSAGE FORM OF AN ACTIVE PROLONGED RELEASE AGENT ADAPTED FOR GASTRIC RETENTION.
JPH1164608A (en) * 1997-08-26 1999-03-05 Dainippon Printing Co Ltd Lenticular lens
US5892008A (en) * 1997-12-16 1999-04-06 Abbott Laboratories Process for the preparation of 6-O-methyl erythromycin a using 9-hydroxy erythromycin derivatives
KR100377159B1 (en) * 1998-09-09 2003-08-19 한미약품공업 주식회사 Method for preparing Form 2 of clarithromycin without residual solvent
DE19845358A1 (en) * 1998-10-02 2000-04-06 Roehm Gmbh Coated drug forms with controlled drug delivery
US6159491A (en) * 1999-02-12 2000-12-12 Biovector Technologies, Inc. Prolonged release bioadhesive vaginal gel dosage form
US6294199B1 (en) 1999-04-13 2001-09-25 Beecham Pharmaceuticals (Pte) Limited Method of treating a bacterial infection comprising administering amoxycillin
US6187768B1 (en) * 1999-06-01 2001-02-13 Becton, Dickinson And Company Kit for flushing medical devices and method of preparation
DE19938704C1 (en) * 1999-08-14 2001-10-31 Ivoclar Vivadent Ag Process for the production of reaction systems for implantation in the human and animal body as a bone substitute, which i.a. Contain calcium and phosphorus
JP2003514019A (en) * 1999-11-15 2003-04-15 スミスクライン・ビーチャム・コーポレイション Carvedilol methanesulfonate
AU3289301A (en) * 2000-01-20 2001-07-31 Delsys Pharmaceutical Corporation Multi-step drug dosage forms
US7025989B2 (en) 2000-02-24 2006-04-11 Advancis Pharmaceutical Corp. Multiple-delayed released antibiotic product, use and formulation thereof
US6623758B2 (en) 2000-02-24 2003-09-23 Advancis Pharmaceutical Corp. Cephalosporin-metronidazole antibiotic composition
US6544555B2 (en) * 2000-02-24 2003-04-08 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
US20020004070A1 (en) 2000-02-24 2002-01-10 Rudnic Edward M. Antineoplastic product, use and formulation thereof
US6565882B2 (en) 2000-02-24 2003-05-20 Advancis Pharmaceutical Corp Antibiotic composition with inhibitor
US6638532B2 (en) 2000-02-24 2003-10-28 Advancis Pharmaceutical Corp. Tetracycline—doxycycline antibiotic composition
US6663891B2 (en) 2000-02-24 2003-12-16 Advancis Pharmaceutical Corp. Erythromyacin antibiotic product, use and formulation thereof
US6667042B2 (en) 2000-02-24 2003-12-23 Advancis Pharmaceutical Corp. Fluroquinilone antibiotic product, use and formulation thereof
US6730320B2 (en) 2000-02-24 2004-05-04 Advancis Pharmaceutical Corp. Tetracycline antibiotic product, use and formulation thereof
US6610328B2 (en) 2000-02-24 2003-08-26 Advancis Pharmaceutical Corp. Amoxicillin-clarithromycin antibiotic composition
US6991807B2 (en) * 2000-02-24 2006-01-31 Advancis Pharmaceutical, Corp. Antibiotic composition
CA2400818C (en) 2000-02-24 2009-01-06 Advancis Pharmaceutical Corporation Antibiotic and antifungal compositions
US6667057B2 (en) 2000-02-24 2003-12-23 Advancis Pharmaceutical Corp. Levofloxacin antibiotic product, use and formulation thereof
US6632453B2 (en) 2000-02-24 2003-10-14 Advancis Pharmaceutical Corp. Ciprofoxacin-metronidazole antibiotic composition
US6627222B2 (en) 2000-02-24 2003-09-30 Advancis Pharmaceutical Corp. Amoxicillin-dicloxacillin antibiotic composition
US6669948B2 (en) 2000-02-24 2003-12-30 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
ES2270226T3 (en) * 2000-03-15 2007-04-01 Hanmi Pharm. Co., Ltd. METHOD FOR OBTAINING CLARITROMYCIN IN NON-PHARMACEUTICAL QUALITY CRYSTALS.
DE60139256D1 (en) * 2000-05-03 2009-08-27 Silva Joe D Method and device for producing liquid administration forms
US6696426B2 (en) * 2000-08-22 2004-02-24 Pharmacia Corporation Preservative free ophthalmic oxazolidinone antibiotic drug delivery systems
PE20020578A1 (en) * 2000-10-10 2002-08-14 Upjohn Co A TOPICAL ANTIBIOTIC COMPOSITION FOR THE TREATMENT OF EYE INFECTIONS
US6541014B2 (en) 2000-10-13 2003-04-01 Advancis Pharmaceutical Corp. Antiviral product, use and formulation thereof
US7074417B2 (en) 2000-10-13 2006-07-11 Advancis Pharmaceutical Corporation Multiple-delayed release anti-viral product, use and formulation thereof
US7108859B2 (en) 2000-10-13 2006-09-19 Advancis Pharmaceutical Corporation Antineoplastic product, use and formulation thereof
US20020068078A1 (en) 2000-10-13 2002-06-06 Rudnic Edward M. Antifungal product, use and formulation thereof
US7105174B2 (en) 2000-10-13 2006-09-12 Advancis Pharmaceutical Corporation Multiple-delayed release anti-neoplastic product, use and formulation thereof
AU3104102A (en) * 2000-12-18 2002-07-01 Univ Texas Local regional chemotherapy and radiotherapy using in situ hydrogel
US20020119168A1 (en) 2001-02-20 2002-08-29 Rudnic Edward M. Therapeutic agent delivery
US20020197314A1 (en) 2001-02-23 2002-12-26 Rudnic Edward M. Anti-fungal composition
WO2003017981A1 (en) * 2001-08-29 2003-03-06 Ranbaxy Laboratories Limited Controlled release formulation of clarithromycin or tinidazol
US6538185B1 (en) 2001-10-10 2003-03-25 Mks Professional Stage Products, Inc. Pedal board assembly
US6723340B2 (en) * 2001-10-25 2004-04-20 Depomed, Inc. Optimal polymer mixtures for gastric retentive tablets
US6682759B2 (en) * 2002-02-01 2004-01-27 Depomed, Inc. Manufacture of oral dosage forms delivering both immediate-release and sustained-release drugs
WO2006012443A1 (en) * 2004-07-22 2006-02-02 Cumbre Pharmaceuticals Inc. (r/s) rifamycin derivatives, their preparation and pharmaceutical compositions

Cited By (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8889187B2 (en) 2000-02-24 2014-11-18 Shionogi Inc. Once a day amoxicillin product comprising immediate and delayed release dosage forms
US6723341B2 (en) 2000-02-24 2004-04-20 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
US20040018234A1 (en) * 2000-02-24 2004-01-29 Rudnic Edward M. Antibiotic composition
US6991807B2 (en) 2000-02-24 2006-01-31 Advancis Pharmaceutical, Corp. Antibiotic composition
US6984401B2 (en) 2000-10-13 2006-01-10 Advancis Pharmaceutical Corp. Antiviral product, use and formulation thereof
US20030099706A1 (en) * 2000-10-13 2003-05-29 Rudnic Edward M. Antiviral product, use and formulation thereof
US6929804B2 (en) 2001-02-23 2005-08-16 Advancis Pharmaceutical Corp. Anti-fungal composition
US6713504B2 (en) * 2002-03-19 2004-03-30 Council Of Scientific & Industrial Research Antifungal molecule 2-(3,4-dimethyl-2,5-dihydro-1H-pyrrol-2-yl)-1-methylethyl pentanoate
US20040114368A1 (en) * 2002-12-13 2004-06-17 Shyu Shing Jy Light device having rotatable or movable view
US8313776B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8425936B2 (en) 2003-07-21 2013-04-23 Shionogi Inc. Antibiotic product, use and formulation thereof
US8313775B2 (en) 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
US8758820B2 (en) 2003-08-11 2014-06-24 Shionogi Inc. Robust pellet
US8062672B2 (en) 2003-08-12 2011-11-22 Shionogi Inc. Antibiotic product, use and formulation thereof
US9144548B2 (en) 2003-08-12 2015-09-29 Shionogi Inc. Antibiotic product, use and formulation thereof
US8246996B2 (en) 2003-08-29 2012-08-21 Shionogi Inc. Antibiotic product, use and formulation thereof
US8460710B2 (en) 2003-09-15 2013-06-11 Shionogi, Inc. Antibiotic product, use and formulation thereof
US20060140990A1 (en) * 2003-09-19 2006-06-29 Drugtech Corporation Composition for topical treatment of mixed vaginal infections
US20050095245A1 (en) * 2003-09-19 2005-05-05 Riley Thomas C. Pharmaceutical delivery system
US9789057B2 (en) 2003-09-19 2017-10-17 Perrigo Pharma International Designated Activity Company Pharmaceutical delivery system
US8715727B2 (en) 2004-07-02 2014-05-06 Shionogi Inc. Tablet for pulsed delivery
US20070110805A1 (en) * 2005-05-09 2007-05-17 Levinson R S Modified-release pharmaceutical compositions
US8357394B2 (en) 2005-12-08 2013-01-22 Shionogi Inc. Compositions and methods for improved efficacy of penicillin-type antibiotics
US20070224226A1 (en) * 2006-01-05 2007-09-27 Drugtech Corporation Composition and method of use thereof
US8299052B2 (en) 2006-05-05 2012-10-30 Shionogi Inc. Pharmaceutical compositions and methods for improved bacterial eradication
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
US20090170876A1 (en) * 2007-12-31 2009-07-02 Camargo Pharmaceutical Services, Llc Novel Topical Formulations of Flucytosine
US9314524B2 (en) 2007-12-31 2016-04-19 Calla Therapeutics Llc Topical formulations of Flucytosine

Also Published As

Publication number Publication date
US6929804B2 (en) 2005-08-16
US20030203023A1 (en) 2003-10-30
US20050238714A1 (en) 2005-10-27

Similar Documents

Publication Publication Date Title
CA2400818C (en) Antibiotic and antifungal compositions
US8303988B2 (en) Antifungal once-a-day product, use and formulation thereof
US20050238714A1 (en) Anti-fungal composition
US6610328B2 (en) Amoxicillin-clarithromycin antibiotic composition
AU2001239841A1 (en) Antibiotic and antifungal compositions
US6541014B2 (en) Antiviral product, use and formulation thereof
US6638532B2 (en) Tetracycline—doxycycline antibiotic composition
US6544555B2 (en) Antibiotic product, use and formulation thereof
US6991807B2 (en) Antibiotic composition
US20020004070A1 (en) Antineoplastic product, use and formulation thereof
US6627222B2 (en) Amoxicillin-dicloxacillin antibiotic composition
US6663891B2 (en) Erythromyacin antibiotic product, use and formulation thereof
US6623758B2 (en) Cephalosporin-metronidazole antibiotic composition
US6667042B2 (en) Fluroquinilone antibiotic product, use and formulation thereof
US6632453B2 (en) Ciprofoxacin-metronidazole antibiotic composition
US7157095B2 (en) Multiple-delayed release antifungal product, use and formulation thereof
EP1545465A1 (en) Delayed release anti-viral product, use and formulation thereof
US20030104058A1 (en) Antineoplastic product, use and formulation thereof
CA2478121A1 (en) Antibiotic composition

Legal Events

Date Code Title Description
AS Assignment

Owner name: ADVANCED PHARMA, INC., MARYLAND

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:RUDNIC, EDWARD M.;ISBISTER, JAMES D.;TREACY, JR., DONALD J.;AND OTHERS;REEL/FRAME:011702/0754;SIGNING DATES FROM 20010321 TO 20010404

AS Assignment

Owner name: HEALTHCARE VENTURES VI, L.P., NEW JERSEY

Free format text: SECURITY INTEREST;ASSIGNOR:ADVANCIS PHARMACEUTICAL CORPORATION;REEL/FRAME:014096/0282

Effective date: 20030328

AS Assignment

Owner name: ADVANCIS PHARMACEUTICAL CORPORATION, MARYLAND

Free format text: RELEASE BY SECURED PARTY;ASSIGNOR:HEALTHCARE VENTURES VI, L.P.;REEL/FRAME:014252/0246

Effective date: 20030701

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION