WO2001062195A1

WO2001062195A1 - Antibiotic and antifungal compositions

Info

Publication number: WO2001062195A1
Application number: PCT/US2001/005856
Authority: WO
Inventors: Edward M. Rudnic; James D. Isbister; Sandra E. Wassink; Donald J. Treacy, Jr.
Original assignee: Advancis Pharmaceutical Corporation
Priority date: 2000-02-24
Filing date: 2001-02-23
Publication date: 2001-08-30
Also published as: CA2400818A1; JP2003523372A; EP1267765A1; AU2001239841B2; US20020004499A1; EP1267765A4; CA2400818C; US6623757B2; AU3984101A

Abstract

An antibiotic product for delivering at least two different antibiotics or antifungals that is comprised of three dosage forms with different release profiles with each antibiotic or antifungal being present in at least one of the dosage forms.

Description

ANTIBIOTIC AND ANTIFUNGAL COMPOSITIONS

This invention relates to antibiotic and antifungal compositions and the use thereof. More particularly, this invention relates to a composition for the delivery of two or more antibiotics or antifungals, and the use thereof.

In many cases, it is desirable to employ two or more different antibiotics or two or more different antifungal agents in the treatment of a bacterial infection or fungus infection, respectively, in that such agents may have complementary mechanisms of action that facilitate treatment of the infection.

The present invention is directed to a new and improved composition that delivers two or more antibiotics or two or more antifungal agents, and the use thereof.

In accordance with an aspect of the present invention, there is provided an antibiotic product or antifungal product for delivering at least two different antibiotics or at least two different antifungals that is comprised of at least three dosage forms each comprised of at least one antibiotic or antifungal and a pharmaceutically acceptable carrier, with one of the dosage forms including at least one of the at least two antibiotics or the at least two antifungals and at least one dosage form including at least a second antibiotic of the at least two antibiotics or at least a second antifungal of the at least two antifungals.

Thus, for example, each of the dosage forms may include two or more antibiotic or antifungals, or one or two of the dosage forms may include only one of the two or more antibiotic or antifungals and each of the remaining dosage forms may include only one or more of the different antibiotics or antifungals or two or more of the antibiotics or antifungals. Thus, in accordance with this aspect of the invention, there is an antibiotic or antifungal product for delivering at least two different antibiotic or antifungals wherein the product includes at least three dosage forms wherein each of the at least two antibiotic or antifungals is present in at least one of the three dosage forms.

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.

In another aspect, the present invention is directed to treating a bacterial or fungal infection by administering to a host in need thereof an antibiotic or antifungal product as hereinabo ve and hereinafter described.

Thus, in accordance with an aspect of the present invention, there is provided a single or unitary antibiotic or antifungal product that has contained therein at least three antibiotic or antifungal dosage forms, each of which has a different release profile, whereby the antibiotic or antifungal 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 antibiotic or antifungal and at least one of the dosage forms includes at least a second antibiotic or antifungal different from the first antibiotic or antifungal.

In accordance with a further aspect of the invention, the antibiotic or antifungal product may be comprised of at least four different dosage forms, each of which starts to release the antibiotic or antifungal contained therein at different times after administration of the antibiotic or antifungal product.

The antibiotic or antifungal product generally does not include more than five dosage forms with different release times.

In accordance with a preferred embodiment, the antibiotic or antifungal product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic or antifungal released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration of the total antibiotic or antifungal released from the antibiotic or antifungal product is achieved no earlier than four hours after administration.

In accordance with one preferred embodiment of the invention, one of the at least three dosage forms is an immediate release dosage form whereby initiation of release of antibiotic or antifungal therefrom is not substantially delayed after administration of the antibiotic or antifungal product. The second and third of the at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antibiotic or antifungal product), whereby antibiotic or antifungal released therefrom is delayed until after initiation of release of antibiotic or antifungal from the immediate release dosage form. More particularly, antibiotic or antifungal release from the second of the at least two dosage forms achieves a C_raax (maximum serum concentration in the serum) at a time after antibiotic or antifungal released from the first of the at least three dosage forms achieves a C_max in fhe serum, and antibiotic or antifungal released from the third dosage form achieves a C_max in the serum after the C_max of antibiotic or antifungal released from the second dosage form.

In one embodiment, the second of the at least two dosage forms initiates release of antibiotic or antifungal contained therein at least one hour after the first dosage form, with the initiation of the release therefrom generally occurring no more than six hours after initiation of release of antibiotic or antifungal from the first dosage form of the at least three dosage forms.

In general, the immediate release dosage form produces a C_max for antibiotic or antifungal released therefrom within from about 0.5 to about 2 hours, with the second dosage form of fhe at least three dosage forms producing a C_ma for antibiotic or antifungal released therefrom in no more than about four hours. In general, the Cmax for such second dosage form is achieved no earlier than two hours after administration of the antibiotic or antifungal product; however, it is possible within the scope of the invention to achieve C_max in a shorter period of time.

As hereinabove indicated, the antibiotic or antifungal product may contain at least three or at least four or more different dosage forms. For example, the antibiotic or antifungal released from the third dosage form reaches a C_maχ at a time later than the C_max is achieved for antibiotic or antifungal released from each of the first and second dosage forms. In a preferred embodiment, release of antibiotic or antifungal from fhe third dosage form is started after initiation of release of antibiotic or antifungal from both the first dosage form and the second dosage form. In one embodiment, C_max for antibiotic or antifungal release from the third dosage form is achieved within eight hours. In another embodiment, the antibiotic or antifungal product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby antibiotic or antifungal released from each of the at least four different dosage forms achieves a C_max at a different time.

As hereinabove indicated, in a preferred embodiment, irrespective of whether the antibiotic or antifungal contains at least three or at least four different dosage forms each with a different release profile, C_maχ for all the antibiotic or antifungal released from the antibiotic or antifungal product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.

In a preferred embodiment, the antibiotic or antifungal product is a once a day product, whereby after administration of the antibiotic or antifungal 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 fhe present invention, there is a single administration of an antibiotic or antifungal product with the antibiotic or antifungal being released in a manner such that overall antibiotic or antifungal release is effected with different release profiles in a manner such that the overall C_max for the antibiotic or antifungal product is reached in less than twelve hours. The term single administration means that the total antibiotic or antifungal administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are administered at essentially the same time.

Thus in accordance with an aspect of the invention, there is provided a single dosage antibiotic or antifungal product comprised of at least three antibiotic or antifungal dosage forms each having a different release profile with each of the dosage forms including at least one of a first or second antibiotic or antifungal and at least one of fhe three dosage forms including at least the first antibiotic or antifungal and at least one of the dosage forms including at least the second antibiotic or antifungal. Each of the dosage forms of antibiotic or antifungal in a pharmaceutically acceptable carrier may have one or more antibiotic or antifungals.

It is to be understood that when it is disclosed herein that a dosage form initiates release after another dosage form, such terminology means that the dosage form is designed and is intended to produce such later initiated release. It is known in the art, however, notwithstanding such design and intent, some "leakage" of antibiotic or antifungal may occur. Such "leakage" is not "release" as used herein.

If at least four dosage forms are used, the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though 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, antibiotic or antifungal 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 antibiotic or antifungal composition that is a mixture of antibiotic or antifungal compositions or dosage forms wherein said composition contains a first composition or dosage form comprising a first antibiotic or antifungal and a pharmaceutically acceptable carrier; a second composition or dosage form comprising the first antibiotic or antifungal and a pharmaceutically acceptable carrier; a third composition or dosage form comprising a second antibiotic or antifungal different from the first antibiotic or antifungal and a pharmaceutically acceptable carrier; and a fourth composition or dosage form comprising fhe second antibiotic or antifungal and a pharmaceutically acceptable carrier; wherein the second and third compositions each .have a release profile that provides a maximum serum concentration of the first antibiotic or antifungal released from the second composition and a maximum serum concentration for the second antibiotic or antifungal released from fhe third composition at a time after the first antibiotic or antifungal released from the first composition reaches a maximum serum concentration, and wherein the fourth composition has a release profile that provides for a maximum serum concentration of the second antibiotic or antifungal released from the fourth composition at a time after the antibiotic or antifungals released from the second and third compositions reach a maximum serum concentration.

In one embodiment, the release profiles of the second and third composition are such that the maximum serum concentration of the first antibiotic or antifungal released from fhe second composition, and the maximum serum concentration of the second antibiotic or antifungal released from the third composition are reached at approximately the same time, or where the first antibiotic or antifungal reaches a maximum serum concentration before or after the second antibiotic or antifungal reaches a maximum serum concentration.

In effect, in accordance with a preferred embodiment of the present invention, there is provided a first pulse in which a first antibiotic or antifungal reaches a maximum serum concentration, a second pulse wherein a further dosage of the first antibiotic or antifungal, and an initial dosage of the second antibiotic or antifungal reach a maximum serum concentration at a time after fhe first pulse of fhe first antibiotic or antifungal reaches a maximum serum concentration, and a third pulse wherein an additional dosage of fhe second antibiotic or antifungal reaches a maximum serum concentration at a time after fhe maximum serum concentration is reached for each of the first and second antibiotic or antifungal dosages provided in the second pulse.

In a preferred embodiment of the present invention, fhe first dosage of the first antibiotic or antifungal achieves a maximum serum concentration within four hours after administration of the antibiotic or antifungal composition; the second dosage of the first antibiotic or antifungal and the first dosage of the second antibiotic or antifungal each reach a maximum serum concentration within four to eight hours after administration of the antibiotic or antifungal composition; and the second dosage of the second antibiotic or antifungal reaches a maximum serum concentration within twelve hours after administration of the antibiotic or antifungal composition.

Thus, in accordance with an aspect of the present invention, there is provided an antibiotic or antifungal composition that includes four different dosage forms, with the first dosage form providing an initial dosage of a first antibiotic or antifungal, the second dosage form providing a further dosage of the first antibiotic or antifungal; the third dosage form providing an initial dosage of a second antibiotic or antifungal; and the fourth dosage form providing an additional dosage of the second antibiotic or antifungal, wherein the antibiotic or antifungals released from the second and third dosage forms reach a maximum serum concentration at a time after the antibiotic or antifungal released from the first dosage form reaches a maximum serum concentration, and the antibiotic or antifungal released from fhe fourth dosage form reaching a maximum serum concentration at a time after fhe times at which the antibiotic or antifungals released from each of the first, second, and third dosage forms reach a maximum serum concentration. In one embodiment of the invention, the first dosage form provides for immediate release, the second and third dosage forms provide for a delayed release (pH or non pH dependent, with the second dosage form preferably being a pH dependent release), and the fourth dosage form provides for pH dependent or non pH dependent release preferably non pH dependent release.

In formulating the antibiotic or antifungal 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 antibiotic or antifungal; the second dosage form contains from about 30 percent to about 80 percent of the first antibiotic or antifungal; the third dosage form contains from about 30 percent to about 80 percent of the second antibiotic or antifungal, and the fourth antibiotic or antifungal dosage form contains from about 30 percent to about 80 percent of the second antibiotic or antifungal. In formulating a composition comprised of such four dosage forms or units, each unit or dosage form is present in an amount of at least 20 percent by weight, with each dosage form or unit being present in the overall composition in an amount that generally does not exceed 60 percent by weight.

Each of the first and second dosage forms include from 20% to 80% of the total dosage of the first antibiotic or antifungal to be provided by the composition, and each of the first and second dosage forms may include the same or different dosages of the first antibiotic or antifungal.

Each of the third and fourth dosage forms include from 20% to 80% of the total dosage of the second antibiotic or antifungal to be delivered by the composition, and each of the third and fourth units may have the same or different dosages of fhe antibiotic or antifungal. In formulating an antibiotic or antifungal product in accordance with the invention, in one embodiment, the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antibiotic or antifungal to be delivered by the product, with such immediate release dosage form generally providing at least 25% of the total dosage of the antibiotic or antifungal to be delivered by the product. In many cases, the immediate release dosage form provides from about 20% to about 30% of the total dosage of antibiotic or antifungal 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 fhe total dosage of antibiotic or antifungal to be delivered by fhe product.

The remaining dosage forms deliver the remainder of the antibiotic or antifungal. If more than one delayed release dosage form is used, in one embodiment, each of the delayed release dosage forms may provide about equal amounts of antibiotic or antifungal; however, they may also be formulated so as to provide different amounts.

In one embodiment, where the composition contains one immediate release component and two delayed release components, the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, of fhe total antibiotic or antifungal; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total antibiotic or antifungal; and where there are four delayed release components, fhe immediate release component provides from 10% to 25%, by weight, of the total antibiotic or antifungal.

With respect to the delayed release components, where there are two delayed release components, the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, of the total antibiotic or antifungal provided by the two delayed release components with the second delayed release component providing the remainder of fhe antibiotic or antifungal.

Where there are three delayed release components, fhe earliest released component provides 20% to 35% by weight of fhe total antibiotic or antifungal provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, of the antibiotic or antifungal provided by the three delayed release components and the last in time providing the remainder of the antibiotic or antifungal provided by the three delayed release components.

When there are four delayed release components, the earliest delayed release component provides from 15% to 30%, by weight, the next in time delayed release component provides from 15% to 30%, fhe next in time delayed release component provides from 20% to 35%, by weight, and the last in time delayed release component provides from 20% to 35%, by weight, in each case of the total antibiotic or antifungal provided b the four delayed release components.

The overall composition includes each of the antibiotic or antifungals in a therapeutically effective amount. The specific amount(s) is dependant on the antibiotic or antifungal used, the disease or infection to be treated, and the number of times of day that fhe composition is to be administered.

The antibiotic or antifungal composition of the present invention may be administered for example, by any one of the following routes of administration: sublingual, fransmucosal, transdermal, parenteral, oral, preferably by oral administration. The antibiotic or antifungal product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the antibiotic or antifungal product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration. In a preferred embodiment, the antibiotic or antifungal product is formulated in a manner such that it is suitable for oral administration.

For example, in formulating fhe antibiotic or antifungal product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an antibiotic or antifungal, 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 fhe oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.

It is also within the scope of the invention to provide an antibiotic or antifungal product in the form of a patch, which includes antibiotic or antifungal dosage forms having different release profiles, as hereinabove described.

In addition, fhe antibiotic or antifungal product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion. For example, the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase of the emulsion.

Furthermore, the antibiotic or antifungal product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal administration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration.

As a further embodiment, the antibiotic or antifungal product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.

In a preferred embodiment, the antibiotic or antifungal product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.

Alternatively, in formulating an oral delivery system, each of the dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic or antifungal product. Thus, for example, antibiotic or antifungal products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release of the antibiotic or antifungal, as hereinabove described;, whereby fhe C_max of the antibiotic or antifungal released from each of the tablets is reached at different times, with the C_max of the total antibiotic or antifungal released from the antibiotic or antifungal product being achieved in less than twelve hours. The formulation of an antibiotic or antifungal 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 antibiotic or antifungals in fhe coating and/or the thickness of the coating.

The first and second antibiotic employed in fhe antibiotic composition may be a wide variety of products. In one embodiment, fhe combination of first and second antibiotics that are used in the composition may be, for example, a penicillin and an aminoglycoside, such as gentamycin, tobramicin, amikacin or vancomycin. Another antibiotic that may be employed is a combination of a sulfonamide, such as sulfamefhoxasol, which would be combined with trimethoporim.

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, butenafme hydrochloride, nystatin, naftifine hydrochloride, oxiconazole nitrate, selenium sulfϊde, econazole nitrate, terconazole, butoconazole nitrate, carbol-fuchsin, clioquinol, methylrosaniline chloride, sodium hiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate salts (calcium undecylenate, copper undecylenate, zinc undecylenate)

In a preferred embodiment, each of the first and second antibiotic or first and second antifungal is each from a different class of antibiotic or antifungal. The Immediate Release Component

The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release fhe antibiotic or antifungal. 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 fhe antibiotic or antifungals for fhe 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, hydroxye hylcellulose, efhylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxyme hyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000- 10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.

It may be useful to have these materials present in the range of 1.0 to 60% (W7W).

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 fhe 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. These materials may be present in the rate of 0.05-15% (WAV).

The Delayed Release Component

The components in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.

Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.

Typically these materials can be present in the range of 0.5-25% (WAV) of this component.

The Enteric Release Component

The components in this composition are the same as the immediate release component, but with additional polymers integrated into fhe 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 p halate salts of cellulose derivatives.

These materials can be present in concentrations from 4-20% (WAV). The invention will be further described with respect to the following examples; however the scope of fhe invention is not limited thereby. All percentages stated in this specification are by weight, unless otherwise specified.

Examples

Immediate Release Component

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.

Ingredient Cone. (% W/W)

Example 1 :

Amoxicillin 65% (W/W)

Microcrystalline cellulose 20 Povidone 10

Croscarmellose sodium 5

Example 2:

Amoxicillin 55% (WAV)

Microcrystalline cellulose 25 Povidone 10

Croscarmellose sodium 10

Example 3:

Amoxicillin 65% (WAV)

Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 4:

Amoxicillin 75% (WAV)

Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5

Example 5:

Amoxicillin 75% (WAV)

Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 6:

Clarithromycin 65% (WAV) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 7:

Clarithromycin 75% (WAV) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5

Example 8:

Clarithromycin 75% (WAV) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5

Example 9:

Clarithromycin 75% (WAV) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5

Example 10:

Ciprofoxacin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 11 :

Ciprofoxacin 75% (WAV) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5

Example 12:

Ciprofoxacin 75% (WAV) Polyethylene glycol 4000 10 Poly heylene glycol 2000 10 Hydroxypropylcellulose 5

Example 13:

Cirpofoxacin 75% (WAV) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 14:

Ceftibuten 75% (WAV)

Example 15:

Ceftibuten 75% (WAV)

Polyethylene 'Glycol 4000 20 Polyvinylpyrrolidone 5

Example 16:

Fluconazole 65% (WAV)

Microcrystalline cellulose 20 Povidone 10

Croscarmellose sodium 5

Example 17:

Fluconazole 55% (W/W)

Microcrystalline cellulose 25 Povidone 10

Croscarmellose sodium 10

Example 18:

Fluconazole 65% (WAV)

Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 19:

Fluconazole 75% (WAV)

Example 20:

Fluconazole 75% (W/W)

Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5

Example 21:

Ketoconazole 65% (WAV) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 22:

Ketoconazole 75% (WAV) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5

Example 23:

Ketoconazole 75% (WAV) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5

Example 24:

Ketoconazole 75% (WAV) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5

Example 25:

Griseofulvin 65% (W/W)

Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 26:

Griseofulvin 75% (WAV)

Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5

Example 27:

Griseofulvin 75% (WAV)

Polyethylene glycol 4000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5

Example 28:

Cirpofloxacin 75% (WAV) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5

Example 29:

Terbinafine HCl 75% (WAV) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 30:

Terbinafine HCl 75% (WAV) Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5

Non pH Sensitive Delayed Release Component

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.

Ingredient Cone. (% WAV)

Example 31:

Amoxicillin 65% (WAV)

Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5

Example 32:

Amoxicillin 55% (WAV)

Microcrystalline cellulose 25

Polyox 10

Glyceryl monooleate 10

Example 33:

Amoxicillin 65% (WAV) Polyox 20

Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 34:

Amoxicillin 75% (WAV)

Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5 Example 35:

Amoxicillin 75% (WAV)

Polyethylene glycol 8000 20 Ethylcellulose 5

Example 36:

Clarithromycin 70% (WAV) Polyox 20

Hydroxypropylcellulose 5 Croscarmellose sodium 5

Example 37:

Clarithromycin 75% (WAV) Polyox 15

Hydroxypropylcellulose 5 Ethylcellulose 5

Example 38:

Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5

Example 39:

Clarithromycin 80% (WAV) Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D 5

Example 40:

Ciprofoxacin 65% (WAV) Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL 30D 5

Example 41:

Ciprofoxacin 75% (WAV) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Ethylcellulose 5

Example 42:

Ciprofoxacin 80% (WAV) Polyethylene glycol 4000 10 Polyethylene glycol 2000 5 Eudgragit RL 30D 5 Example 43:

Ciprofoxacin 75% (WAV) Polyethylene glycol 8000 20 Ethylcellulose 5

Example 44:

Ceftibuten 75% (WAV)

Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5

Example 45:

Ceftibuten 75% (WAV)

Polyethylene glycol 8000 20 Ethylcellulose 5

Example 46:

Gentamicin 20% (WAV) Sodium lauryl sulfate 2 Sodium monoglycerides 10 Sodium diglycerides 20 Diethyleneglycohnethylether 5 Microcrystalline cellulose 43

Example 47:

Gentamicin 10% (W/W) Glyvceryl behanate 30 Pluronic 10 Carbopol 94P 30 Microcrystalline cellulose 20

Example 48:

Gentamicin 25% (WAV)

Carbopol 94P 35

Microcrystalline cellulose 20

Vitamin E TPGS 15

Sodium monoglycerate 5

1

Example 49:

Amikacin 25% (WAV)

Carbopol 94P 10

Sodium monoglycerate 15

Sodium diglycerate 15

Pluronic 10

Lactose 25 Example 50:

Gentamicin 30% (WAV)

Triacetin 15

Capryol 90 5

Poloxamer Synperonic PE/F66 10

Cab-O-Sil 5

Microcrystalline cellulose 35

Ingredient Cone. (% WAV)

Example 51:

Fluconazole 65% (WAV)

Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5

Example 52:

Fluconazole 55% (WAV)

Microcrystalline cellulose 25

Polyox 10

Glyceryl monooleate 10

Example 53:

Fluconazole 65% (WAV) Polyox 20

Hydroxypropylcellulose 10 Croscarmellose sodium 5

Example 54:

Fluconazole 75% (WAV)

Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5

Example 55:

Fluconazole 75% (WAV)

Polyethylene glycol 8000 20 Ethylcellulose 5

Example 56:

Ketoconazole 70% (WAV) Polyox 20

Hydroxypropylcellulose 5 Croscarmellose sodium 5

Example 57:

Ketoconazole 75% (WAV) Polyox 15

Hydroxypropylcellulose 5 Ethylcellulose 5 Example 58:

Ketoconazole 75% (WAV) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5

Example 59:

Ketoconazole 80% (WAV) Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D 5

Example 60:

Griseofulvin 65% (WAV)

Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL 30D 5

Example 61.

Griseofulvin 75% (WAV)

Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Ethylcellulose 5

Example 62:

Griseofulvin 80% (WAV)

Polyethylene glycol 4000 10 Polyethylene glycol 2000 5 Eudgragit RL 30D 5

Example 63

Griseofulvin 75% (WAV)

Polyethylene glycol 8000 20 Ethylcellulose 5

Example 64.

Terbinafine HCl 75% (WAV) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5

Example 65:

Terbinafine HCl 75% (WAV) Polyethylene glycol 8000 20 Ethylcellulose 5 Enteric Release Component

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.

Example 66:

Clarithromycin 70% (WAV)

Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10

Example 67:

Clarithromycin 70% (WAV) Eudragit E30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5

Example 68:

Clarithromycin 75% (WAV) Polyethylene glycol 2000 10 Eudragit E 30D 15

Example 69:

Clarithromycin 40% (WAV) Lactose 50

Eudgragit E 30D 10

Example 70:

Ciprofoxacin 65% (WAV)

Microcrystalline Cellulose 20 Eudragit E 30D 10

Example 71:

Ciprofoxacin 75% (WAV)

Microcrystalline Cellulose 15

Hydroxypropylcellulose pthalate 10

Example 72:

Ciprofoxacin 80% (WAV) Lactose 10 Eudragit E 30D 10 Example 73:

Ciprofoxacin 70% (WAV) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10

Example 74:

Ceftibuten 60% (WAV)

Polyethylene glycol 2000 10 Lactose 20

Eudragit E 30D 10

Example 75:

Ceftibuten 70% (W/W)

Microcrystalline cellulose 20 Cellulose acetate pthalate 10

Example 76:

Amoxicillin 65% (WAV)

Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15

Example 77:

Amoxicillin 55% (WAV)

Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10

Hydroxypropylmethylcellulose 10

Example 78:

Amoxicillin 65% (WAV) Polyox 20

Hydroxypropylcellulose pthalate 10 Eudragit E30D 5

Example 79:

Amoxicillin 75% (WAV)

Polyethylene glycol 2000 10 Eudragit E30D 10 Eudragit RL 30D 5

Example 80:

Amoxicillin 40% (WAV)

Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10

Example 81:

Ceftibuten 75% (WAV)

Polyethylene glycol 8000 20 Ethylcellulose 5 Example 82:

Gentamicin 20% (WAV) Sodium lauryl sulfate 2 Sodium monoglycerides 10 Sodium diglycerides 20 Diethyleneglycolmethylether 5 Microcrystalline cellulose 30 Cellulose acetate pthalate 13

Example 83:

Gentamicin 10% (W/W) Glyceryl behanate 30 Pluronic 10

Carbopol 94P 10 Microcrystalline cellulose 20 Eudragit E30D 20

Example 84:

Gentamicin 25% (WAV) Carbopol 94P 15 Microcrystalline cellulose 20 Vitamin E TPGS 15

Sodium Monoglycerate 5 Eudragit E30D 20

Example 85:

Amikacin ^; 25% (WAV) Carbopol 94P 10 Sodium monoglycerate 15 Sodium diglycerate 15 Pluronic 10

Lactose 15

Cellulose acetate pthalate 10

Example 86:

Gentamicin 30% (WAV) Triacetin 15

Capryol 90 5

Poloxamer SynperonicPE/F66 10

CaVO-Sil 5

Microcrystalline cellulose 25 Eudragit E30D 10

Ingredient Cone. (% W/W)

Example 87:

Fluconazole 65% (WAV)

Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 88:

Fluconazole 55% (WAV)

Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10

Hydroxypropylmethylcellulose 10

Example 89:

Fluconazole 65% (WAV) Polyox 20

Hydroxypropylcellulose pthalate 10 Eudragit L30D 5

Example 90:

Fluconazole 75% (WAV)

Polyethylene glycol 2000 10 Eudragit L 30D 10 Eudragit RL 30D 5

Example 91 :

Fluconazole 40% (WAV)

Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10

Example 92:

Ketoconazole 70% (WAV)

Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10

Example 93:

Ketoconazole 70% (W/W) Eudragit L 30D 15

Hydroxypropylcellulose 10 Ethylcellulose 5

Example 94:

Ketoconazole 75% (WAV) Polyethylene glycol 2000 10 Eudragit L 30D 15

Example 95:

Ketoconazole 40% (WAV) Lactose 50

Eudgragit L 30D 10

Example 96:

Griseofulvin 65% (WAV)

Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 97:

Griseofulvin 75% (WAV)

Microcrystalline Cellulose 15

Hydroxypropylcellulose pthalate 10

Example 98:

Griseofulvin 80% (WAV)

Lactose 10

Eudragit L 30D 10

Example 99:

Griseofulvin 70% (WAV)

Polyethylene glycol 4000 20

Cellulose acetate pthalate 10

Example 100.

Terbinafine HCl 60% (WAV)

Polyethylene glycol 2000 10

Lactose 20

Eudragit L 30D 10

Example 101:

Terbinafine HCl 70% (WAV)

Microcrystalline cellulose 20

Cellulose acetate pthalate 10

Three Pulses

Example 102.

1. Antibiotic Matrix Pellet Formulation and Preparation Procedure (Immediate Release)

A. Pellet Formulation

The composition of the antibiotic matrix pellets provided in Table 1.

Table 1 Composition of Antibiotic Pellets

Component Percentage (%)

Antibiotic 50

Avicel PH 101 20

Lactose 20

PVP K29/32* 10

Purified Water

Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

B. Preparation Procedure for antibiotic Matrix Pellets

1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.

1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.

1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.0 mm.

1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

1.2.5 Dry fhe spheronized pellets at 50°C overnight.

1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.

The above procedure is used to make pellets of a first antibiotic and pellets of a second different antibiotic.

1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

A. Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 2.

Table 2 Eudragit® L 30 D-55 Aqueous Coating Dispersion

Component Percentage (%)

Eudragit® L 30 D-55 55.0

Triethyl Citrate 1.6

Talc 8.0

Purified Water 37.4

Solids Content 25.5

Polymer Content 15.9

B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 1.3.1 Suspend triethyl citrate and talc in deionized water.

1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the antibiotic matrix pellets.

1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

A. Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 3.

Table 3 Eudragit® S 100 Aqueous Coating Dispersion

Component Percentage (%)

Part A

Eudragit® S 100 12.0

1 N Ammonium Hydroxide 6.1

Triethyl Citrate 6.0

Purified Water 65.9

Part B

Talc 2.0

Purified Water 8.0

Solid Content 20.0

Polymer Content 12.0

B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part I:

(i) Dispense Eudragit® S 100 powder in deionized water with stirring.

(ii) Add ammonium hydroxide solution drop- wise into the dispersion with stirring. (iii) Allow fhe partially neutralized dispersion to stir for 60 minutes.

(iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. Part II:

(i) Disperse talc in the required amount of water

(ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.

(iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

1.5 Coating Conditions for the Application of Aqueous Coating Dispersions

The following coating parameters are used to coat matrix pellets with each of the

Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.

Coating Equipment , STREA 1™ Table Top Laboratory Fluid Bed

Coater '

Spray nozzle diameter 1.0 mm

Material Charge 300 gram

Inlet Air Temperature 40 to 45 °C

Outlet Air Temperature 30 to 33 °C

Atomization Air Pressure 1.8 Bar

Pump Rate 2 gram per minute

(i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

(ii) Coat matrix pellets with S 100 dispersion such that you apply 20% coat weight gain to the pellets.

1.6 Encapsulation o the Antibiotic Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%: Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and SI 00 coated pellets respectively. The capsule is filled with fhe three different pellets to achieve a the desire dosage.

The immediate release matrix pellets include the first antibiotic, the L30 D-55 coated pellets are made by coating matrix pellets that contain the second antibiotic and the SI 00 coated pellets are made by coating matrix pellets that contain the first antibiotic. Three Pulses

Example 103.

Antibiotic Pellet Formulation and Preparation Procedure

103.1 Pellet Formulations for subsequent coating

The composition of the Antibiotictrihydrate matrix pellets provided in Table 4. Table 4 Composition of AntibioticMatrix Pellets

Component Percentage (%)

AntibioticTrihydrate powder 92

Avicel PH lOl 7.0

Hydroxypropyl methylcellulose, NF* 1.0

Total 100

*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

103.2 Preparation Procedure for AntibioticMatrix Pellets

103.2.1 Blend Antibioticand Avicel® PH 101 using a low shear blender.

103.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

103.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of fhe screen of the Bench Top Granulator is 0.8 mm.

103.2.4 Spheronize fhe extrudate using a QJ-230 Spheronizer using a small cross section plate.

103.2.5 Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.

103.2.6 Pellets between 20 and 40 Mesh were collected for further processing.

103.2.7 The above procedure is used to produce pellets that contain a first antibiotic and pellets that contain a second and different antibiotic. 103.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

103.3.1 Dispersion Formulation

The composition of the aqueous Eudragit L30D-55 dispersion applied to fhe Antibioticmatrix pellets is provided below in Table 5.

Table 5 Eudragit® L 30 D-55 Aqueous Coating Dispersion

Component Percentage (%)

Eudragit® L 30 D-55 41.6

Triethyl Citrate 2.5

Talc 5.0

Purified Water 50.9

Solids Content 20.0

Polymer Content 12.5

103.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

103.4.1 Suspend triethyl citrate and talc in deionized water.

103.4.2 The TEC/talc suspension is mixed using laboratory mixer.

103.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.

103.4.4 Allow the coating dispersion to stir for one hour prior to application onto the Antibioticmatrix pellets.

103.5 Preparation of an Eudragit® S 100, Aqueous Coating Dispersion 103.5.1 Dispersion Formulation

The composition of fhe aqueous Eudragit® S 100 dispersion applied to fhe Antibioticmatrix 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

103.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion

Part A: ^:

103.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

103.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

103.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.

103.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B .

Part B:

103.6.5 Disperse talc in the required amount of water

103.6.6 Stir the dispersion using an overhead laboratory mixer.

103.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

103.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters are used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes.

Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C

Atomization Air Pressure 1.8 Bar

Pump Rate 2-6 gram per minute 103.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

103.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.

103.8 Preparation of AntibioticGranulation (Immediate Release Component) for tabletting

Table 7 Composition of AntibioticGranulation

Component Percentage (%)

AntibioticTrihydrate powder 92

Avicel PH lOl 7.0

Hydroxypropyl methylcellulose, NF* 1.0

Total 100

*Hydroxyρroρyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

103.8.1 Blend Antibioticand Avicel® PH 101 using a low shear blender.

103.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

103.8.3 Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.

103.8.4 Granules between 20 and 40 Mesh are collected for further processing.

103.9 Tabletting of the AntibioticPellets

Table 8 Composition of AntibioticTablets

Component

Percentage (%)

First antibioticgranules

¹ 32.5

Avicel PH 200

5.0

Second antibioticL30D-55 coated pellets

30 First antibiotics 100 coated pellets

30

Colloidal silicon dioxide 1.5

Magnesium stearate 1.0

Total 100

103.9.1 Blend the Antibioticgranules, Avicel PH-200, Antibioticpellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

103.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.

103.9.3 Compress the blend on a rotary tablet press. 103.9.4 The¹ fill weight should be adjusted to achieve the desired dosage.

Four pulses

Example 104.

1 Antibiotic Matrix Pellet Formulation and Preparation Procedure

104.1 Pellet Formulation

The composition of the antibiotic matrix pellets provided in Table 9.

Table 9 Composition of Antibiotic Pellets

Component Percentage (%)

Antibiotic 50

Avicel PH 101 20

Lactose 20

PVP K29/32* 10

Purified Water

Total 100

*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

104.2 Preparation Procedure for Antibiotic Matrix Pellets 104.2.1 Blend antibiotic and Avicel® PH 101 using a Robot Coupe high shear granulator. 104.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. 104.2.3 Extrude fhe wet mass using an LCI Bench Top Granulator. The diameter of fhe screen of the Bench Top Granulator was 1.0 mm.

104.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

104.2.5 Dry the spheronized pellets at 50°C overnight.

104.2.6 Pellets between 16 and 30 Mesh were collected for further processing.

104.2.7 The above procedure is used to prepare pellets that contain a first antibiotic and pellets that contain a second antibiotic.

104.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion

104.3.1 Dispersion Formulation

The composition of fhe aqueous Eudragit L30D-55 dispersion applied to the antibiotic matrix pellets is provided below in Table 10.

Table 10 Eudragit® L 30 D-55 Aqueous Coating Dispersion

Component Percentage (%)

Eudragit® L 30 D-55 55.0

Triethyl Citrate 1.6

Talc 8.0

Purified Water 37.4

Solids Content 25.5

Polymer Content 15.9

104.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion

104.4.1 Suspend triethyl citrate and talc in deionized water.

104.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.

104.4.3 Add the TEC/talc suspension slowly to fhe Eudragit® L 30 D- 55 latex dispersion while stirring. 104.4.4 Allow fhe coating dispersion to stir for one hour prior to application onto the antibiotic matrix pellets.

104.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion

104.5.1 Dispersion Formulation

The composition of the aqueous Eudragit® S 100 dispersion applied to the antibiotic matrix pellets is provided below in Table 11.

Table 11 Eudragit® S 100 Aqueous Coating Dispersion

Component Percentage (%)

Part A

Eudragit® S 100 12.0

1 N Ammonium Hydroxide 6.1

Triethyl Citrate 6.0

Purified Water 65.9

Part B

Talc 2.0

Purified Water 8.0

Solid Content 20.0

Polymer Content 12.0

104.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: _!

104.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring. 104.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

104.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.

104.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.

PartB: 104.6.5 Disperse talc in the required amount of water 104.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

104.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.

104.7 Coating Conditions for fhe Application of Aqueous Coating Dispersions

The following coating parameters are used for coating with each of the Eudragit® L

30 D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed

Coater

Spray nozzle diameter 1.0 mm

Material Charge 300 gram

Inlet Air Temperature 40 to 45 °C

Outlet Air Temperature 30 to 33 °C

Atomization Air Pressure 1.8 Bar

Pump Rate 2 gram per minute

104.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to fhe pellets.

104.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.

104.7.3 Coat matrix pellets with S 100 dispersion such that you apply 20% coat weight gain to fhe pellets.

104.8 Encapsulation of the Antibiotic Pellets

Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and SI 00 coated pellets respectively. The capsule is filled with the four different pellets to achieve the desired dosage.

The immediate release pellets contain fhe first antibiotic; the L30 D-55 12% weight gain coated pellets contain the second antibiotic; the L30 D-55 30% weight gain coated pellets contain the first antibiotic and the SI 00 coated pellets contain the second antibiotic.

The procedure of Examples 102-104 may be used to produce an antifungal product that contains two different antifungal agents. The present invention is advantageous in that a syήergistic antibiotic or antifungal will be dosed in an alternate pulse to another, synergistic antibiotic or antifungal. This will alternate the exposure to fhe bacteria in such a way as to make both antibiotics or antifungals more effective than if they were co-administered, and thereby competing with each other for sites on the bacterial or fungal cell wall receptors, or sites within the bacterial or fungal cells.

Numerous modifications and variations of the present invention are possible in light of the above teachings; therefore, within the scope of the appended claims, the invention may be practiced otherwise than as particularly described.

Claims

What is claimed is:

1. A therapeutic product comprising:

at least three dosage forms, each dosage form comprising a therapeutic agent and a pharmaceutically acceptable carrier, one of said dosage forms including at least a first a therapeutic agent and a second of said dosage forms including at least a second therapeutic agent that is different than the first therapeutic agent, wherein said therapeutic product is an antibiotic or an anti-fungal product and the first and second therapeutic agents are either each an antibiotic or an 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 a therapeutic agent released from the second dosage form reaches a C_max in serum after therapeutic agent released from the first dosage form reaches C_max in serum.

6. The product of Claim 5 wherein a therapeutic agent released from the third dosage form reaches C_max in serum after therapeutic agent released from the second dosage form reaches C_maχ in serum.

7. The product of Claim 6 wherein total therapeutic agent released from the product reaches C_max 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 therapeutic agent.

10. The product of Claim 1 wherein the first dosage form includes the first therapeutic agent, the second dosage form includes fhe first and second therapeutic agent and the fourth dosage form includes the second therapeutic agent.

11. A therapeutic product comprising: a first, second, third and fourth dosage form, said first dosage form comprising a first therapeutic agent and a pharmaceutically acceptable carrier; said second dosage form comprising said first therapeutic agent and a pharmaceutically acceptable carrier; said third dosage form comprising a second therapeutic agent different from the first therapeutic agent and a pharmaceutically acceptable carrier; said fourth dosage form comprising said second therapeutic agent and a pharmaceutically acceptable carrier, said second and third dosage forms having a release profile whereby the maximum serum concentration of the first therapeutic agent and the second therapeutic agent released from the second and third dosage forms is reached at a time later than fhe maximum serum concentration of the first therapeutic agent released from the first dosage form, and wherein the maximum serum concentration of the second therapeutic agent released from the fourth dosage form reaches a maximum serum concentration at a time after the maximum serum concentration for fhe therapeutic agent released from each of the first, second and third dosage forms is reached, wherein each of said therapeutic agents is either an antibiotic or an anti-fungal.

12. The composition of Claim 1 wherein the first therapeutic agent released from fhe second dosage form, and the second therapeutic agent released from the third dosage form reach a maximum serum concentration at about the same time.

13. A process for treating an infection in a host comprising: administering to the host the product of Claim 1.

14. A process for treating an infection in a host comprising: administering to the host the product of Claim 2.

15. A process for treating an infection in a host comprising: administering to the host the product of Claim 3.

16. A process for treating an infection in a host comprising: administering to the host the product of Claim 4.

17. A process for treating an infection in a host comprising: administering to the host the product of Claim 5.

18. A process for treating an infection in a host comprising: administering to the host the product of Claim 6.

19. A process for treating an infection in a host comprising: administering to the host the product of Claim 7.

20. A process for treating an infection in a host comprising: administering to the host the product of Claim 8.

¹ 1