AU2006201923B2 - Therapeutic product, use and formulation thereof - Google Patents

Description

S&FRef: 605830D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name and Address of Applicant Actual Inventor(s): Address for Service: Invention Title: Advancis Pharmaceutical Corporation, of 942 Clopper Road, Gaithersburg, Maryland, 20878, United States of America Edward M. Rudnic James D. Isbister Donald J. Treacy Sandra E. Wassink Spruson Ferguson St Martins Tower Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Therapeutic product, use and formulation thereof The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c -1- 00 Therapeutic Product, Use and Formulation Thereof This invention relates to a therapeutic product, as well as the use and formulation d thereof.

00 A wide variety of antibiotics, anti-fungal, anti-viral and anti-neoplastic agents have been used, and will be used, in order to treat a patient. In general, such therapeutics can be administered by a repeated dosing of immediate release dosage forms, which results in 'i poor compliance or as a controlled release formulation (slow release) at higher administered doses. The present invention is directed to providing for an improved therapeutic product. IND A first aspect of the present invention provides a once-a-day therapeutic product C, comprising: first, second, and third therapeutic dosage forms, each of said therapeutic dosage forms comprising at least one therapeutic agent and a pharmaceutically acceptable carrier, said first therapeutic dosage form being an immediate release dosage form, said second and third therapeutic dosage forms being delayed release dosage forms, and is wherein each of said first, second, and third therapeutic dosage forms initiates release at different times and Cna,, of the total therapeutic agent released from said therapeutic product is achieved in less than about 12 hours from administration; said once-a-day therapeutic product contains the total dosage of the at least one therapeutic agent for a twenty-four hour period; and said at least one therapeutic agent is selected from the group consisting of antibiotics, anti-fungals, anti-virals and anti-neoplastics.

As used in this application the term "therapeutic" or "therapeutic agent" means an antibiotic, or an anti-fungal or an anti-viral or an anti-neoplastic agent.

Each dosage form has a different release profile and the release profile of each of the dosage forms is such that the dosage forms each start release of the therapeutic contained therein at different times after administration of the therapeutic product.

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

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

In accordance with the first aspect of the present invention described above, the therapeutic product has an overall release profile such that when administered the maximum serum concentration of the total therapeutic released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, 1185531 I:JJP -2- 00 C the maximum serum concentration of the total therapeutic released from the therapeutic N product is achieved no earlier than four hours after administration.

In accordance with the first aspect of the invention, there are at least three oO therapeutic dosage forms. One of the at least three dosage forms is an immediate release dosage form whereby initiation of release of the therapeutic therefrom is not substantially Cc delayed after administration of the therapeutic 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 nonpH sensitive delayed dosage form, depending on the type of therapeutic product), \whereby the therapeutic released therefrom is delayed until after initiation of release of the therapeutic from the immediate release dosage form. More particularly, the therapeutic release from the second of the at least two dosage forms 1185531 I:JJP achieves a (maximum serum concentration in the serum) at a time after the therapeutic released from the first of the at least three dosage forms achieves a C. in the serum, and the therapeutic released from the third dosage form achieves a Ca in the serum after the of therapeutic released from the second dosage form.

In one embodiment, the second of the at least two dosage forms initiates release of the therapeutic 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 therapeutic from the first dosage form of the at least three dosage forms.

In general, the immediate release dosage form produces a for the therapeutic 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 for the therapeutic released therefrom in no more than about four hours. In general, the C,, for such second dosage form is achieved no earlier than two hours after administration of the therapeutic product; however, it is possible within the scope of the invention to achieve in a shorter period of time.

As hereinabove indicated, the therapeutic product may contain at least three or at least four or mre different dosage forms. For example, where the therapeutic product includes a third dosage form, the therapeutic released therefrom reaches a at a time later than the Cmax is achieved for the therapeutic released from each of the first and second dosage forms. In a preferred embodiment, release of therapeutic from the third dosage form is started after initiation of release of therapeutic from both the first dosage form and the second dosage form. In one embodiment, Cm,, for therapeutic released from the third dosage form is achieved within eight hours.

In another embodiment, the therapeutic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby the therapeutic released from each of the at least four different dosage forms achieves a Cma,,, at a different time.

As hereinabove indicated, in a preferred embodiment, irrespective of whether oO the therapeutic contains at least three or at least four different dosage forms each Swith a different release profile, C for all the therapeutic agent released from max the therapeutic product is achieved in less than twelve hours, and more generally is 00 achieved in less than eleven hours.

In a preferred embodiment, the therapeutic product is a once a day product, N whereby after administration of the therapeutic product, no further product is administered during the day; the preferred regimen is that the product is OS administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of a therapeutic product with the therapeutic being released in a manner such that overall therapeutic release is effected with different release profiles in a manner such that the overall for the therapeutic product is reached in less than twelve hours. The term single administration means that the total therapeutic 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.

Applicant has found that a single dosage therapeutic product comprised of at least three therapeutic dosage forms each having a different release profile is an improvement over a single dosage therapeutic product comprised of an therapeutic dosage form having a single release profile. Each of the dosage forms of therapeutic in a pharmaceutically acceptable carrier may have one or more therapeutics of the same type (for example, one or more antibiotics; one or more anti-viral agents, etc.) and each of the dosage forms may have the same therapeutic or different therapeutics, each of the same type (the same or different antibiotics; the same or different antivirals, etc.).

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 therapeutic 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 of the fourth dosage form of the at least four dosage forms is reached after the of each of the other dosage forms is reached, therapeutic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.

The therapeutic product of the present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the therapeutic 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 therapeutic product is formulated in a manner such that it is suitable for oral administration.

For example, in formulating the therapeutic product for topical administration, such as by application to the skin, the at least two different dosage forms, each of which contains an therapeutic, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion.

In such a formulation, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in-oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.

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

In addition, the therapeutic 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 therapeutic 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 therapeutic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.

In a preferred embodiment, the therapeutic 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 therapeutic product. Thus, for example, therapeutic 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 therapeutic, as hereinabove described, whereby the Cmax of the therapeutic released from each of the tablets is reached at different times, with the Cmax of the total therapeutic released from the therapeutic product being achieved in less than twelve hours.

The formulation of an therapeutic 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 therapeutics in the coating and/or the thickness of the coating.

In formulating a therapeutic 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 therapeutic to be delivered by the product, with such immediate release dosage forms generally providing at least of the total dosage of the therapeutic 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 therapeutic 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 therapeutic to be delivered by the product.

The remaining dosage forms deliver the remainder of the therapeutic. 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 therapeutic; however, they may also be formulated so as to provide different amounts.

In accordance with the present invention, each of the dosage forms contains the same therapeutic; however, each of the dosage forms may contain more than one therapeutic.

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 by weight, of the total therapeutic; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, of the total therapeutic; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, of the total therapeutic.

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 therapeutic provided by the two delayed release components with the second delayed release component providing the remainder of the therapeutic.

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

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

The Immediate Release Component The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the therapeutic. 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 therapeutics 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, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PVP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000-10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.

It may be useful to have these materials present in the range of 1.0 to 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.

These materials may be present in the rate of 0.05-15% The non-pH Sensitive 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% of this component.

The pH Sensitive (Enteric) Release Component The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.

The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives.

These materials can be present in concentrations from 4-20% Sustained Release Component The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.

The kind of materials useful for this purpose can be, but are not limited to, ethylcellulose,hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons.

These materials can be present in concentrations from 4-20% As hereinabove indicated, the units comprising the therapeutic composition of the present invention can be in the form of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension.

The therapeutic composition of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably is administered orally. The composition includes a therapeutically effective amount of the therapeutic, which amount will vary with the therapeutic to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day. The composition is administered to a host in an amount effective for treating the disease or infection.

Thus, the therapeutic composition or product may be used for treating an infection in a host that is caused by bacteria or virus or fungus and may be used to treat cancer.

This system will be especially useful in extending the practial therapeutic activity for antibiotics with elimination half lives of less than 20 hours and more particularly with elimination half-lives of less than 12 hours, and will be particularly useful for those drugs with half-lives of 2-10 hours. The following are examples of some antibiotics with half-lives of about 1 to 12 hours: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine, cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefjodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefitetazole, cefotetan, cefoxitin, loracarbef, imipenem, erythromycin (and erythromycin salts such as estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycoin, dirithromycin, troleanomycin, penicillin V, peniciliin salts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and cIavulanate potassium, ampicillin, bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin) mezlocillin, piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin and clavulanate potassium, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HCI and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfioxacin, ofloxacin, sparfioxacin, sulfacytine, suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine, sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, cotriamoxazole, pentamidine, and trimetrexate.

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, carbolfuchsin, cIioquinol, methyirosaniline chloride, sodium thiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate salts (calcium undecylenate, copper undecylenate, zinc undecylenate) The following are representative examples of some antivirals that may be used in the invention: Acyclovir, Amantadine, Amprenavir, Cidofovir, Delavirdine, Didanosine, Famciclovir, Foscamet, Ganciclovir, Indinavir, Interferon, Lamivudine, Nelfinavir, Nevirapine, Palivizumab, Penciclovir, Ribavirin, Rimantadine, Ritonavir, Saquinavir, Stavudine, Trifluridine, Valacyclovir, Vidarabine, Zalcitabine, Zidovudine The following are representative examples of agents for the treatment of cancer that may be used in accordance with the invention: carboplatin, busulfan, cisplatin, thiotepa, meiphalan hydrochloride, cyclophosphanide, ifosfamide, chiorambucil, mechlorethamine hydrochloride, carmustine, lomustine, streptozocin, polifeprosan 20, dexrazoxane, dronabinol, granisetron hydrochloride, fluconazole, erythropoietin, octreotide acetate, pilocarpine hydrochloride, etidronate disodium, pamidronate disodium, allopurinol sodium, amifostine, filgrastir, mesna, ondansetron hydrochloride, dolasetron mesylate, leucovorin calcium, sargramostim, levamisole hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, mitomycin, daunorubicin citrate, plicamycin, daunorubicin hydrochloride, bleomycin sulfate, mitoxantrone hydrochloride, vairubicin, dactinomycin, fludarabine phosphate, cytarabine, mercaptopurine, thioguanine, methotrexate sodium, cladribine, floxuridine, capecitabine, anastrozole, bicalutamide, tamoxifen citrate, testolactone, nilutamide, methyltestosterone, flutamide, toremifene citrate, goserelin acetate, estramustine phosphate sodium, ethinyl estradiol, esterified estrogen, leuprolide acetate, conjugated estrogens, megestrol acetate, aldesleukin, medroxyprogesterone acetate, dacarbazine, hydroxyurea, etoposide phosphate, megestrol acetate, paclitaxel, etoposide, teniposide, trastuzumab, rituximab, vinorelbine tartrate, denileukin diftitox, gemcitabine hydrochloride, vincristine sulfate, vinbiastine sulfate, asparaginase, edrophonium chloride, bacillus calmette and guerin, irinotecan hydrochloride, pegaspargase, docetaxel, interferon alfa-2a, recombinant, tretinoin, porfimer sodium, interferon alfa-2b, recombinant, procarbazine hydrochloride, topotecan hydrochloride, altretamine, fluorouracil, prednisolone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone sodium sulfate, dexamethasone acetate, hydrocortisone sodium phosphate, hydrocortisone, prednisolone, methyiprednisolone sodium succinate, betamethasone sodium phosphate, betamethasone acetate, letrozole, mithramycin, mitotane, pentostatin, perfosfamide, raloxifene "00 0 In accordance with another aspect of the present invention there is provided a N' procedure or regimen for treating a patient with a therapeutic agent that is an S antibiotic, anti-viral, anti-fungal or anti-neoplastic agent by injection thereof that 00 provides results similar to those achieved by the use of a product as hereinabove described that includes at least three dosage forms.

In accordance with this aspect of the invention, there is provided a regimen for treating a patient with a therapeutic agent wherein the therapeutic agent is administered by injection, with the daily dosage being delivered over a period that is less than eleven hours (which period is measured from the first injection), and Swherein there are at least two delivery pulses, and no more than thirty-two delivery pulses during a period of less than eleven hours, and preferably a period of less than eight hours. As used herein, "delivery pulses" means and may be accomplished by at least two spaced injections with periods between such spaced injections wherein essentially no therapeutic agent is injected into the host or alternatively, between the spaced injections, therapeutic agent is continuously injected in an amount different than that which is injected in the spaced injections. In addition, at least two delivery pulses can be achieved by continuous injection of the agent at one dosage, followed by continuous injection at a different dosage. In such a case there is a first continuous delivery pulse over a period of time, followed by a second continuous delivery pulse over a period of time. Thus, for example, in the latter case, there can be an initial injection wherein the therapeutic agent is continuously administered over a period of time followed by an increase in the dosage of the therapeutic agent that is administered by injection over a period of time whereby in effect there are two delivery pulses even though there may be continuous administration of the therapeutic agent.

In one embodiment, in less than an eleven hour period, there is at least two spaced injections of the therapeutic agent and generally no more than thirty-two spaced injections of the therapeutic agent. There may or may not be a continuous injection of the agent between the spaced injections and if there is such a continuous injection, the dosage of the agent is less than or more than the spaced injections. In a preferred embodiment, there is no injection of agent between the spaced injections.

In one preferred embodiment wherein there are spaced injections of the therapeutic agent, up to about sixty percent, and preferably up to about fifty percent of the dosage that is to be injected in a period of less than eleven hours is injected during the first four hours of such period.

In one embodiment, there is provided two injections in less than a six hour period. In another there is provided no more than six injections preferably in less than six hours. In a further embodiment there is provided at least four injections preferably over less than 6 hours.

In a preferred embodiment, the delivery pulses are accomplished by spaced injections of the therapeutic agent in a pharmaceutically acceptable carrier. There are at least two and no more than 32 spaced injections, all of which are delivered within 11 hours and preferably within 8 hours of the first injection. The daily dosage is delivered within such eleven or eight hour period and the spaced injections provide for at least 75%, preferably at least 90% and more preferably at least 100% of the agent that is to be delivered.

The therapeutic agent may be injected by any procedures known in the art. In a preferred embodiment, the therapeutic agent may be injected by use of a controlled pump of a type known in the art for injecting pharmaceutical products.

Alternatively, the regimen of the invention may be employed in a hospital wherein controlled injections are administered by use of a catheter. Injections can be made into any body structure, organ or blood vessel, such as intravenous, intramuscular, subcutaneous, intradermal, intrathecal, intraperitoneal, intraarticular, intraocular, or other routes of injectable delivery.

In accordance with the invention by employing delivery pulses for injecting the therapeutic agent in a period that is less than eleven hours and preferably less than eight hours, there is provided distinct maximum serum concentration pulses of the therapeutic agent in the blood of the patient in a period of less than 11 hours. In a preferred embodiment, such distinct Cmax pulses occur in a period of less than eight hours and preferably within a period of six hours.

In accordance with a preferred embodiment, all of the Cmax pulses are achieved in a period of less than 11 hours, preferably less than eight hours, and such pulses provide the daily dosage of the therapeutic agent; the therapeutic agent is injected in at least two delivery pulses within eleven hours and there is no further administration over the remainder of a twenty-four hour period.

All or a portion of the delivery pulses of the therapeutic agent delivered by spaced injections may be the same or different dosages of the therapeutic agent.

In general at a minimum each spaced injection provides at least 5% of the total daily dosage of the therapeutic agent.

It is to be understood that each delivery pulse may include one or more different therapeutic agents (for example two or more different antibiotics), and each delivery pulse may contain the same or different therapeutic agents (for example, one delivery pulse may contain two or more antibiotics and one may contain only one of the two or more antibiotics).

As hereinabove indicated the therapeutic agent is preferably an antibiotic or an anti-viral agent or an anti-fungal agent or an anti-neoplastic agent.

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.

Examples Immediate Release Component (Antibiotic) 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 over 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: Example 2: Example 3: Example 4: Example Example 6: Amoxicillin Microcrystalline cellulose Povidone Croscarmellose sodium Amoxicillin Microcrystalline cellulose Povidone Croscarmellose sodium Amoxicillin Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Amoxicillin Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Amoxicillin Polyethylene glycol 8000 Polyvinylpyrrolidone Clarithromycin Microcrystalline cellulose Hydroxypropylcellulose 65% (W/W) 55% (W/W) 65% (W/W) 75% (W/W) 75% (W/W) 65% (W/W) Example 7: Example 8: Example 9: Example Example 11: Example 12: Example 13: Example 14: Example Croscarmellose sodium Clarithromycin Microcrystal line cellulose 1-ydroxypropylcellulose Croscarmellose sodium Clarithromycin Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Clarithromycin Polyethylene glycol 8000 Polyvinylpyrrolidone Ciprofloxacin Microcrystal line cellulose Hydroxypropyl cellulose Croscarmellose sodium Ciprofloxacin Microcrystal line cellulose Hydroxypropylcellulose Croscarmellose sodium Ciprofloxacin Polyethylene glycol 4000 Polytheylene glycol 2000 Hydroxypropylcel lulose Cirpofloxacin Polyethylene glycol 8000 Polyvinylpyrrolidone Ceflibuten Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropyl cellulose Ceftibuten 75% (W/W) 75% (W/W) 75% (W/W) 65% (W/W) 75% (WMW 75% (W/W) 75% (W/W) 75% (WMW 75% (W/W) Polyethylene Glycol 4000 Polyvinylpyrrolidone non-pH Sensitive Delayed Release Component (Antibiotic) 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 over 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. W/W) Example 16: Example 17: Example 18: Example 19: Example Example 21: Amoxicillin Microcrystalline cellulose Polyox Croscarmellose sodium Amoxicillin Microcrystalline cellulose Polyox Glyceryl monooleate Amoxicillin Polyox Hydroxypropylcellulose Croscarmellose sodium Amoxicillin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Amoxicillin Polyethylene glycol 8000 Ethylcellulose Clarithromycin 65% (W/W) 55% (W/W) 65% (W/W) 75% (W/W) 75% (W/W) 70% (W/W) Example 22: Example 23: Example 24: Example Example 26: Polyox Hydroxypropyl cellulose Croscarmellose sodium Clarithromycin Polyox Hydroxypropyl cellulose Ethylcellulose Clarithromycin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Clarithromycin Polyethylene glycol 8000 Polyvinylpyrrolidone Eudgragit R 30D Ciprofloxacin Polyethylene glycol 4000 Hydroxypropylcellulose Eudragit RL 30D Ciprofloxacin Microcrystalline cellulose Hydroxypropylcellulose Ethylcellulose Ciprofloxacin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudgragit RI 30D Ciprofloxacin Polyethylene glycol 8000 Ethylcellulose Ceftibuten Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D 75% (W/W) 75% (W/W) 80% (WIW) 65% (WMW 75% (W/W) 80% (W/W) 75% (W/W) 75% (W/WT) Example 27: Example 28: Example 29: Example Ceftibuten Polyethylene glycol 8000 Ethylcellulose Enteric Release Component (Antibiotic) 75% (W/W 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 over 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 Conc. W/W) Example 31: Example 32: Example 33: Example 34: Example Amoxicillin Microcrystalline cellulose Cellulose Acetate Pthalate Amoxicillin Microcrystalline cellulose Cellulose Acetate Pthalate Hydroxypropylmethylcellulose Amoxicillin Polyox Hydroxypropylcellulose pthalate Eudragit L30D Amoxicillin Polyethylene glycol 2000 Eudragit L30D Eudragit RL 30D Amoxicillin Microcrystalline Cellulose Cellulose Acetate Pthalate 65% (W/W) 55% (W/W) 65% (W/W) 75% (W/W) 40% (W/W) Example 36: Example 37: Example 38: Example 39: Clarithromycin Hydroxypropyl cellulose pthalate Croscarmellose sodium Clarithromycin Eudragit E30D Hydroxypropyl cellulose Ethyl cellulose Clarithromycin Polyethylene glycol 2000 Eudragit E 30D Clarithromycin Lactose Eudg-ragit L 30D Ciprofloxacin Microcrystalline Cellulose Eudragit L 30D Ojprofloxacin Microcrystalline Cellulose Hydroxypropylcellulose pthalate Ciprofloxacin Lactose Eudgragit L 30D Example Example 4 1: Example 42: 70% (W/W) 70% (W/Wr) 75% (WIW) 40% (WIW) 65% (WIW) 75% (W/W) 80% (WMW 70% (WAV) 60% (W/W) Example 43: Example 44: Ciprofloxacin Polyethylene glycol 4000 Cellulose acetate pthalate Ceftibuten Polyethylene glycol 2000 Lactose Eudragit L 30D Example Ceftibuten Microcrystalline cellulose Cellulose acetate pthalate 70% (W/W) Sustained Release Component (Antibiotic) 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 over 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. W/W) Example 46: Example 47: Example 48: Example 49: Example Amoxicillin Ethylcellulose Polyox Hydroxypropylmethylcellulose Amoxicillin Lactose Polyox Glyceryl monooleate Amoxicillin Polyox Hydroxypropylcellulose Clarithromycin Lactose Hydroxypropylcellulose Ethylcellulose Clarithromycin Polyethylene glycol 4000 Lactose Eudragit RL 30D 65% (W/W) 55% (W/W) 70% (W/W) 75% (W/W) 75% (W/W) Example 51: Example 52: Example 53: Example 54: Example Clarithromycin Polyethylene glycol 8000 Hydroxypropylmethylcellulose Eudgragit RS 30D Ciprofloxacin Hydroxyethylcellulose Polyethylene glycol 4000 Hydroxypropylcellulose Ciprofloxacin Lactose Povidone (PVP) Polyethylene glycol 2000 Ceftibuten Polyethylene glycol 4000 Povidone (PVP) Hydroxypropylcellulose Ceftibuten Lactose Polyethylene glycol 4000 Polyvinylpyrrolidone 80% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Immediate Release Component (Anti-fungal) 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.

Example 56: Fluconazole Microcrystalline cellulose Povidone Croscarmellose sodium 65% (W/W) Example 57: Example 58: Example 59: Example Example 6 1: Example 62: Example 63: Example 64: Example Fluconazole Mi crocrystal line cellulose Povidone Croscarmellose sodium Fluconazole Microcrystal line cellulose Hydroxypropylcellulose Croscar-mellose sodium Fluconazole Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Fluconazole Polyethylene glycol 8000 Polyvinylpyrrolidone Ketoconazole Microcrystalline cellulose Hydroxypropylcellulose Croscar-mellose sodium Ketoconazole Microcrystalline, cellulose Hydroxypropylcellulose Croscarmellose sodium Ketoconazole Polyethylene glycol 4000 Polyethylene glycol 2000 H ydroxypropyl cellulose Ketoconazole Polyethylene glycol 8000 Polyvinylpyrrolidone Griscofulvin Microcrystalline cellulose 55% (WMW 65% (WMW 75% (W/W) 75% (W/W) 65% (WIW) 75% (WMW 75% (WMW 75% (W/W 65% (W/W) Example 66: Example 67: Example 68: Example 69: Example Hydroxypropylcellulose Croscarmellose sodium Griseofulvin Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Griseofulvin Polyethylene glycol 4000 Polytheylene glycol 2000 Hydroxypropylcellulose Cirpofloxacin Polyethylene glycol 8000 Polyvinylpyrrolidone Terbinafine HCI Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Terbinafine HCI Polyethylene Glycol 4000 Polyvinylpyrrolidone 75% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Non pH Sensitive Delayed Release Component (Anti-fungal) 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 Conc. W/W) Example 71: Fluconazole Microcrystalline cellulose 65% (W/W) Example 72: Example 73: Example 74: Example Example 76: Example 77: Polyox Croscarmellose sodium Fluconazole Microcrystalline cellulose Polyox Glyceryl monooleate Fluconazole Polyox Hydroxypropylcellulose Croscarmellose sodium Fluconazole Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Fluconazole Polyethylene glycol 8000 Ethylcellulose Ketoconazole Polyox.

Hydroxypropyl cellulose Croscarmellose sodium Ketoconazole Polyox Hydroxypropyl cellulose Ethylcellulose Ketoconazole Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Ketoconazole Polyethylene glycol 8000 Polyvinylpyrrolidone Eudgragit R 30D 55% (W/W) 65% (W/W) 75% (W/W) 75% (W/W) 70% (W/W) 75% (W/W) 75% (W/W) 80% (W/W) Example 78: Example 79: Example Example 81: Example 82: Example 83: Example 84: Example Griseofulvin Polyethylene glycol 4000 Hydroxypropylcellulose Eudragit RL 30D Griseofulvin Microcrystalline cellulose Hydroxypropylcellulose Ethylcellulose Griseofulvin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudgragit RL 30D Griseofulvin Polyethylene glycol 8000 Ethylcellulose Terbinafine HCI Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Terbinafine HCI Polyethylene glycol 8000 Ethylcellulose 65% (W/W) 75% (W/W) 80% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Enteric Release Component (Anti-fungal) 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.

Ingredient Conc. W/W)

I

Example 86: Example 87: Example 88: Example 89: Example Example 91: Example 92: Example 93: Fluconazole Microcrystalline cellulose Cellulose Acetate Pthalate Fluconazole Microcrystalline cellulose Cellulose Acetate Pthalate Hydroxypropylmethylcellulose Fluconazole Polyox Hydroxypropylcellulose pthalate Eudragit L30D Fluconazole Polyethylene glycol 2000 Eudragit L 30D Eudragit RL 30D Fluconazole Microcrystalline Cellulose Cellulose Acetate Pthalate Ketoconazole Hydroxypropylcellulose pthalate Croscarmellose sodium Ketoconazole Eudragit L 30D Hydroxypropylcellulose Ethylcellulose Ketoconazole Polyethylene glycol 2000 Eudragit L 30D 65% (W/W) 55% (W/WI) 65% (WIW1) 75% (WIW) 40% (W/W) 70% (W/W) 70% (W/W) 75% (W/W) 40% (WMW Example 94: Ketoconazole Lactose Eudgragit L 30D Example Example 96: Example 97: Example 98: Example 99: Example 100: Griseofulvin Microcrystalline Cellulose Eudragit L 30D Griseofulvin Microcrystalline Cellulose Hydroxypropylcellulose pthalate Griseofulvin Lactose Eudragit L 30D Griseofulvin Polyethylene glycol 4000 Cellulose acetate pthalate Terbinafine HCI Polyethylene glycol 2000 Lactose Eudragit L 30D Terbinafine HCI Microcrystalline cellulose Cellulose acetate pthalate 65% (W/W) 75% (W/W) 80% (W/W) 70% (W/W) 60% (W/W) 70% (W/W) Sustained Release Component (Anti-fungal) 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 Conc. W/W) Example 101: Fluconazole Ethylcellulose Polyox Hydroxypropylmethyl cellulose Example 102: Example 103: Example 104: Fluconazole Lactose Polyox Glyceryl monooleate Fluconazole Polyox Hydroxypropylcellulose Ketoconazole, Lactose Hydroxypropylcellulose Ethylcellulose Example 105: Example 106: Example 107: Ketoconazole Polyethylene glycol 4000 Lactose Eudragit RL 30D Ketoconazole Polyethylene glycol 8000 Hydroxypropylmethylcellulose Eudgragit RS 30D Griseofulvin.

H ydroxyethyl cellulose Polyethylene glycol 4000 Hydroxypropylcellulose Griseofulvin Lactose Povidone (PVP) Polyethylene glycol 2000 Terbinafine HCI Polyethylene glycol 4000 Povidone (PVP) 65% (WIW) 55% (W/W) 70% (WIW) 75% (WJW) 75% (W/W) 80% (WMW 75% (WMW 75% (W/W) 75% (WIW) Example 108: Example 109: Hydroxypropylcellulose Example 110: Example 111: Example 112: Example 113: Terbinafine HC1 Lactose Polyethylene glycol 4000 Polyvinylpyrrolidone Ketoconazole Eudragit S100 Triethyl Citrate Ketoconazole Sureteric Ketoconazole Eudragit S100 Triethyl Citrate 75% (W/W) 40% (W/W) 50% (W/W) 50% (W/W) Immediate Release Component (Anti-viral) 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 over or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary table press.

Ingredient Conc. W/W) Example 114: Example 115: Acyclovir Microcrystalline cellulose Povidone Croscarmellose sodium Acyclovir Microcrystalline cellulose Povidone Croscarmellose sodium 65% (W/W) 55% (W/W) Example 116: Example 117: Example 118: Example 119: Example 120: Acyclovir Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Acyclovir Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropyl cellulose Acyclovir Polyethylene glycol 8000 Pol yvinylpyrroli done Zidovudine Mi crocrystal line cellulose H-ydroxypropylcellulose Croscarmellose sodium Zidovudine Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Zidovudine Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Zidovudine Polyethylene glycol 8000 Pol yvinylpyrroli done Valacyclovir Microcrystalline cellulose Hydroxypropyl cellulose Croscarmnellose sodium 65% (W/W) 75% (W/W)

S

75% (WIW) 65% (W/W) 75% (W/W) 75% (WIW)

S

75% (W/W) 65% (W/W) Example 121: Example 122: Example 123: Example 124: Example 125: Example 126: Example 127: Example 128: Valacyclovir Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Valacyclovir Polyethylene glycol 4000 Polytheylene glycol 2000 Hydroxypropylcellulose Cirpofloxacin Polyethylene glycol 8000 Polyvinylpyrrolidone Ribavirin Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Ribavirin Polyethylene Glycol 4000 Polyvinylpyrrolidone 75% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Non pH Sensitive Delayed Release Component (Anti-viral) 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 over 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. W/W) Example 129: Acyclovir Microcrystalline cellulose Polyox Croscarmellose sodium 65% (W/W) Example 130: Example 13 1: Example 132: Example 133: Example 134: Example 135: Acyclovir Microcrystalline cellulose Polyox Glyceryl monooleate Acyclovir Polyox Hydroxypropylcellulose Croscarmellose sodium Acyclovir Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Acyclovir Polyethylene glycol 8000 Ethylcellulose Zidovudine Polyox Hydroxypropylcellulose Croscarmellose sodium Zidovudine Polyox Hydroxypropylcellulose Ethylcellulose Zidovudine Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Zidovudine Polyethylene glycol 8000 Polyvinylpyrrolidone Eudgragit R 30D 55% (W/W) 65% (W/W) 75% (W/W) 75% (WIW) 70% (W/W) 75% (W/W) Example 136: Example 137: 75% (WIW) 80% (WIW) Example 138: Example 139: Example 140: Example 141: Example 142: Example 143: Valacyclovir Polyethylene glycol 4000 Hydroxypropylcellulose Eudragit RL 30D Valacyclovir Microcrystalline cellulose Hydroxypropylcellulose Ethylcellulose Valacyclovir Polyethylene glycol 4000 Polyethylene glycol 2000 Eudgragit RL 30D Valacyclovir Polyethylene glycol 8000 Ethylcellulose Ribavirin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Ribavirin Polyethylene glycol 8000 Ethylcellulose 65% (W/W) 75% (W/W) 80% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Enteric Release Component (Anti-viral) 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 over 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 Conc. W/W) Example 144: Example 145: Example 146: Example 147: Example 148: Example 149: Example 150: Example 15 1: Example 152: Acyclovir Microcrystalline cellulose Cellulose Acetate Pthalate Acyclovir Microcrystalline cellulose Cellulose Acetate Pthalate Hydroxypropylmethylcellulose Acyclovir Polyox Hydroxypropylcellulose pthalate Eudragit L30D Acyclovir Polyethylene glycol 2000 Eudragit L 30D Eudragit RL 30D Acyclovir Mi crocrystal line Cellulose Cellulose Acetate Pthalate Zidovudine H-ydroxypropyl cellulose pthalate Croscarmnellose sodium Zidovudine Eudragit L 30D Hydroxypropylcellulose Ethylcellulose Zidovudine Polyethylene glycol 2000 Eudragit L 30D Zidovudine Lactose Eudgragit L 30D 65% (W/W7) 55% (W/W) 65% (WIW) 75% (W/W) 40% (WIW) 70% (WMW 70% (W/W) 75% (W/W) 40% (WIW) Example 153: Valacyclovir Microcrystalline Cellulose Eudragit L 30D Example 154: Example 155: Example 156: Example 157: Example 158: Valacyclovir Microcrystalline Cellulose Hydroxypropylcellulose pthalate Valacyclovir Lactose Eudragit L 30D Valacyclovir Polyethylene glycol 4000 Cellulose acetate pthalate Ribavirin Polyethylene glycol 2000 Lactose Eudragit L 30D Ribavirin Microcrystalline cellulose Cellulose acetate pthalate 65% (W/W) 75% (W/W) 80% (W/W) 70% (W/W) 60% (WAW) 70% (W/W) Sustained Release Component (Anti-viral) 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 over 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. W/W) Example 159: Acyclovir Ethylcellulose Polyox Hydroxypropylmethylcellulose Example 160: Acyclovir Lactose Polyox Glyceryl monooleate Example 161: Example 162: Example 163: Example 164: Example 165: Acyclovir Polyox Hydroxypropylcellulose Zidovudine Lactose Hydroxypropylcel lulose Ethylcellulose Zidovudine Polyethylene glycol 4000 Lactose Eudragit RL 30D Zidovudine Polyethylene glycol 8000 Hydroxypropylmethylcellulose Eudgragit RS 30D Valacyclovir Hydroxyethylcellulose Polyethylene glycol 4000 Hydroxypropylcellulose Valacyclovir Lactose Povidone (PVP) Polyethylene glycol 2000 65% (WIW) 55% (W/W) 70% (W/W) 75% (W/WI) 75% (W/W) 80% (W/W) 75% (W/W 75% (WMW Example 166: Example 167: Example 168: Example 169: Example 170: Example 171: Ribavirin Polyethylene glycol 4000 Povidone (PVP) Hydroxypropylcellulose Ribavirin Lactose Polyethylene glycol 4000 Polyvinylpyrrolidone Zidovudine Eudragit S100 Triethyl Citrate Zidovudine Sureteric Zidovudine Eudragit S100 Triethyl Citrate 75% (W/W) 75% (W/W) 40% (W/W) 50% (W/W) 50% (W/W) Immediate Release Component (Cancer) 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.

Example 172: Example 173: Fluorouracil Microcrystalline cellulose Povidone Croscarmellose sodium Fluorouracil Microcrystalline cellulose Povidone 65% (W/W) 55% (W/W) Example 174: Example 175: Example 176: Example 177: Example 178: Croscarmellose sodium Fluorouracil Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose, sodium Fluorouracil Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Fluorouracil Polyethylene glycol 8000 Polyvinylpyrrolidone Dexamethasone Microcrystalline cellulose Hydroxypropyl cellulose Croscarmellose sodium Dexamethasone, Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Dexamethasone Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Dexamethasone Polyethylene glycol 8000 Polyvinylpyrrolidone Valrubicin Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose, sodium Valrubicin 65% (W/W) 75% (W/W 75% (W/W) 65% (W/W) 75% (WIW) 75% (W/W) 75% (W/W) 65% (W/W) 75% (WIW) Example 179: Example 180: Example 181: Example 182: Example 183: Example 184: Example 185: Example 186: Microcrystalline cellulose Hydroxypropylcellulose Croscarmellose sodium Valrubicin Polyethylene glycol 4000 Polytheylene glycol 2000 Hydroxypropylcellulose Cirpofloxacin Polyethylene glycol 8000 Polyvinylpyrrolidone Tretinoin Polyethylene glycol 4000 Polyethylene glycol 2000 Hydroxypropylcellulose Tretinoin Polyethylene Glycol 4000 Polyvinylpyrrolidone 75% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Non pH Sensitive Delayed Release Component (Cancer) 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. W/W) Example 187: Fluorouracil Microcrystalline cellulose Polyox Croscarmellose sodium 65% (W/W) Example 188: Example 189: Example 190: Example 191: Example 192: Fluorouracil Microcrystalline cellulose Polyox Glyceryl monooleate Fluorouracil Polyox Hydroxypropylcellulose Croscarmellose sodium Fluorouracil Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Fluorouraci 1 Polyethylene glycol 8000 Ethylcellulose Dexamethasone Polyox Hydroxypropyl cellulose Croscarmellose sodium Dexamethasone Polyox Hydroxypropylcellulose Ethylcellulose Dexamethasone Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Dexamethasone Polyethylene glycol 8000 Polyvinylpyrrolidone Eudgragit R 30D Vairubicin Polyethylene glycol 4000 55% (WIW) 65% (W/W7) 75% (WMW 75% (W/W) 70% (W/W) 75% (W/W) 75% (WIW) 80% (WIW) 65% (W/W) Example 193: Example 194: Example 195: Example 196: Example 197: Example 198: Example 199: Example 200: Example 201: Hydroxypropylcellulose Eudragit RL Valrubicin Microcrystalline cellulose Hydroxypropylcellulose Ethylcellulose Valrubicin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudgragit RL 30D Valrubicin Polyethylene glycol 8000 Ethylcellulose Tretinoin Polyethylene glycol 4000 Polyethylene glycol 2000 Eudragit RL 30D Tretinoin Polyethylene glycol 8000 Ethylcellulose 75% (W/W) 80% (W/W) 75% (W/W) 75% (W/W) 75% (W/W) Enteric Release Component (Cancer) 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.

Ingredient Cone. W/W) Example 202: Example 203: Example 204: Example 205: Example 206: Example 207: Example 208: Example 209: Fluorouracil Microcrystal.line cellulose Cellulose Acetate Pthalate Fluorouracil Microcrystalline cellulose Cellulose Acetate Pthalate Hydroxypropylmethylcellulose Fluorouracil Polyox Hydroxypropylcellulose pthalate Eudragit L30D Fluorouracil Polyethylene glycol 2000 Eudragit L. 30D Eudragit RL 30D Fluorouracil Mi crocrystal line Cellulose Cellulose Acetate Pthalate Dexamethasone Hydroxypropylcellulose pthalate Croscarmellose sodium Dexamethasone Eudragit L 30D Hydroxypropylcellulose Ethylcellulose Dexamethasone Polyethylene glycol 2000 Eudragit L 30D 65% 55% (WIW) 65% (W/Wr) 7 5 %(WIW) 40% (W/W) 70% (WMW 70% (WIW) 75% (WIW) 40% (W/W) 65% (W/W) Example 2 Dexamethasone Lactose Eudgragit L 30D Example 211: Valrubicin Example 212: Example 213: Example 214: Example 215: Example 216: Microcrystalline Cellulose Eudragit L Valrubicin Microcrystalline Cellulose Hydroxypropylcellulose pthalate Valrubicin Lactose Eudragit L 30D Valrubicin Polyethylene glycol 4000 Cellulose acetate pthalate Tretinoin Polyethylene glycol 2000 Lactose Eudragit L 30D Tretinoin Microcrystalline cellulose Cellulose acetate pthalate 75% (W/W) 80% (W/W) 70% (W/W) 60% (W/W) 70% (W/W) Sustained Release Component (Cancer) 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 Example 217: Cone. W/W) 65% (W/W) Fluorouracil Ethylcellulose Polyox Hydroxypropylmethylcellulose Example 218: Example 219: Example 220: Fluorouracil Lactose Polyox Glyceryl monooleate Fluorouracil Polyox Hydroxypropyl cellulose Dexamethasone Lactose Hydroxypropyl cel lu lose Ethylcellulose Example 22 1: Example 222: Example 223: Example 224: Example 225: Dexamethasone Polyethylene glycol 4000 Lactose Eudragit RL 30D Dexamethasone Polyethylene glycol 8000 Hydroxypropylmethyl cell ul ose Eudgragit RS 30D Vairubicin Hydroxyethyl cellulose Polyethylene glycol 4000 Hydroxypropyl cellulose Valrubicin Lactose Poyidone (PVP) Polyethylene glycol 2000 Tretinoin Polyethylene glycol 4000 Povidone (PVP) Hydroxypropylcellulose 55% (W/W) 70% (WIW) 75% (W/W) 75% (WMW 80% (WIW) 75% (W/W) 75% (WIW) 75% (W/W) Example 226: Tretinoin Lactose Polyethylene glycol 4000 Polyvinylpyrrolidone Example 227: Example 228: Example 229: Dexamethasone Eudragit S100 Triethyl Citrate Dexamethasone Sureteric Dexamethasone Eudragit S100 Triethyl Citrate 75% (W/W) 40% (W/W) 50% (W/W) 50% (W/W) Three Pulses Example 230.

1. Metronidazole Matrix Pellet Formulation and Preparation Procedure (Immediate Release) A. Pellet Formulation The composition of the metronidazole matrix pellets provided in Table 1.

Table 1 Composition of Metronidazole Pellets Component Percentage Metronidazole Avicel PH 101 Lactose PVP K29/32* Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

B. Preparation Procedure for Metronidazole Matrix Pellets 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.

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

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

1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

1.2.5 Dry the spheronized pellets at 50C overnight.

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

1.1 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 metronidazole 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 Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9 B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 1.2.7 Suspend triethyl citrate and talc in deionized water.

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

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

1.2.10 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets.

1.3 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion A. Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the metronidazole 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 Purified Water 65.9 Part B Talc Purified Water Solid Content 20.0 Polymer Content 12.0 B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part 1: Dispense Eudragit® S 100 powder in deionized water with stirring.

(ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

(iii) Allow the partially neutralized dispersion to stir for 60 minutes.

(iv) Add triethyl citrate drop-wise into the dispersion with stirring.

Stir for about 2 hours prior to the addition of Part B.

Part II: 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.

1.4 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used to coat matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.

Coating Equipment STREA I T 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 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

(ii) Coat matrix pellets with S100 dispersion such that you apply coat weight gain to the pellets.

Encapsulation of the Metronidazole Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 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 total dose of 375mg/capsule.

Three Pulses Example 231 Amoxicillin Pellet Formulation and Preparation Procedure 231.1 Pellet Formulations for subsequent coating The composition of the Amoxicillin trihydrate matrix pellets provided in Table 4.

Table 4 Composition of Amoxicillin Matrix Pellets Component Percentage Amoxicillin Trihydrate powder 92 Avicel PH 101 Hydroxypropyl methylcellulose, NF* Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

231.2 Preparation Procedure for Amoxicillin Matrix Pellets 231.2.1 blender.

231.2.2 231.2.3 231.2.4 Blend Amoxicillin and Avicel® PH 101 using a low shear Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

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

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

231.2.5 231.2.6 Dry the spheronized pellets at 60 0 C using a fluid bed dryer until the exhaust temperature reaches 40 0

C.

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

231.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 231.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table Table 5 Eudragit® L 30 D-55 Aqueous Coating Dispersion Component Percentage Eudragit® L 30 D-55 41.6 Triethyl Citrate Talc Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5 231.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 231.4.1 Suspend triethyl citrate and talc in deionized water.

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

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

231.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.

231.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 231.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 6.

Table 6 Eudragit® S 100 Aqueous Coating Dispersion Component Percentage Part A Eudragit® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate Water 64.9 Part B Talc Water 10.0 Solid Content 25.0 Polymer Content 10.0 231.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 231.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

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

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

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

Part B: 231.6.5 Disperse talc in the required amount of water 231.6.6 Stir the dispersion using an overhead laboratory mixer.

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

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

Coating Equipment STREA 1TM 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 231.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

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

231.8 Preparation of Amoxicillin Granulation (Immediate Release Component) for tabletting Table 7 Composition of Amoxicillin Granulation Avicel PH 101 Hydroxypropyl methylcellulose, NF* Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

231.8.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

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

231.8.3 Dry the granulation at 60 0 C using a fluid bed dryer until the exhaust temperature reaches 40 0

C.

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

231.9 Tabletting of the Amoxicillin Pellets Table 8 Composition of Amoxicillin Tablets Component Percentage Amoxicillin granules 32.5 Avicel PH 200 Amoxicillin L30D-55 coated pellets Amoxicillin S100 coated pellets Colloidal silicon dioxide Magnesium stearate Total 100 231.9.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

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

231.9.3 Compress the blend on a rotary tablet press.

231.9.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.

Three Pulses Example 232 Clarithromycin Pellet Formulation and Preparation Procedure 232.1 Pellet Formulation The composition of the clarithromycin matrix pellets provided in Table 1.

Table 9 Composition of Clarithromycin Pellets Component Percentage Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1 Silicified microcrystalline cellulose 14.6 Polyoxyl 35 Castor Oil* 1.7 Hydroxypropyl methylcellulose* Total 100 *Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.

232.2 Preparation Procedure for Clarithromycin Matrix Pellets 232.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.

232.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.

232.2.3 Add binder solution slowly into the powder blend under continuous mixing.

232.2.4 Granulate the powders in the high shear granulator with the binder solution.

232.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.2 mm.

232.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

232.2.7 Dry the spheronized pellets at 50 0 C overnight.

232.2.8 Pellets between 18 and 30 Mesh were collected for further processing.

232.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 232.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table Table 10 Eudragit® L 30 D-55 Aqueous Coating Dispersion Component Percentage Eudragit® L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1 Water 51.7 Solids Content 20.0 Polymer Content 12.1 232.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 232.4.1 Suspend triethyl citrate and talc in deionized water.

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

232.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 Dlatex dispersion while stirring.

232.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.

232.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 232.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the clarithromycin matrix pellets is provided below in Table 11.

Table 11 Eudragit® S 100 Aqueous Coating Dispersion Component Percentage Part A Eudragit® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate Water 64.9 Part B Talc Water 10.0 Solid Content 25.0 Polymer Content 10.0 232.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 232.6.1 232.6.2 232.6.3 Dispense Eudragit® S 100 powder in deionized water with stirring.

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

Allow the partially neutralized dispersion to stir for 60 minutes 232.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for minutes prior to the addition of Part B.

Part B: 232.6.5 Disperse talc in the required amount of water 232.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

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

232.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating the matrix pellets with each of the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.

Coating Equipment STREA ITM 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 1.6 Bar Pump Rate 2 gram per minute 232.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

232.7.2 Coat matrix pellets with S 100 dispersion such that you apply 37% coat weight gain to the pellets.

4. Capsules were filled with the uncoated pellets, the L3OD-55 coated pellets and SI 00 coated pellets in weight percentages of 30%:30%:40%, respectively to provide 250 mg. capsules.

64 Four pulses Example 233.

1 Metronidazole Matrix Pellet Formulation and Preparation Procedure 233..1 Pellet Formulation The composition of the metronidazole matrix pellets provided in Table 12.

Table 12 Composition of Metronidazole Pellets Component Percentage Metronidazole Avicel PH 101 Lactose PVP K29/32* Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.

233.2 Preparation Procedure for Metronidazole Matrix Pellets 233.2.1 233.2.2 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.

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

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

233.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

233.2.5 Dry the spheronized pellets at 50 0 C overnight.

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

233.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 233.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 13.

Table 13 Eudragit® L 30 D-55 Aqueous Coating Dispersion Component Percentage Eudragit® L 30 D-55 55.0 Triethyl Citrate 1.6 Talc Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9 233.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 233.4.1 Suspend triethyl citrate and talc in deionized water.

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

233.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 Dlatex dispersion while stirring.

233.4.4 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets.

233.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 233.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 14.

Table 14 Eudragit® S 100 Aqueous Coating Dispersion Component Percentage Part A Eudragit® S 100 12.0 1 N Ammonium Hydroxide 6.1 Triethyl Citrate Purified Water 65.9 Part B Talc Purified Water Solid Content 20.0 Polymer Content 12.0 233.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 233.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.

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

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

233.6.4 Add triethyl citrate drop-wise into the dispersion with stirring.

Stir for about 2 hours prior to the addition of Part B.

Part B: 233.6.5 Disperse talc in the required amount of water 233.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

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

233.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each of the Eudragit® L D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA I T M 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 233.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

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

233.7.3 Coat matrix pellets with S 100 dispersion such that you apply coat weight gain to the pellets.

233.8 Encapsulation of the Metronidazole Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 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 a total dose of 375mg/capsule.

Four Pulses Example 234 Amoxicillin Pellet Formulation and Preparation Procedure 234.1 Pellet Formulations The composition of the Amoxicillin trihydrate matrix pellets provided in Table Table 15 Composition of Amoxicillin Matrix Pellets Component Percentage Amoxicillin Trihydrate powder 92 Avicel PH 101 Hydroxypropyl methylcellulose, NF* Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

234.2 Preparation Procedure for Amoxicillin Matrix Pellets 234.2.1 blender.

234.2.2 234.2.3 234.2.4 234.2.5 234.2.6 Blend Amoxicillin and Avicel® PH 101 using a low shear Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing: Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.

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

Dry the spheronized pellets at 60 0 C using a fluid bed dryer until the exhaust temperature reaches 40 0

C.

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

234.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 234.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 16.

Table 16 Eudragit® L 30 D-55 Aqueous Coating Dispersion Component Percentage Eudragit® L 30 D-55 41.6 Triethyl Citrate Talc Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5 234.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 234.4.1 Suspend triethyl citrate and talc in deionized water.

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

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

234.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.

234.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 234.6 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 17.

Table 17 Eudragit® S 100 Aqueous Coating Dispersion Component Percentage Part A Eudragit® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate Water 64.9 Part B Talc Water 10.0 Solid Content 25.0 Polymer Content 10.0 234.7 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 234.7.1 234.7.2 234.7.3 234.7.4 Dispense Eudragit® S 100 powder in deionized water with stirring.

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

Allow the partially neutralized dispersion to stir for 60 minutes.

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

Part B: 234.7.5 Disperse talc in the required amount of water 234.7.6 Stir the dispersion using an overhead laboratory mixer.

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

234.8 Preparation of Aquacoat Coating Dispersion 234.8.1 Dispersion Formulation The composition of the aqueous Aquacoat dispersion applied to Amoxicillin L30 Dcoated pellets is provided below in Table 18.

Table 18 Component Percentage Aquacoat ECD 79.3 Hydroxypropyl methylcellulose 15.9 Dibutyl Sebacate 4.8 Purified Water (300g) 234.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel El solution by dispersing in water with continuous stirring.

234.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with stirring and continue to stir overnight.

234.9 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each of the Eudragit® L D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA 1TM 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 234.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim to achieve a 20% coat weight gain.

234.9.2 Coat another batch of Amoxicillin matrix pellets with L30 Ddispersion to achieve a 20% weight gain. Coat the L30 Dpellets with the Aquacoat Dispersion to achieve a 10% coat weight gain.

234.9.3 Coat Amoxicillin matrix pellets with S 100 dispersion to achieve a 37% coat weight gain.

234.10 Preparation of Amoxicillin Granulation for tabletting Table 19 Composition of Amoxicillin Granulation (Immediate Release) Component Percentage Amoxicillin Trihydrate powder 92 Avicel PH 101 Hydroxypropyl methylcellulose, NF* Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

234.10.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.

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

234.10.3 Dry the granulation at 60 0 C using a fluid bed dryer until the exhaust temperature reaches 40 0

C.

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

234.11 Tabletting of the Amoxicillin Pellets Table 20 Composition of Amoxicillin Tablets Component Percentage Amoxicillin granules 32.5 Avicel PH 200 Amoxicillin L30D-55 coated pellets Amoxicillin Aquacoated pellets Amoxicillin S100 coated pellets Colloidal silicon dioxide Magnesium stearate Total 100 234.11.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.

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

234.11.3 Compress the blend on a rotary tablet press.

234.11.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.

Four Pulses Example 235 Clarithromycin Pellet Formulation and Preparation Procedure 235.1 Pellet Formulation The composition of the clarithromycin matrix pellets provided in Table 21.

Table 21 Composition of Clarithromycin Pellets Component Percentage Clarithromycin 50.6 Lactose monohydrate, spray dried 32.1 Silicified microcrystalline cellulose 14.6 Polyoxyl 35 Castor Oil* 1.7 Hydroxypropyl methylcellulose* Total 100 *Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.

235.2 Preparation Procedure for Clarithromycin Matrix Pellets 235.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.

235.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.

235.2.3 Add binder solution slowly into the powder blend under continuous mixing.

235.2.4 Granulate the powders in the high shear granulator with the binder solution.

235.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator was 1.2 mm.

235.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.

235.2.7 Dry the spheronized pellets at 50 0 C overnight.

235.2.8 Pellets between 18 and 30 Mesh were collected for further processing.

235.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 235.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 22.

Table 22 Eudragit® L 30 D-55 Aqueous Coating Dispersion Component Percentage Eudragit® L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1 Water 51.7 Solids Content 20.0 Polymer Content 12.1 235.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 235.4.1 Suspend triethyl citrate and talc in deionized water.

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

235.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 Dlatex dispersion while stirring.

235.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.

235.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 235.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S 100 dispersion applied to the clarithromycin matrix pellets is provided below in Table 23.

Table 23 Eudragit® S 100 Aqueous Coating Dispersion Component Percentage Part A Eudragit® S 100 10.0 1 N Ammonium Hydroxide 5.1 Triethyl Citrate Water 64.9 Part B Talc Water 10.0 Solid Content 25.0 Polymer Content 10.0 235.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A: 235.6.1 235.6.2 235.6.3 Dispense Eudragit® S 100 powder in deionized water with stirring.

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

Allow the partially neutralized dispersion to stir for 60 minutes 235.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for minutes prior to the addition of Part B.

Part B: 235.6.5 Disperse talc in the required amount of water 235.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.

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

235.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each of the Eudragit® L D-55 and Eudragit® S 100 aqueous film coatings.

Coating Equipment STREA T 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 1.6 Bar Pump Rate 2 gram per minute 235.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.

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

235.7.3 Coat matrix pellets with S 100 dispersion such that you apply 37% coat weight gain to the pellets.

235.8 Encapsulation of the Clarithromycin Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 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 a total dose of 250mg/capsule.

The antifungal, antiviral and antineoplastic dosage forms can be formulated into a single product (for example, a product containing three or four dosage forms of an antifungal) by a procedure similar to Examples 230-235, substituting the desired antifungal or antiviral or antineoplastic agent for the antibiotic.

The present invention is particularly advantageous in that there is provided an therapeutic product which provides an improvement over twice a day administration of the therapeutic and an improvement over a once a day administration of the therapeutic.

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

Claims (24)

1. A once-a-day therapeutic product comprising: first, second, and third therapeutic dosage forms, each of said therapeutic dosage forms comprising at least one 00 therapeutic agent and a pharmaceutically acceptable carrier, said first therapeutic dosage form being an immediate release dosage form, said second and third therapeutic dosage forms being delayed release dosage forms, and wherein each of said first, second, and N third therapeutic dosage forms initiates release at different times and Cmax,, of the total therapeutic agent released from said therapeutic product is achieved in less than about 12 N, hours from administration; said once-a-day therapeutic product contains the total dosage of the at least one therapeutic agent for a twenty-four hour period; and said at least one Stherapeutic agent is selected from the group consisting of antibiotics, anti-fungals, anti- virals and anti-neoplastics.

2. The product of Claim 1, wherein the Cmax for the product is reached no earlier than four hours after administration.

3. The product of claim 1, wherein the therapeutic agent released from the first dosage form reaches a within from about 0.5 hours to about 2 hours after administration of the product.

4. The product of claim 1, wherein the therapeutic agent released from the second dosage form reaches a Cmax,, in no more than about 4 hours after administration of the product.

The product of claim 1, wherein the therapeutic agent released from the third dosage form reaches a Cmax within 8 hours after administration of the product.

6. The product of any one of claims 1 to 5, wherein the immediate release dosage form contains at least 20% and no more than 50% of the total dosage of therapeutic agent.

7. The product of any one of claims 1 to 6, wherein the product is an oral dosage form.

8. The product of Claim 1, wherein the therapeutic agent released from the second dosage form reaches a Cma, after is reached for the therapeutic agent released from the first dosage form.

9. The product of Claim 1, wherein the therapeutic agent released from the third dosage form reaches a after Cmax is reached for the therapeutic agent released from the second dosage form.

The product of Claim 1 further comprising a fourth therapeutic dosage form, said fourth therapeutic dosage form being a delayed release dosage form and comprising 1185531 I:JJP 83 00 oO at least one therapeutic agent and a pharmaceutically acceptable carrier and wherein said at least one therapeutic agent released from said fourth therapeutic dosage form reaches a Cma,, after C,,,mx is achieved for therapeutic agent released from each of said first, second, 00 and third dosage forms.

11. The product of claim 10, wherein the Cmax for the product is reached no earlier than four hours after administration.

12. The product of claim 10, wherein the therapeutic agent released from the first dosage form reaches a Cmax within from about 0.5 hours to about 2 hours after N administration of the product.

13. The product of claim 10, wherein the therapeutic agent released from the second dosage form reaches a Cmax,, in no more than about 4 hours after administration of the product.

14. The product of claim 10, wherein the therapeutic agent released from the third dosage form reaches a Cmax within 8 hours after administration of the product.

15. The product of claim 10, wherein said second dosage form initiates release of said therapeutic agent before said third dosage form, wherein said third dosage form initiates release of said therapeutic agent before said fourth dosage form, wherein said second dosage form provides 20% to 35% by weight of the total therapeutic agent released by said second, third, and fourth dosage forms, wherein said third dosage form provides from 20% to 40% by weight of the total therapeutic agent released by said second, third, and fourth dosage forms, and wherein said fourth dosage form provides the remainder of the total therapeutic agent released by said second, third, and fourth dosage forms.

16. The product of any one of claims 10 to 15, wherein the product is an oral dosage form.

17. The product of claim 10, wherein the therapeutic agent released from the second dosage form reaches a Cmax after Cmax is reached for the therapeutic agent released from the first dosage form.

18. The product of claim 10, wherein the therapeutic agent released from the third dosage form reaches a Cmax after Cmax is reached for the therapeutic agent released from the second dosage form.

19. A method for treating either an infection or a cancer in a host comprising: administering to a host the therapeutic product of any one of claims 1 to 18, once-a-day. A once-a-day therapeutic product comprising: first, second, and third therapeutic dosage forms, each of said therapeutic dosage forms comprising at least one 11855311 :JJP -84- 00 0 therapeutic agent and a pharmaceutically acceptable carrier, said first therapeutic dosage N form being an immediate release dosage form, said second and third therapeutic dosage forms being delayed release dosage forms, and wherein each of said first, second, and 00 third therapeutic dosage forms initiates release at different times and Cmax of the total therapeutic agent released from said therapeutic product is achieved in less than about 12 hours from administration; said once-a-day therapeutic product contains the total dosage of the at least one therapeutic agent for a twenty-four hour period; and said at least one therapeutic agent is selected from the group consisting of antibiotics, anti-fungals, c antivirals and antineoplastics substantially as hereinbefore described with reference to any io one of the examples.

C

21. The product of any one of claims 1 to 18, wherein said therapeutic agent is an antibiotic.

22. The product of claim 21, wherein said antibiotic is selected from the group consisting of: levofloxacin, metronidazole, erythromycin, clarithromycin, fluroquinilone, ciprofloxacin, cefuroxime, cefpodoxime, penicillin, amoxicillin, and dicloxacillin.

23. The product of claim 22, wherein said antibiotic is amoxicillin.

24. A method for treating an infection in a host comprising: administering to a host the therapeutic product of any one of claims 21 to 23. Dated 7 April, 2008 Advancis Pharmaceutical Corporation Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 1185531 1:JJP