CA2400784C - Therapeutic product, use and formulation thereof - Google Patents

Abstract

A therapeutic product comprising: a first therapeutic dosage form, a second therapeutic dosage form, and a third therapeutic dosage form, each of said first, second and third therapeutic dosage forms comprising at least one therapeutic agent and a pharmaceutically acceptable carrier, said three dosage forms having different release profiles, said therapeutic product reaching a C max in less than about twelve hours wherein said therapeutic is an antibiotic, an anti-fungal, an anti-viral or an anti-neoplastic agent.</SDOA B>

Description

THERAPEUTIC PRODUCT, USE AND FORMULATION THEREOF

This invention relates to an therapeutic product, as well as the use and formulation thereof.

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 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.

In accordance with one aspect of the present invention, there is provided a pharmaceutical product which is comprised of at least two, preferably at least three, dosage forms, each comprised of at least one therapeutic agent and a pharmaceutically acceptable carrier. Such dosage forms are formulated so that each of the dosage forms has a different release profile. 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.

In a particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each of which 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 an aspect of the present invention, there is provided a single or unitary therapeutic product that has contained therein at least two, preferably at least three therapeutic dosage forms, each of which has a different release profile, whereby the therapeutic contained in each of such dosage forms is released at different times.

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 a preferred embodiment, 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, the maximum serum concentration of the total therapeutic released from the therapeutic product is achieved no earlier than four hours after administration.

In accordance with one preferred embodiment of the invention, there are at least three 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 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 non-pH 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 achieves a Cmax (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 Cma,, in the serum, and the therapeutic released from the third dosage form achieves a CJ. in the serum after the Cmax 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 Cmax 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 C,,,ax for the therapeutic released therefrom in no more than about four hours. In general, the Cmax for such second dosage form is achieved no earlier than two hours after administration of the therapeutic product; however, it is possible within the scope of the invention to achieve C,,,ax in a shorter period of time.

As hereinabove indicated, the therapeutic product may contain at least three or at least four or more different dosage forms. For example, if the therapeutic product includes a third dosage form, the therapeutic released therefrom reaches a Cmax at a time later than the C,,,ax 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, CIõax 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 C,,,ax at a different time.

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

In a preferred embodiment, the therapeutic product is a once a day product, whereby after administration of the therapeutic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of 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 Cmax 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 anti-virals, 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 Cmax of the fourth dosage form of the at least four dosage forms is reached after the Cmax of each of the other dosage forms is reached, 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 WO 01/62229 PCT/USOl/05758 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 25%
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 30%), 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 60%
(W/W).

In addition, it may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration. These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glviceryl 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% (WIW).
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, PolyoxTM), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (EudragitTM), propylene glycol, and ethylcellulose.

Typically these materials can be present in the range of 0.5-25% (W/W) 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% (W/W).

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,hydroxypropylmethyl cellulose,hydroxypropylcellul ose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, CarbopolTM, or polyethylene glycols with molecular weights in excess of 8,000 daltons.

These materials can be present in concentrations from 4-20% (W/W).

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, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefinetazole, 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 clavulanate 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 HC 1 and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine, sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, co-triamoxazole, 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, carbol-fuchsin, clioquinol, methylrosaniline chloride, sodium thiosulfate, sulconazole nitrate, terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and undecylenate salts (calcium undecylenate, copper undecylenate, zinc undecylenate) WO 01/62229 PCT/USOi/05758 The following are representative examples of some antivirals that may be used in the invention: Acyclovir, Amantadine, Amprenavir, Cidofovir, Delavirdine, Didanosine, Famciclovir, Foscarnet, 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, melphalan hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine hydrochloride, carmustine, lomustine, streptozocin, polifeprosan 20, dexrazoxane, dronabinol, granisetron hydrochloride, fluconazole, erythropoietin, octreotide acetate, pilocarpine hydrochloride, etidronate disodium, pamidronate disodium, allopurinol sodium, amifostine, filgrastim, mesna, ondansetron hydrochloride, dolasetron mesylate, leucovorin calcium, sargramostim, levamisole hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, mitomycin, daunorubicin citrate, plicamycin, daunorubicin hydrochloride, bleomycin sulfate, mitoxantrone hydrochloride, valrubicin, 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, vinblastine 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, methylprednisolone sodium succinate, betamethasone sodium phosphate, betamethasone acetate, letrozole, mithramycin, mitotane, pentostatin, perfosfamide, raloxifene In accordance with another aspect of the present invention there is provided a procedure or regimen for treating a patient with a therapeutic agent that is an antibiotic, anti-viral, anti-fungal or anti-neoplastic agent by injection thereof that provides results similar to those achieved by the use of a product as hereinabove described that includes at least two and preferably 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 wherein 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; i.e., 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 Conc. (% W/W) Example 1:
Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5 Example 2:
Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10 Example 3:
Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 4:
Amoxicillin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 5:
Amoxicillin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 6:
Clarithromycin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 7:
Clarithromycin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 8:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 9:
Clarithromycin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 10:
Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 11:
Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 12:
Ciprofloxacin 75% (W/W) Polyethylene glyco14000 10 Polytheylene glyco12000 10 Hydroxypropylcellulose 5 Example 13:
Cirpofloxacin 75% (W/W) Polyethylene glyco18000 20 Polyvinylpyrrolidone 5 Example 14:
Ceftibuten 75% (W/W) Polyethylene glyco14000 10 Polyethylene glyco12000 10 Hydroxypropylcellulose 5 Example 15:
Ceftibuten 75% (W/W) Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5 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.

In reg dient Conc. (% W/W) Example 16:
Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5 Example 17:
Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example 18:
Amoxicillin 65% (W/W) Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 19:
Clarithromycin 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Enteric Release Component (Antibiotic) 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 20:
Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 21:
Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 22:
Amoxicillin 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5 Example 23:
Amoxicillin 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10 Example 24:
Clarithromycin 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 25:
Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15 Example 26:
Clarithromycin 40% (W/W) Lactose 50 Eudgragit L 30D 10 Example 27:
Ciprofloxacin 65% (W/W) Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 28:
Ciprofloxacin 75% (W/W) Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example 29:
Ciprofloxacin 80% (W/W) Lactose 10 Eudgragit L 30D 10 Example 30:
Ciprofloxacin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 31:
Ceftibuten 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 Eudragit L 30D 10 Example 32:
Ceftibuten 70% (W/W) Microcrystalline cellulose 20 Cellulose acetate pthalate 10 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 Conc. (% W/W) Example 33:
Amoxicillin 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 34:
Amoxicillin 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 35:
Amoxicillin 70% (W/W) Polyox 20 Hydroxypropylcellulose 10 Example 36:
Clarithromycin 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 37:
Clarithromycin 75% (W; W) Polyethylene glycol 4000 10 Lactose 10 Eudragit RL 30D 5 Example 38:
Clarithromycin 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5 Example 39:
Ciprofloxacin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 40:
Ciprofloxacin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene glyco12000 5 Example 41:
Ceftibuten 75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example 42:
Ceftibuten 75% (W/W) Lactose 15 Polyethylene glycol 4000 5 Polyvinylpyrrolidone 5 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 43:
Fluconazole 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5 Example 44:
Fluconazole 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10 Example 45:
Fluconazole 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 46:
Fluconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 47:
Fluconazole 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 48:
Ketoconazole 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 49:
Ketoconazole 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 50:
Ketoconazole 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 51:
Ketoconazole 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 52:
Griseofulvin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 53:
Griseofulvin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 54:
Griseofulvin 75% (W/W) Polyethylene glyco14000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5 Example 55:
Cirpofloxacin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 56:
Terbinafine HCl 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 57:
Terbinafine HC1 75% (W/W) Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5 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 58:
Fluconazole 65% (W/W) Microcrvstalline cellulose 20 Polyox 10 Croscannellose sodium 5 Example 59:
Fluconazole 55% (W/W) Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example 60:
Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 61:
Ketoconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5 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) Example 62:
Fluconazole 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 63:
Fluconazole 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 64:
Fluconazole 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5 Example 65:
Fluconazole 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10 Example 66:
Ketoconazole 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 67:
Ketoconazole 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 15 Example 68:
Ketoconazole 40% (W/W) Lactose 50 Eudgragit L 30D 10 Example 69:
Griseofulvin 65% (W/W) Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 70:
Griseofulvin 75% (W/W) Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example 71:
Griseofulvin 80% (W/W) Lactose 10 Eudragit L. 30D 10 Example 72:
Griseofulvin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 73:
Terbinafine HC1 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 Eudragit L 3 OD 10 Example 74:
Terbinafine HC1 70% (W/W) Microcrystalline cellulose 20 Cellulose acetate pthalate 10 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 75:

Fluconazole 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 76:
Fluconazole 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 77:
Fluconazole 70% (W/W) Polyox 20 Hydroxypropylcellulose 10 Example 78:
Ketoconazole 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 79:
Ketoconazole 75% (W/W) Polyethylene glyco14000 10 Lactose 10 Eudragit RL 30D 5 Example 80:
Ketoconazole 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5 Example 81:
Griseofulvin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 82:
Griseofulvin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene glycol 2000 5 Example 83:
Terbinafine HCI 75% (W; W) Polyethylene glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example 84:
Terbinafine HCI 75% (W/W) Lactose 15 Polyethylene glycol 4000 5 Polyvinylpyrrolidone 5 Example 85:
Ketoconazole 40% (W/W) Eudragit S 100 50 Triethyl Citrate 10 Example 86:
Ketoconazole 50% (W/W) Sureteric 50 Example 87:
Ketoconazole 50% (W/W) Eudragit S 100 45 Triethyl Citrate 5 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.

In redient Conc. (% W/W) Example 88:
Acyclovir 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5 Example 89:
Acyclovir 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10 =

Example 90:
Acyclovir 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 91:
Acyclovir 75% (W/W) Polyethylene glyco14000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 92:
Acyclovir 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 93:
Zidovudine 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 94:
Zidovudine 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 95:
Zidovudine 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 96:
Zidovudine 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 97:
Valacyclovir 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 98:
Valacyclovir 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 99:
Valacyclovir 75% (W/W) Polyethylene glyco14000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5 Example 100:
Cirpofloxacin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 101:
Ribavirin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 102:
Ribavirin 75% (W/W) Polyethylene Glyco14000 20 Polyvinylpyrrolidone 5 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 Conc. (% W/W) Example 103:
Acyclovir 65% (W/W) Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5 Example 104:
Acyclovir 55% (W/W) Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example 105:
Acyclovir 65% (W/W) Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 106:
Zidovudine 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5 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 107:
Acyclovir 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 108:
Acyclovir 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 109:
Acyclovir 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit L30D 5 Example 110:
Acyclovir 40% (W/W) Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10 Example 111:
Zidovudine 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 112:
Zidovudine 75% (W/W) Polyethylene glycol 2000 10 Eudragit L. 30D 15 Example 113:
Zidovudine 40% (W/W) Lactose 50 Eudgragit L 30D 10 Example 114:
Valacyclovir 65% (W/W) Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 115:
Valacyclovir 75% (W/W) Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example 116:
Valacyclovir 80% (W/W) Lactose 10 Eudragit L. 30D 10 Example 117:
Valacyclovir 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 118:
Ribavirin 60% (W/W) Polyethylene glycol 2000 10 Lactose 20 Eudragit L 30D 10 Example 119:
Ribavirin 70% (W/W) Microcrystalline cellulose 20 Cellulose acetate pthalate 10 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 Conc. (% W/W) Example 120:
Acyclovir 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 121:
Acyclovir 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 122:
Acyclovir 70% (W/W) Polyox 20 Hydroxypropylcellulose 10 Example 123:
Zidovudine 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 124:
Zidovudine 75% (W/W) Polyethylene glyco14000 10 Lactose 10 Eudragit RL 30D 5 Example 125:
Zidovudine 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5 Example 126:
Valacyclovir 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5 Example 127:
Valacyclovir 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene glycol 2000 5 Example 128:
Ribavirin 75% (W/W) Polyethylene glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example 129:
Ribavirin 75% (W/W) Lactose 15 Polyethylene glyco14000 5 Polyvinylpyrrolidone 5 Example 130:
Zidovudine 40% (W/W) Eudragit S 100 50 Triethyl Citrate 10 Example 131:
Zidovudine 50% (W/W) Sureteric 50 Example 132:
Zidovudine 50% (W/W) Eudragit S 100 45 Triethyl Citrate 5 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 133:
Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Povidone 10 Croscarmellose sodium 5 Example 134:
Fluorouracil 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10 Example 135:
Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 136:
Fluorouracil 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 137:
Fluorouracil 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 138:
Dexamethasone 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 139:
Dexamethasone 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 140:
Dexamethasone 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 141:
Dexamethasone 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5 Example 142:
Valrubicin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 143:
Valrubicin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5 Example 144:
Valrubicin 75% (W/W) Polyethylene glyco14000 10 Polytheylene glyco12000 10 Hydroxypropylcellulose 5 Example 145:
Cirpofloxacin 75% (W/W) Polyethylene glyco18000 20 Polyvinylpyrrolidone 5 Example 146:
Tretinoin 75% (W/W) Polyethylene glyco14000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5 Example 147:
Tretinoin 75% (W/W) Polyethylene Glycol 4000 20 Polyvinylpyrrolidone 5 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 Conc. ( /a W/W) Example 148:
Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5 Example 149:
Fluorouracil 55% (W/W) Microcrystalline cellulose 25 Polyox 10 Glyceryl monooleate 10 Example 150:
Fluorouracil 65% (W/W) Polyox 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 151:
Dexamethasone 70% (W/W) Polyox 20 Hydroxypropylcellulose 5 Croscarmellose sodium 5 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 Conc. (% W/W) Example 152:

Fluorouracil 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15 Example 153:
Fluorouracil 55% (W/W) Microcrystalline cellulose 25 Cellulose Acetate Pthalate 10 Hydroxypropylmethylcellulose 10 Example 154:
Fluorouracil 65% (W/W) Polyox 20 Hydroxypropylcellulose pthalate 10 Eudragit I:_30D 5 Example 155:
Dexamethasone 70% (W/W) Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10 Example 156:
Dexamethasone 70% (W/W) Eudragit I., 30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5 Example 157:
Dexamethasone 75% (W/W) Polyethylene glycol 2000 10 Eudragit L 30D 15 Example 158:
Dexamethasone 40% (W/W) Lactose 50 Eudgragit 1, 30D 10 Example 159:
Valrubicin 65% (W/W) Microcrystalline Cellulose 20 Eudragit I. 30D 10 Example 160:
Valrubicin 75% (W/W) Microcrystalline Cellulose 15 Hydroxypropylcellulose pthalate 10 Example 161:
Valrubicin 80% (W/W) Lactose 10 Eudragit L 30D 10 Example 162:
Valrubicin 70% (W/W) Polyethylene glycol 4000 20 Cellulose acetate pthalate 10 Example 163:
Tretinoin 60% (W/W) Polyethylene glyco12000 10 Lactose 20 Eudragit L 30D 10 Example 164:
Tretinoin 70% (W/W) Microcrystalline cellulose 20 Cellulose acetate pthalate 10 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 Conc. (% W/W) Example 165:
Fluorouracil 65% (W/W) Ethylcellulose 20 Polyox 10 Hydroxypropylmethylcellulose 5 Example 166:
Fluorouracil 55% (W/W) Lactose 25 Polyox 10 Glyceryl monooleate 10 Example 167:
Fluorouracil 70% (W/W) Polyox 20 Hydroxypropylcellulose 10 Example 168:
Dexamethasone 75% (W/W) Lactose 15 Hydroxypropylcellulose 5 Ethylcellulose 5 Example 169:
Dexamethasone 75% (W/W) Polyethylene glyco14000 10 Lactose 10 Eudragit RL 30D 5 Example 170:
Dexamethasone 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellul.ose 5 Eudgragit RS 30D 5 Example 171:
Valrubicin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glyco14000 10 Hydroxypropylcellulose 5 Example 172:
Valrubicin 75% (W/W) Lactose 10 Povidone (PVP) 10 Polyethylene glycol 2000 5 Example 173:
Tretinoin 75% (W/W) Polvethylene glycol 4000 10 Povidone (PVP) 10 Hydroxypropylcellulose 5 Example 174:
Tretinoin 75% (W/W) Lactose 15 Polyethylene glyco14000 5 Polyvinylpyrrolidone 5 Example 175:
Dexamethasone 40% (W/W) Eudragit S 100 50 Triethyl Citrate 10 Example 176:
Dexamethasone 50% (W/W) Sureteric 50 Example 177:
Dexamethasone 50% (W/W) Eudragit S 100 45 Triethyl Citrate 5 Three Pulses Example 178.

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 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
B. Preparation Procedure for 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 SPH2O Caleva Spheronizer.
1.2.5 Dry the spheronized pellets at 50 C overnight.

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

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 8.0 Purified Water 37.4 Solids Content 25.5 Polymer Content 15.9 B. Preparation Procedure for an Eudragit L 30 D-55 Aqueous Dispersion 1.2.7 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 Eudragit0 S 100 Aqueous Coating Dispersion A. Dispersion Formulation The composition of the aqueous Eudragit0 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 6.0 Purified Water 65.9 Part B

Talc 2.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0 B. Preparation Procedure for an Eudragit S 100 Aqueous Dispersion Part I:
(i) Dispense Eudragit S 100 powder in deionized water with stirring.
(ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
(iii) Allow the partially neutralized dispersion to stir for 60 minutes.
(iv) Add triethyl citrate drop-wise into the dispersion with stirring.
Stir for about 2 hours prior to the addition of Part B.

Part II:
(i) Disperse talc in the required amount of water (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.
(iii) Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
1.4 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 1 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 (i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
(ii) Coat matrix pellets with S 100 dispersion such that you apply 20% coat weight gain to the pellets.

1.5 Encapsulation of the Metronidazole Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%:
40%:
Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S 100 coated pellets respectively.
The capsule is filled with the three different pellets to achieve a total dose of 375mg/capsule.

Three Pulses Example 179 Amoxicillin Pellet Formulation and Preparation Procedure 179.1 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 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

179.2 Preparation Procedure for Amoxicillin Matrix Pellets 179.2.1 Blend Amoxicillin and Avicel0 PH 101 using a low shear blender.

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

179.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
179.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.

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

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

179.3 Preparation of an Eudragit0 L 30 D-55 Aqueous Coating Dispersion 179.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 5.

Table 5 Eudragit0 L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit0 L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0 Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5 179.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion 179.4.1 Suspend triethyl citrate and talc in deionized water.
179.4.2 The TEC/taic suspension is mixed using laboratory mixer.
179.4.3 Add the TEC/talc suspension from slowly to the Eudragit0 L

30 D-55 latex dispersion while stirring.
179.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.

179.5 Preparation of an Eudragit S 100 Aqueous Coating Dispersion 179.5.1 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 5.0 Water 64.9 Part B

Talc 5.0 Water 10.0 Solid Content 25.0 Polymer Content 10.0 179.6 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion Part A:

179.6.1 Dispense Eudragit S 100 powder in deionized water with stirring.

179.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
179.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
179.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.

Part B:
179.6.5 Disperse talc in the required amount of water 179.6.6 Stir the dispersion using an overhead laboratory mixer.
179.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
179.7 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 1T"" 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 179.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

179.7.2 Coat matrix pellets with S 100 dispersion such that you apply 37% coat weight gain to the pellets.
179.8 Preparation of Amoxicillin Granulation (Immediate Release Component) for tabletting Table 7 Composition of Amoxicillin Granulation Component Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

179.8.1 Blend Amoxicillin and Avicel PH 101 using a low shear blender.
179.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.

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

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

179.9 Tabletting of the Amoxicillin Pellets Table 8 Composition of Amoxicillin Tablets Component Percentage (%) Amoxicillin granules 32.5 Avicel PH 200 5.0 Amoxicillin L30D-55 coated pellets 30 Amoxicillin S 100 coated pellets 30 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 100 179.9.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
179.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
179.9.3 Compress the blend on a rotary tablet press.
179.9.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.

Three Pulses Example 180 Clarithromycin Pellet Formulation and Preparation Procedure 180.1 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* 1.0 Total 100 *Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.

180.2 Preparation Procedure for Clarithromycin Matrix Pellets 180.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.

180.2.2 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.

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

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

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

180.2.6 Spheronize the extrudate using a Model SPH2O Caleva Spheronizer.

180.2.7 Dry the spheronized pellets at 50 C overnight.

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

180.3 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion 180.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 10.

Table 10 Eudragit L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit0 L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1 Water 51.7 Solids Content 20.0 Polymer Content 12.1 180.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion 180.4.1 Suspend triethyl citrate and talc in deionized water.
180.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
180.4.3 Add the suspension from 4.2.2 slowly to the Eudragit0 L 30 D-55 latex dispersion while stirring.
180.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.

180.5 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion 180.5.1 Dispersion Formulation The composition of the aqueous Eudragit0 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 I N Ammonium Hydroxide 5.1 Triethyl Citrate 5.0 Water 64.9 Part B

Talc 5.0 Water 10.0 Solid Content 25.0 Polymer Content 10.0 180.6 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion Part A:
180.6.1 Dispense Eudragit S 100 powder in deionized water with stirring.
180.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.

180.6.3 Allow the partially neutralized dispersion to stir for 60 minutes 180.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for 60 minutes prior to the addition of Part B.

Part B:
180.6.5 Disperse talc in the required amount of water 180.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
180.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.

180.7 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 IT"' 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 180.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.

180.7.2 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 L30D-55 coated pellets and S100 coated pellets in weight percentages of 30%:30%:40%, respectively to provide 250 mg. capsules.

Four pulses Example 181.

1 Metronidazole Matrix Pellet Formulation and Preparation Procedure 181.1 Pellet Formulation The composition of the metronidazole matrix pellets provided in Table 12.
Table 12 Composition of Metronidazole Pellets Component Percentage (%) Metronidazole 50 Avicel PH 101 20 Lactose 20 PVP K29/32* 10 Purified Water Total 100 *PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
181.2 Preparation Procedure for Metronidazole Matrix Pellets 181.2.1 Blend metronidazole and Avicel0 PH 101 using a Robot Coupe high shear granulator.

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

65 "

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

181.2.4 Spheronize the extrudate using a Model SPH2O Caleva Spheronizer.

181.2.5 Dry the spheronized pellets at 50 C overnight.

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

181.3 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion 181.3.1 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 8.0 Puri fied Water 37.4 Solids Content 25.5 Polymer Content 15.9 181.4 Preparation Procedure for an Eudragit L 30 D-55 Aqueous Dispersion 181.4.1 Suspend triethyl citrate and talc in deionized water.
181.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
181.4.3 Add the TEC/talc suspension slowly to the Eudragit L 30 D-55 latex dispersion while stirring.
181.4.4 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets.

181.5 Preparation of an Eudragit S 100 Aqueous Coating Dispersion 181.5.1 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 6.0 Purified Water 65.9 Part B

Talc ?.0 Purified Water 8.0 Solid Content 20.0 Polymer Content 12.0 181.6 Preparation Procedure for an Eudragit0 S 100 Aqueous Dispersion Part A:
181.6.1 Dispense Eudragit0 S 100 powder in deionized water with stirring.
181.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
181.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
181.6.4 Add triethyl citrate drop-wise into the dispersion with stirring.
Stir for about 2 hours prior to the addition of Part B.

Part B:
181.6.5 Disperse talc in the required amount of water 181.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
181.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
181.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each of the Eudragit0 L
30 D-55 and Eudragit0 S 100 aqueous film coatings.

Coating Equipment STREA 1 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 181.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
181.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.

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

181.8 Encapsulation of the Metronidazole Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%:
20%: 30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12%
weight gain, L30D-55 coated pellets 30% weight gain and S 100 coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of 375mg/capsule.

Four Pulses Example 182 Amoxicillin Pellet Formulation and Preparation Procedure 182.1 Pellet Formulations The composition of the Amoxicillin trihydrate matrix pellets provided in Table 15.
Table 15 Composition of Amoxicillin Matrix Pellets Component Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.

182.2 Preparation Procedure for Amoxicillin Matrix Pellets 182.2.1 Blend Amoxicillin and Avicel PH 101 using a low shear blender.

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

182.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter of the screen of the Bench Top Granulator is 0.8 mm.
182.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.

182.2.5 Dry the spheronized pellets at 60 C using a fluid bed dryer until the exhaust temperature reaches 40 C.
182.2.6 Pellets between 20 and 40 Mesh were collected for further processing.

182.3 Preparation of an Eudragit0 L 30 D-55 Aqueous Coating Dispersion 182.3.1 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 Eudragit0 L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit0 L 30 D-55 41.6 Triethyl Citrate 2.5 Talc 5.0 Purified Water 50.9 Solids Content 20.0 Polymer Content 12.5 182.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion 182.4.1 Suspend triethyl citrate and talc in deionized water.
182.4.2 The TEC/taic suspension is mixed using laboratory mixer.
182.4.3 Add the TEC/taic suspension from slowly to the Eudragit0 L
30 D-55 latex dispersion while stirring.
182.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.

182.5 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion 182.6 Dispersion Formulation The composition of the aqueous Eudragit0 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 5.0 Water 64.9 Part B

Talc 2.0 Water 10.0 Solid Content 25.0 Polymer Content 10.0 182.7 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion Part A:
182.7.1 Dispense Eudragit S 100 powder in deionized water with stirring.
182.7.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
182.7.3 Allow the partially neutralized dispersion to stir for 60 minutes.
1822.7.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.

Part B:

182.7.5 Disperse talc in the required amount of water 182.7.6 Stir the dispersion using an overhead laboratory mixer.
182.7.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.

182.8 Preparation of Aquacoat Coating Dispersion 182.8.1 Dispersion Formulation The composition of the aqueous Aquacoat dispersion applied to Amoxicillin L30 D-55 coated 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) 182.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel E15) solution by dispersing in water with continuous stirring.
182.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with stirring and continue to stir overnight.
182.9 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each of the Eudragit0 L
30 D-55 and Eudragit0 S 100 aqueous film coatings.

Coating Equipment STREA 1 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 2-6 gram per minute 182.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim to achieve a 20% coat weight gain.

182.9.2 Coat another batch of Amoxicillin matrix pellets with L30 D-55 dispersion to achieve a 20% weight gain. Coat the L30 D-55 pellets with the Aquacoat Dispersion to achieve a 10% coat weight gain.
182.9.3 Coat Amoxicillin matrix pellets with S 100 dispersion to achieve a 37% coat weight gain.

182.10 Preparation of Amoxicillin Granulation for tabletting Table 19 Composition of Amoxicillin Granulation (Immediate Release) Component Percentage (%) Amoxicillin Trihydrate powder 92 Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0 Total 100 *Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
182.10.1 Blend Amoxicillin and Avicel PH 101 using a low shear blender.

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

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

182.10.4 Granules between 20 and 40 Mesh are collected for further processing.
182.11 Tabletting of the Amoxicillin Pellets Table 20 Composition of Amoxicillin Tablets Component Percentage (%) Amoxicillin granules 32.5 Avicel PH 200 5.0 Amoxicillin L30D-55 coated pellets 20 Amoxicillin Aquacoated pellets 20 Amoxicillin S 100 coated pellets 20 Colloidal silicon dioxide 1.5 Magnesium stearate 1.0 Total 100 182.11.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
182.11.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
182.11.3 Compress the blend on a rotary tablet press.
182.11.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.

Four Pulses Example 183 Clarithromycin Pellet Formulation and Preparation Procedure 183.1 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 Polyoxy135 Castor Oil* 1.7 Hydroxypropyl methylcellulose* 1.0 Total 100 *Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.

183.2 Preparation Procedure for Clarithromycin Matrix Pellets 183.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.

183.2.2 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.

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

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

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

183.2.6 Spheronize the extrudate using a Model SPH2O Caleva Spheronizer.

183.2.7 Dry the spheronized pellets at 50 C overnight.

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

183.3 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion 183.3.1 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 Eudragit0 L 30 D-55 Aqueous Coating Dispersion Component Percentage (%) Eudragit0 L 30 D-55 40.4 Triethyl Citrate 1.8 Talc 6.1 Water 51.7 Solids Content 20.0 Polymer Content 12.1 183.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion 183.4.1 Suspend triethyl citrate and talc in deionized water.
183.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
183.4.3 Add the suspension from 4.2.2 slowly to the Eudragit0 L 30 D-55 latex dispersion while stirring.
183.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.

183.5 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion 183.5.1 Dispersion Formulation The composition of the aqueous Eudragit0 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 5.0 Water 64.9 Part B

Talc 5.0 Water 10.0 Solid Content 25.0 Polymer Content 10.0 183.6 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion Part A:
183.6.1 Dispense Eudragit S 100 powder in deionized water with stirring.
183.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
183.6.3 Allow the partially neutralized dispersion to stir for 60 minutes 183.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for 60 minutes prior to the addition of Part B.
Part B:
183.6.5 Disperse talc in the required amount of water 183.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
183.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
183.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each of the Eudragit L
30 D-55 and Eudragit S 100 aqueous film coatings.

Coating Equipment STREA 1T"' 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 183.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
183.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.
183.7.3 Coat matrix pellets with S 100 dispersion such that you apply 37% coat weight gain to the pellets.

183.8 Encapsulation of the Clarithromycin Pellets Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%:
20%: 30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12%
weight gain, L30D-55 coated pellets 30% weight gain and S 100 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 (34)

CLAIMS:

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 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 third therapeutic dosage forms are for initiation of release at different times and Cmax of total therapeutic agent for administration from said therapeutic product is for delivery in less than about 12 hours from administration; wherein said once-a-day therapeutic product comprises a total dosage of the at least one therapeutic agent for a twenty-four hour period; and wherein said at least one therapeutic agent is selected from the group consisting of antibiotics, antifungals, antivirals, and antineoplastics.

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

3. The product of claim 1, wherein the at least one therapeutic agent for release from the first dosage form is for reaching a Cmax within from about 0.5 hours to about 2 hours after administration of the product.

4. The product of claim 1, wherein the at least one therapeutic agent for release from the second dosage form is for reaching a Cmax in no more than about 4 hours after administration of the product.

5. The product of claim 1, wherein the at least one therapeutic agent for release from the third dosage form is for reaching a Cmax within 8 hours after administration of the product.

6. The product of claim 1, wherein the immediate release dosage form comprises at least 20% and no more than 50% of the total dosage of the at least one therapeutic agent.

7. The product of claim 1, wherein the product is an oral dosage form.

8. The product of claim 1, wherein the at least one therapeutic agent for release from the second dosage form is for reaching a Cmax after Cmax for the at least one therapeutic agent for release from the first dosage form.

9. The product of claim 1, wherein the at least one therapeutic agent for release from the third dosage form is for reaching a Cmax after Cmax for the at least one therapeutic agent for release from the second dosage form.

10. 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 at least one therapeutic agent and a pharmaceutically acceptable carrier and wherein said at least one therapeutic agent for release from said fourth therapeutic dosage form is for reaching a Cmax after Cmax for the at least one therapeutic agent for release from each of said first, second, and third dosage forms.

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

12. The product of claim 10, wherein the at least one therapeutic agent for release from the first dosage form is for reaching a Cmax within from about 0.5 hours to about 2 hours after administration of the product.

13. The product of claim 10, wherein the at least one therapeutic agent for release from the second dosage form is for reaching a Cmax in no more than about 4 hours after administration of the product.

14. The product of claim 10, wherein the at least one therapeutic agent for release from the third dosage form is for reaching a Cmax within 8 hours after administration of the product.

15. The product of claim 10, wherein said second dosage form is for release of said at least one therapeutic agent in the second dosage form before the at least one therapeutic agent in said third dosage form, wherein said third dosage form is for release of said at least one therapeutic agent in the dosage form before the at least one therapeutic agent in said fourth dosage form, wherein said second dosage form is for provision of 20% to 35% by weight of the total at least one therapeutic agent for release by said second, third, and fourth dosage forms, wherein said third dosage form is for provision of from 20% to 401 by weight of the total at least one therapeutic agent for release by said second, third, and fourth dosage forms, and wherein said fourth dosage form is for provision of the remainder of the total at least one therapeutic agent for release by said second, third, and fourth dosage forms.

16. The product of claim 10, wherein the product is an oral dosage form.

17. The product of claim 10, wherein the at least one therapeutic agent for release from the second dosage form is for reaching a Cmax after Cmax is reached for the at least one therapeutic agent for release from the first dosage form.

18. The product of claim 10, wherein the at least one therapeutic agent for release from the third dosage form is for reaching a Cmax after Cmax for the at least one therapeutic agent for release from the second dosage form.

19. The product of claim 1, wherein each of said second and third delayed release dosage forms comprise an immediate release dosage form and at least one member selected from the group consisting of: pH-sensitive components and non-pH-sensitive components, for delay release of the at least one therapeutic agent.

20. The product of claim 1, wherein said at least one therapeutic agent is an antibiotic.

21. The product of claim 1, wherein said at least one therapeutic agent is an antifungal.

22. The product of claim 1, wherein said at least one therapeutic agent is an antiviral.

23. The product of claim 1, wherein said at least one therapeutic agent is an antineoplastic.

24. The product of any one of claims 1 to 23 for treating an infection or cancer in a host.

25. Use of the product defined in any one of claims 1 to 23 for treating an infection or cancer in a host.

26. A once-a-day antibiotic product comprising: first, second, and third antibiotic dosage forms, each of said antibiotic dosage forms comprising at least one antibiotic and a pharmaceutically acceptable carrier, said first antibiotic dosage form being an immediate release dosage form, said second and third antibiotic dosage forms being delayed release dosage forms, and wherein each of said first, second, and third antibiotic dosage forms is for initiation of release at different times and Cmax of the total antibiotic for administration from said antibiotic product is for delivery in less than about 12 hours from administration; and wherein said once-a-day antibiotic product comprises a total dosage of the at least one antibiotic for a twenty-four hour period.

27. The product of claim 26, wherein each of said second and third delayed release dosage forms comprise an immediate release dosage form and at least one member selected from the group consisting of: pH-sensitive components and non-pH-sensitive components, for delay of release of the therapeutic agent.

28. The product of claim 26 or 27, wherein said antibiotic is amoxicillin.

29. The product of claim 26 or 27, wherein said antibiotic is cephalexin.

30. The product of any one of claims 26 to 29 for treating an infection in a host.

31. Use of the product defined in any one of claims 26 to 29 for treating an infection in a host.

32. The product of any one of claims 1 to 20, 24, 26 and 27, wherein said antibiotic is selected from the group consisting of: levofloxacin, metronidazole, erythromycin, clarithromycin, fluroquinilone, ciprofloxacin, cefuroxime, cefpodoxime, penicillin, amoxicillin and dicloxacillin.

33. The product of claim 32 for treating an infection in a host.

34. Use of the product defined in claim 32 for treating an infection in a host.