JP2003523378A - Therapeutic agent products, their use and formulation - Google Patents

Abstract

  (57) [Summary] A therapeutic product comprising a first therapeutic dosage form, a second therapeutic dosage form, and a third therapeutic dosage form, wherein each of said first, second and third therapeutic dosage forms comprises at least one type of treatment. An agent and a pharmaceutically acceptable carrier, wherein the three dosage forms have different release profiles, the therapeutic product reaches Cmax in less than about 12 hours, and the therapeutic agent is an antibiotic, an antiviral A therapeutic agent product that is an agent, an antifungal or an anti-neoplastic agent.

Description

Detailed Description of the Invention

This invention relates to therapeutic agent products, and their uses and dosage forms. A wide variety of antibiotics, antibacterial, antiviral and antineoplastic agents have been and will be used to treat patients. Generally, such therapeutic agents are
It is administered by multiple dose immediate release dosage forms with inadequate compliance or as a higher dose controlled release dosage form (slow release). The present invention relates to providing improved therapeutic product.

According to one aspect of the present invention there is provided a medicament comprising at least two, preferably at least three dosage forms, each comprising at least one therapeutic agent and a pharmaceutically acceptable carrier. Such dosage forms are formulated so that each dosage form has a different release profile. As used in this application, the term "therapeutic
) ”Or“ therapeutic agent ”means an antibiotic, or an antifungal or antiviral or antineoplastic agent. In a particularly preferred embodiment, at least two, preferably at least three agents Have different release profiles, and each dosage form has a profile
The dosage form is such a profile that it begins to release the therapeutic agent contained in the dosage form at different times after administration of the therapeutic agent product.

Therefore, according to one aspect of the invention, at least two, preferably at least three dosage forms are included, each having a different release profile, whereby each of the dosage forms is released at different times. Single or unitary therapeutic agent products are provided. According to a further aspect of the invention, a therapeutic agent product comprising at least 4 different dosage forms, each dosage form releasing a therapeutic agent contained therein at a different time after administration of said therapeutic agent product. A therapeutic agent product is provided that begins. The therapeutic product generally does not contain more than 5 dosage forms with different release times. According to a preferred embodiment, the therapeutic product, when administered, has an overall release profile such that the maximum serum concentration of total therapeutic agent released from the product is reached in less than 12 hours, preferably less than 11 hours. Have. In one embodiment, the maximum serum concentration of total therapeutic agent released from the therapeutic product is reached as early as 4 hours after administration.

According to one preferred embodiment of the present invention, there are at least three dosage forms. One of the at least three dosage forms is an immediate release dosage form in which the onset of release of the therapeutic agent from the therapeutic agent product is not substantially delayed after administration of the therapeutic agent product. The second and third of the at least three dosage forms are protracted dosage forms (which may be pH sensitive or non-pH sensitive protracted dosage forms, depending on the type of therapeutic agent product), thereby The released therapeutic agent is delayed until after the onset of release of the therapeutic agent released from the immediate release dosage form. More specifically, the therapeutic agent released from the second dosage form of at least two dosage forms is that the therapeutic agent released from the first dosage form of at least three dosage forms is Cmax in serum.
Cmax (maximum serum concentration in serum) is continuously achieved, and the third
The therapeutic agent released from the dosage form achieves a serum Cmax after the Cmax of the therapeutic agent released from the second dosage form.

In one embodiment, the second dosage form of the at least two dosage forms initiates the release of the therapeutic agent contained in the second dosage form at least 1 hour after the first dosage form and starts from the second dosage form. The onset of the release of the drug usually occurs at most 6 hours after the onset of release of the therapeutic agent from the first dosage form of at least three dosage forms. Generally, an immediate release dosage form achieves a Cmax of therapeutic agent released from the dosage form within about 0.5 to about 2 hours, and a second dosage form of at least three dosage forms has a maximum of about about 3 Achieve the Cmax of the therapeutic agent released from the dosage form within 4 hours. Generally, the Cmax of the second dosage form is not reached more than 2 hours after administration of the therapeutic agent product; however, achieving Cmax in a short time is practicable within the scope of the present invention.

As mentioned above, the therapeutic product can include at least 3 or at least 4 or more dosage forms. For example, if the therapeutic product comprises a third dosage form,
The therapeutic agent released therefrom reaches Cmax in rapid succession after the Cmax is reached for the therapeutic agent released from each of the first and second dosage forms. In a preferred embodiment, the release of the therapeutic agent from the third dosage form begins after the release of the therapeutic agent from both the first and second dosage forms begins. In one embodiment, the C of the therapeutic agent released from the third dosage form.
The max is achieved within 8 hours. In another embodiment, the therapeutic product comprises at least 4 dosage forms, each at least 4 dosage form having a different release profile, thereby providing at least 4
The therapeutic agents released from each of the different dosage forms achieve Cmax at different times.

As mentioned above, in a preferred embodiment, the therapeutic agent is released from the therapeutic agent product regardless of whether it comprises at least two or at least three or at least four different dosage forms each having a different release profile. Cmax of all therapeutic agents
It is achieved in less than 12 hours, more preferably in less than 11 hours. In a preferred embodiment, the therapeutic product is a once daily product, whereby
After administration of the therapeutic product, no further product is administered during the day; that is, the preferred therapy is that the product is administered only once every 24 hours. Accordingly, the present invention provides a single dose therapeutic agent product in which the overall release of the therapeutic agent takes place with different release profiles such that the total Cmax of the therapeutic agent product is reached in less than 12 hours.
The term "single dose" means that all therapeutic agents administered during a 24 hour period are administered simultaneously, provided that they are administered essentially simultaneously, in a single tablet or capsule or It can be two or more.

The Applicant has found that a single dose therapeutic agent product comprising at least three therapeutic dosage forms each having a different release profile is a single dose therapeutic agent comprising a therapeutic dosage form having a single release profile. We found that there are improvements over the product. Each dosage form of the therapeutic agent in a pharmaceutically acceptable carrier may have one or more therapeutic agents of the same type (eg, one or more antibiotics; one or more antiviral agents, etc.), And each dosage form may have the same therapeutic agent or different therapeutic agents of the same type (same or different antibiotics; same or different antiviral agents etc.). Where a dosage form is described herein as starting release after another dosage form, such terms are designed so that the dosage form achieves a later initiated release. And should be understood to mean what is intended.
However, despite such design and intent, it is known in the art that some "leakage" of therapeutic agent can occur. Such a "leak" is not a "release" as used herein.

When at least four dosage forms are used, the fourth dosage form of the at least four dosage forms may be a sustained release dosage form or a delayed release dosage form. When the fourth dosage form is a sustained release dosage form, the Cmax of the fourth dosage form of at least four dosage forms is the Cmax of each of the other dosage forms.
The release of the therapeutic agent from the fourth dosage form may be initiated before or after the release from the second or third dosage form, even if it is reached after. As mentioned above, the therapeutic agent products of the present invention can be formulated for administration by various routes of administration. For example, a therapeutic product may be formulated in a suitable manner for topical administration; ocular or intraocular administration; rectal or vaginal administration; nasal drops; by inhalation; by injection; or by oral administration. In a preferred embodiment, the therapeutic product is formulated in a manner suitable for oral administration.

In the formulation of therapeutic agent products for topical administration, eg, for application to the skin, at least two different dosage forms, each containing a therapeutic agent, include the oil-in-water emulsion or the water-in-oil emulsion. It can thus be formulated for topical administration. In such dosage forms, the immediate release dosage form is in the continuous phase and the delayed release dosage form is in the discontinuous phase. This dosage form may also be realized in a manner for delivery of three dosage forms as described above. For example, an oil that is a continuous phase containing an immediate release component, water dispersed in an oil containing a first delayed release dosage form, and an oil dispersed in water containing a third delayed release dosage form. An oil-in-water-in-oil emulsion having can be provided. It is also within the scope of the present invention to provide a therapeutic agent product in the form of a patch comprising therapeutic dosage forms having different release profiles as described above.

Further, the therapeutic product may be formulated for use in the eye or ear or nose, for example as a liquid emulsion. For example, there may be a dosage form coated with a hydrophobic polymer and being in an oil phase state of an emulsion, and a dosage form coated with a hydrophilic polymer and being in an aqueous phase state of an emulsion. Further, therapeutic agent products having at least three different dosage forms with different release profiles can be formulated for rectal or vaginal administration as known in the art. It may take the form of a cream or emulsion or other soluble dosage form similar to those used for topical administration. In a further embodiment, the therapeutic product can be formulated for use in inhalation therapy by coating the particles and micronizing the inhalable particles.

In a preferred embodiment, the therapeutic product is formulated in a manner suitable for oral administration.
Thus, for example, for oral administration, each dosage form is used as a pellet or particle, which pellet or particle is embedded in, for example, a capsule, or in a tablet, or unit dosage form suspended in a liquid for oral administration. It is formed. Also, in the formulation of oral delivery systems, each dosage form of the product may be formulated as a tablet, and each tablet may be encapsulated to produce a unit therapeutic product. Thus, for example, a therapeutic agent product comprises a first dosage form in the form of a tablet that is an immediate release tablet, and also as described above, two or more additional tablets, each of which provides a delayed release of the therapeutic agent. Thereby, the Cmax of the therapeutic agent released from each tablet can be achieved at different times and the Cmax of all therapeutic agents released from the therapeutic agent product can be achieved in less than 12 hours. It is considered within the skill of the art, given the teachings herein, to formulate a therapeutic product comprising at least three dosage forms having different release profiles for different routes of administration. For delayed release, as is known in the art, the release time can be controlled by the concentration of therapeutic agent in the coating and / or the thickness of the coating.

When formulating a therapeutic product of the present invention, in one embodiment, the immediate release dosage form of the product typically comprises from about 20% to about 50% of the total dose of therapeutic agent delivered by the product. Offer to,
Such immediate release dosage forms typically provide at least 25% of the total dose of therapeutic agent delivered by the product. Often, immediate release dosage forms provide about 20% to about 30% of the total dose of therapeutic agent delivered by the product; however, about 45% of the total dose of therapeutic agent delivered by the product. In some cases it may be desirable to provide from about 50% to the immediate release dosage form. The remaining dosage form delivers the rest of the therapeutic agent. If more than one delayed release dosage form is used, in one embodiment, each delayed release dosage form may provide approximately equal amounts of therapeutic agent; however, formulated to provide different amounts. You may. In accordance with the present invention, each dosage form contains the same therapeutic agent; however, each dosage form may contain more than one therapeutic agent.

In one embodiment, when the composition contains one immediate release component and two delayed release components, the immediate release component is from 20% to 35% (preferably by weight) of the total therapeutic agent. Is 20
% To 30% by weight; when there are 3 delayed release components, the immediate release component provides 15% to 30% by weight of the total therapeutic agent; and 4 delayed release components. If present, the immediate release component provides 10% to 25% by weight of the total therapeutic agent. For delayed release components, if there are two delayed release components, the first delayed release component (the component that is released earlier in time) is the total therapeutic agent provided by the two delayed release components. 30% to 60% by weight of the second delayed release component to provide the rest of the therapeutic agent.

When there are three delayed release components, the earliest released component provides 20% to 35% by weight of the total therapeutic agent provided by the three delayed release components, and is temporal. The next delayed release component is 20% of all therapeutic agents provided by the three delayed release components.
% To 40% by weight and the time-delayed delayed release component provides the balance of the therapeutic agent provided by the three delayed release components. If there are four delayed release components, the earliest released component of all therapeutic agents provided by these four delayed release components provides 15% to 30% by weight, and Of the delayed release component of 15% to 30% by weight, the next delayed release component of time provides 20% to 35% by weight, and the last delayed release component of time is 20% to 35% by weight.
% To 35% by weight is provided.

Immediate Release Component The immediate release portion of the system may be a mixture of components that rapidly degrades after administration to release the therapeutic agent. It may take the form of separate pellets or granules that are mixed with the other three ingredients or compressed together. The substances added to the therapeutic agent for immediate release ingredients include, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium glycolate starch, hydroxypropyl cellulose, hydroxypropyl. Methylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylated chitosan, crosslinked chitosan, crosslinked hydroxymethylchitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, lebroth, sucrose, polyvinylpyrrolidone (PVP ), Acrylic acid derivatives (Carbopol, Eudragit, etc.), low molecular weight PEGs (PEG2000-1000) and high molecular weight PEGs with molecular weights above 20,000 daltons ( Polyox) may be a polyethylene glycol. It is useful for these substances to be present in the range of 1.0-60% (W / W).

In addition, it is useful to have other ingredients in the system to aid in dissolution of the drug or degradation of the components after ingestion or administration. These formulations include interfacial agents such as sodium dodecyl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate. Surfactants, nonionic surfactants such as Pluronic family of surfactants,
Or it may be another substance having surface-active properties, or a combination of any of the above. These substances may be present in a proportion of 0.05-15% (W / W).

Non-pH Sensitive Delayed Release Ingredient The ingredients in this composition are the same immediate release unit but additionally include a polymer in the composition or as a coating over the pellets or granules. Suitable materials for this component of the invention that can be used to obtain delayed release have, but are not limited to, molecular weights above 4,000 daltons (Carbowax, Polyox
) Polyethylene glycol (PEG), waxes such as white or beeswax, paraffins, acrylic acid derivatives (Eudragit), propylene glycol, and ethyl cellulose. Typically, these materials may be present in the range of 0.2-25% (W / W) of this component.

PH Sensitive (Enteric) Release Ingredient This ingredient in this composition is the same as the immediate release ingredient, but further polymer is included in the composition or as a coating to cover the pellets or granules. ing. Types of materials useful for this purpose can be, but are not limited to, cellulose acetate phthalate, Eudragit L, and other phthalates of cellulose derivatives. These substances may be present in concentrations of 4-20% (W / W).

Sustained Release Ingredient This ingredient in this composition is the same as the immediate release ingredient, but additionally a polymer is included in the composition or as a coating over the pellets or granules. Types of materials useful for this purpose include, but are not limited to, ethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, methyl cellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or 8,000 daltons. It can be a polyethylene glycol with a molecular weight above. These substances may be present in concentrations of 4-20% (W / W).

As mentioned above, the unit comprising the therapeutic composition of the present invention may be a separate pellet or particle contained in a capsule, or particles embedded in a tablet or suspended in a liquid buffer. Can be in the form of The therapeutic composition of the present invention can be administered by any administration route such as sublingual, transmucosal, transdermal, and parenteral administration, and is preferably orally administered. The composition comprises a therapeutically effective amount of a therapeutic agent, which will vary depending on the therapeutic agent used, the disease or infection being treated, and the number of times the composition is delivered daily. The composition is administered to the host in an amount effective to treat the disease or infection. Thus, the therapeutic composition or product can be used to treat infections in the host caused by bacteria or viruses or fungi, and can be used to treat cancer.

This system is particularly useful for extending the actual therapeutic activity of antibiotics having an elimination half-life of less than 20 hours, more preferably less than 12 hours, and especially 2-10 hours. It is useful for drugs having a half-life of. The following are examples of some antibiotics with half-lives of about 1 to 12 hours: cefadroxil, cefazolin, cephalexin, cephalotin, cephapirin, cephacerol, cefaprodil, cefadrine, cefamandole, cefonicid, ceforanide, cefuroxime, cefixime. , Cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibutene, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef
, Imipenem, erythromycin (and erythromycin salts such as estrate, ethyl succinate, gluceptate, lactobiomate, threarate)
, Azithromycin, clarithromycin, dilithromycin, troleanomycin, penicillin V, penicillin salt, and complex, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and potassium clavulanate, ampicillin, Bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin), mezlocillin, piperacillin, piperacillin and taxobactam, ticarcillin,
Ticarcillin and potassium clavulanate, clindamycin, vancomycin,
Novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin, sulfacitin, sulfamelazine,
Sulfamethazine, sulfamethoxol, sulfasalazine, sulfisoxazole, sulfapyridine, sulfadiazine, sulfamethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, cotriamoki Co-triamoxazole, pentamidine, and trimetrexa
te).

The following are representative examples of some antifungal agents that can be utilized in the compositions of the present invention: amphotericin B, flucytosine, fluconazole, griseofulvin, miconazole nitrate, terbinafine hydrochloride, ketoconazole, itraconazole, undecylenic acid and chloroxylenol. , Ciclopirox, clotrimazole, butenafine hydrochloride, nystatin, naphthifine hydrochloride, oxyconazole nitrate, selenium sulfide, econazole nitrate, terconazole, butoconazole nitrate, carbol-fuchsin, clioquinol, methylrosaniline hydrochloride, sodium thiosulfate, nitrate Sulconazole, terbinafine hydrochloride, thioconazole, tolnaftate, undecylenic acid and undecylenate (calcium undecylenate, copper undecylenate (I), Decylene acid zinc).

The following are representative examples of some antiviral agents that can be used in the present invention: acyclovir, amantadine, amprenavir, cidophobia, delavirdine, didanosine, famciclovir, foscarnet, ganciclovir, indinavir,
Interferon, lamivudine, nelfinavir, nevirapine, palivizumab (P
alivizumab), penciclovir, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, trifluidine, valacyclovir, vidarabine, salcitabine, zidovudine.

The following are representative examples of agents for the treatment of cancer that can be used according to the invention: carboplatin, busulfan, cisplatin, thiotepa, melphalan hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, mechlorethamine hydrochloride, carmustine, lomustine, Streptozocin, polyfeprozan 20, dexrazoxane, doeonavinol, granisetron hydrochloride, fluconazole, erythropoietin, octreotide acetate, pilocarpine hydrochloride, disodium etidronate, disodium pamidronate, sodium allopurinol, amifostine, filgrastim, mesna, on hydrochloride Dansetron, Doracetone Mesylate, Leucovorin Calcium, Sargramostatin, Levamisole Hydrochloride, Doxorubicin Hydrochloride, Idal Hydrochloride Singh, mitomycin, citric acid daunorubicin, plicamycin,
Daunorubicin hydrochloride, bleomycin sulfate, mitoxantrone hydrochloride, valrubicin, dactinomycin, fludarabine phosphate, cytarabine, mercaptopurine,
Thioguanine, sodium methotrexate, cladribine, floxouridine
(floxuridine), capecitabine, anastrozole, bicalutamide, tamoxifen citrate, goserelin acetate, estramustine phosphate phosphate, ethinyl estradiol, estrogen ester, leuprolide acetate, conjugated estrogen, megestrol acetate, aldesleukin, medroxyacetate. Progesterone, dacarbazine, hydroxyurea, etoposide phosphate, megestrol acetate, paclitaxel, etoposide, teniposide, trasutuzumab, rituximab, vinorelbine tartrate, denileukin diftitox (den)
ileukin diftitox), gemcitabine hydrochloride, vincristine sulfate, vinblastine sulfate, asparaginase, edrophonium chloride, bacillus calmette and guelin, irinotecan hydrochloride, pegaspargase, docetaxel, interferon alfa-2a, recombinant, tretinoin, porfimer sodium, interferon. Alpha-2b, recombinant, procarbazine hydrochloride, topotecan hydrochloride, altretamine, fluorouracil, brednisolone sodium phosphate, cortisone acetate, dexamethasone, dexamethasone sodium sulfate, dexamethasone acetate,
Hydrocortisone sodium phosphate, hydrocortisone, prednisolone, methylprednisolone sodium citrate, betamethasone sodium phosphate, betamethasone acetate, letrozole, mithramycin, mitotan, pentostatin, perfosfamide, raloxifene.

According to another aspect of the invention, at least two, preferably at least 3, by injecting a therapeutic agent which is an antibiotic, antiviral, antifungal or antineoplastic agent.
There is provided a method of treatment or therapy for a patient, which provides results similar to those obtained by using the above-mentioned products comprising different dosage forms. There is provided a procedure or therapy for treating a patient by injection thereof, which gives similar results as achieved by the use of a product as described above comprising at least 2, preferably at least 3 dosage forms . According to this aspect of the invention, a therapy for treating a patient with a therapeutic agent, wherein the therapeutic agent is administered by injection and the daily dose is less than 11 hours (time measured from the first injection). A therapy is provided that is delivered over time and has at least 2 delivery pulses, and at most 32 delivery pulses during a period of less than 11 hours, preferably less than 8 hours. As used herein, a "delivery pulse" is at least two discontinuous injections with an interval between injections, during which essentially no therapeutic agent is injected into the host, or Or between discontinuous injections means and is achieved by continuous injection of a therapeutic agent in an amount different from that injected by the discontinuous injections. Further, at least two delivery pulses can also be achieved by continuous injection of the drug at one dose and then at different doses. In such a case, there is a first continuous delivery pulse over time, and then a second continuous delivery pulse over time. Thus, for example, in the latter case, if there is an initial injection in which the therapeutic agent is administered sequentially over time, then increasing the dose of the therapeutic agent administered by injection over time may result in continuous administration of the therapeutic agent. , There are effectively two delivery pulses.

In one embodiment, there are at least two discontinuous injections of the therapeutic agent, and usually at most 32 discontinuous injections of the therapeutic agent, within less than 11 hours. There may or may not be a continuous injection of the drug during this discontinuous injection, and if there is such a continuous injection, the dose of the drug will be lower or higher than the discontinuous injection. In a preferred embodiment,
No drug injections between discontinuous injections. In one preferred embodiment in which there is a discontinuous injection of therapeutic agent, up to about 60%, preferably up to about 50% of the dose injected in less than 11 hours is injected during the first 4 hours of that time. It In one embodiment, two injections are given in less than 6 hours. In another embodiment, at most 6 injections are given, preferably in less than 6 hours. In yet another embodiment, preferably at least 4 injections are given in less than 6 hours.

In a preferred embodiment, the delivery pulse is achieved by discontinuous injection of the therapeutic agent in a pharmaceutically acceptable carrier. There are at least 2 and at most 32 discontinuous injections, all delivered within 11 hours, preferably within 8 hours of the first injection. The daily dose is delivered within the 11 or 8 hours and the discontinuous injection is
It comprises at least 75% of the drug to be delivered, preferably at least 90%, more preferably at least about 100%. The therapeutic agent can be injected by any procedure known in the art. In a preferred embodiment, the therapeutic agent can be injected using a controlled pump of the type known in the art for injecting pharmaceuticals.

Alternatively, the therapy of the present invention can be used in hospitals and control injections are administered using a catheter. Injection is into any body structure, organ or blood vessel, such as intravenous, intramuscular, subcutaneous, transdermal, intrathecal, intraperitoneal, intraarticular, intraocular, or other routes that allow injection delivery. Can also be done. By utilizing a delivery pulse for injecting a therapeutic agent in less than 11 hours, preferably less than 8 hours, in accordance with the present invention, a clear maximum of therapeutic agent in a patient's blood in less than 11 hours. A serum concentration pulse is provided. In a preferred embodiment, such well-defined Cmax pulses occur in less than 8 hours, preferably in 6 hours.

According to a preferred embodiment, all Cmax pulses are achieved in less than 11 hours, preferably less than 8 hours, and the pulses provide a daily dose of therapeutic agent: It is injected with at least two delivery pulses within 11 hours and no further administration during the rest of the 24 hours. All or part of the delivery pulse of therapeutic agent delivered by discontinuous injection may be at the same or different doses of therapeutic agent. Generally, each discrete injection provides a minimum of at least 5% of the total daily dose of therapeutic agent.

It is to be understood that each delivery pulse can include one or more different therapeutic agents (eg, two or more different antibiotics), and each delivery pulse can include the same or different therapeutic agents. (Eg, a delivery pulse contains more than one antibiotic and a delivery pulse can contain only one of the two or more antibiotics). As mentioned above, the therapeutic agent is preferably an antibiotic or antiviral or antifungal or antineoplastic agent. The present invention will be further described with reference to the following examples; however, the scope of the present invention is not limited by the following examples. All percentages in this specification are% by weight unless otherwise stated.

Examples Immediate Release Components (Antibiotics) Presence of water or other solvent in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. The composition is prepared by mixing the ingredients underneath or in a dry blend. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

Non-pH Sensitive Delayed Release Component (Antibiotic) Water or other solvent in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. The composition is prepared by mixing the compounding agents in the presence of the above or by the hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0037]

[Table 4]

[0038]

[Table 5]

[0039]

[Table 6]

Enteric-release components (antibiotics) 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. Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0041]

[Table 7]

[0042]

[Table 8]

[0043]

[Table 9]

Sustained Release Components (Antibiotics) 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. Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0045]

[Table 10]

[0046]

[Table 11]

Immediate Release Component (Antifungal) 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, Alternatively, the composition is prepared by mixing the ingredients in a dry blend. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0048]

[Table 12]

[0049]

[Table 13]

[0050]

[Table 14]

Non-pH Sensitive Delayed Release Component (Antifungal) Water or other solvent in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. The composition is prepared by mixing the compounding agents in the presence of the above or by the hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0052]

[Table 15]

[0053]

[Table 16]

[0054]

[Table 17]

Enteric-release component (antifungal) 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. Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0056]

[Table 18]

[0057]

[Table 19]

[0058]

[Table 20]

Sustained Release Components (Antifungal) 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. Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0060]

[Table 21]

[0061]

[Table 22]

[0062]

[Table 23]

Immediate Release Component (Antiviral) 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, Alternatively, the composition is prepared by mixing the ingredients in a dry blend. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0064]

[Table 24]

[0065]

[Table 25]

[0066]

[Table 26]

[0067]

[Table 27]

Non-pH Sensitive Delayed Release Component (Antiviral) Water or other solvent in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. The composition is prepared by mixing the compounding agents in the presence of the above or by the hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0069]

[Table 28]

[0070]

[Table 29]

[0071]

[Table 30]

[0072]

[Table 31]

Enteric-Coated Release Component (Antiviral) 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. Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0074]

[Table 32]

[0075]

[Table 33]

[0076]

[Table 34]

[0077]

[Table 35]

Sustained Release Components (Antiviral) 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. Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0079]

[Table 36]

[0080]

[Table 37]

[0081]

[Table 38]

Immediate Release Components (Cancer) 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 The composition is prepared by mixing the ingredients in a dry blend. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0083]

[Table 39]

[0084]

[Table 40]

[0085]

[Table 41]

Non-pH Sensitive Delayed Release Component (Cancer) Water or other solvent in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. The composition is prepared in the presence or by mixing the ingredients by the hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0087]

[Table 42]

[0088]

[Table 43]

[0089]

[Table 44]

Enteric-Coated Release Component (Cancer) 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, Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0091]

[Table 45]

[0092]

[Table 46]

[0093]

[Table 47]

Sustained Release Components (Cancer) 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, Alternatively, the composition is prepared by mixing the ingredients by a hot melt method. If water or other solvent is used, dry the blend in a suitable pharmaceutical dryer, such as a vacuum dryer or forced air dryer. The product can be cooled, screened or granulated and compressed using a suitable tablet press, such as a rotary tablet press.

[0095]

[Table 48]

[0096]

[Table 49]

[0097]

[Table 50]

[0098]   3 pulses   Example 230. 1. Metronidazole matrix pellet formulation and preparation procedure (immediate release)   A. Pellet formulation   The composition of metronidazole matrix pellets is shown in Table 1.

[0099]

[Table 51]

B. Procedure for preparing metronidazole matrix pellets 1.2.1 Blend metronidazole with Avicel® PH 101 using a robotic coupe high shear granulator. 1.2.2 20% Povidone K29 in its powder blend with continuous mixing
/ 32 Add binder solution slowly. 1.2.3 Extrude the wet mass on a LCI benchtop granulator. The screen diameter of the benchtop granulator was 1.0 mm. 1.2.4 Spheronization of the extrudate with a model SPH20 Caleva Spheronizer. 1.2.5 Dry the spheroidized pellets at 50 ° C overnight. 1.2.6 16-30 mesh pellets were collected for further processing.

1.1 Preparation of Eudragit® L30D-55 Aqueous Coating Dispersion A. Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to metronidazole matrix pellets is shown in Table 2 below.

[0102]

[Table 52]

B. Eudragit® L30D-55 Aqueous Dispersion Preparation Procedure 1.2.7 Suspending triethyl citrate and talc in deionized water. 1.2.8 Homogenize the TEC / talc suspension in a PowerGen 700 high shear mixer. 1.2.9 Slowly mix the TEC / talc suspension with stirring Eudragit® L30D-55
Added to latex dispersion. 1.2.10 Stir the coating dispersion for 1 hour and then coat onto metronidazole matrix pellets.

1.3 Preparation of Eudragit® S100 Aqueous Coating Dispersion A. Dispersed formulation Aqueous Eudragit® applied to metronidazole matrix pellets
The composition of the S100 dispersion is shown in Table 3 below.

[0105]

[Table 53]

B. Eudragit® S100 Aqueous Dispersion Preparation Procedure Part I: (i) Dispensing Eudragit® S100 powder in deionized water with stirring. (ii) Add ammonium hydroxide solution drop by drop into the dispersion with stirring. (iii) Stir the partially neutralized dispersion for 60 minutes. (iv) Add triethyl citrate drop by drop into the dispersion with stirring. About 2
After stirring for an hour, add Part B. Part II: (i) Disperse talc in the required amount of water. (ii) Homogenize the dispersion with a PowerGen 700D high shear mixer. (iii) Add Part B slowly to the polymer dispersion of Part A with gentle stirring.

1.4 Coating Conditions for Aqueous Coating Dispersion Coating The matrix pellets were Eudragit () using the following coating parameters.
Coated with each of the registered trademark L30D-55 and Eudragit® S100 aqueous film coatings. Coating Equipment STREA 1 (TM) Table Top Laboratory Fluidized Bed Coater Spray Nozzle Diameter 1.0mm Material Fill 300g Inlet Air Temperature 40-45 ° C Outlet Air Temperature 30-33 ° C Spray Air Pressure 1.8bar Pump Speed 2g / min (i) Coat matrix pellets with L30D-55 dispersion to give 12% coating weight gain to pellets. (ii) Coating matrix pellets with S100 dispersion to give 20% coating weight gain to the pellets.

1.5 Encapsulation of Metronidazole Pellets Uncoated immediate release matrix pellets, L30D-55 coated pellets and S100 coated pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40% respectively. Fill with 3 different pellets to obtain a total dose of 375 mg / capsule.

[0109]   3 pulses   Example 231   Amoxicillin pellet formulation and preparation procedure   231.1 Pellet formulation for next coating   The composition of amoxicillin trihydrate matrix pellets is shown in Table 4.

[0110]

[Table 54]

231.2. Procedure for Preparing Amoxicillin Matrix Pellets 231.2.1 Blend Amoxicillin with Avicel® PH101 in a low shear blender. 231.2.2 Slowly add the hydroxypropylmethylcellulose binder solution into the powder blend with continuous mixing. 231.2.3 Extrude the wet mass on a LCI benchtop granulator. The screen diameter of the benchtop granulator was 0.8 mm. 231.2.4 Spheronization of the extrudate with a QJ-230 spheronizer using a small cross section plate. 231.2.5 Dry the spheroidized pellets at 60 ° C using a fluid bed dryer until the exhaust temperature reaches 40 ° C. 231.2.6 20-40 mesh pellets were collected for further processing.

231.3 Preparation of Eudragit® L30D-55 Aqueous Coating Dispersion 231.3.1 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to amoxicillin matrix pellets is shown in Table 5 below.

[0113]

[Table 55]

231.4 Eudragit® L30D-55 Aqueous Dispersion Preparation Procedure 231.4.1 Suspending triethyl citrate and talc in deionized water. 231.4.2 Mix the TEC / talc suspension in a laboratory mixer. 231.4.3 Slowly mix the TEC / talc suspension with stirring Eudragit® L30D-
55 Added to latex dispersion. 231.4.4 Stir the coating dispersion for 1 hour and then coat on amoxicillin matrix pellets.

231.5 Preparation of Eudragit® S100 Aqueous Coating Dispersion 231.5.1 Dispersion Formulation Aqueous Eudragit® S1 applied to amoxicillin matrix pellets.
The composition of the 00 dispersion is shown in Table 6 below.

[0116]

[Table 56]

B. Eudragit® S100 Aqueous Dispersion Preparation Procedure Part A: 231.6.1 Eudragit® S100 powder in deionized water with stirring. 231.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. 231.6.3 Stir the partially neutralized dispersion for 60 minutes. 231.6.4 Add triethyl citrate drop by drop into the dispersion with stirring and stir overnight then add Part B. Part B: 231.6.5 Disperse talc in the required amount of water. 231.6.6 Stir the dispersion with an overhead laboratory mixer. 231.6.7 While gently stirring into the polymer dispersion of Part A, slowly add Part B.
Added.

231.7 Coating Conditions for Aqueous Coating Dispersion Coating The following coating parameters were used for both Eudragit® L30D-55 and Eudragit® S100 aqueous film coating processes. Coating Equipment STREA 1 ™ Table Top Laboratory Fluidized Bed Coater Spray Nozzle Diameter 1.0mm Material Filling 300g Inlet Air Temperature 40-45 ° C Outlet Air Temperature 30-33 ° C Spray Air Pressure 1.8bar Pump Speed 2-6g / min 231.7 .1 Matrix pellets coated with L30D-55 dispersion to give 20% coating weight gain to pellets. 231.7.2 Coat matrix pellets with S100 dispersion to give 37% coating weight gain to pellets.

[0119]   231.8 Preparation of amoxicillin granulation (immediate release ingredient) for tableting

[Table 57]

231.8.1 Blend amoxicillin with Avicel® PH101 in a low shear blender. 231.8.2 Slowly add the hydroxypropylmethylcellulose binder solution into the powder blend with continuous stirring. 231.8.3 Use a fluid bed dryer to remove the granules until the exhaust temperature reaches 40 ° C.
Dry at 0 ° C. 231.8.4 20-40 mesh granules are collected for further processing.

[0121]   231.9 Tableting of amoxicillin pellets

[Table 58]

231.9.1 Blend amoxicillin granules, Avicel PH-200, amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender. 231.9.2 Add magnesium stearate to the blender and blend for 5 minutes. 231.9.3 Compress the blend on a rotary tablet press. 231.9.4 The fill weight was adjusted to give a 500 mg dose tablet.

[0123]   3 pulses   Example 232   Clarithromycin pellet formulation and preparation procedure   232.1 Pellet formulation   The composition of clarithromycin matrix pellets is shown in Table 9.

[0124]

[Table 59]

232.2 Procedure for preparing clarithromycin matrix pellets 232.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate in a robot coupe high shear granulator. 232.2.2 Prepare a binder solution by adding polyoxyl to pure water while stirring. After mixing it, slowly add hydroxypropyl methylcellulose and continue stirring until a solution is obtained. 232.2.3 Slowly add binder solution into powder blend under continuous mixing. 232.2.4 Granulate powder with binder solution in high shear granulator. 232.2.5 The wet mass was extruded on a LCI benchtop granulator. The screen diameter of the benchtop granulator was 1.2 mm. 232.2.6 Spheronization of the extrudate with a model SPH20 Caleva Spheronizer. 232.2.7 Dry the spheronized pellets at 50 ° C overnight. 232.2.8 18-30 mesh pellets were collected for further processing.

232.3 Eudragit® L30D-55 Preparation of Aqueous Coating Dispersion 232.3.1 Dispersion Formulation Aqueous Eudragit L30D-55 applied to clarithromycin matrix pellets.
The composition of the dispersion is shown in Table 10 below.

[0127]

[Table 60]

232.4 Preparation Procedure for Eudragit® L30D-55 Aqueous Dispersion 232.4.1 Suspending triethyl citrate and talc in deionized water. 232.4.2 Homogenize the TEC / talc suspension in a PowerGen 700 high shear mixer. 232.4.3 Slowly add the suspension from 4.2.2 to the Eudragit® L30D-55 latex dispersion with stirring. 232.4.4 Stir the coating dispersion for 1 hour and then coat onto clarithromycin matrix pellets.

232.5 Preparation of Eudragit® S100 Aqueous Coating Dispersion 232.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S100 dispersion applied to clarithromycin matrix pellets is shown in Table 11 below. Be done.

[0130]

[Table 61]

232.6 Eudragit® S100 Aqueous Dispersion Preparation Procedure Part A: 232.6.1 Eudragit® S100 powder in deionized water with stirring. 232.6.2 Add ammonium hydroxide solution drop by drop into the dispersion with stirring. 232.6.3 Stir the partially neutralized dispersion for 60 minutes. 232.6.4 Add triethyl citrate drop by drop into the dispersion with stirring and after stirring for 60 minutes add Part B. Part B: 232.6.5 Disperse talc in the required amount of water. 232.6.6 Homogenize the dispersion with a PowerGen 700D high shear mixer. 232.6.7 While gently stirring into the polymer dispersion of Part A, slowly mix Part B
Added.

232.7 Coating Conditions for Aqueous Coating Dispersion Coating Applications The following coating parameters were used for coating matrix pellets with each of Eudragit® L30D-55 and Eudragit® S100 aqueous film coatings. Coating Equipment STREA 1 ™ Table Top Laboratory Fluidized Bed Coater Spray Nozzle Diameter 1.0mm Material Filling 300g Inlet Air Temperature 40-45 ° C Outlet Air Temperature 30-33 ° C Spray Air Pressure 1.6bar Pump Speed 2g / min 232.7.1 Coat matrix pellets with L30D-55 dispersion to give 20% coating weight gain to pellets. 232.7.2 Coat matrix pellets with S100 dispersion to give 37% coating weight gain to pellets. 4. The capsules were filled with 30%: 30%: 40% wt% uncoated pellets, L30D-55 coated pellets and S100 coated pellets respectively to give 250 mg capsules.

[0133]   4 pulses   Example 233. 1. Metronidazole matrix pellet formulation and preparation procedure   233.1 Pellet formulation   The composition of metronidazole matrix pellets is shown in Table 12.

[0134]

[Table 62]

233.2 Metronidazole Matrix Pellet Preparation Procedure 232.2.1 Blend Metronidazole and Avicel® PH 101 using a Robot Coupe High Shear Granulator. 232.2.2 20% Povidone K in its powder blend with continuous mixing
29/32 Add binder solution slowly. 232.2.3 Extrude the wet mass with LCI Benchtop Granulator. The screen diameter of the benchtop granulator was 1.0 mm. 232.2.4 Spheronization of the extrudate with a model SPH20 Caleva Spheronizer. 232.2.5 Dry the spheronized pellets at 50 ° C overnight. 232.2.6 16-30 mesh pellets were collected for further processing.

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

[0137]

[Table 63]

233.4 Eudragit® L30D-55 Aqueous Dispersion Preparation Procedure 233.4.1 Suspending triethyl citrate and talc in deionized water. 233.4.2 Homogenize the TEC / talc suspension in a PowerGen 700 high shear mixer. 233.4.3 Slowly add the TEC / talc suspension to the Eudragit® L30D-55 latex dispersion with stirring. 233.4.4 Stir the coating dispersion for 1 hour and then coat onto metronidazole matrix pellets.

233.5 Preparation of Eudragit® S100 Aqueous Coating Dispersion 233.5.1 Dispersion Formulation Aqueous Eudragit® applied to metronidazole matrix pellets.
The composition of the S100 dispersion is shown in Table 14 below.

[0140]

[Table 64]

233.6 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A: 233.6.1 Eudragit® S100 powder in deionized water with stirring. 233.6.2 Add ammonium hydroxide solution drop by drop into the dispersion with stirring. 233.6.3 Stir the partially neutralized dispersion for 60 minutes. 233.6.4 Add triethyl citrate drop by drop into the dispersion with stirring.
Add Part B after stirring for about 2 hours. Part B: 233.6.5 Disperse talc in the required amount of water. 233.6.6 Homogenize the dispersion with a PowerGen 700D high shear mixer. 233.6.7 While gently stirring into the polymer dispersion of Part A, slowly add Part B.
Added.

233.7 Coating Conditions for Aqueous Coating Dispersion Coating Applications The following coating parameters were used for each coating with Eudragit® L30D-55 and Eudragit® S100 aqueous film coatings. Coating Equipment STREA 1 ™ Table Top Laboratory Fluidized Bed Coater Spray Nozzle Diameter 1.0mm Material Fill 300g Inlet Air Temperature 40-45 ° C Outlet Air Temperature 30-33 ° C Spray Air Pressure 1.8bar Pump Speed 2g / min 233.7.1 Coat matrix pellets with L30D-55 dispersion to give 12% coating weight gain to pellets. 233.7.2 Coat matrix pellets with L30D-55 dispersion to give 30% coating weight gain to pellets. 233.7.3 Coat matrix pellets with S100 dispersion to give 20% coating weight gain to pellets.

1.5 Encapsulation of Metronidazole Pellets Immediate release matrix pellets (uncoated), L30D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets, 20% each.
Fill in size 00 hard gelatin capsules at the ratio of 30%: 20%: 30%. Fill with 4 different pellets to get a total dose of 375 mg / capsule.

[0144]   4 pulses   Example 234   Amoxicillin pellet formulation and preparation procedure   234.1 Pellet formulation   The composition of amoxicillin trihydrate matrix pellets is shown in Table 15.

[0145]

[Table 65]

234.2. Procedure for preparing amoxicillin matrix pellets 234.2.1 Blend amoxicillin with Avicel® PH101 in a low shear blender. 234.2.2 Slowly add the hydroxypropylmethylcellulose binder solution into the powder blend with continuous mixing. 234.2.3 Extrude the wet mass on a LCI benchtop granulator. The screen diameter of the benchtop granulator was 0.8 mm. 234.2.4 Spheronization of the extrudate with a QJ-230 spheronizer using a small cross section plate. 234.2.5 Dry the spheroidized pellets at 60 ° C using a fluid bed dryer until the exhaust temperature reaches 40 ° C. 234.2.6 20-40 mesh pellets were collected for further processing.

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

[0148]

[Table 66]

234.4 Eudragit® L30D-55 Aqueous Dispersion Preparation Procedure 234.4.1 Suspending triethyl citrate and talc in deionized water. 234.4.2 Mix the TEC / talc suspension in a laboratory mixer. 234.4.3 The Eudragit® L30D-55 latex dispersion with stirring and the TEC /
Add talc suspension slowly. 234.4.4 Stir the coating dispersion for 1 hour and then coat on amoxicillin matrix pellets.

234.5 Preparation of Eudragit® S100 Aqueous Coating Dispersion 234.6 Dispersion Formulation Aqueous Eudragit® S1 applied to amoxicillin matrix pellets.
The composition of the 00 dispersion is shown in Table 17 below.

[0151]

[Table 67]

234.7 Preparation Procedure of Eudragit® S100 Aqueous Dispersion Part A: 234.7.1 Eudragit® S100 powder in deionized water with stirring. 234.7.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. 234.7.3 Stir the partially neutralized dispersion for 60 minutes. 234.7.4 Add triethyl citrate drop-wise into the dispersion with stirring and after overnight stirring, add Part B. Part B: 234.7.5 Disperse talc in the required amount of water. 234.7.6 Stir the dispersion with an overhead lab mixer. 234.7.7 While gently stirring into the polymer dispersion of Part A, slowly add Part B.
Added.

234.8 Preparation of Aqueous Coating Dispersion 234.8.1 Dispersion Formulation The composition of the aqueous Aquacoat dispersion applied to Amoxicillin L30D-55 coated pellets is shown in Table 18 below.

[0154]

[Table 68]

234.8.1.1 Prepare hydroxypropylmethylcellulose (Methocel E15) solution by dispersing in water with continuous stirring. 234.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with stirring and stir overnight.

234.9 Coating Conditions for Aqueous Coating Dispersion Coating Applications The following coating parameters were used for coating with Eudragit® L30D-55 and Eudragit® S100 aqueous film coatings, respectively. Coating Equipment STREA 1 ™ Table Top Laboratory Fluidized Bed Coater Spray Nozzle Diameter 1.0mm Material Fill 300g Inlet Air Temperature 40-45 ° C Outlet Air Temperature 30-33 ° C Spray Air Pressure 1.8bar Pump Speed 2-6g / min 234.9 .1 Amoxicillin matrix pellets coated with L30D-55 dispersion to give 20% coating weight gain to pellets. 234.9.2 Another batch of amoxicillin matrix pellets is coated with the L30D-55 dispersion to obtain a 20% weight gain. The L30D-55 pellets are coated with Aquacoat dispersion to obtain a 10% coating weight gain. 234.9.3 Amoxicillin matrix pellets are coated with S100 dispersion to
% Coating weight gain is obtained.

[0157]   234.10 Preparation of amoxicillin granulation for tableting

[Table 69]

234.10.1 Blend amoxicillin with Avicel® PH101 in a low shear blender. 234.10.2 Slowly add the hydroxypropylmethylcellulose binder solution into the powder blend with continuous stirring. 234.10.3 Use a fluidized bed dryer until the exhaust temperature reaches 40 ° C.
Dry at 60 ° C. 234.10.4 20-40 mesh granules are collected for further processing.

[0159]   234.11 Tableting of amoxicillin pellets

[Table 70]

234.11.1 Blend amoxicillin granules, Avicel PH-200, amoxicillin pellets and colloidal silicon dioxide in a tumble blender for 15 minutes. 234.11.2 Add magnesium stearate to the blender and blend for 5 minutes. 234.11.3 Compress the blend on a rotary tablet press. 234.11.4 Adjust the fill weight to obtain a 500 mg dose tablet.

[0161]   4 pulses   Example 235   Clarithromycin pellet formulation and preparation procedure   235.1 Pellet formulation   The composition of clarithromycin matrix pellets is shown in Table 21.

[0162]

[Table 71]

235.2 Clarithromycin Matrix Pellet Preparation Procedure 235.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate in a robot coupe high shear granulator. 235.2.2 Prepare binder solution by adding polyoxyl to pure water while stirring. After mixing it, slowly add hydroxypropyl methylcellulose and continue stirring until a solution is obtained. 235.2.3 Slowly add binder solution into powder blend under continuous mixing. 235.2.4 Granulate powder with binder solution in high shear granulator. 235.2.5 Extrude the wet mass on a LCI benchtop granulator. The screen diameter of the benchtop granulator was 1.2 mm. 235.2.6 Spheronization of the extrudate with a model SPH20 Caleva Spheronizer. 235.2.7 Dry the spheronized pellets at 50 ° C overnight. 235.2.8 18-30 mesh pellets were collected for further processing.

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

[0165]

[Table 72]

235.4 Eudragit® L30D-55 Aqueous Dispersion Preparation Procedure 235.4.1 Suspending triethyl citrate and talc in deionized water. 235.4.2 Homogenize the TEC / talc suspension in a PowerGen 700 high shear mixer. 235.4.3 Slowly add the suspension from 4.2.2 to the Eudragit® L30D-55 latex dispersion while stirring. 235.4.4 Stir the coating dispersion for 1 hour and then coat onto clarithromycin matrix pellets.

235.5 Preparation of Eudragit® S100 Aqueous Coating Dispersion 235.5.1 Dispersion Formulation The composition of the aqueous Eudragit® S100 dispersion applied to clarithromycin matrix pellets is shown in Table 23 below. Be done.

[0168]

[Table 73]

235.6 Eudragit® S100 Aqueous Dispersion Preparation Procedure Part A: 235.6.1 Eudragit® S100 Powders are dispensed in deionized water with stirring. 235.6.2 Add ammonium hydroxide solution drop by drop into the dispersion with stirring. 235.6.3 Stir the partially neutralized dispersion for 60 minutes. 235.6.4 Add triethyl citrate drop by drop to the dispersion, stir for 60 minutes and add Part B. Part B: 235.6.5 Disperse talc in the required amount of water. 235.6.6 Homogenize the dispersion with a PowerGen 700D high shear mixer. 235.6.7 While gently stirring into the polymer dispersion of Part A, slowly add Part B.
Added.

235.7 Coating Conditions for Aqueous Coating Dispersion Coating Applications The following coating parameters were used for coating with Eudragit® L30D-55 and Eudragit® S100 aqueous film coatings, respectively. Coating Equipment STREA 1 ™ Table Top Laboratory Fluidized Bed Coater Spray Nozzle Diameter 1.0mm Material Filling 300g Inlet Air Temperature 40-45 ° C Outlet Air Temperature 30-33 ° C Spray Air Pressure 1.6bar Pump Speed 2g / min 235.7.1 Coat matrix pellets with L30D-55 dispersion to give 12% coating weight gain to pellets. 235.7.2 Coat matrix pellets with L30D-55 dispersion to give 30% coating weight gain to pellets. 235.7.3 Coat matrix pellets with S100 dispersion to give 37% coating weight gain to pellets.

235.8 Encapsulation of Clarithromycin Pellets Immediate release matrix pellets (uncoated), L30D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and S100 coated pellets, 20% each.
Fill in size 00 hard gelatin capsules at the ratio of 30%: 20%: 30%. Fill with 4 different pellets to get a total dose of 250 mg / capsule.

In a procedure similar to Examples 230-235, the antifungal, antiviral and antineoplastic dosage forms are combined into a single product by substituting the antifungal or antiviral or neoplastic agent for the antibiotic. Products containing 3 or 4 antifungal dosage forms). The present invention is particularly advantageous in that it provides therapeutic agent products which provide improvements over twice daily administration of therapeutic agents and improvements over once daily administration of therapeutic agents. Many modifications and variations of the present invention are possible in light of the above teachings, and therefore they may be practiced otherwise than as described in detail within the scope of the appended claims.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/496 A61K 31/496 31/513 31/513 31/522 31/522 31/573 31/573 31 / 704 31/704 31/7048 31/7048 31/7052 31/7052 31/7072 31/7072 45/00 45/00 (31) Priority claim number 09 / 687,236 (32) Priority date 2000 13th (October 13, 2000) (33) Priority claiming country United States (US) (31) Priority claim number 09/687, 235 (32) Priority date October 13, 2000 (2000.10. 13) (33) Priority claiming country United States (US) (31) Priority claim number 09/687, 237 (32) Priority date October 13, 2000 (October 13, 2000) (33) Priority claim Country United States (US) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I , LU, MC, NL, PT, SE, TR), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH , GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB , GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, S D, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, UZ, VN, YU, ZA, ZW (72) Inventor Tracy Donald J. Junior, Maryland, USA 21012 Arnold Fairy Court 1335 (72) Inventor Wasink Sandra I Maryland, USA 21704 Frederick Reels Mills Road 5103 F Term (reference) 4C076 AA37 BB01 BB11 CC27 CC32 CC35 EE23H EE31H EE32H EE33H FF31 4C084 AA03 AAZBZZBZBZ ZBZ ZBZ MAB 52ZZ BC43 BC50 BC60 CB07 CC02 DA10 EA01 EA10 EA13 GA02 GA06 GA07 GA12 MA01 MA04 MA52 MA66 NA12 ZB26 ZB32 ZB33 ZB35 4C206 DA12 FA07 GA18 GA28 MA01 MA04 MA72 MA86 ZB26 ZB32 ZB33 ZB35

Claims (23)

[Claims] 1. A therapeutic agent product comprising a first therapeutic dosage form, a second therapeutic dosage form and a third therapeutic dosage form, said first therapeutic dosage form, second therapeutic dosage form and third therapeutic dosage form. Each of the forms comprises at least one therapeutic agent and a pharmaceutically acceptable carrier, the three dosage forms have different release profiles, and the therapeutic agent product has a C in less than about 12 hours.
Said therapeutic agent product which has reached max and said therapeutic agent is an antibiotic, antifungal, antiviral or antineoplastic agent. 2. The product of claim 1, wherein the first dosage form is an immediate release dosage form. 3. The product according to claim 2, wherein the serum concentration of the product reaches Cmax at least 4 hours after administration. 4. The product of claim 2, wherein the immediate release dosage form contains at least 20% and at most 50% of the total dose of therapeutic agent. 5. The product of claim 4, wherein the product is an oral dosage form. 6. The serum concentration of the therapeutic agent released from the second dosage form reaches Cmax after the serum concentration of the therapeutic agent released from the first dosage form reaches Cmax.
The product according to claim 5. 7. The serum concentration of the therapeutic agent released from the third dosage form reaches Cmax after the serum concentration of the therapeutic agent released from the second dosage form reaches Cmax.
The product according to claim 6. 8. The product of claim 1, wherein the therapeutic product comprises a total dose of therapeutic that is effective for 24 hours. 9. A fourth method further comprising a therapeutic agent and a pharmaceutically acceptable carrier.
In the dosage form, the serum concentration of the therapeutic agent released from the fourth dosage form has reached Cmax in the serum concentration of the therapeutic agent released from each of the first, second and third dosage forms. later,
The product of claim 1, comprising a fourth dosage form that reaches Cmax. 10. The product of claim 1, wherein the therapeutic agent is an antibiotic. 11. The product of claim 1, wherein the therapeutic agent is an antifungal agent. 12. The product of claim 1, wherein the therapeutic agent is an antiviral agent. 13. A method of treating a disease or infection in a patient, said method comprising the step of administering to a patient in need thereof an effective amount of the product of claim 1. 14. Use of a therapeutic agent for the preparation of a product for the treatment of a disease or infection, said therapeutic product being as defined in claim 1. 15. A method of treating a patient with a therapeutic agent, the method comprising treating the patient by injecting the therapeutic agent into the patient with no less than 2 and no more than 32 delivery pulses within at most 11 hours. Comprising the therapeutic agent being selected from the group consisting of antibiotics, antiviral agents, antifungal agents and anti-neoplastic agents. 16. The method of claim 15, wherein the delivery pulse is provided by discontinuous injection. 17. The method of claim 16, wherein essentially no therapeutic agent is administered during at least a portion of the discontinuous injection. 18. The method of claim 16, wherein a dose of the therapeutic agent that is different from the dose of the discontinuous injection is continuously injected during at least a portion of the discontinuous injection. 19. The method of claim 16, wherein at least some of the discontinuous injections deliver different doses of therapeutic agent. 20. The method of claim 15, wherein there are at least 4 delivery pulses. 21. The method of claim 20, wherein there are at most 6 delivery pulses. 22. The total dose of the therapeutic agent is injected within at most 6 hours,
The method of claim 21. 23. A therapy for preparing a product for use in treating a patient by injecting the therapeutic agent into the patient with a delivery pulse of no less than 2 and no more than 32 times within a period of at most 11 hours. The use of an agent, wherein the therapeutic agent is an antibiotic, an antiviral agent,
Said use selected from the group consisting of antifungal agents and antineoplastic agents.