JP5377465B2 - Therapeutic products, their use and formulation - 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 Cmax in less than about twelve hours wherein said therapeutic is an antibiotic, an anti-fungal, an anti-viral or an anti-neoplastic agent.

Description

  This invention relates to therapeutic products, as well as their use and dosage forms.

  A wide variety of antibiotics, antibacterial, antiviral and anti-neoplastic agents are and will be used to treat patients. In general, such therapeutic agents are administered by multiple doses of immediate release dosage forms that result in poor compliance or as higher dose controlled release dosage forms (slow release). The present invention relates to providing improved therapeutic products.

According to one aspect of the present invention, there is provided a pharmaceutical product 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, there are at least two, preferably at least three dosage forms, each having a different release profile, wherein each dosage form has a profile at different times after administration of the therapeutic product. A profile that initiates the release of the therapeutic agent contained in the dosage form.

Thus, according to one aspect of the present 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 or A unitary therapeutic product is provided.
In accordance with a further aspect of the invention, therapeutic products comprising at least four different dosage forms, each dosage form releasing the therapeutic agent contained in the dosage form at different times after administration of the therapeutic product. A therapeutic product is provided.
The therapeutic product generally does not contain more than five dosage forms with different release times.
According to a preferred embodiment, the therapeutic product has an overall release profile such that once administered, the maximum serum concentration of all therapeutic agents 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 all therapeutic agents released from the therapeutic product is achieved as early as 4 hours after administration.

  In accordance with a 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 that does not substantially delay the onset of release of the therapeutic agent from the therapeutic agent product after administration of the therapeutic agent product. The second and third of the at least three dosage forms are delayed dosage forms (which may be pH sensitive or non-pH sensitive delayed dosage forms, depending on the type of therapeutic agent product), and thereby from the therapeutic agent product The released therapeutic agent is delayed until after the onset of release of the therapeutic agent released from the immediate release dosage form. More particularly, the therapeutic agent released from the second dosage form of at least two dosage forms is obtained after the therapeutic agent released from the first dosage form of at least three dosage forms achieves a serum Cmax. The therapeutic agent that subsequently achieves Cmax (maximum serum concentration in serum) and is released from the third dosage form achieves a serum Cmax after 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 releases the release from the second dosage form. Initiation typically occurs no later than 6 hours after initiation of release of the therapeutic agent from the first dosage form of at least three dosage forms.
In general, immediate release dosage forms achieve a Cmax of therapeutic agent released from the dosage form within about 0.5 to about 2 hours, and the second dosage form of at least three dosage forms has a maximum of about Realize the Cmax of the therapeutic agent released from the dosage form within 4 hours. In general, the Cmax of the second dosage form is not achieved earlier than 2 hours after administration of the therapeutic product; however, achieving Cmax in a short time is feasible within the scope of the present invention.

As noted above, the therapeutic product can include at least three or at least four or more dosage forms. For example, if the therapeutic product comprises a third dosage form, the therapeutic agent released therefrom will continue to Cmax after Cmax is achieved for the therapeutic agent released from each of the first and second dosage forms. Reach. 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. In one embodiment, the Cmax of the therapeutic agent released from the third dosage form is achieved within 8 hours.
In another embodiment, the therapeutic agent product comprises at least four dosage forms, each of the at least four dosage forms having a different release profile, thereby releasing the therapeutic agent from at least four different dosage forms. Achieves Cmax at different times.

As noted above, in a preferred embodiment, all of the therapeutic agent released from the therapeutic agent product, regardless of whether the therapeutic agent comprises at least two or at least three or at least four different dosage forms, each having a different release profile. The Cmax of the therapeutic agent 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 no further product is administered during the day after administration of the therapeutic product; that is, the preferred therapy is that the product is in 24 hours. It is to be administered only once. Accordingly, the present invention provides a single dose therapeutic product wherein the entire therapeutic agent release is performed with different release profiles so that the total Cmax of the therapeutic product is reached in less than 12 hours. The term “single administration” means that all therapeutic agents administered during a 24 hour period are administered simultaneously, provided that they are administered essentially simultaneously, a single tablet or capsule or There may be two or more of them.

Applicants believe that a single dose therapeutic product comprising at least three therapeutic dosage forms each having a different release profile exceeds a single dose therapeutic product comprising a therapeutic dosage form having a single release profile I found that there are improvements. The therapeutic agent for each dosage form in a pharmaceutically acceptable carrier may have one or more of the same type of therapeutic agent (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 it is described herein that a dosage form initiates 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, it is known in the art that in spite of such a design and intent, some “leakage” of the therapeutic agent can occur. Such “leakage” is not “emission” as used herein.

If 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, even if the Cmax of the fourth dosage form of at least four dosage forms is reached after the Cmax of each of the other dosage forms is reached, the fourth dosage form Release of the therapeutic agent from the form may be initiated before or after release from the second or third dosage form.
As mentioned above, the therapeutic product of the present invention can be formulated for administration by various routes of administration. For example, the therapeutic product can be formulated in a manner suitable for topical administration; ocular or otic administration; rectal or vaginal administration; as a nasal spray; by inhalation; as an injection; In a preferred embodiment, the therapeutic product is formulated in a manner suitable for oral administration.

For example, in the formulation of a therapeutic product for topical administration, such as application to the skin, at least two different dosage forms each containing the therapeutic agent are applied locally by including the dosage form of an oil-in-water emulsion or a water-in-oil emulsion. It can be formulated for 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 can also be realized in a three-dose delivery mode 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. Having an oil-in-water emulsion can be provided.
It is also within the scope of the present invention to provide a therapeutic product in the form of a patch comprising therapeutic dosage forms having different release profiles as described above.

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

In preferred embodiments, 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, wherein the pellet or particle is, for example, in a capsule or tablet, or in a unit pharmaceutical product suspended in a liquid for oral administration. It is formed.
Also, in the formulation of an oral delivery system, each dosage form of the product can be formulated as a tablet, and each tablet can be packed into a capsule to produce a unit therapeutic product. Thus, for example, a therapeutic product includes a first dosage form in the form of a tablet that is an immediate release tablet, and also includes two or more additional tablets that each provide a delayed release of the therapeutic agent, as described above. Thus, 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 in the art from the teachings herein to formulate a therapeutic product comprising at least three dosage forms having different release profiles for different routes of administration. As is known in the art, for delayed release, the release time can be controlled by the concentration of the therapeutic agent in the coating and / or the thickness of the coating.

When formulating a therapeutic product of the invention, in one embodiment, the immediate release dosage form of the product typically provides from about 20% to about 50% of the total dose of therapeutic agent delivered by the product; Such immediate release dosage forms typically provide at least 25% of the total dose of therapeutic agent delivered by the product. Often, the immediate release dosage form provides 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 It may be desirable to provide ˜50% in an immediate release dosage form.
The remaining dosage form delivers the remainder of the therapeutic agent. Where more than one delayed release dosage form is used, in one embodiment, each delayed release dosage form may provide approximately the same amount of therapeutic agent; but formulated to provide different amounts May be.
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 20% to 35% (preferably 20%) by weight of the total therapeutic agent. If there are three delayed release components, the immediate release component provides 15-30% by weight of the total therapeutic agent; and the four delayed release components are In some cases, 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 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 provides the remainder 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 The delayed release component provides 20% to 40% by weight of the total therapeutic agent provided by the three delayed release components, and the last delayed release component in time is the three delayed release components The remainder of the therapeutic agent provided by the ingredient is provided.
When 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, followed by time Of the delayed release component provides 15% to 30% by weight, the next delayed release component provides 20% to 35% by weight, and the last delayed release component 20 Provide weight percent to 35 weight percent.

Immediate release component The immediate release portion of the system may be a mixture of components that rapidly degrade after administration to release the therapeutic agent. This can take the form of separate pellets or granules that are mixed together or compressed together with the other three components.
Substances added to the therapeutic agent for the immediate release component 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, levulose, sucrose, polyvinylpyrrolidone (PVP ), Acrylic acid derivatives (Carbopol, Eudragit, etc.), low molecular weight PEGs (PEG2000-1000) and high molecular weight PEGs with molecular weights exceeding 20,000 daltons ( Polyox).
It is useful that these materials are present in the range of 1.0-60% (W / W).

In addition, it is useful for this system to have other formulations to help dissolve the drug after ingestion or administration, or to break down the components. These formulations are interfacial such as sodium dodecyl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate It can be an active agent, a nonionic surfactant such as a Pluronic family of surfactants, or other substances having surfactant properties, or any combination of the above.
These substances may be present in a proportion of 0.05-15% (W / W).

Non-pH Sensitive Delayed Release Ingredients The ingredients in this composition are the same immediate release unit, but the polymer is further included 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 include, but are not limited to, molecular weights greater than 4,000 daltons (Carbowax, Polyox) polyethylene glycol (PEG), white wax or beeswax Waxes, 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 component This component in the composition is the same as the immediate release component, but further polymer is included in the composition or as a coating over the pellets or granules.
The 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 at a concentration of 4-20% (W / W).

Sustained release component This component in the composition is the same as the immediate release component, but the polymer is further included in the composition or as a coating over the pellets or granules.
The types of materials useful for this purpose include, but are not limited to, ethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or 8,000 daltons Polyethylene glycol having a molecular weight greater than
These substances may be present at a concentration of 4-20% (W / W).

As described above, the unit comprising the therapeutic composition of the present invention may be in the form of separate pellets or particles contained in a capsule, or particles embedded in a tablet or suspended in a liquid buffer. possible.
The therapeutic agent composition of the present invention can be administered by any route of administration, for example, sublingual, transmucosal, transdermal, extraintestinal and the like, and is preferably administered orally. The composition includes a therapeutically effective amount of the therapeutic agent, which amount will vary depending on the therapeutic agent used, the disease or infection being treated, and the number of times the composition is delivered per day. 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 infection in a 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 with an elimination half-life of less than 20 hours, more preferably less than 12 hours, and in particular a half-life of 2-10 hours It is useful for drugs having The following are examples of some antibiotics having a half-life of about 1-12 hours: cefadroxil, cefazolin, cephalexin, cephalotin, cefapirin, cefacerol, cefaprodil, cefadrine, cefamandole, cefoniside, cefranide, cefuroxime, cefixime , Cefoperazone, cefotaxime, cefpodoxime, ceftoxydim, ceftibutene, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef (loracarbef), imipenem, erythromycin (and estrate, ethyl succinate, septate, succinate Erythromycin salts such as slearate), azithromycin, clarithromycin, dirithromycin, troeanomic Troleanomycin, penicillin V, penicillin salts and complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and potassium clavulanate, ampicillin, bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin) , Mezulocillin, piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin and potassium clavulanate, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid, ciprofloxide Sasin (ciprofloxacin), levofloxacin, lomefloxacin, norfloxacin, ofloxacin, sparfloxacin , Sulfacitin, sulfamerazine, sulfamethazine, sulfamethoxol, sulfasalazine, sulfisoxazole, sulfapyridine, sulfadiazine, sulfamethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, Trimethoprim, clofazimine, co-triamoxazole, pentamidine, and trimetrexate.

  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, cyclopirenol Rox, clotrimazole, butenafine hydrochloride, nystatin, naphthifine hydrochloride, oxyconazole nitrate, selenium sulfide, econazole nitrate, terconazole, butconazole nitrate, carbol-fuchsin, clioquinol, methylrosaniline hydrochloride, sodium thiosulfate, sulconazole nitrate, hydrochloric acid Terbinafine, thioconazole, tolnaftate, undecylenic acid and undecylenate (calcium undecylenate, copper (I) undecylenate, undecylenous acid lead).

  The following are representative examples of some antiviral agents that can be used in the present invention: acyclovir, amantadine, amprenavia, cidophobia, delavirdine, didanosine, famciclovia, foscarnet, ganciclovir, indinavir, interferon, lamivudine, nelfinavir, Nevirapine, Palivizumab, penciclovir, ribavirin, rimantadine, ritonavir, saquinavir, stavudine, trifluidine, valacyclovir, vidarabine, zalcitabine, zidovudine.

  The following are representative examples of cancer therapeutics that can be used according to the present invention: carboplatin, busulfan, cisplatin, thiotepa, melphalan hydrochloride, cyclophosphamide, ifosfamide, chlorambucil, mechloretamine hydrochloride, carmustine, lomustine, streptozocin, Polyfeprozan 20, dexirazoxane, doeoninol, granisetron hydrochloride, fluconazole, erythropoietin, octreotide acetate, pilocarpine hydrochloride, disodium etidronate, disodium pamidronate, sodium allopurinol, amifostine, filgrastim, mesna, ondansetron hydrochloride, Dorasetron mesylate, leucovorin calcium, salgramostine, levamisole hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, my Mycin, daunorubicin citrate, pricamycin, daunorubicin hydrochloride, bleomycin sulfate, mitoxantrone hydrochloride, valrubicin, dactinomycin, fludarabine phosphate, cytarabine, mercaptopurine, thioguanine, sodium methotrexate, cladribine, floxuridine, capecitabine , Anastrozole, bicalutamide, tamoxifen citrate, goserelin acetate, estramustine phosphate sodium, ethinyl estradiol, estrogen ester, leuprolide acetate, conjugated estrogen, megestrol acetate, aldesleukin, medroxyprogesterone acetate, dacarbazine, hydroxy Urea, etoposide phosphate, megestrol acetate, paclitaxel, etoposide, teniposide, truss Zumab (trasutuzumab), Rituximab (rituximab), vinorelbine tartrate, denileukin diftitox, gemcitabine hydrochloride, vincristine sulfate, vinblastine sulfate, asparaginase, edrohonium chloride, basilas calmette Interferon alfa-2a, recombinant, tretinoin, porfimer sodium, interferon alfa-2b, recombinant, procarbazine hydrochloride, topotecan hydrochloride, altretamine, fluorouracil, sodium brendonizolone phosphate, cortisone acetate, dexamethasone, dexamethasone sodium sulfate, Dexamethasone acetate, hydrocortisone sodium phosphate, hydrocortisone, prednisolone, methyl citrate Denis pyrazolone sodium, betamethasone sodium phosphate, betamethasone acetate, letrozole, mithramycin, mitotane, pentostatin, peroxide Foss cyclophosphamide, raloxifene.

In accordance with another aspect of the present invention, as described above, comprising at least two, preferably at least three dosage forms by injecting a therapeutic agent which is an antibiotic, antiviral, antifungal or antineoplastic agent. Provide a method or therapy for treating a patient that produces results similar to those obtained by using the product. Procedures or therapies for treating patients by their injection are provided that give similar results as achieved by the use of a product as described above comprising at least two, preferably at least three 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, at most 32 delivery pulses, for a time of less than 11 hours, preferably less than 8 hours. As used herein, a “delivery pulse” is at least two discontinuous injections between injections, during which essentially no therapeutic agent is injected into the host, Or during and between discontinuous injections, means and is realized by continuous injection with a different amount of therapeutic agent than the amount injected with discontinuous injection. In addition, at least two delivery pulses can also be achieved by sequentially injecting the drug at one dose and then sequentially in different amounts. In such a case, there is a first continuous delivery pulse over time followed by a second continuous delivery pulse over time. Thus, for example, in the latter case, if there is an initial injection where the therapeutic agent is administered sequentially over time, then increasing the dose of the therapeutic agent administered over time may result in a continuous administration of the therapeutic agent. There are effectively two delivery pulses.

In one embodiment, there are at least two discontinuous injections of therapeutic agent, usually at most 32 discontinuous injections of therapeutic agent within a time period of 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 drug is less or greater than the discontinuous injection. In preferred embodiments, there are no drug injections during the discontinuous injection.
In one preferred embodiment where there are discontinuous injections of the 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. The
In one embodiment, two injections are given within a period of less than 6 hours. In another embodiment, at most 6 injections are given, preferably within a period of less than 6 hours. In yet another embodiment, at least 4 injections are given, preferably in less than 6 hours.

In preferred embodiments, 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 of which are 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 comprises at least 75%, preferably at least 90%, more preferably at least about 100% of the drug to be delivered.
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 a type known in the art for injecting pharmaceuticals.

Alternatively, the therapy of the present invention can be used in hospitals and controlled 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 capable of injection delivery. Can also be done.
In accordance with the present invention, by utilizing a delivery pulse to inject a therapeutic agent in less than 11 hours, preferably in less than 8 hours, a clear maximum of therapeutic agent in the patient's blood in less than 11 hours Serum concentration pulses are provided. In a preferred embodiment, such a distinct Cmax pulse occurs within a time of less than 8 hours, preferably within a time of 6 hours.

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

It should be understood that each delivery pulse can contain one or more different therapeutic agents (eg, two or more different antibiotics), and each delivery pulse can contain the same or different therapeutic agents ( For example, a delivery pulse may contain more than one antibiotic and a delivery pulse may 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 invention will be further described in the following examples; however, the scope of the invention is not limited by the following examples. All percentages in this specification are weight percent unless otherwise stated.

Immediate release ingredients (antibiotics)
Mix the compound in the presence of water or other solvent or in a dry blend in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder To prepare the composition. If water or other solvent is used, the blend is dried 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.

Non-pH sensitive delayed release components (antibiotics)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Enteric release ingredients (antibiotics)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Sustained release components (antibiotics)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Immediate release component (antifungal)
Mix the compound in the presence of water or other solvent or in a dry blend in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder To prepare the composition. If water or other solvent is used, the blend is dried 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.

Non-pH sensitive delayed release component (antifungal)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Enteric release component (antifungal)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

  Sustained 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, or hot The composition is prepared by mixing the compounding agent by the melt method. If water or other solvent is used, the blend is dried 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.

Immediate release component (antiviral)
Mix the compound in the presence of water or other solvent or in a dry blend in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder To prepare the composition. If water or other solvent is used, the blend is dried 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.

Non-pH sensitive delayed release component (antiviral)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Enteric release component (antiviral)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Sustained release component (antiviral)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Immediate release component (cancer)
Mix the compound in the presence of water or other solvent or in a dry blend in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder To prepare the composition. If water or other solvent is used, the blend is dried 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.

Non-pH sensitive delayed release component (cancer)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Enteric release component (cancer)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Sustained release component (cancer)
Mix the compound in the presence of water or other solvent or in a hot melt process in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high shear granulator, fluid bed granulator, or extruder. To prepare the composition. If water or other solvent is used, the blend is dried 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.

Three 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.

B. Preparation procedure for metronidazole matrix pellets
1.2.1 Blend of metronidazole and Avicel (R) PH 101 using a robot coupe high shear granulator.
1.2.2 Slowly add 20% povidone K29 / 32 binder solution into the powder blend while continuously mixing.
1.2.3 Extrude the wet mass with an LCI bench top granulator. The screen diameter of the bench top granulator was 1.0mm.
1.2.4 The extrudate is spheronized 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 Dispersion Formulation The composition of the aqueous Eudragit L30D-55 dispersion applied to metronidazole matrix pellets is shown in Table 2 below.

B. Eudragit (R) L30D-55 aqueous dispersion preparation procedure
1.2.7 Suspend triethyl citrate and talc in deionized water.
1.2.8 Homogenize the TEC / talc suspension with a PowerGen 700 high shear mixer.
1.2.9 Slowly add TEC / talc suspension to Eudragit® L30D-55 latex dispersion with stirring.
1.2.10 The coating dispersion was stirred for 1 hour and then applied onto metronidazole matrix pellets.

1.3 Preparation of Eudragit® S100 aqueous coating dispersion Dispersion Formulation The composition of the aqueous Eudragit® S100 dispersion applied to metronidazole matrix pellets is shown in Table 3 below.

B. Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part I:
(i) Dispensing Eudragit® S100 powder with stirring in deionized water.
(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. Add Part B after stirring for about 2 hours.
Part II:
(i) Disperse talc in the required amount of water.
(ii) The dispersion was homogenized with a PowerGen 700D high shear mixer.
(iii) Slowly add Part B to Part A polymer dispersion with gentle agitation.

1.4 Coating Conditions for Application of Aqueous Coating Dispersion System Matrix pellets were coated with each of Eudragit® L30D-55 and Eudragit® S100 aqueous film coating using the following coating parameters.
Coating Equipment STREA 1 (TM) Table Top Laboratory Fluid Bed Coater Spray Nozzle Diameter 1.0mm
Material filling 300g Inlet air temperature 40 ~ 45 ℃
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump speed 2g / min
(i) Coating the matrix pellet with L30D-55 dispersion to give the pellet a 12% increase in coating weight.
(ii) Coating the matrix pellet with S100 dispersion to give the pellet a 20% increase in coating weight.

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 in a ratio of 30%: 30%: 40%, respectively.
Fill with 3 different pellets to obtain a total dose of 375 mg / capsule.

Three 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.

231.2. Preparation of amoxicillin matrix pellets
231.2.1 Amoxicillin and Avicel® PH101 blended in a low shear blender.
231.2.2 Slowly add the hydroxypropyl methylcellulose binder solution into the powder blend while continuously mixing.
231.2.3 Extrude the wet mass with an LCI bench top granulator. The screen diameter of the bench top granulator was 0.8mm.
231.2.4 The extrudate was spheronized with a QJ-230 spheronizer using a small section plate.
231.2.5 The spheroidized pellets are dried 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.

231.4 Eudragit® L30D-55 aqueous dispersion preparation procedure
231.4.1 Suspend triethyl citrate and talc in deionized water.
231.4.2 Mix the TEC / talc suspension with a laboratory mixer.
231.4.3 TEC / talc suspension is slowly added to Eudragit® L30D-55 latex dispersion with stirring.
231.4.4 The coating dispersion was stirred for 1 hour and then applied onto amoxicillin matrix pellets.

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

B. Procedure for preparing Eudragit® S100 aqueous dispersion Part A:
231.6.1 Eudragit® S100 powder dispensed in deionized water with stirring.
231.6.2 Ammonium hydroxide solution was added dropwise to 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 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 Slowly add Part B to Part A polymer dispersion with gentle agitation.

231.7 Coating Conditions for Aqueous Coating Dispersion Application The following coating parameters were used for both Eudragit® L30D-55 and Eudragit® S100 aqueous film coating processes.
Coating Equipment STREA 1 (TM) Table Top Laboratory Fluid Bed Coater Spray Nozzle Diameter 1.0mm
Material filling 300g Inlet air temperature 40 ~ 45 ℃
Outlet air temperature 30 ~ 33 ℃
Spray pressure 1.8 bar Pump speed 2-6 g / min
231.7.1 Coated matrix pellets with L30D-55 dispersion to give the pellets a 20% increase in coating weight.
231.7.2 Coated matrix pellets with S100 dispersion to give the pellets a 37% increase in coating weight.

231.8.1 Amoxicillin and Avicel (R) PH101 blended in a low shear blender.
231.8.2 Slowly add hydroxypropylmethylcellulose binder solution into the powder blend with continuous stirring.
231.8.3 Dry the granulation at 60 ° C until the exhaust temperature reaches 40 ° C using a fluid bed dryer.
231.8.4 Collect 20-40 mesh granules for further processing.

231.9 Tableting of amoxicillin pellets

231.9.1 Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide are blended for 15 minutes in a tumble blender.
231.9.2 Add magnesium stearate to the blender and blend for 5 minutes.
231.9.3 The blend is compressed on a rotary tablet press.
231.9.4 The fill mass was adjusted to obtain 500 mg dose tablets.

Three Pulses Example 232 Clarithromycin Pellet Formulation and Preparation Procedure
232.1 Pellet Formulation The composition of clarithromycin matrix pellets is shown in Table 9.

232.2 Preparation Procedure for Clarithromycin Matrix Pellets
232.2.1 Blended clarithromycin, silicified microcrystalline cellulose and lactose monohydrate in a robotic coupe high shear granulator.
232.2.2 A binder solution is prepared by adding polyoxyl to pure water during stirring. After mixing it, slowly add hydroxypropylmethylcellulose and continue to stir until a solution is obtained.
232.2.3 Slowly add the binder solution into the powder blend under continuous mixing.
232.2.4 Granulate powder with binder solution in high shear granulator.
232.2.5 Extrude the wet mass with an LCI bench top granulator. The screen diameter of the bench top granulator was 1.2mm.
232.2.6 The extrudate was spheronized with a model SPH20 Caleva spheronizer.
232.2.7 The spheroidized pellets are dried overnight at 50 ° C.
232.2.8 18-30 mesh pellets were collected for further processing.

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

232.4 Preparation Procedure for Eudragit® L30D-55 Aqueous Dispersion
232.4.1 Suspend triethyl citrate and talc in deionized water.
232.4.2 Homogenize the TEC / talc suspension with a PowerGen700 high shear mixer.
232.4.3 Slowly add suspension from 4.2.2 to stirring Eudragit® L30D-55 latex dispersion.
232.4.4 The coating dispersion was stirred for 1 hour and then applied 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.

232.6 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
232.6.1 Eudragit® S100 powder dispensed in deionized water with stirring.
232.6.2 Ammonium hydroxide solution was added dropwise to the dispersion with stirring.
232.6.3 Stir the partially neutralized dispersion for 60 minutes.
232.6.4 Triethyl citrate is added dropwise to the dispersion with stirring, and after stirring for 60 minutes, Part B is added.
Part B:
232.6.5 Disperse talc in the required amount of water.
232.6.6 The dispersion was homogenized with a PowerGen700D high shear mixer.
232.6.7 Slowly add Part B to Part A polymer dispersion with gentle agitation.

232.7 Coating Conditions for Aqueous Coating Dispersion Application The following coating parameters were used for coating matrix pellets with each of Eudragit® L30D-55 and Eudragit® S100 aqueous film coating.
Coating Equipment STREA 1 (TM) Table Top Laboratory Fluid Bed Coater Spray Nozzle Diameter 1.0mm
Material filling 300g Inlet air temperature 40 ~ 45 ℃
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.6 bar Pump speed 2g / min
232.7.1 Coated matrix pellets with L30D-55 dispersion to give the pellets a 20% increase in coating weight.
232.7.2 Coat the matrix pellets with S100 dispersion to give the pellets a 37% increase in coating weight.
4). Capsules were filled with 30%: 30%: 40% by weight uncoated pellets, L30D-55 coated pellets and S100 coated pellets, respectively, to obtain 250 mg capsules.

Four 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.

233.2 Procedure for preparing metronidazole matrix pellets
232.2.1 A blend of metronidazole and Avicel® PH 101 using a robotic coupe high shear granulator.
232.2.2 Slowly add 20% povidone K29 / 32 binder solution into the powder blend while continuously mixing.
232.2.3 The wet mass is extruded with an LCI bench top granulator. The screen diameter of the bench top granulator was 1.0mm.
232.2.4 The extrudate was spheronized with a model SPH20 Caleva spheronizer.
232.2.5 Dry the spheroidized 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.

233.4 Eudragit® L30D-55 aqueous dispersion preparation procedure
233.4.1 Suspend triethyl citrate and talc in deionized water.
233.4.2 Homogenize the TEC / talc suspension with a PowerGen 700 high shear mixer.
233.4.3 Slowly add TEC / talc suspension to Eudragit® L30D-55 latex dispersion while stirring.
233.4.4 The coating dispersion was stirred for 1 hour and then applied onto metronidazole matrix pellets.

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

233.6 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
233.6.1 Dispensing Eudragit® S100 powder in deionized water with stirring.
233.6.2 Ammonium hydroxide solution was added dropwise to the dispersion with stirring.
233.6.3 Stir the partially neutralized dispersion for 60 minutes.
233.6.4 Triethyl citrate was added dropwise to 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 The dispersion was homogenized with a PowerGen 700D high shear mixer.
233.6.7 Slowly add Part B to Part A polymer dispersion with gentle agitation.

233.7 Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters were used for each coating with Eudragit® L30D-55 and Eudragit® S100 aqueous film coating.
Coating Equipment STREA 1 (TM) Table Top Laboratory Fluid Bed Coater Spray Nozzle Diameter 1.0mm
Material filling 300g Inlet air temperature 40 ~ 45 ℃
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.8 bar Pump speed 2g / min
233.7.1 Coated matrix pellets with L30D-55 dispersion to give the pellets a 12% increase in coating weight.
233.7.2 Coating the matrix pellets with L30D-55 dispersion to give the pellets a 30% increase in coating weight.
233.7.3 Coated matrix pellets with S100 dispersion to give pellets a 20% increase in coating weight.

1.5 Encapsulation of metronidazole pellets Immediate release matrix pellets (uncoated), L30D-55 coated pellets 12% mass increase, L30D-55 coated pellets 30% mass increase and S100 coated pellets 20%: 30%: 20% respectively: Fill into size 00 hard gelatin capsules at a rate of 30%.
Fill with 4 different pellets to obtain a total dose of 375 mg / capsule.

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.

234.2. Preparation of Amoxicillin Matrix Pellets
234.2.1 Blend Amoxicillin and Avicel® PH101 in a low shear blender.
234.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend while mixing continuously.
234.2.3 Extrude the wet mass with an LCI bench top granulator. The screen diameter of the bench top granulator was 0.8mm.
234.2.4 The extrudate was spheronized with a QJ-230 spheronizer using a small section plate.
234.2.5 The spheroidized pellets are dried 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.

234.4 Preparation Procedure for Eudragit® L30D-55 Aqueous Dispersion
234.4.1 Suspend triethyl citrate and talc in deionized water.
234.4.2 Mix the TEC / talc suspension with a laboratory mixer.
234.4.3 Slowly add the TEC / talc suspension to the stirred Eudragit® L30D-55 latex dispersion.
234.4.4 The coating dispersion was stirred for 1 hour and then applied onto amoxicillin matrix pellets.

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

234.7 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
234.7.1 Dispensing Eudragit® S100 powder in deionized water with stirring.
234.7.2 Add ammonium hydroxide solution drop by drop into the dispersion.
234.7.3 Stir the partially neutralized dispersion for 60 minutes.
234.7.4 Add triethyl citrate drop by drop into the dispersion, stir overnight, then 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 laboratory mixer.
234.7.7 Slowly add Part B to Part A polymer dispersion with gentle agitation.

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.

234.8.1.1 Prepare hydroxypropyl methylcellulose (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 water-based coating dispersion application
The following coating parameters were used for coating with Eudragit® L30D-55 and Eudragit® S100 aqueous film coating, respectively.
Coating Equipment STREA 1 (TM) Table Top Laboratory Fluid Bed Coater Spray Nozzle Diameter 1.0mm
Material filling 300g Inlet air temperature 40 ~ 45 ℃
Outlet air temperature 30 ~ 33 ℃
Spray pressure 1.8 bar Pump speed 2-6 g / min
234.9.1 Coated amoxicillin matrix pellets with L30D-55 dispersion to give the pellets a 20% increase in coating mass.
234.9.2 Coat another batch of amoxicillin matrix pellets with L30D-55 dispersion to obtain a 20% mass gain. The L30D-55 pellets are coated with an aquacoat dispersion to obtain a 10% coat weight increase.
234.9.3 Amoxicillin matrix pellets are coated with S100 dispersion to obtain a 37% coat weight increase.

234.10.1 Amoxicillin and Avicel® PH101 blended in a low shear blender.
234.10.2 Slowly add the hydroxypropyl methylcellulose binder solution into the powder blend with continuous stirring.
234.10.3 Dry the granulation at 60 ° C until the exhaust temperature reaches 40 ° C using a fluid bed dryer.
234.10.4 Collect 20-40 mesh granules for further processing.

234.11.1 Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide are blended for 15 minutes in a tumble blender.
234.11.2 Add magnesium stearate to the blender and blend for 5 minutes.
234.11.3 The blend is compressed on a rotary tablet press.
234.11.4 Adjust the fill mass to obtain a 500 mg dose tablet.

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

235.2 Preparation Procedure for Clarithromycin Matrix Pellets
235.2.1 Blended clarithromycin, silicified microcrystalline cellulose and lactose monohydrate in a robotic coupe high shear granulator.
235.2.2 Binder solution is prepared by adding polyoxyl to pure water during stirring. After mixing it, slowly add hydroxypropylmethylcellulose and continue to stir 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 with an LCI bench top granulator. The screen diameter of the bench top granulator was 1.2mm.
235.2.6 The extrudate was spheronized with a model SPH20 Caleva spheronizer.
235.2.7 The spheroidized pellets are dried overnight at 50 ° C.
235.2.8 18-30 mesh pellets were collected for further processing.

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

235.4 Preparation Procedure for Eudragit® L30D-55 Aqueous Dispersion
235.4.1 Suspend triethyl citrate and talc in deionized water.
235.4.2 Homogenize the TEC / talc suspension with a PowerGen700 high shear mixer.
235.4.3 Slowly add the suspension from 4.2.2 to the stirring Eudragit® L30D-55 latex dispersion.
235.4.4 The coating dispersion is stirred for 1 hour and then applied 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.

235.6 Preparation Procedure for Eudragit® S100 Aqueous Dispersion Part A:
235.6.1 Eudragit® S100 powder dispensed in deionized water with stirring.
235.6.2 Ammonium hydroxide solution was added dropwise to the dispersion with stirring.
235.6.3 Stir the partially neutralized dispersion for 60 minutes.
235.6.4 Add triethyl citrate dropwise to the dispersion and stir for 60 minutes, then add Part B. Part B:
235.6.5 Disperse talc in the required amount of water.
235.6.6 The dispersion was homogenized with a PowerGen700D high shear mixer.
235.6.7 Slowly add Part B to Part A polymer dispersion with gentle agitation.

235.7 Coating Conditions for Application of Aqueous Coating Dispersion The following coating parameters were used for coating with each of Eudragit® L30D-55 and Eudragit® S100 aqueous film coating.
Coating Equipment STREA 1 (TM) Table Top Laboratory Fluid Bed Coater Spray Nozzle Diameter 1.0mm
Material filling 300g Inlet air temperature 40 ~ 45 ℃
Outlet air temperature 30 ~ 33 ℃
Nebulization air pressure 1.6 bar Pump speed 2g / min
235.7.1 Coat matrix pellets with L30D-55 dispersion to give the pellets a 12% increase in coating weight.
235.7.2 Coat matrix pellets with L30D-55 dispersion to give the pellets a 30% increase in coating weight.
235.7.3 Coated matrix pellets with S100 dispersion to give the pellets a 37% increase in coating weight.

235.8 Encapsulation of clarithromycin pellets Immediate release matrix pellets (uncoated), L30D-55 coated pellets 12% mass increase, L30D-55 coated pellets 30% mass increase and S100 coated pellets 20%: 30%: 20 respectively Filled in size 00 hard gelatin capsules in a percentage of 30%.
Fill with 4 different pellets to obtain a total dose of 250 mg / capsule.

The antifungal, antiviral and anti-neoplastic dosage forms can be converted to a single product (e.g. 3 or 3) by using an antifungal or antiviral or neoplastic agent instead of antibiotics in a similar procedure to Examples 230-235. Product containing 4 antifungal dosage forms).
The present invention is particularly advantageous in that it provides therapeutic products that 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, the invention may be practiced otherwise than as specifically described within the scope of the appended claims.

Claims (11)

A once-daily oral amoxicillin tablet comprising first, second and third antibiotic dosage forms comprising:
Each of the antibiotic dosage forms comprises amoxicillin and a pharmaceutically acceptable carrier and is embedded in a tablet;
The first antibiotic dosage form is an immediate release dosage form, and the first antibiotic dosage form comprises microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium glycolate starch, hydroxy Propylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylated chitosan, crosslinked chitosan, crosslinked hydroxymethylchitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose An additive component selected from the group consisting of polyvinylpyrrolidone (PVP), acrylic acid derivatives, and polyethylene glycol,
It includes amoxicillin in said second antibiotic dosage form is delayed release agent forms, the second antibiotic dosage forms, cellulose acetate phthalate, Eudragit L, and from the group consisting of other phthalic acid salts of cellulose derivatives A pH-sensitive release component selected, wherein the third antibiotic dosage form comprises amoxicillin in a delayed release dosage form;
The third antibiotic dosage form comprises a pH sensitive release component selected from the group consisting of cellulose acetate phthalate, Eudragit L, and other phthalates of cellulose derivatives;
Each of the first, second and third antibiotic dosage forms initiates release at different times, and the serum concentration of total amoxicillin released from the amoxicillin tablets reaches Cmax in less than about 11 hours after administration. the once daily dosage form antibiotic comprises at least one antibiotic in an effective total dose over a 24-hour, the once daily dosage form oral amoxicillin tablet. The tablets, reach Cmax after 4 hours after dosing, once daily dosage form oral amoxicillin tablet according to claim 1. The antibiotic is released from the first antibiotic dosage form reaches the Cmax between about 0.5 to about 2 hours from the administration of a tablet, once daily dosage form orally according to claim 1 or 2 Amoxicillin tablets . The antibiotic is released from the second antibiotic dosage form reaches the Cmax within about 4 hours from the administration of a tablet, once daily dosage form oral amoxicillin according to claim 1 Tablets . Antibiotic released from the third antibiotic dosage form reaches the Cmax within 8 hours from the administration of a tablet, once daily dosage form oral amoxicillin tablet according to any one of claims 1-4 . 6. A once-daily oral amoxicillin tablet according to any one of the preceding claims, wherein the immediate release dosage form contains at least 20% and at most 50% of the total antibiotic dose. After the serum concentration of antibiotic released from the first antibiotic dosage form has reached the Cmax, the serum concentration of antibiotic released from the second antibiotic dosage form reaches Cmax, claim The once-daily oral amoxicillin tablet according to any one of 1 to 6. The serum concentration of antibiotic released from the third antibiotic dosage form reaches Cmax after the serum concentration of antibiotic released from the second antibiotic dosage form reaches Cmax. The once-daily oral amoxicillin tablet according to any one of 1 to 7.   The first antibiotic dosage form provides 20-35% by weight of the total dose of amoxicillin, the second antibiotic dosage form provides 30-60% by weight of the total dose of amoxicillin; 9. A once-daily oral amoxicillin tablet according to any one of claims 1 to 8, wherein the substance dosage form gives the remainder of the total dose of amoxicillin.   The antibiotic released from the first antibiotic dosage form reaches Cmax between about 0.5 and about 2 hours after administration of the product, and the constituent released from the second antibiotic dosage form is 10. The Cmax is reached within about 4 hours after administration of the product, and the antibiotic released from the third antibiotic dosage form reaches Cmax within 8 hours after administration of the product. The once-daily oral amoxicillin tablet according to one item.   The once-daily oral amoxicillin tablet according to any one of claims 1 to 10, wherein the tablet further comprises an additional dosage form.