MXPA00001417A

MXPA00001417A - Matrix controlled release device

Info

Publication number: MXPA00001417A
Application number: MXPA/A/2000/001417A
Authority: MX
Inventors: Govind Thombre Avinash; John Curatolo William; Thomas Friesen Dwayne; Alan Schriver Nightingale James; Elizabeth Appel Leah
Original assignee: Pfizer Products Inc
Priority date: 1999-02-10
Filing date: 2000-02-09
Publication date: 2002-05-09

Abstract

There is disclosed a controlled release dosage form for a low solubility drug that is a spray-dried or spray-coated amorphous solid dispersion of the drug in an ionizable cellulosic polymer matrix that is in turn incorporated into a secondary erodible polymeric matrix and a method of treating a disease or disorder comprising administering such a dosage form.

Description

CONTROLLED RELEASE DEVICE OF MATRIX TYPE The priority date of the provisional patent application being processed is claimed together with the present, serial number 60 / 119,400, filed on February 10, 1999.

BACKGROUND OF THE INVENTION It is well known that the bioavailability of poorly water soluble drugs is limited and that it is profoundly affected by factors such as the patient's fed state, the rate of metabolism in relation to the rate of absorption in the gastrointestinal tract and the dosage form. Many attempts have been made to improve the dosage form for such low solubility drugs, generally with a view to obtaining an increase in the concentration of the drug, thereby improving the absorption or bioavailability of the drug. Although many of these attempts have met with some success, they provide an immediate and frequently temporary increase in absorption in the sense that the levels of the drug in the blood reach an undesirably high level very rapidly. It would be more desirable to associate simultaneously, in a single dosage form, a high bioavailability for poorly soluble drugs with a controlled and sustained release of the drugs. Only a few attempts to achieve this goal have been published as procedures to improve bioavailability and it is generally considered that the procedures for achieving a controlled release of a drug are not compatible, the general opinion being that the use of controlled release techniques tends to to decrease the bioavailability. Examples of sustained release dosage forms include crystalline drug particles dispersed in a matrix core of an inflatable hydrogel that releases the drug by diffusion into the environment of use, described in U.S. Patent No. 4,624,848; a hydrogel-type receptacle containing a multiplicity of tiny pills in which each minute pill consists of a wall surrounding a crystalline drug core, described in U.S. Patent No. 4,851,232; and a two-layer tablet in which one layer is a crystalline drug mixed with a hydrogel and the other layer is a huidrogel, described in U.S. Patent No. 5,516,527. A sustained release dosage form consists of a tablet coated with a core of a solid drug dispersion in extremely hydrophilic polyoxamyte hydrogels that releases the drug by diffusion from the mass of the swollen tablet and by erosion of the surface of the tablet, described in PCT application No. 97/02017. This is in accordance with the view that water-soluble polymers are most suitable for forming amorphous solid dispersions of drugs in polymers [see Ford, Pharm. Acta Helv., 61, 3 (1986)]. United States patents us. 4,343,789, 4,404,183 and 4,673,564 present the same description of a sustained-release composition of the vasodilator nicardipine, comprising a solid amorphous dispersion of the drug in microcrystalline cellulose, poly (ethylene oxide), polyvinylpyrrolidone and the cellulosic polymers hydroxypropylcellulose , hydroxypropylmethylcellulose and hydroxypropylmethylcellulose phthalate. However, the preferred process for obtaining the dispersion is by means of a ball mill, a process that is long and laborious, and there is no recognition of the stabilizing properties of the amorphous state and of increasing the concentration of ionic alkaline cellulosic polymers to obtain the dispersion of the drug. Dosage forms of solid dispersions can be obtained by evaporation of the solvent, spray drying, spray coating, spraying a drug solution on the vehicle in a fluid bed granulator, twin screw extrusion, melt processing, mechanical mixing with ball mill and mechanical mixing at a high temperature but not at the melting temperature. See, for example, PCT application n ° 93/11749; European Patent Application No. 0 552 708; U.S. Patent No. 5,456,923; Chowdary et al., Indian Drugs, 32, 477 (1995); Dangprasirt et al., Drug Development & Ind. Pharm., 21, 2.323 (1995); and Goracinova et al., Drug Development & Ind. Pharm., 22, 255 (1996). Most drug release systems based on solid dispersions have been aimed at the release of poorly water soluble drugs because they generally tend to be immediate release forms; as a result, for drugs with short half-life of elimination, they have the drawbacks, inherent to these forms, of very high concentration peaks in the blood, short times after administration when the concentrations of the drug in the blood reach a maximum level (tmax ) and relatively short duration of effective levels of concentration in the blood. Furthermore, although better bioavailability has been reported with respect to that of crystalline drugs, however, the bioavailability of said dosage forms is often low in an absolute sense. Specifically, said drug delivery systems often exhibit a small total improvement of the concentration of the drug in the blood of a patient in a given period of time (commonly referred to as "AUC"), by reference to the calculation of the low area of the obtained curve. by representing the concentration of the drug in a patient's blood versus time). In the case of dispersion in a solid polyoxamer, described in PCT 97/02017, the dosage form suffers from a slow and incomplete release in cases where the drug is released by diffusion through a coating of a membrane due to the inherent low solubility of the drug; on the contrary, in cases in which the drug is released by erosion of the drug / polyoxamer dispersion, the release of the drug is typically variable and of order other than zero, depending on the state of the patient's feeding and the time of gastric retention . In addition, because the described polyoxamer dispersant polymers are highly hydrophilic and generally require aqueous solvents for dissolution, these polymers can not be used to form dispersions with hydrophobic drugs by processing in a solvent because it is difficult or impossible to dissolve the drug and the polymer in a common solvent. Therefore, there is still a need in the art for a controlled release dosage form for the release of a drug of low solubility with a short elimination half-life that provides improved bioavailability of the drug. These needs and others that will be apparent to those skilled in the art are satisfied by the present invention, which is summarized and described below in detail.

BRIEF DESCRIPTION OF THE INVENTION The present invention in its simplest form is a controlled release dosage composition comprising a substantially homogeneous solid amorphous dispersion of a drug of low solubility in a dispersion polymer which increases the concentration, in which the dispersion in turn is incorporated in an erodible (or hydrophilic) polymer matrix. The dispersion polymer is an ionizable cellulosic polymer, preferably containing alkylate substituents and carboxylic acids linked by ester bonds. At least a significant portion of the drug, that is, at least about 60%, is amorphous (compared to crystalline). More preferably, practically all of the drug, that is, at least about 75%, is amorphous. Most preferably, essentially all of the drug, that is, at least about 90%, is amorphous. The mechanism of drug release is by erosion or diffusion to gradually release the drug to the environment of use.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1-4 are graphs depicting drug release rates contributed by the controlled release composition of the present invention and comparative release rates of controls.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a dosage form specifically designed to provide the controlled release by an erosion or diffusion mechanism of a "low solubility" drug (defined below) that uses the drug in the form of a solid dispersion amorphous in which the majority of the drug (60%) is in an amorphous form, in comparison with the crystalline one, incorporating the dispersion in an erodible or hydrophilic polymer matrix. The term "drug" is conventional, and refers to a compound that has beneficial prophylactic and / or therapeutic properties when administered to an an, especially a man. "Erodable" matrix means an erodible matrix in water or water-swellable in the sense that it is erodible or swellable or soluble in pure water or that it requires the presence of an acid or a base to ionize the polymeric matrix sufficiently to originate erosion or dissolution. The shape of the device can be any conventional known form, including a tablet, a capsule, a microcapsule, a bead, a multiparticulate, a powder or combinations thereof, and is generally useful in mammals and particularly useful for therapeutic uses in man . The drug can be provided in the form of a gel or suspension of solids in water, or mainly in the form of a drug solution, so that extensive dissolution takes place before erosion. Without wishing to be limited by any particular theory of release mechanism, it is believed that the release takes place by one or more of the following mechanisms: (1) dissolution of the amorphous drug dispersion in the dosage form before erosion, together with diffusion from the dosage form, directly or through a coating, (2) dissolution of the dispersion when the matrix is eroded, with release mainly in the form of a solution, or (3) release as a solid suspension when the matrix is eroded , followed by dissolution in the gastrointestinal tract.

Both the amorphous solid dispersion component and the erodible matrix may contain osmogens, osmopolymers, solubility enhancing agents and excipients. In addition, delayed or sustained release characteristics can be added by coating the dosage form with controlled release coating formulations known in the art. The dosage form of the present invention generally provides a controlled release of the drug to an environment of use so that (1) the concentration of drug in the environment is increased in vitro or in vivo and, in turn, increases the bioavailability of the drug with respect to a comparable dosage form in which the drug is present in the non-dispersed state, ie, not incorporated in a solid dispersion prior to formulation, and (2) read time at which it is achieved that the maximum drug concentration (Cmax) in an in vitro or in vivo environment of use is delayed from 30 min to 24 hours. More specifically, the dosage forms of the invention provide one or more of the following characteristics: (1) they provide a Cmax in an in vitro aqueous environment assay, which is at least 1.5 times that achieved by an identical composition of controlled release dosage containing the same amount of drug in the non-dispersed state, (2) provide a Cmax in an in vitro aqueous environment test at a time (tmax) that is at least 30 minutes higher, but not more than 24 hours greater than the tmax observed when the solid dispersion is tested without incorporating it into a sustained release polymer matrix, (3) provide an AUC of drug concentration in an aqueous environment of use that is at least 1.25 times that achieved by an identical controlled release dosage composition containing the same amount of drug in an undispersed state, (4) when dosed orally to a man or another imal, provide a blood Cmax (in plasma or serum) that is achieved at a time tmax that is at least 30 minutes greater than that observed when dosing a control composition, the control composition comprising only the drug dispersion, is, has not been formulated in a sustained-release polymer matrix, (5) when dosed orally to a man or another animal, they provide a blood Cmax (in plasma or serum) that is at least 1, 25 times that observed when dosing a control composition, the control composition being identical to the test composition with the exception that the drug is formulated in an undispersed state, and (6) when dosed orally to one man or another animal, they provide an AUC of drug concentration in the blood that is at least 1.25 times that observed when dosing a control composition, the control composition being the same as that described in (5) .THE DRUG Prior to the formation of the dispersion, the drug in its pure state can be crystalline or amorphous but, when dispersed in the solid dispersion polymer, a major portion of the drug is in an amorphous or non-crystalline state so that its nature is not crystalline is demonstrable by powder X-ray diffraction analysis or by differential scanning calorimetry or by any other standard quantitative measurement. Preferably, the drug is substantially amorphous and more preferably is amorphous in its entirety. As used herein, the term "a significant portion" of the drug means that at least 60% of the drug in the dispersion is in an amorphous form rather than in a crystalline form. Preferably, the drug in the dispersion is substantially amorphous. As used herein, the term "substantially amorphous" means that the amount of the drug in crystalline form does not exceed 25%. More preferably, the drug in the dispersion is essentially completely amorphous, meaning that the amount of drug in crystalline form does not exceed 10%, measured by any of the above-mentioned procedures. "Amorphous" state means that the drug may be present in (a) drug-rich discrete amorphous domains, (b) homogeneously distributed throughout the dispersion polymer (e.g., a solid solution), or (c) any state or combination of states between the extremes of (a) and (b).

Preferably the solid dispersion is substantially homogeneous so that the drug is dispersed as homogeneously as possible by the polymer. As used herein, "substantially homogeneous" means that the drug present in relatively pure amorphous domains in the solid dispersion is relatively small, less than 20% and preferably less than 10%. Although the dispersion may have some drug-rich domains, it is preferred that the dispersion itself have a single glass transition temperature (Tg), which demonstrates that the dispersion is substantially homogeneous. This contrasts with a physical mixture of pure amorphous drug particles and pure amorphous polymer particles which generally exhibits two different vitreous transition temperatures, one that of the drug and another that of the polymer. Since the solubility of a given drug frequently depends on the pH, the device of the present invention is suitable for delivering any drug whose solubility, within any portion of the physiologically relevant pH range, falls within the ranges of solubility indicated herein. . In general, the class of drugs can be characterized as having a sufficiently low solubility so it is desirable to increase the solubility of the drug (a) in the dosage form to improve its release characteristics or (b) out of the dosage form to improve the speed or extent of drug absorption. The drug is a "low solubility drug", meaning that the drug has a minimum aqueous solubility, at a physiologically relevant pH (eg, pH 1-8), of about 40 mg / ml or less. Therefore, the drug can be "substantially insoluble in water", that is, have a minimum aqueous solubility, at a physiologically relevant pH, less than 0.01 mg / ml, or "poorly soluble in water", that is, have a solubility in water of up to about 1 to 2 mg / ml, or even a moderate solubility when the solubility is 20 to 40 mg / ml. In general, it can be said that the drug has an aqueous dose / solubility ratio greater than 5 ml when the solubility of the drug is the minimum value observed in any physiologically relevant aqueous solution, including gastric and intestinal tampons simulated according to the Pharmacopoeia of the U.S. In some cases, it is also desirable to increase the solubility of the drug in the dosage form to increase the rate of diffusion or release from the dosage form or to improve the absorption of drug in the colon. In such cases, the invention can be applied to drugs with a minimum aqueous solubility of 20 to 40 mg / ml. This is particularly true when it is desired to provide a solution of the drug. In such cases, the dose / aqueous solubility ratio may be only 1 ml. As a drug in the present invention practically any beneficial therapeutic agent can be used. In addition, the drug can be used in the form of its pharmaceutically acceptable salts as well as in its anhydrous and hydrated forms and prodrugs. Preferred classes of drugs include, but are not limited to, antihypertensives, antidepressants, antianxiety agents, antiatherosclerotic agents, anticoagulants, anticonvulsants, agents that reduce the level of glucose in the blood, decongestants, antihistamines, antitussives, anti-inflammatories, antipsychotic agents, cognitive function enhancers, cholesterol-lowering agents, anti-obesity agents, agents against autoimmune disorders, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, antiparkinson agents, antibiotics, antiviral agents, antineoplastic agents, barbiturates, sedatives, nutritional agents, beta-blockers, emetics, antiemetics, diuretics, anticoagulants, cardiotonic, androgens, corticosteroids, anabolic agents, antidepressant agents, anti-infective agents, coronary vasodilators, carbonic anhydrase inhibitors, antiprotozoals, gastrointestinal agents, serotonin antagonists, anesthetics, hypoglycemic agents, dopaminergic agents, agents against Alzheimer's disease, antiulcer agents, platelet inhibitors and glycogen phosphorylase inhibitors. The following are specific examples of these and of other classes of drugs and therapeutic agents provided by the invention, by way of example only. Specific examples of antihypertensives include prazosin, nifedipine, trimazosin and doxazosin mesylate; a specific example of an anti-anxiety agent is hydroxyzine; a specific example of an agent that reduces the level of glucose in the blood is glipizide; a specific example of agent against impotence is sildenafil citrate; specific examples of antineoplastics include chlorambucil, lomustine and equinomycin; Specific examples of anti-inflammatory agents include betamethasone, prednisolone, aspirin, flurbiprofen and (+) - N-. { 4- [3- (4-fluorophenoxy) phenoxy] -2-cyclopentene-1-yl} -N-hydroxycarbamide; a specific example of barbiturate is phenobarbital; specific examples of antivirals include acyclovir and virazole; specific examples of vitamins / nutritional agents include retinol and vitamin E; specific examples of beta-blockers include timolol and nadolol; A specific example of emetic is apomorphine; Specific examples of diuretics include chlorthalidone and spironolactone; A specific example of anticoagulant is dicumarol; specific examples of cardiotonics include digoxin and digitoxin; Specific examples of androgens include 17-methyltestosterone and testosterone; a specific example of a mineral corticoid is deoxycorticosterone; A specific example of a hypnotic / steroidal anesthetic is alfaxalone; specific examples of anabolic agents include fluoxymesterone and methanstenolone; Specific examples of antidepressant agents include fluoxetine, paroxitin, venlafaxine, sertraline, sulpiride, [3,6-dimethyl-2- (2,4,6-trimethylphenoxy) pyridin-4-yl] - (1-ethylpropyl) amine and 3,5-dimethyl-4- (3'-pentoxy) -2- (2 ', 4,, 6, -trimethenoxy) pyridine, specific examples of antibiotics include ampicillin and phenylpenicillin; specific examples of disinfectants include benzalkonium chloride and chlorhexidine; Specific examples of coronary vasodilators include nitroglycerin and myoflazine; a specific hypnotic example is etomidate; specific examples of carbonic anhydrase inhibitor include acetazolamide and chlorzolamide; Specific examples of antifungals include econazole, terconazole and griseofulvin; a specific example of an antiprotozoan is metronidazole; a specific example of an imidazole-type antineoplastic is tubulazole; specific examples of anthelminthic agents include thiabendazole and oxfendazole; Specific examples of antihistamines include astemizole, levocabastine and cinnarizine; Specific examples of antipsychotics include fluspirilene, penfluridol and ziprasidone; specific examples of gastrointestinal agents include loperamide and cisapride; specific examples of serotonin antagonists include ketanserin and mianserin; A specific example of an anesthetic is lidocaine; a specific example of hypoglycemic agent is acetohexamide; A specific example of an antiemetic is dimenhydrinate; a specific example of antibacterial is cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA; Specific examples of agents against Alzheimer's disease are THA and donepezil; a specific example of antiulcer agent / H2 antagonist is famotidine; Specific examples of sedatives / hypnotics include chlordiazepoxide and triazolam; a specific example of a vasodilator is alprostadil; a specific example of platelet inhibitor is prostacyclin; specific examples of ACE / antihypertensive inhibitors include enalapril and lisinopril acid; specific examples of tetracycline antibiotics include oxytetracycline and minocycline; Specific examples of macrolide antibiotics include azithromycin, clarithromycin, erythromycin and espriamycin; Specific examples of glycogen phosphorylase inhibitors include [R- (R * S *)] - 5-chloro-N-. { 2-hydroxy-3- [methoxymethylamino-3-oxo-1- (phenylmethyl) -propyl] propyl} -1 H-indole-2-carboxamide and 5-chloro- [(1S) -benzyl-3 - [(3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxypropyl] -amide 1 H-indole-2-carboxylic acid. Additional examples of drugs provided by the invention are the drug that reduces the level of glucose chlorpropamide, the antifungal drug fluconazole, the antihypercholesterolemic atorvastatin calcium, the antisychotic thiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride and doxepin hydrochloride, the amylodipine besylate antihypertensive drugs, the iroxicam antiinflammatories, valdecoxib and celicoxib and the antibiotics carbenicilinindanil sodium, bacampicillin hydrochloride, troleandomycin and doxycycline hyclate.

THE DISPERSION POLYMER Polymers suitable for forming the solid dispersion of the drug are preferably polymeric, capable of increasing the concentration, processable in a non-aqueous solvent, non-toxic and inert. "Non-aqueous solvent" means solvents comprising up to about 30% by weight of water. "Processable in a non-aqueous solvent" means that the polymer can be processed with the drug in a common non-aqueous solvent to form the solid dispersion, that is, it is generally adaptable to techniques using non-aqueous solvents in the formation of solid dispersions. Such techniques include spray drying or spray coating. The polymer has a preferred solubility in the non-aqueous solvent of at least 0.1 mg / ml, more preferably greater than 1 mg / ml and most preferably greater than 10 mg / ml. This property is critical for forming the solid amorphous dispersion of the drug and the dispersion polymer by processing in a solvent because the drug and the dispersion polymer must be dissolved in a common solvent and said solvents can not be substantially aqueous because the drugs, for definition, they have a relatively low aqueous solubility. Said dispersion polymers are water soluble in the sense that they are sufficiently soluble (> 1 mg / ml) in at least a portion of the pH range 1 to 8 to exhibit a property "capable of increasing the concentration" , "capable of increasing the concentration" means that the concentration of the drug provided by a solid dispersion in aqueous media is at least 1.5 times that provided by an equivalent amount of undispersed drug. "Non-toxic" means that they must be acceptable to be administered orally to a mammal, especially a man. "Inert" means that they are not reactive or bioactive in a negative sense but that they can positively affect the bioavailability of the drug.

The amount of the dispersion-enhancing polymer present in the dispersion generally ranges from about 10 to about 95% by weight, preferably from 30 to 80% by weight. A preferred class of concentration-enhancing polymers comprises ionizable cellulosic polymers (including those having ether or ester substituents or a mixture of esters / ethers and copolymers thereof, including the so-called "enteric" and "non-enteric" polymers). Examples of ionic cellulosic polymers include carboxymethylcellulose (CMC) and its sodium salt, carboxyethylcellulose (CEC), hydroxyethylmethylcellulose acetate phthalate (HEMCAP), hydroxyethylmethylcellulose acetate succinate (HEMCAS), hydroxypropylmethylcellulose phthalate (HMPCP), hydroxypropylmethylcellulose succinate (HPMCS) ), hydroxypropylcellulose acetate-phthalate (HPCAP), hydroxypropylcellulose acetate-succinate (HPCAS), hydroxypropylmethylcellulose acetate-phthalate (HPMCAP), hydroxypropylmethylcellulose acetate-succinate (HPMCAS), hydroxypropylmethylcellulose acetate-trimellitate (HPMCAT), acetate-phthalate of hydroxypropylmethylcellulose (HPMCAP), hydroxypropylcellulose butyrate-phthalate (HPCBP), carboxymethylethylcellulose (CMEC) and its sodium salt, cellulose acetate-phthalate (CAP), methylcellulose acetate-phthalate (MCAP), cellulose acetate-trimellitate (CAT) , cellulose acetate-terephthalate, cellulose acetate-isophthalate, cellulose propionate phthalate, propionate trimellitate of cellulose and cellulose trimellitate butyrate. Of these cellulosic polymers, it has been found that an even more preferred class of concentration-enhancing polymers are ionic cellulosic polymers that have a significant substitution with an alkylate substituent and with a carboxylic acid substituent linked by an ester linkage. Examples of alkylate substituents are acetate, propionate and butyrate. Examples of carboxylic acid substituents linked by an ester linkage are phthalate, succinate, trimellitate, terephthalate, isophthalate, pyridinedicarboxylate and salicylate. Such polymers are preferred because they generally produce drug dispersions having a particularly advantageous combination of excellent concentration enhancing properties as well as good physical stability. "Good physical stability" means that the drug present in the amorphous solid dispersions tends to remain in its amorphous state, after storage, with respect to dispersions of other polymers. Good physical stability of solid amorphous dispersions of drug and such ionic cellulosic polymers alkylate substituent and carboxylic acids linked by esters may well be the result of the relatively high glass transition temperature of such dispersions, especially in the presence of moisture, as well as its tendency to inhibit the crystallization of the drug. Furthermore, its tendency to inhibit the crystallization of the drug in aqueous solution can also cause its excellent concentration increasing properties and, in turn, its tendency to favor an increased bioavailability in drugs of low solubility. Examples of ionic cellulosic polymers alkylate substituent and carboxylic acids linked by an ester bond include HEMCAP, HEMCAS, HPCAP, HPCAS, HPMCAP, HPMCAS, HPMCAT, HMPCAP, HPCBP, CAP, MCAP, CAT, acetate terephthalate, cellulose acetate isophthalate of cellulose, cellulose propionate-phthalate, cellulose propionate trimellitate, cellulose butyrate-tri-cellulose and mixtures thereof. Of these, the most preferred ones are HPMCAS, CAP and CAT. It is noted that in the above nomenclature of polymers, the substituents attached by an ether linkage are listed after "cellulose" as the moiety attached to the ether group (for example, "ethylbenzoic cellulose-acid" has having substituents benzoic acids) and substituents linked by an ester bond are mentioned before "cellulose" as the carboxylate (for example, "cellulose phthalate" has one carboxylic acid of each phthalate moiety attached by an ester to polymer bond and the other carboxylic acid unreacted ). It should also be noted that the name of a polymer, as "acetate phthalate" refers to any of the family of cellulosic polymers that have acetate and phthalate groups attached via ester bonds to a significant fraction of the hydroxyl groups of the cellulosic polymer . Generally, the degree of substitution of each substituent group can vary from 0.1 to 2.8 as long as the other polymer criteria are met. "Degree of substitution" refers to the average number of three hydroxyl per repeating unit of saccharide in the cellulose chain that has been replaced. For example, if all of the hydroxyls of the cellulose have been replaced by phthalate degree of substitution is 3. phthalate Within each type of polymer families also include cellulosic polymers having relatively small additional substituents added in amounts so they do not substantially alter the behavior of the polymer.

THE SOLID AMORFA DISPERSION The solid dispersion generally contains from about 5 to about 90% by weight of drug, preferably from 20 to 70% by weight. However, when the dose of the drug is less than 25 mg, the drug content in the dispersion may be less than 5% by weight. In some cases, the solid amorphous drug dispersion can be prepared essentially by any known method, such as melt processing, trituration with a ball mill or processing in a solvent. However, the preferred method is processing in a solvent, such as spray drying or spray coating, which removes the solvent relatively quickly. When prepared by such rapid processing in a solvent, a major portion of the drug (> 60%) is almost always in the amorphous state and often substantially all (> 75%), if not essentially all (> 90%), It is in an amorphous state. "Amorphous" means that the drug may be present in the dispersion in any of the three general classes of forms: (a) in drug-rich discrete domains, (b) homogeneously distributed in the dispersion, that is, a solid solution, or (c) any state or combination of states between the extremes of (a) and (b). As mentioned above, preferably the solid amorphous dispersion is substantially homogeneous. The processing in a solvent is preferred because it tends to give more homogeneous dispersions and because the processing in the molten state is not suitable for use with many of the dipping polymer capable of increasing the preferred concentration. In particular, processing in a solvent is preferred in a manner such as spray drying or spray coating, in which the polymer / drug solution is solidified by rapid removal of the solvent (preferably in less than 1 second) because it has been found to originate more homogeneous dispersions. When prepared by such processing in a solvent, a homogeneous solution of the drug and dispersion polymer is formed in a common solvent, alone or together with other excipients which may or may not be dissolved, and is then prepared relatively quickly. solvent by precipitation or evaporation. "Common solvent" means one or more solvents in which both the drug and the dispersion polymer are soluble at a given pressure and temperature. The reason why said processing in a solvent is preferred is that it allows the drug and the dispersion polymer to be intimately mixed at the molecular level, thereby achieving homogeneity (difficult to achieve by mechanical processing) without applying excessive heating (required in melt processing) and causes a major portion of the drug (> 60%) to be in an amorphous state, compared to crystalline. Crystallization is typically induced by contacting the matrix / drug solution with a non-solvent, such as water, a liquid hydrocarbon or supercritical CO2. A particularly preferred method for forming the dispersion is to dissolve the drug and the matrix polymer in a common solvent, remove the solvent by drying the mixture by spraying or by spraying the mixture. Spray drying and spray coating methods and equipment are generally described in Perry's Chemical Engineer Handbook (6th edition, 1984), p. 20-54 to 20-57. More details on spray drying procedures and equipment are described by Marshal at 50 Chem. Eng. Prog. Monogr. Series 2 (1954). The terms "spray drying" and "spray coating" in relation to the present invention are conventionally used and generally refer to processes which involve breaking liquid mixtures into small droplets (atomization) and rapidly separating the solvent from the mixtures in a container such as a spray drying apparatus, a fluidized bed coating apparatus or a tray coating apparatus, in which there is an intense motive force for the evaporation of the solvent from the droplets. In the case of spray coating, the droplets collide on a particle, bead, pill, tablet or capsule, causing a coating comprising the amorphous solid dispersion. Spray coating can also be carried out on a metal, glass or plastic surface and subsequently the coated layer can be separated and crushed to the desired particle size. In the case of spray drying, the droplets are generally dried before hitting a surface, thereby forming amorphous solid dispersion particles with a diameter of the order of 1 to 100 μm. The strong driving force for the evaporation of the solvent is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus below the vapor pressure of the solvent at the drying temperature of the droplets. This is accomplished by (1) maintaining the pressure in the partial vacuum spray drying apparatus (eg, from 0.01 to 0.50 * 105 Pa), (2) mixing the liquid droplets with a hot drying gas, or (3) by both procedures. For example, a drug solution and a dispersion polymer, such as HPMCAS, can be conveniently dried in acetone by atomizing the solution at a temperature of 50 ° C (the vapor pressure of the acetone at 50 ° C is approximately 0.8 * 105 Pa) in a chamber maintained at a total pressure of 0.01 to 0.2 * 105 Pa by connecting the outlet to a vacuum pump. Alternatively, this solution can be sprayed in a chamber where it is mixed with nitrogen gas at a temperature of 80 to 250 ° C and at a pressure of 1.0 to 1.2 * 105 Pa. Generally, the temperature and flow rate are chosen. of the drying gas so that the droplets of the drug / dispersion polymer solution dry sufficiently long as they reach the wall of the apparatus so that they are essentially solid so that they form a fine powder and do not adhere to the appliance wall. The actual time to achieve this level of dryness depends on the size of the droplets. The droplets generally have a diameter greater than 1 μm, a diameter of 5 to 100 μm being typical. The large surface / volume ratio of the droplets and the strong motive power for solvent evaporation result in real drying times of a few seconds or less. For some drug / dispersion / solvent polymer mixtures, this rapid drying is critical for the formation of a homogeneous uniform composition and generally to prevent the mixture from separating into a drug-rich phase and a polymer-rich phase, although a limited degree of phase separation. Said dispersions having a homogeneous composition can be considered as solid solutions and can be supersaturated with drug. Such homogeneous dispersions are preferred because the maximum drug concentration (MFC) value obtained when dosing a large drug amount may be greater for said dispersions with respect to dispersions in which at least a portion of the drug is present as a phase. crystalline or amorphous drug-rich. The solidification times must be less than 100 seconds, preferably less than a few seconds and more preferably less than 1 second. In general, in order to achieve such rapid solidification of the drug / polymer solution, it is preferred that the diameter of the droplets formed during the spray drying process be less than 100 μm, preferably less than 50 μm and it is most preferable that it be less than 25 μm. The particles thus formed resulting from the solidification of these droplets generally tend to have a diameter of 2 to 40 μm. After solidification, typically the solid powder remains in the spray-drying chamber for 5 to 60 seconds, evaporating more solvent. The final solvent content in the solid dispersion when it leaves the dryer should be low since a low solvent content tends to reduce the mobility of the drug molecules in the dispersion thereby improving its stability. Generally, the residual solvent content in the dispersion should be less than 10% by weight, preferably less than 2% by weight. The spray-dried solution for forming the drug / polymer dispersion can be quite simple, containing only drug and polymer in a solvent. Generally, the ratio of polymer to drug in the solution ranges from 0.1 to 20 and preferably ranges from 0.5 to 5.

However, when the drug dose is low (less than 20 mg), the ratio of polymer to drug can be even higher than 5. Other excipients can be added to the spray solution, dissolved together in the solvent together with the drug and dispersion polymer or suspended in the solution forming a suspension. Said excipients may include: acids, bases or buffers for modifying the ionic state and the dissolution properties of the resulting dispersion, fillers, binders, dragees or other materials to improve the tablet manufacturing process or the final properties of the dosage form; antioxidants to improve the stability of the dispersions; osmotic agents, including water-swellable hydrophilic polymers and osmogens, such as hygroscopic sugars, organic acids and polyols; and surfactants to influence the wetting of the dosage form. Suitable solvents for spray drying can generally be characterized as "non-aqueous" in the same sense as mentioned above, that is, they comprise less than 30% by weight of water. Essentially, they can be any organic compound in which the drug and the polymer or mixtures of water and / or organic compounds are mutually soluble. In the case of mixtures of water and organic compounds, up to 30% by weight of water can be advantageously included, particularly in cases where the organic solvent is more hydrophobic than the drug. Preferably, the solvent is also relatively volatile, with a boiling point of 150 ° C or less. Although solvents with lower volatility can also be used, they are generally less preferred. In cases where the solubility of the drug in the volatile solvent is low, it may be desirable to include a small amount, such as from 2 to 25% by weight, of a low volatility solvent, such as N-methylpyrrolidone (NMP). or dimethyl sulfoxide (DMSO) in order to increase the solubility of the drug. In addition, the solvent should have a relatively low toxicity and should be able to be separated from the dispersion at a level that is acceptable according to the guidelines of the International Harmonization Committee. The separation of solvent at this level may require a processing step, such as spray drying, subsequent to the spray dispersion drying process or spray dispersion coating. Preferred solvents include alcoholkes, such as methanol, ethanol, n-propanol, isopropanol and butanol; ketones, such as acetone, methyl ethyl ketone and methyl isobutyl ketone; esters, such as ethyl acetate and propyl acetate; and various other solvents, such as acetonitrile, emethylene chloride, toluene and 1,1,1-trichloroethane. Solvents of lower volatility, such as acetamide or DMSO, can also be used. Mixtures of solvents, such as mixtures of up to 30% by weight of water, can also be used, provided that the polymer and the drug are sufficiently soluble to make the spray-drying process practical. In general, the solid amorphous dispersion provides a Cmax in an environment of use that is at least 1.25 times that of a control dosage form comprising an equivalent amount of undispersed drug (typically the control is simply the crystalline drug). only in its thermodynamically more stable state unless the crystalline form of the drug is not known, in which case the control is the amorphous drug alone). Alternatively, the dispersion of the present invention, when tested in vitro in a physiologically relevant aqueous solution, provides an AUC value of at least 1.5 times that measured for an equivalent amount of undispersed drug. Preferably, when administered orally, the dispersion also provides an AUC (area under the curve of the drug concentration plot in the blood versus time) in vivo that is at least 1.25 times that observed when dosing an equivalent amount of undispersed drug.

OTHER COMPONENTS OF THE DISPERSION The solid dispersion of the amorphous drug of the drug delivery device may contain a wide variety of additives and excipients, the purpose of which is to increase the bioavailability of the drug. The dispersion may include osmotically effective solutes, often referred to as "osmogens". Typical useful osmogens include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose and mixtures thereof. Particularly preferred osmogens are glucose, lactose, sucrose, sodium chloride, mannitol and xylitol. The solid dispersion may also include from about 1 to about 20% by weight of agents that increase or reduce solubility, which promote or retard the dissolution rate of the dispersion, including the drug. Examples of suitable agents that increase solubility include surfactants; pH control agents, such as buffers, organic acids, salts of organic acids and organic and inorganic bases; glycerides; partial glycerides; glyceride derivatives; esters of polyhydric alcohols; esters of polyethylene glycol (PEG) and of polypropylene glycol (PPG); sorbitan esters; polyoxyethylene sorbitan esters; carbonate salts; alkylsulfonates; and cyclodextrins. Examples of agents that increase or reduce the solubility are; organic acids, such as citric acid; salts of organic acids, such as calcium acetate; partial glycerides, such as glyceryl monostearate; glycerides, such as triacetin; glyceride derivatives, such as glyceryl succinate; polyethylene glycol esters, such as polyoxyethylene laurate; polypropylene glycol esters, such as polyoxypropylene stearate; esters of polyhydric alcohols, such as glucose laurate; sorbitan esters, such as polysorbate 80; carbonate salts, such as calcium carbonate; alkylsulfonates, such as sodium lauryl sulphonate; and cyclodextrins, such as sulfobutyl ether-β-cyclodextrin. The solid dispersion may include additives or excipients that promote stability, tablet formation or dispersion processing. Such components include adjuvants from the manufacture of tablets, surfactants, water-soluble polymers, pH modifiers, fillers, binders, pigments, disintegrants, lubricants and flavorings. Examples of said components are microcrystalline cellulose; metal salts of acids, such as aluminum stearate, calcium stearate, magnesium stearate, sodium stearate and zinc stearate; fatty acids, hydrocarbons and fatty alcohols, such as stearic acid, palmitic acid, liquid paraffin, stearyl alcohol and palmitol; fatty acid esters, such as (glyceryl mono- and di-) stearates, triglycerides, glyceryl palmitic-stearic ester, sorbitan monostearate, sucrose monostearate, sucrose monopalmitate and sodium stearyl fumarate; alkyl sulphates, such as sodium lauryl sulfate and magnesium lauryl sulfate; and inorganic materials, such as talc and dicalcium phosphate. All these additives and excipients can be added directly to the solution to be spray dried so that the additive is dissolved or suspended in the solution as a suspension. Alternatively, said components may be added after the spray drying process to help obtain the final dosage form.

THE EROSIONABLE MATRIX The erodible polymeric matrix in which the solid dispersion is incorporated can generally be described as a set of excipients which mix with the dispersion after its formation and which, when brought into contact with the aqueous environment of use, imbibe water and form a swollen gel of water or "matrix" that traps the dispersion. The release of the drug can occur by a variety of mechanisms: the matrix can disintegrate or dissolve from around the particles or granules of the dispersion; or the drug can be dissolved in the embedded aqueous solution and diffused from the tablets, beads or granules of the dosage form. A key ingredient of this swollen water matrix is the soluble, erodible or water swellable polymer which can generally be described as an osmopolymer, hydrogel or water swellable polymer. Said polymers can be linear, branched or crosslinked. They can be homopolymers or copolymers. Although they may be synthetic polymers derived from vinyl, acrylate, methacrylate, urethane, ester and oxide monomers, they are preferably derived from natural polymers, such as polysaccharides or proteins. Such materials include natural polysaccharides, such as chitin, chitosan, dextran and pullulan; agar gum, gum arabic, karaya gum, locust bean gum, tragacanth gum, carrageenans, ghatti gum, guar gum, xanthan gum and scleroglucan; starches, such as dextrin and maltodextrin; hydrophilic colloids, such as pectin; phosphatides, such as lecithin; alginates, such as ammonium, sodium, potassium, calcium or propylene glycol alginate; jelly; collagen and cellulosic polymers. A preferred class of cellulosic polymers for the erodible matrix comprises water soluble and water erodible cellulosic polymers, such as ethyl cellulose (EC), methyl ethyl cellulose (MEC), CMC, CMEC, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), cellulose acetate ( CA), cellulose propionate (CP), cellulose butyrate (CB), cellulose acetate-butyrate (CAB), CAP, CAT, HPMC, HPMCP, HPMCAS, HPMCAT and ethylhydroxyethylcellulose (EHEC). A particularly preferred class of such cellulosic polymers comprises various grades of HPMC of low viscosity (molecular weight equal to or less than 50,000 daltons) and of high viscosity (molecular weight equal to or greater than 50,000 daltons). Low viscosity HPMC polymers, commercially available, include the E5, E15LV, E50LV and K100LY series from METHOCEL, Dow, while high viscosity HPMC polymers include E4MCR, E10MCR, K4M, K15M and K100M; from this group, the METHOCEL® K-series is especially preferred. Other commercially available types of HPMC include the METOLOSE 90SH series from Shinetsu. Although the main function of the erodible matrix material is to control the rate of release of the drug to the environment of use, the present inventors have found that the choice of matrix material can have a significant effect on the maximum drug concentration obtained by the drug. controlled release dosage form as well as the maintenance of a high concentration of drug. The appropriate choice of polymer, in turn, affects the bioavailability of the drug, it has been found that water-swellable cellulosic polymers, such as certain qualities of methylcellulose (MC) or HPMC, when used as the main matrix material of the matrix speed controller, can cause higher maximum drug concentrations in vitro than other conventional matrix polymers, such as polyoxamers (eg, PEO or PEG) or polymers of carboxylic acids, such as CMC or calcic CMC or poly (acrylic acids) ) as Carbopol. Therefore, a particularly preferred embodiment of the invention comprises a substantially amorphous solid dispersion of drug in a cellulosic polymer incorporated in beads, granules or controlled release tablets, wherein the matrix polymer comprises a water soluble cellulosic polymer. It has been found that, in the aqueous environment of use, said dosage forms provide an area under the curve of the graph of drug concentration versus time that is at least 1.25 times that of an identical control dosage composition. except for the fact that the polymer matrix comprises poly (ethylene oxide) (PEO), in which the PEO has a molecular weight such that the time for 50% release of the drug from the control is greater than 80% but less than 120% of the time that 50% of the drug is released from the dosage composition of the present invention. Examples of said cellulosic polymers are MC, HEC, HPC, hydroxyethylmethylcellulose, HPMC and other intimately related water-soluble polymers. Preferably, the matrix material comprises MC or HPMC. Other materials useful as erodible matrix material include, but are not limited to, pullulan, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol esters of fatty acids, polyacrylamide, poly (acrylic acid), copolymers of ethacrylic acid or methacrylic acid (EUDRAGIT®, Rohm America Inc., Piscataway, New Jersey) and other acrylic acid derivatives, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate , 2-dimethylaminoethyl methacrylate and trimethylaminoethyl methacrylate-chloride. The erodible matrix polymer may contain dispersion polymers that increase the concentration of the type discussed above. In addition, the erodible matrix polymer can contain a wide variety of the same types of additives and excipients known in the pharmaceutical art and discussed above, including osmopolymers, osmogens, agents that increase or delay solubility and excipients, to promote stability or the processing of the dosage form.

ENTRERIC COATINGS The dosage compositions of the present invention can also be coated with one or more pH-sensitive coating compositions, commonly referred to in the art as "enteric coatings," according to conventional methods for delaying drug release. Suitable pH sensitive polymers include those which are relatively insoluble and impervious to the pH of the stomach, but which are more soluble or disintegrable or permeable to the pH of the small intestine and colon. Such pH-sensitive polymers include polyacrylamides, phthalate derivatives, such as acid phthalate of carbohydrates, amyl acetate-phthalate, cellulose acetate phthalate (CAP), other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate (HPCP) ), hydroxypropyl ethylcellulose phthalate (HPECP), hydroxypropylmethylcellulose phthalate (HPMCP), HPMCAS, methylcellulose phthalate (MCP), poly (vinyl acetate) phthalate (PVAcP), poly (vinyl acetate-phthalate acid), sodium CAP, starch acid phthalate, cellulose acetate trimellitate (CAT), styrene-maleic acid copolymer and dibutyl phthalate, styrene-maleic acid / poly (vinyl acetate phthalate) copolymers, styrene-maleic acid copolymers, poly (acrylic acid), such as copolymers of acrylic acid and acrylic esters, poly (methacrylic acid) and esters thereof, copolymers of poly (acrylic acid) and poly (methacrylic acid), shellac and c vinyl acetate and crotonic acid copolymers.

Preferred pH-sensitive polymers include shellac, phthalate derivatives, CAT, HPMCAS, poly (acrylic acid) derivatives, particularly copolymers comprising acrylic acid and at least one ester of acrylic acid, poly (methyl methacrylate) mixed with acrylic acid and with copolymers of acrylic esters, and copolymers of vinyl acetate and crotonic acid. A particularly preferred group of pH sensitive polymers include CAP, PVAcP, HPMCP, HPMCAS, anionic acrylic copolymers of methacrylic acid and methyl methacrylate, and osmopolymers comprising acrylic acid and at least one acrylic acid ester. The cellulose acetate phthalate can be applied as an enteric coating to the dosage forms of the invention to provide a delayed release of the drug until the dosage form has left the stomach. The CAP coating solution may also contain one or more plasticizers, such as diethyl phthalate, polyethylene glycol 400, triacetin, triacetin citrate, propylene glycol and others known in the art. Preferred plasticizers are diethyl phthalate and triacetin. The CAP coating formulation may also contain one or more emulsifiers, such as polysorbate 80. Anionic acrylic copolymers of methacrylic acid and methyl methacrylate are also particularly useful coating materials for delaying drug release until the tablets have been moved to a position in the gastrointestinal tract distal to the stomach. Copolymers of this type from Rohm America Inc. are available under the trade names EUDRAGIT-L® and EUDRAGIT-S®. EUDRAGIT-L® and EUDRAGIT-S® are anionic copolymers of methacrylic acid and methyl methacrylate. The ratio of free carboxyl groups to esters is approximately 1: 1 in EUDRAGIT-L® and approximately 1: 2 in EUDRAGIT-S®. Mixtures of EUDRAGIT-L® and EUDRAGIT-S® can also be used. For coating, these acrylic coating polymers can be dissolved in an organic solvent or in a mixture of organic solvents or suspended in aqueous media. Solvents useful for this purpose are acetone, isopropyl alcohol and methylene chloride. In coating formulations of acrylic copolymers it is generally advisable to include a -20% by weight of a plasticizer. Useful plasticizers include polyethylene glycols, propylene glycols, diethyl phthalate, dibutyl phthalate, castor oil and triacetin. EUDRAGIT-L® is preferred because it dissolves relatively quickly at the pH of the intestine. In addition to the aforementioned pH sensitive polymers, the delayed release coatings may consist of a mixture of two or more pH sensitive polymers or may consist of a mixture of one or more pH sensitive polymers and one or more non-sensitive polymers. pH. The addition of a non-pH-sensitive polymer to the pH-sensitive polymer is useful for modulating the duration of the delay or the rate of drug release from the granule, bead or tablet. For example, the delay can be lengthened by mixing a water-insoluble polymer with the pH-sensitive polymers, while the delay can be shortened by mixing a water-soluble polymer with the pH-sensitive polymers. Preferred non-pH-sensitive and water-insoluble polymers include cellulose esters, cellulose ethers, polyacrylates, polyamides, polyesters and vinyl polymers. Preferred non-pH-soluble and water-soluble polymers include cellulosic polymers such as HPC, HEC and HPMC substituted with hydroxyalkyls, copolymers of PVA, PEG, PEO and PEG / PPG, and polyamides, polysaccharides and water-soluble polyacrylates. Various additives may be included in said coatings, including emulsifiers, plasticizers, surfactants, fillers and buffers. Finally, the polymeric coating can be described as "quasi-etheric" in the sense that it remains substantially intact for a significant period of time (eg, greater than one hour) after the dosage form has left the stomach, thereafter being sufficiently permeable to the drug to allow the gradual release of drug by diffusion through the coating.

USE AND MANUFACTURE When used, the solid dispersion in the erodible matrix absorbs water from the environment of use forming an inflatable mass in water. The drug can be released by diffusion from the dispersion or by slow erosion of the dispersion in the environment of use. Therefore the drug is released mainly as a drug solution or as a drug suspension; when it is added as a suspension, the formulation of the drug is subsequently dissolved in the environment of use, such as the intestinal tract. The dosage forms of the present invention can be obtained essentially by any known process suitable for the manufacture of tablets, microcapsules, capsules, beads, multi-particulate formulations, suspensions powders or unit dosage containers, commonly called sachets, in which the drug crystalline has been replaced by solid dispersion. For example, the ingredients can be mixed, crushed and granulated wet or dry to form a homogeneous mixture of ingredients. The blended ingredients may be tableted using conventional presses, or the ingredients may be segregated and then compressed to form tablets with a coated or layered geometry. Additionally, when the dosage form comprises multiparticulate shapes, beads or powders, said materials are prepared, for example, by melt aggregation on a rotating disk, spherical forming by extrusion or granulation in a fluidized bed or coating non-pareil seeds. a mixture of water or an organic solvent and the components of the dosage form. After transformation of the solid dispersion of the drug and the erodible polymer matrix into tablets, microcapsules, beads, powders, multiparticulate formulations or capsules, they can be additionally coated with a pH-sensitive enteric or quasi-stent coating or with a coating that masks the taste , improve the appearance or facilitate the taking of the dosage form. Said coatings can be manufactured by any conventional means, including fluidized bed coating, spray coating, tray coating and powder coating using aqueous or organic solvents. Additionally, the dosage form may comprise an intermediate release layer thereof or a deferent drug which is used to form the solid dispersion, the drug being, or drugs, in crystalline, amorphous or dispersion form. The dosage forms of this invention are useful for treating a variety of conditions and diseases, including those exemplified herein, by administering the dosage forms described herein to a mammal in need of such treatment.

EXAMPLE 1 Typical dosage forms of the present invention were made by first forming a batch of a 1: 2 solid dispersion ("SD") comprising 1 part of a drug of low solubility and 2 parts of dispersion polymer, mixing the drug [(1S ) -benzyl-3 - [(3R, 4S) -dihydroxy-pyrrolidin-1-yl- (2R) -hydroxy-3-oxypropyl] amide of 5-chloro-1 H-indole-2-carboxylic acid (a glycogen phosphorylase inhibitor, from Pfizer Inc.) having a solubility in water of 80 μg / ml, in the solvent acetone together with a "good average" quality (MF) of HPMCAS (AQUOT, from Shinetsu, Tokyo, Japan) to form a solution. The composition of the solution was 2.5% by weight of drug, 5% by weight of polymer and 92.5% by weight of solvent. This solution was then spray dried by directing a spray device using a Niro two fluid nozzle at 2.8 * 105 Pa and 200 g / min of feed rate in a stainless steel chamber of a Niro portable spray dryer maintained at 180 ° C at the entrance and 70 ° C at the exit. Portions of the drug dispersion were collected and subjected to analysis by observing the dispersion with a scanning electron microscope to verify that the drug was in an amorphous state, not crystalline. To incorporate the resulting SD into the erodible polymer matrix, then, 0.05 g of the SD particles were mixed with 1.7 g of HPMC (METHOCEL K 100 LV Prem., Dow Chemical, Midland, Michigan), 0, 70 g of the FAST FLOW lactose load (from Foremost / Van Water and Rogers, Baraboo, Wisconsin) and 0.0525 g of the magnesium stearate lubricant, mixing for 20 minutes in a TURBULA mixer (by Willy A. Bachofen AG Muschinenfabrik, Basel , Switzerland) to make the mixture homogeneous. The homogeneous mixture thus formed contained 10% by weight of drug, 20% by weight of HPMCAS-MF, 48.5% by weight of METHOCEL, 20% by weight of lactose and 1.5% by weight of magnesium stearate. This homogeneous mixture was formed into granules using an F-3 press (from Manesty, Liverpool, England) with 8.73 mm tooling. The weight of the tablets was approximately 350 mg. As control (control A), tablets are prepared in a similar manner except that, instead of using the drug SD / HPMMCAS-MF, a non-dispersed mixture of 1 part crystalline drug and 2 parts dispersion polymer was used. (HPMCAS-MF). As a second control (control B) 37.4 mg of crystalline drug without erodible matrix was used. As a third control (control C) 106.1 mg of the SD were used with non-erodible polymer matrix. A phosphate buffered saline (PBS) was prepared comprising 20 mM sodium phosphate, 466 mM potassium phosphate, 87 mM NaCl and 0.2 mM KCl, adjusted to pH 6.5. Four in vitro dissolution tests were performed in 35 ml of the PBS solution at 37 ° C to test the release efficiency of the drug from the dosage composition of the invention, measured against controls A, B and C. Drug concentrations over time periodically taking samples from each of the four solutions, centrifuging the samples for 1 minute at 13,000 rpm to granulate the undissolved drug, collecting the supernatant and analyzing the sample by high-performance liquid chromatography ( HPLC) to calculate the drug concentrations. The results are given in table 1 and are illustrated graphically in figure 1. As is evident from table 1 and figure 1, the dosage form of the present invention exhibited a gradual and continuous increase in the concentration of the drug in the PBS solution over a period of approximately 8 hours, reaching a maximum value of approximately 563 μm / ml, or approximately three times that achieved by control A or control B. Finally, the data obtained show that concentrations can be achieved supersaturated drugs by the present invention. The matrix tablets were completely disintegrated in the course of the 12 hour dissolution tests, indicating that the controlled release mechanism was mainly by erosion.

TABLE 1 EXAMPLE 2 Dosage forms of the present invention were manufactured by first forming a batch of SD 2: 1 comprising 2 parts of a drug of low solubility and 1 part of dispersion polymer, mixing HPMCAS-MF with the drug [R- (R * S *)] - 5-chloro-N-. { 2-hydroxy-3 - [(methoxymethyl-amino) -3-oxo-1- (phenylmethyl) propyl] propyl} -1 H-indole-2-carboxamide (another inhibitor of glycogen phosphorylase, from Pfizer Inc.) having a solubility in water of 1 μg / ml. The solid dispersion was obtained as described in example 1, except that the composition of the solution was 5.0% by weight of drug, 2.5% by weight of HPMCAS-MF and 92.5% by weight of solvent and the solution was spray-dried using a rotary atomizer nozzle regulated at 7.5 * 105 Pa with an inlet temperature of 120 ° C. It was found that the drug was in the dispersion in an amorphous, non-crystalline state. To incorporate the resulting SD into an erodible matrix, 1.05 g of the resulting solid particles were mixed with 1.7 g of METHOCEL K100LV Prem, 0.70 g of the FAST FLOW lactose load and 0.0525 of the magnesium stearate lubricant and they were then transformed into tablets as described in example 1. The resulting tablets had 20% by weight of drug, 10% by weight of HPMCAS-MF, 48.5% by weight of METHOCEL, 20% by weight of lactose weight and 1.5% by weight of magnesium stearate. The weight of the tablets was 350 mg. As control (control D) tablets were prepared in a similar manner except that, instead of using the drug SD / HPMCAS-MF, a mixture of 2 parts of crystalline drug and 1 part of HPMCAS-MF was used. As a second control (control E) 70 mg of the undispersed crystalline drug without erodible matrix was used. As a third control (control F), 107 mg of the SD were used with non-erodible matrix. A rapid type duodenal solution (MFD) simulating the chemical environment existing in the small intestine was prepared, comprising the PBS solution described in example 1 mixed with 14.7 mM taurocholic acid and 1-palmitoyl-2-oleyl-sn- 2.8 mM glycero-3-phosphocholine. Four in vitro dissolution tests were performed on 500 ml of the MFD solution thus prepared, to test the release efficiency of the drug from the dosage composition of the invention against controls D, E and F. The sampling and the The analysis was performed as in Example 1. The results are shown in Table 2 and are illustrated graphically in Figure 2. As is evident from Table 2 and Figure 2, the dosage form of the present invention exhibited an increase in gradual and continuous concentration of the drug in the MFD solution for a period of 20 hours, reaching a maximum value of approximately 82 μ / ml, 12 times that achieved by control D and 4.6 times that achieved by the control AND.

TABLE 2 This example also demonstrates that the dosage form of the present invention is capable of a much more desirable tmax, compared to that of an SD alone, reached its maximum concentration in at least 20 hours, while the drug released from the SD alone (control F) reached a constant concentration near its maximum concentration in less than 90 minutes. The tablets of the matrix completely disintegrated within 20 hours, indicating that the mechanism of controlled release was primarily by erosion.

EXAMPLE 3 Typical dosage forms of the present invention were made by first forming a 1: 3 SD batch of 1 part of a low solubility drug and 3 parts of the dispersion polymer, mixing the same drug of Example 1 with CAP to form a solution . Spray drying was performed as described in example 1, except that the solution contained 0.75% by weight of drug, 2.25% by weight of CAP and 97% by weight of acetone and the apparatus of spray was regulated at 1, 9 * 105 Pa. The formation of an amorphous drug dispersion was confirmed, not crystalline. To incorporate the solid dispersion into an erodible matrix, 1.071 g of the resulting solid particles were mixed with 1.7315 g of METHOCEL, 0.714 g of the lactose load and 0.0536 g of the magnesium stearate lubricant. The weight of the tablets was 350 mg. As a control (control G) tablets were prepared in a similar manner except that, instead of using the solid drug dispersion / CAP, a mixture of 1 part crystalline drug and 3 parts CAP was used. As a second control (control H), 26 mg of crystalline drug alone was used. As a third control (control I), 105.3 mg of the solid dispersion with non-erodible matrix was used. To determine the drug release profile of the dosage form of the present invention, compared to that of the controls, in vitro dissolution tests were performed on 40 ml of the PBS solution of example 1 at 37 ° C, as in Example 1. The results are shown in Table 3 and are illustrated graphically in Figure 3 and, as is evident from them, the dosage form of the present invention exhibited a gradual and continuous increase in the concentration of the drug in the MFD solution for a period of approximately 9 hours, reaching a maximum value of approximately 560 μ / ml, more than three times greater than that achieved by control G or control H. This example further demonstrates that the dosage form of the present invention has a much more desirable tmax than that of SD alone, reaching its maximum drug concentration in about 9 hours, while the maximum concentration for SD alone (c ontrol I) is reached in less than 10 minutes. Finally, the data obtained show that supersaturated concentrations of drug can be achieved, more than three times that achieved by the crystalline drug alone (control H) or by the crystalline drug mixed with CAP (control G). The tablets of the matrix completely disintegrated within 12 hours, indicating that the mechanism of controlled release was mainly by erosion.

TABLE 3 EXAMPLE 4 Tablets of a solid drug dispersion incorporated in an erodible matrix were prepared, as in example 2, and then coated with an enteric coating 100 A thick to retard drug release, the coating comprising 90% by weight of CAP and 10% by weight of triacetin. The coating was applied by spraying a solution comprising 9% by weight of CAP and 1% by weight of triacetin in acetone onto the tablets using a conventional tray coating apparatus. The release profile of this coated dosage form was tested by exposing the tablets to simulated gastric buffer according to the United States Pharmacopoeia for two hours and then transferring the tablets to the MFD solution of Example 2. The release delay of the drug was two to four hours, showing the effectiveness of the coating to retard drug release while the tablets are in the gastric environment.

EXAMPLE 5 Typical dosage forms of the present invention were manufactured as in Example 1 by first forming a batch of an SD comprising 1 part of the drug of low solubility (1S) - (cis) -4- (3,4-dichlorophenyl) hydrochloride) -1, 2,3,4-tetrahydro-N-methyl-1-naphthalenamine having a solubility in water of 70 μg / ml and 1 part of dispersion polymer HPMCP-55, except that the drug and the polymer were sprayed from a 1: 1 (by weight) mixture of methanol: acetone with a solution composed of 2.5% by weight of drug, 2.5% by weight of polymer and 92.5% by weight of solvent. The solution was sprayed at a pressure of 1, 8 * 105 Pa with a feed rate of 190 g / min at an inlet temperature of 230 ° C and an outlet temperature of 70 ° C. It was verified that the drug in the dispersion was in an amorphous, non-crystalline form. To incorporate the resulting SD into an erodible matrix, a homogeneous mixture of 30% SD, 48.5% METHOCEL K100LV Prem, 20% FAST FLOW lactose and 1.5% magnesium stearate was prepared. The tablets were made as described in Example 1. As a control (control J), tablets were prepared in a similar manner except that, instead of using the drug SD / HMPCP, a mixture of 1 part of crystalline drug was used. and 1 part of the same quality of HMPCP. As a second control (control K) 62 mg of the undispersed crystalline drug was used. As a third control (control L), 122 mg of SD with non-erodible matrix were used. An MFD solution was prepared as in Example 2. Four in vitro dissolution tests were performed on 30 ml of the MFD solution to test the drug release efficiency from the dosage composition of the invention against the J, K and L. Sampling and analysis were performed as in example 1.

The results are shown in Table 4 and are illustrated graphically in Figure 4 and it is evident from them that the dosage form of the present invention exhibited a gradual and continuous increase in the concentration of the drug in the MFD solution over a period of time. at 12 o'clock, reaching its maximum value of approximately 600 μ / mg at 12 o'clock. At 9 hours, the drug concentration achieved by the dosage composition of the invention was 4 times that of control K.

TABLE 4 The terms and expressions that have been used in the previous description are used as descriptive terms and not as limiting and there is no intention, when using such terms and expressions, to exclude equivalents of the characteristics shown and described or portions thereof , admitting that the scope of the invention is defined and limited only by the claims that follow.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. A controlled release dosage composition comprising: (a) a solid dispersion comprising a drug of low solubility dispersed in a cellulosic polymer, a major portion of said drug being amorphous, and (b) a water soluble cellulosic polymer matrix. which has the said dispersion incorporated.

2. A controlled release dosage composition comprising: (a) a solid dispersion comprising a drug of low solubility dispersed substantially homogeneously in an ionizable cellulosic polymer, said drug being amorphous, and (b) a polymeric matrix erodible that said dispersion has incorporated.

3. A controlled release dosage composition comprising: (a) a solid dispersion comprising a drug of low solubility dispersed in an ionizable cellulosic polymer having an alkylate substituent and a carboxylic acid substituent linked by an ester bond, being amorphous a major portion of said drug, and (b) an erodible polymer matrix having said dispersion incorporated therein.

4. The dosage composition according to claim 1, wherein said cellulosic polymer of said dispersion is an ionizable cellulosic polymer.

5. The dosage composition according to claim 2 or 4, wherein said ionizable cellulosic polymer of said dispersion has an alkylate substituent and a carboxylic acid substituent attached by ester linkage.

6. The dosage composition according to claim 3 or 5, wherein said alkylate substituent is selected from the group consisting of acetate, propionate and butyrate and the degree of substitution of said alkylate substituent is at least 0.1.

7. The dosage composition according to claim 3 or 5, wherein said carboxylic acid substituent linked by an ester bond is selected from the group consisting of phthalate, trimellitate, succinate, terephthalate and isophthalate and the degree of substitution of the cited carboxylic acid substituent attached by an ester linkage is at least 0.1.

8. The dosage composition according to any of claims 2-4, wherein the ionizable cellulosic polymer of said dispersion is selected from the group consisting of hydroxyethylmethylcellulose acetate phthalate, hydroxyethylmethylcellulose acetate succinate, acetate phthalate of hydroxypropylcellulose, hydroxypropylcellulose acetate succinate, hydroxypropylmethylcellulose acetate-phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate trimellitate, hydroxypropylcellulose butyrate phthalate, cellulose acetate phthalate, methylcellulose acetate phthalate, cellulose acetate trimellitate , cellulose acetate-terephthalate, cellulose acetate-isophthalate, cellulose propionate phthalate, cellulose propionate trimellitate and cellulose butyrate trimellitate.

9. The dosage composition according to any of claims 2-4, wherein said ionizable cellulosic polymer of said dispersion is selected from the group consisting of cellulose acetate phthalate, cellulose acetate trimellitate and acetate. hydroxypropylmethylcellulose succinate.

10. The dosage composition according to claim 2 or 3, wherein said polymer matrix comprises a second ionizable cellulosic polymer.

11. The dosage composition according to claim 1, wherein said water-soluble cellulosic polymer is selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxymethylmethylcellulose and hydroxypropylmethylcellulose.

12. The dosage composition according to claim 8, wherein said water-soluble cellulosic polymer is selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.

13. The dosage composition according to claim 1 or 3, wherein substantially all said drug is substantially amorphous.

14. The dosage composition according to claim 1 or 3, wherein essentially all of said drug is substantially amorphous.

15. - The dosage composition according to claim 2 or 3, wherein said erodible polymer matrix is formed from a polymer selected from the group consisting of polyoxamers, water-soluble cellulosic polymers, water-erodible cellulosic polymers, derivatives of the acrylic acid and polymers thereof, natural polysaccharides and derivatives thereof; and natural proteins.

16. The dosage composition according to claim 15, wherein said erodible polymer matrix is formed from a polymer selected from the group consisting of water soluble cellulosic polymers, water-erodible cellulosic polymers, natural polysaccharides and derivatives thereof.

17. The dosage composition according to claim 16, wherein said erodible matrix is formed from a polymer selected from the group consisting of methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose.

18. The dosage composition according to any of claims 1-3, wherein said polymer matrix is coated with a pH sensitive polymer to retard the release of said drug.

19. The dosage composition according to claim 18, wherein said pH-sensitive polymer is selected from the group consisting of amylose acetate phthalate, cellulose acetate phthalate and its sodium salt, cellulose ester phthalates , cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, methyl cellulose phthalate, poly (vinyl acetate phthalate), poly (vinyl acetate phthalate), phthalate starch acid, cellulose acetate trimellitate, styrene-maleic acid copolymer and dibutyl phthalate, styrene-maleic acid / poly (vinyl acetate phthalate) copolymer, styrene-maleic acid copolymers, acrylic acid copolymers and esters acrylics, poly (methacrylic acid) and esters thereof, copolymers of poly (acrylic acid) and poly (methacrylic acid), shellac and copolymers of acetates vinyl and crotonic acid.

20. The dosage composition according to claim 18, wherein the pH sensitive polymer is selected from the group consisting of cellulose acetate phthalate, poly (vinyl acetate phthalate), hydroxypropylmethylcellulose phthalate, acetate succinate of hydroxypropylmethylcellulose, acrylic anionic copolymers of methacrylic acid and methyl methacrylate and copolymers comprising acrylic acid and at least one acrylic acid ester.

21. The dosage composition according to claim 18, wherein said coating further comprises at least one non-pH sensitive polymer for modulating the release delay or release rate of said drug.

22. The dosage composition according to any of claims 1-3 in a form selected from the group consisting of a tablet, a microcapsule, a capsule, a bead, a sachet, a multiparticulate and combinations thereof.

23. The dosage composition according to any of claims 1-3, wherein said dispersion includes an agent that increases the solubility.

24. The composition according to claim 23, wherein said agent that increases the solubility is selected from the group consisting of organic acids and salts of organic acids, partial glycerides, glycerides, glyceride derivatives, polyethylene glycol esters, esters of polypropylene glycol, esters of polyhydric alcohols, sorbitan esters, salts carbonates, alkylsulfonates and cyclodextrins.

25. The dosage composition according to any of claims 1-3, wherein said dispersion is formed by spray drying.

26. The dosage composition according to claim 25, wherein said dispersion comprises said drug dispersed in hydroxypropylmethylcellulose acetate succinate.

27. The dosage composition according to claim 25, wherein, before the formation of said dispersion, said drug in its pure state is amorphous.

28. The dosage composition according to claim 25, wherein, before the formation of said dispersion, said drug in its pure state is crystalline.

29. The dosage composition according to any of claims 1-3, wherein said dispersion includes excipients.

30. The dosage composition according to claim 29, wherein said excipients are selected from the group consisting of surfactants, water-soluble polymers, pH modifiers, fillers, binders, pigments, lubricants, antioxidants and flavorings.

31. The dosage composition according to any of claims 1-3, wherein the drug is selected from the group consisting of an antihypertensive agent, an anti-anxiety agent, an anticoagulant agent, an agent that reduces the level of glucose in the blood, a decongestant, an antihistamine, an antitussive, an anti-inflammatory, an antipsychotic agent, an enhancer of cognitive functions, an agent that reduces cholesterol, an anti-obesity agent, an agent against autoimmune disorders, a hypnotic agent, an antiparkinson agent, an antibiotic agent, an antiviral agent, an anti-impotence agent, an antineoplastic agent, a sedative, a barbiturate, a nutritional agent, a beta-blocker, an emetic, an antiemetic, a diuretic, an anticoagulant, a cardiotonic, an androgen, a corticoid, an anabolic agent, an antidepressant agent, a disinfecting agent, a coronary vasodilator, an anhydrase inhibitor carbonic acid, an antifungal agent, an antiprotozoal agent, a gastrointestinal agent, a dopaminergic agent, an agent against Alzheimer's disease, an antiulcer agent, a platelet inhibitor and an inhibitor of glycogen phosphorylase.

32. The dosage composition according to claim 31, wherein said drug is an antihypertensive agent selected from the group foramed by prazosin, nifedipine, trimazosin and doxazosin.

33. The dosage composition according to claim 31, wherein said drug is an anti-anxiety agent selected from the group consisting of fluoxetine, piroxidine, sertraline, venlafaxine, [3,6-dimethyl-2- (2,3,6-Trimethylphenoxy) pyridin-4-yl] - (1-ethylpropyl) amine and 3,5-dimethyl-4 (3, -petroxy) -2- (2,, 4,, 6, -trimethylphenoxy) pyridine.

34. The dosage composition according to claim 31, wherein said drug is an antipsychotic agent selected from the group consisting of ziprasidone and its pharmaceutically acceptable salts.

35.- The dosage composition according to claim 31, wherein said drug is an agent against the impotence selected from the group formed by sildenafil and its pharmaceutically acceptable salts.

36.- The dosage composition according to claim 31, wherein said drug is the glipizide blood glucose level reducing agent.

37.- The dosage composition according to claim 31, wherein said drug is an inhibitor of glycogen phosphorylase selected from the group consisting of [R- (R *, S *)] - 5-chloro-N- . { 2- hydroxy-3- [methoxymethylamino-3-oxo-1- (phenylmethyl) propyl] propyl} -1 H-indole-2-carboxamide and [(1 S) -benzyl-3- (3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxypropyl-amide of 5-chloro-1 H -indole-2-carboxylic acid.

38.- The dosage composition according to any of claims 1-3, wherein said dosage composition provides a maximum concentration of said drug in an aqueous in vitro assay that is at least 1.5 times that achieved by a identical dosage composition containing the same amount of drug in the non-dispersed state.

39.- The dosage composition according to any of claims 1-3, wherein, when dosed orally to a mammal, said dosage composition provides a maximum concentration of said drug in the blood that is at least 1.25 times that achieved by an identical dosage composition containing the same amount of drug in undispersed state.

40.- The dosage composition according to any of claims 1-3, wherein, when dosed orally to a mammal, said dosage composition provides an area under the curve of the drug concentration graph in the blood against time that is at least 1.25 times that achieved by an identical dosage composition containing the same amount of drug in the non-dispersed state.

41. The dosage composition according to claim 1, wherein, in an aqueous environment of use, said dosage composition provides an area under the curve of the drug concentration graph versus time which is at least 1.25. times that of a control dosage composition that is identical except for the fact that said polymer matrix comprises poly (ethylene oxide) having a molecular weight such that the time to release 50% of said drug from said control it is greater than 80% but less than 120% of the time when 50% of said drug is released from said dosage composition.