MXPA00001418A - Osmotic system for delivery of solid amorphous dispersions of drugs - Google Patents

Abstract

Controlled release dosage forms for low solubility drugs are disclosed wherein an amorphous solid dispersion of the drug is coated with a non-dissolving and non-eroding coating that controls the influx of water to the core so as to cause extrusion of a portion of the core, as well as a method of treating a disease or disorder comprising administering such dosage form to a person.

Description

CONTROLLED RELEASE OF DRUGS BY EXTRUSION OF SOLID AMORPAS DISPERSIONS The priority date of provisional application serial number 60 / 119,406, filed on February 10, 1999, is claimed.

BACKGROUND OF THE INVENTION It is well known that the bioavailability of drugs that are poorly soluble in water is limited and is profoundly affected by factors such as the state of the patient's diet, the speed of metabolism in relation to the speed of absorption in the gastrointestinal tract (Gl), and the dosage form. Many attempts have been made to improve the dosage form for such drugs with poor solubility, generally, for the purpose of improving the bioavailability of such drugs. Most such formulations were by nature immediate release, since this generally maximizes the amount of drug absorbed. In a few cases, sustained or delayed release dosage forms have been formulated for the purpose of obtaining a rate of constant release of the drug in the intestine for a sufficiently long period of time. However, most attempts have been unsuccessful, leading to dosage forms that usually provide only immediate release or poor bioavailability.

Exemplary sustained dosage forms have included an osmotic tablet comprising a semipermeable wall surrounding a compartment containing the drug and an inflatable hydrogel layer, the crystalline drug being released through a semi-permeable wall passage opening upon swelling of the hydrogel, as described in U.S. Patent No. 4,327,725; another osmotic tablet comprising a wall permeable to an external fluid but impermeable to the drug, and surrounding the wall a compartment containing two osmotic agents, as well as two expandable polymers and the drug, as described in U.S. Pat. 4,612,008; a drug dispersed in a core with an inflatable hydrogel matrix that releases the drug by diffusion in the environment of use, as described in U.S. Patent No. 4,624,848; a hydrogel reservoir containing a multiplicity of tiny pills, each tiny pill consisting of a wall surrounding a drug core, as described in U.S. Patent No. 4,851,232; and a two-layer tablet in which one layer is a drug mixed with a hydrogel and the other layer is a hydrogel, as 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 dispersion of drug in an inflatable poloxamer hydrogel that releases the drug by diffusion from the swollen tablet mass and by erosion of the surface of the tablet, as described in the PCT application No. 97/02017. The solid dispersion dosage forms can be formed by evaporation of a solvent, by spray drying, by spraying the drug solution on the support in a fluidized bed granulator, by twin-screw extrusion, by melt-melting, by mechanical mixing as a ball mill and by mechanical mixing at an elevated temperature but not reaching 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., 32 Indian Drugs 477 (1995); Dangprasirt et al., 21 Drug Development & Ind. Pharm. 2323 (1995); and Goracinova et al., 22 Drug Development & Ind. Pharm. 255 (1996). However, said drug delivery systems in solid dispersion have had very limited success in the release of poorly water soluble drugs since they tend to be immediate release forms which have the intrinsic drawbacks of such forms as they are. maximum concentrations of high blood drug, short times after administration in which drug concentrations reach a maximum ("tmax") and a relatively short duration of effective blood concentration levels. Furthermore, although improved bioavailability with respect to the crystalline drug is explained, however, the bioavailability of such dosage forms is often low in an absolute sense. Specifically, such drug delivery systems frequently present a small overall increase in the concentration of drug in the patient's blood during a given period of time (commonly referred to as "AUC" in reference to the calculation of the area under the curve comprising a representation of concentration versus time). In the case of a dispersive dosage form of a solid poloxamer 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 membrane due to the low intrinsic solubility of the drug; on the contrary, when the drug is released from a dosage form by erosion of the poloxamer, the release of the drug is not of zero order and is variable, depending on the patient's feeding state and the gastric retention time. Furthermore, since the described poloxamer dispersion polymers are highly hydrophilic and generally require aqueous solvents for dissolution, these polymers can not be used to form dispersions with hydrophobic drugs by their solvent processing, since it is difficult or impossible to dissolve the drug. and the polymer in a common solvent. There is thus still a need in the art for a controlled release dosage form to release 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 in detail below.

BRIEF DESCRIPTION OF THE INVENTION The present invention comprises a controlled release dosage form having two components: (a) a core containing a drug of low solubility in the form of an amorphous solid dispersion; and (b) a non-erodible and non-soluble coating surrounding the core, the coating controlling the entry of water into the core from an aqueous environment of use in a manner that causes release of the drug by extrusion of part or all of the core to the environment of use. At least a major portion of the drug, ie, at least about 60%, is amorphous (compared to crystalline). More preferably, substantially all of the drug, ie, at least about 75%, is amorphous. Most preferably, essentially all of the drug, ie, at least about 90%, is amorphous. The term "drug" is conventional, representing a compound that has beneficial, prophylactic and / or therapeutic properties when administered to an animal, especially a human being.

BRIEF DESCRIPTION OF THE DRAWINGS Figures 1 to 4 are schematic example embodiments of the invention. Figures 5 to 7 are graphs comprising representations of the release rates of various drugs released by the controlled release device of the present invention and the comparative release rates of various controls.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided a dosage form specifically designed to provide controlled release by an extrusion-like mechanism of a "low solubility" drug (defined below) using a core of said drug in the form of a solid dispersion. , a majority portion of the drug being in amorphous form. As used herein, the term "a major portion" of the drug means that at least 60% of the drug in the dispersion is in an amorphous form, and not in a crystalline form. Preferably, the drug in the dispersion is substantially amorphous. As used herein, "substantially amorphous" means that the amount of drug in crystalline form does not exceed 25%, as measured by powder X-ray diffraction analysis or by differential scanning calorimetry or by any other means conventional quantitative More preferably, the drug in the dispersion is essentially amorphous. As used herein "essentially amorphous" means that the amount of drug in crystalline form does not exceed 10%, as measured by the methods described above. The term "extrusion", when referring to the drug release mechanism, refers to expelling or forcing part or all of the core through at least one delivery hole. "At least one release hole" means one or more perforations, slots, passage openings, or one or more channels or pores that may have a size ranging from 0.1 to more than 2000 μm in diameter, which allows to release the drug from the dosage form. The drug can be released by extrusion either in the form of a suspension of solids in water or mainly as a drug solution, until the desired solution in the core has taken place. The shape of the device can be any conventional form, including a tablet, a capsule, a microcapsule, a microsphere, a multiparticulate, suspension powders or unit dosage containers or combinations thereof, and is generally useful in mammals and particularly useful for therapeutic uses in humans. The drug is released to the environment of use, such as to the gastrointestinal tract (Gl) as a result of water entering the core and extrusion resulting from an aqueous solution or suspension of the drug through one or more holes or pores of the drug. release in the coating. The solid amorphous drug dispersion can (1) dissolve in the nucleus and be released primarily in solution form; or (2) be released as a solid suspension and dissolve in the Gl tract after its release. 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 is within the ranges set forth herein. The reference to "release" of the drug as used herein, means (1) transport of the drug from the interior of the dosage form to its exterior when the dosage form is a tablet, or from the inside to the outside of the dosage form. outside of the microspheres or granules when the dosage form includes multiparticulates, so that it comes into contact with the fluid of the Gl tract of a mammal after its release or (2) transport of the drug from the inside of the dosage form so which comes in contact with a test medium for the evaluation of the dosage form by an in vitro assay. The reference to "environment of use" can therefore be Gl fluids in vivo or an in vitro test medium. The "introduction" to an environment of use includes ingesting or swallowing or the use of implants or suppositories, being the environment of use in vivo, or placing in a test medium being the environment of in vitro use. The device basically comprises two components: (1) a core containing the drug and an osmotic agent; and (2) a coating. The core comprises a solid amorphous drug dispersion containing an osmotic agent such as one or more osmogens and / or osmopolymers, and optionally contains solubility improving agents and other excipients. The coating is preferably polymeric, is permeable to water, has at least one orifice of release and does not dissolve or erode in the environment of use. The dosage form of the present invention generally provides a controlled release of the drug and in turn (1) the bioavailability of the drug is improved relative to a comparable dosage form in which the drug is present in an undispersed state and ( 2) the time in which the maximum drug concentration (Cmax) is obtained in an environment of in vitro or in vivo use is delayed from 30 minutes to 24 hours. "Not dispersed" means that the drug is not formed in an amorphous solid dispersion. Instead, the undispersed drug is simply the crystalline drug only in its thermodynamically more stable form, unless a crystalline form of the drug is unknown, in which case the control is the amorphous form alone. 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 assay in an aqueous environment, which is at least 1.2 times that which is achieved by a form of identical controlled release dosage containing the same amount of undispersed drug; (2) provide a Cmax in an in vitro assay in an aqueous environment, at a time (tmax) that is at least 30 minutes longer, but not more than 24 hours greater than the tmax observed when the solid dispersion is assayed without incorporating it into a sustained release dosage form; (3) provide an AUC in an aqueous in vitro assay that is at least 1.25 times that achieved by an identical controlled release dosage form containing the same amount of undispersed drug; (4) when dosing a human or other animal, they provide a C max of the drug in the blood which is achieved in a time tmax which is at least 30 minutes longer than that observed when dosing a control composition, comprising control composition only the drug dispersion, ie, without being formulated in a sustained release dosage form; (5) when dosed to a human or other animal they provide a Cmax in the blood 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 undispersed prior to formulation in a sustained release dosage form; and (6) when dosed to a human or other animal, they provide an AUC in the concentration of drug 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 earlier in (5). The dosage forms of the present invention can be evaluated in vitro by placing the dosage form in a test medium so that if all the drug is dissolved, this theoretical concentration would exceed the equilibrium concentration of the drug without dispersing in the same medium as the drug. assay at a factor of at least 2. The concentration of dissolved drug is typically measured as a function of time, sampling the drug and plotting the concentration versus time so that Cma ?. To avoid the formation of drug particles that would give an erroneous determination, the test solution is filtered or centrifuged. "Dissolved drug" is typically considered a material passing through a 0.45 μm syringe filter or, alternatively, the material remaining in the supernatant after centrifugation. The filtration can be carried out using a 0.45 μm polyvinylidene difluoride syringe filter marketed by Scientific Resources under the name TITAN®. Centrifugation is typically carried out in a polypropylene microcentrifuge tube by centrifuging at 13,000 G for 60 seconds. Other similar filtration or centrifugation methods can be employed and useful results are obtained. For example, using other types of microfilters, somewhat higher or lower values (+10 - 40%) than those obtained with the filter specified above may be obtained, but allow the identification of preferred dispersions. It is known that this definition of "dissolved drug" encompasses not only monomeric solvated drug molecules, but also a wide range of species such as polymer / drug entities having submicron dimensions, drug aggregates, aggregates of polymer and drug mixtures, micelles, polymeric micelles, colloidal particles or nanocrystals, polymer / drug complexes and other drug-containing species that are present in the filtrate or in the supernatant in the specified dissolution test. The dosage forms of the present invention can be tested in vivo in animals or humans using conventional methods to perform said determination. An in vivo assay, such as a crossover study, can be used to determine whether a test dosage form provides an increased concentration of drug in the blood (serum or plasma) versus the area under the curve over time (AUC in vivo ) for a test subject dosed with the assay dosage form with respect to the AUC in vivo for a subject dosed with a control dosage form such as that described above. In an in vivo crossover study, a "trial dosage form" is dosed to half a group of 12 or more and, after an appropriate washout period (eg, a week), the same subjects are dosed a "control dosage form" comprising an equivalent amount of undispersed drug as "assay dosage form." The other half of the group is dosed with the control dosage form first, followed by the assay dosage form. Bioavailability is measured as the AUC determined for each group. In vivo determinations of the AUC can be performed by plotting the serum or plasma concentration of the drug on the ordinate axis (y axis) versus time on the abscissa axis (x axis). In general, AUC values in vivo represent a series of values taken from all subjects in a population of test patients and, therefore, are averaged values for the entire test population. Measuring the AUC in vivo for a population to which the test dosage form is administered and comparing it with the AUC in vivo for the same population to which the dosage form has been administered, the assay dosage form can be evaluated. The determination of AUC is a well-known procedure and is described, for example, in the same monograph cited above, Welling, ACS Monograph. In Figures 1 to 4, four arrangements of example dosage forms are shown schematically.

Figure 1 depicts a tablet (10) with a "granular core" comprising a core (12), a coating (18) and at least one release hole (19). The core comprises a composition (11) containing the drug and several granules of composition (14) containing a swelling agent homogeneously mixed with the composition (11) containing the drug. Figure 2 depicts a "double layer" tablet (20) comprising a core (21) having a layer (22) with the drug composition and a layer (24) with the composition of swelling agent and, surrounding the core, a coating (28) having at least one delivery hole (29) through the coating, connecting the drug layer (22) to the exterior of the dosage form. Figure 3 depicts a tablet (30) with "concentric core" comprising a core (21) having a layer (22) with the drug composition surrounding a layer (24) with the composition of swelling agent and, surrounding the core, a coating (28) having at least one release hole (29) through the coating, connecting the drug layer (22) to the exterior of the dosage form. Figure 4 depicts a tablet (40) "with three layers" comprising a core (21) having two layers with drug composition (22a) and (22b) on each side of a layer (24) with the swelling composition, surrounding the core, a coating (28) having at least one release hole (29) through the coating connecting each of the drug layers (22a) and (22b) with the exterior of the dosage form.

THE DRUG Before the dispersion is formed, the drug in its pure state can be crystalline or amorphous, although when dispersed in the solid dispersion polymer, a greater part of the drug is preferably in an amorphous or non-crystalline state, so that its non-crystalline nature is demonstrated by X-ray diffraction analysis or by differential scanning calorimetry. The dispersion may contain from about 5 to 90% by weight of drug, preferably from 20 to 70% by weight. The drug is a "drug of low solubility", which means that the drug has a minimum solubility in water of about 40 mg / ml or less than a physiologically relevant pH (eg, pH 1 to 8). Thus, the drug can be substantially insoluble in water, which means that the drug has a minimum solubility in water of less than 10 micrograms / ml at a physiologically relevant pH, or it is poorly soluble in water, i.e. it has a minimal solubility in water of about 10 micrograms / ml to about 1-2 mg / ml, or even a moderate solubility, such as a minimum solubility in water of up to 20 to 40 mg / ml. In general, it can be stated that the drug has a dose-solubility ratio in water greater than about 5 ml, the solubility of the drug being the minimum value observed in any physiologically relevant aqueous solution, including unbuffered water and buffered gastric and intestinal solutions. simulated according to the USP (Pharmacopoeia of the United States). In some cases, it is also desirable to enhance the solubility of the drug within the dosage form to increase the rate of release of the dosage form or to improve absorption of the drug in the colon. In such cases, the invention can be applied to drugs with solubilities of up to 20 to 40 mg / ml. This is particularly true when it is desired to release a solution of the drug. In such cases, the aqueous dose-solubility ratio may be as low as 1 ml. Virtually any beneficial therapeutic agent that meets the solubility criteria as a drug in the present invention can be used. In addition, the drug can be used in the form of its pharmaceutically acceptable salts, as well as in the anhydrous, hydrated and solvated forms and in the form of prodrugs. Preferred drug classes include, although they are not limited to them, antihypertensive, anxiolytics, antidepressants, bartituratos, anticoagulant agents, anticonvulsants, agents to reduce the level of glucose in blood, decongestants, antihistamines, antitussives, antineoplastics, beta-blockers, anti-inflammatory, antipsychotic agents, enhancers of cognition, cholesterol-lowering agents, anti-obesity agents, agents for autoimmune disorders, anti-impotence agents, antibacterial and antifungal agents, hypnotic agents, anti-Parkinson's agents, agents for the treatment of Alzheimer's disease, antibiotics and antiviral agents. The following are examples of the classes of drugs and therapeutic agents above and others that the invention can provide, by way of example only. Specific examples of antihypertensive drugs include prazosin, nifedipine, trimazosin and doxazosin; a specific example of an agent for reducing blood glucose levels is glipizide; a specific example of an agent against impotence is sildenafil citrate; Specific examples of antineoplastics include chlorambucil, lomustine and equinomycin; a specific example of an imidazole type antineoplastic is tubulazole; 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 a barbiturate is phenobarbital; specific examples of antivirals include acyclovir and virazole; specific examples of vitamin / nutritional agents include retinol and vitamin E; specific examples of beta-blockers include timolol and nadolol; A specific example of an emetic is apomorphine; Specific examples of a diuretic include chlorthalidone and spironolactone; a specific example of an 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 hypnotic / steroidal anesthetic is alfaxalone; specific examples of anabolic agents include fluoxymesterone and methanestenolone; Specific examples of antidepressant agents include sulpiride, fluoxetine, paroxetine, venlafaxine, sertraline, [3,6-dimethyl-2- (2,4,6-trimethi-phenoxy) -pyridin-4-yl] - (1-ethylpropyl) - amine and 3,5-dimethyl-4- (3'-pentoxy) -2- (2,, 4,, 6'-trimethylfenoxy) pyridine; Specific examples of antibiotics include ampicillin and benzylpenicillin; specific examples of anti-infectives include benzalkonium chloride and chlorhexidine; Specific examples of coronary vasodilators include nitroglycerin and myoflazine; a specific example of a hypnotic is etomidate; specific examples of carbonic anhydrase inhibitors include acetazolamide and chlorzolamide; Specific examples of antifungals include econazole, terconazole and griseofulvin; specific examples of anthelminthic agents include thiabendazole and oxfendazole; Specific examples of antihistamines include astemizole, levocabastine, cetirizine 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 quetanserin and mianserin; A specific example of an anesthetic is lidocaine; a specific example of a hypoglycemic agent is acetohexamide; a specific example of an antiemetic is dimenhydrinate; a specific example of an antibacterial is cotrimoxazole; a specific example of a dopaminergic agent is L-DOPA, specific examples of agents against Alzheimer's disease are THA and donezepil; a specific example of an antiulcer agent / H2 antagonist is famotidine; specific examples of sedative / hypnotic agents include chlordiazepoxide and triazolam; a specific example of a vasodilator is alprostadil; a specific example of a platelet inhibitor is prostacyclin; specific examples of ACE inhibitor / antihypertensive agents include enalaprilic acid and lisinopril; specific examples of tetracycline antibiotics include tetracyclines and minocyclines; specific examples of macrolide antibiotics include azithromycin, clarithromycin, erythromycin and spiramycin; * * specific examples of glycogen phosphorylase inhibitors include [R- (RS)] - 5-chloro-N- [2-hydroxy-3- [methoxymethyl] amino] -3-oxo-1- (phenylmethyl) propyl] propyl ] -1 H -indole-2-carboxamide and [(1 S) -benzyl-3 - ((3R, 4S) -d-hydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxypropyl-amide of 5- Chloro-1 H-indole-2-carboxylic acid. Further examples of drugs provided by the invention are the drug to reduce the level of glucose chlorpropamide, the antifungal drug fluconazole, the antihypercholesterolemic atorvastatin calcium, the antipsychotic thiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride and doxepin hydrochloride, the antihypertensive agent besylate of amlodipine, the anti-inflammatory agents iroxicam, valdecoxib and celicoxib and the antibiotics carbenicillin indanil sodium, becampicillin hydrochloride, troleandomycin and doxycycline hyclate.

THE DISPERSION POLYMER Suitable polymers for forming the solid drug dispersion are preferably concentration-increasing polymers, processable in non-aqueous and inert solvents. "Non-aqueous solvent" refers to solvents that comprise less than 30% water. "Processable in non-aqueous solvents" means that the polymer can be processed with the drug in a conventional non-aqueous solvent forming the solid dispersion, that is, it can generally be adapted to techniques that use non-aqueous solvents in the formation of solid dispersions . Such techniques include evaporation, spray drying or spray coating. The polymer has a preferred solubility in the nonaqueous 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 amorphous solid dispersion of the drug and the dispersion polymer by solvent processing since the drug and the dispersion polymer should be dissolved in a common solvent and such solvents can not be substantially aqueous since the drugs are definition have a relatively low aqueous solubility. Such 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 of 1 to 8 in which they exhibit a property of "increase in concentration". "Increase in concentration" means that the concentration of pure drug in aqueous medium increases substantially when formulated in a solid dispersion with the polymer, with the concentration increase being in the order of at least 20%. "Inert" means that it is not reactive or bioactively adverse, being able to still positively affect the bioavailability of the drug. The amount of polymer present in the dispersion generally ranges from about 10 to about 95% by weight, preferably from 30 to 80% by weight. One class of preferred polymers comprises ionizable and non-ionizing cellulosic polymers (including those with ether or ester substituents or a mixture of ester / ether and their copolymers, including so-called "enteric" and "non-enteric" polymers); and vinyl polymers and copolymers having hydroxyl, alkylacyloxy and cyclic amide substituents. Exemplary ionic cellulosic polymers include carboxymethylcellulose (CMC) and its sodium salt, carboxyethylcellulose (CEC), hydroxyethylmethylcellulose acetate phthalate, hydroxyethylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate phthalate (HPCAP), acetate hydroxypropylcellulose succinate (HPCAS), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylmethylcellulose acetate trimellitate (HPMCAT), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), hydroxypropylcellulose butylate phthalate, carboxymethylethylcellulose and its sodium salt , cellulose acetate phthalate (CAP), methyl cellulose acetate phthalate, cellulose trimellitate acetate (CAT), cellulose acetate terephthalate, cellulose acetate isophthalate, cellulose propionate phthalate, cellulose trimellitate propionate, cellulose trimellitate butyrate and s mixtures thereof. Example nonionic cellulosic polymers include methylcellulose (MC), ethylcellulose (EC), hydroxyethylcellulose (HEC) hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxypropylmethylcellulose acetate, hydroxyethylmethylcellulose, hydroxyethylcellulose acetate, hydroxyethylethylcellulose and mixtures thereof. Exemplary vinyl polymers and copolymers useful as dispersion polymers for increasing concentration include copolymers of methacrylic acid, aminoalkyl methacrylate copolymers, polymethacrylates functionalized with a carboxylic acid and amine-functionalized polymethacrylates, poly (vinyl acetal), diethylaminoacetate, polyvinylpyrrolidone (PVP), poly (vinyl alcohol) (PVA), copolymers of poly (vinyl alcohol) / poIi (vinyl acetate) (PVA / PVAc) and mixtures thereof. Other useful dispersion polymers include polyethylene glycol / polypropylene glycol (PEG / PPG) copolymers, polyethylene / polyvinyl alcohol (PE / PVA) copolymers, dextrin, pullulan, gum arabic, tragacanth, sodium alginate, propylene glycol alginate, agar, gelatin, starch, processed starch, glucomannan, chitosan and mixtures thereof. Particularly preferred dispersion polymers are PVA, PVP, PVA / PVAc copolymers and cellulosic polymers which are water soluble during at least a portion of the pH range of 1 to 8, including HPMC, HPMCP, HPMCAS, CAP, CAT and mixtures thereof.

THE DISPERSION The solid amorphous drug dispersion can be prepared by any of the known forms mentioned above, including, for example, by melting in the molten state, by mechanical processing as in a twin-screw extruder or in a ball mill, or by processing in a solvent. When the dispersion is prepared by mechanical means, such as in a ball mill or by extrusion, a major portion of the drug (> 60%) is typically in an amorphous state, the remaining portion being in a crystalline state. When prepared by solvent processing, a major portion of the drug is virtually always in an amorphous state, usually practically all of the drug (> 75%) is in the amorphous state and often essentially all (> 90%). "Amorphous state" means that the drug may be present in the dispersion in any of the three classes of more extended forms: (a) in drug-rich discrete domains; (b) distributed homogeneously in it, that is, a solid solution; or (c) any state or combination of states between extremes (a) and (b). In the solvent processing, a homogeneous solution of drug and dispersion polymer is formed, alone or with other excipients which may or may not be dissolved, followed by removal of the solvent by precipitation or evaporation. Precipitation is typically induced by contacting the drug / dispersion polymer solution with a non-solvent medium such as water, a liquid hydrocarbon or supercritical CO2. A preferred method of forming the dispersion is by dissolving the drug and the dispersion polymer in a common solvent, then removing the solvent by spray-drying the mixture. Spray drying and spray coating processes and equipment are described generally in Perry's Chemical Engineers' Handbook, pages 20-54 to 20-57 (6th Ed., 1984). In Marshal, 50 Chem. Eng. Prog. Monogr. series 2 (1954) can be found in more details of spray drying procedures. The terms "spray drying" and "spray coating" in the context of the present invention are used in a conventional manner and refer broadly to processes involving the decomposition of liquid mixtures into small droplets (atomization) and the rapid removal of the solvent of the mixture in a container such as a spray drying apparatus or a fluidized bed coater or tray, in which there is an intense driving force for the evaporation of the solvent from the droplets. In the case of spray coating, droplets collide on a particle, microsphere, pill, tablet or capsule resulting in a coating comprising the solid amorphous dispersion. The spray coating can also be carried out on a metal, glass or plastic surface and the coated layer can be subsequently removed and milled to a desired particle size. In the case of spray drying, the droplets are usually dried before hitting a surface, thereby forming solid amorphous dispersion particles of the order of 1 to 100 micrometers in diameter. The strong driving force for solvent evaporation is generally provided by maintaining the partial pressure of the solvent in the spray drying apparatus well below the vapor pressure of the solvent at the drying temperature of the droplets. This is carried out (1) by maintaining the pressure in the spray drying apparatus at a partial vacuum (eg, 1013 Pa to 50665 Pa); (2) mixing the liquid droplets with a hot drying gas; or (3) (1) and (2). For example, a solution of drug and dispersion polymer such as HPMCAS in acetone can be spray dried in an appropriate manner by spraying the solution at a temperature of 50 ° C (the vapor pressure of the acetone at 50 ° C is approximately 81060 Pa. ) in a chamber maintained at 1013 Pa to 20265 Pa of total pressure by connecting the outlet to a vacuum pump. As an alternative, said solution can be sprayed in a chamber in which it is mixed with nitrogen gas at a temperature of 80 ° C to 250 ° C and a pressure of 101325 to 121590 Pa. In general, the temperature and flow rate of the drying gas is they choose so that the droplets of dispersion polymer / drug 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 stick to the appliance wall. The actual period of time to achieve this level of drying depends on the size of the droplets. The sizes of the droplets are generally greater than about 1 μm in diameter, typical being from 5 to 100 μm. The large surface / volume ratio of the droplets and the large driving force for the evaporation of the solvent leads to actual drying times of a few seconds or less. For some drug / polymer dispersion / solvent mixtures, this rapid drying is critical for the formation of a relatively uniform homogeneous composition, as compared to an undesirable separation in a drug-rich phase and a polymer-rich phase. Such dispersions having a homogeneous composition can be considered solid solutions and can be supersaturated in drug. The solidification times will be less than 100 seconds, preferably less than a few seconds and more preferably, less than 1 second. In general, 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, most preferably, lower at 25 μm. The solid particles thus formed caused by the solidification of these droplets generally tend to have a diameter of 2 to 40 μm. After solidification, the solid powder typically remains in the spray-drying chamber for 5 to 60 seconds, evaporating more solvent. The final solvent content in the solid dispersion when leaving the dryer will be low, since a low solvent content tends to reduce the mobility of the drug molecules in the dispersion, thereby improving its stability. In general, the residual solvent content of the dispersion will be less than 10% by weight and preferably less than 2% by weight. The spray-dried solution for forming the polymer / drug dispersion can be quite simple, containing only drug and polymer in a solvent. Typically, the weight ratio of polymer / drug in the solution varies from 0.1 to 20 and preferably from 0.5 to 5. However, when the drug dose is low (less than 20 mg), the ratio may be even greater than 5. Other excipients may be added to the sprayed solution, either co-dissolved in the solvent together with the drug and dispersion polymer or suspended in the solution to form a suspension. Such excipients may include: acids, bases or buffers to modify the ionic state and dissolution properties of the resulting dispersion; fillers, binders, disintegrants and other materials to improve the tablet preparation process or the final properties of the tablet; antioxidants to improve dispersion stability; osmotic agents, including osmotically effective solutes such as sugars, salts and polyols and hydrophilic water-swellable polymers; and surfactants that affect the rate of wetting or dissolution of the core of the tablet. Suitable solvents for spray drying can be basically any organic compound or mixtures of an organic compound and water in which the drug and the polymer are mutually soluble. Because the invention uses drugs with low solubility in water, water alone is not usually a suitable solvent. However, mixtures of water and organic compounds are often suitable. Preferably, the solvent is also relatively volatile with a boiling point of 150 ° C or lower. However, in those cases in which the solubility of the drug in the volatile solvent is low, it may be desirable to include a small amount, ie, 2 to 25% of a low volatility solvent such as N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO) or dimethylacetamide (DMAc) in order to improve the solubility of the drug. Preferred solvents include alcohols 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 solvents such as acetonitrile, methylene chloride, toluene and 1,1,1-trichloroethane.

THE OSMOTIC AGENT In addition to the amorphous solid drug dispersions, the core of the drug delivery device of the present invention includes an "osmotic agent". "Osmotic agent" refers to any agent that creates a driving force for the transport of water from the environment of use to the interior of the core of the device. Exemplary osmotic agents are water-swellable hydrophilic polymers and osmogens (or osmagents). Thus, the core can include hydrophilic water-swellable polymers, both ionic and non-ionic, often referred to as "osmopolymers" and "hydrogels". The amount of hydrophilic water-swellable polymers present in the core can vary from about 5 to about 80% by weight, preferably from 10 to 50% by weight. Exemplary materials include hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, PEO, PEG, PPG, poly (2-hydroxyethyl methacrylate), poly (acrylic acid), poly (methacrylic acid), PVP and cross-linked PVP, PVA, copolymers of PVA / PVP and PVP PVA copolymers with hydrophobic monomers such as methyl methacrylate, vinyl acetate and the like, hydrophilic polyurethanes containing large blocks of PEO, croscarrhoeoalum sodium, carrageenan, HEC, HPC, HPMC, CMC and CEC, sodium alginate , polycarbophil, gelatin, xanthan gum and sodium starch glycolate. Other materials include hydrogels that comprise interpenetrating networks of polymers that can be formed by addition or condensation polymerization, which components can comprise hydrophilic and hydrophobic monomers such as those just listed. Preferred polymers for use as hydrophilic water-swellable polymers include PEO, PEG, PVP, croscarmellose sodium, HPMC, sodium starch glycolate, poly (acrylic acid) and crosslinked versions or mixtures thereof. In one embodiment of the invention, the osmotic agent and the dispersion polymer may comprise the same polymeric material. "Osmotically effective solutes" refers to any water-soluble compound that is often referred to in the pharmaceutical art as an "osmogen" or an "osmagent". The amount of osmogen present in the core can vary from about 2 to about 70% by weight, preferably from 10 to 50% by weight. Typical classes of suitable osmogens are organic acids, salts and water-soluble sugars that can imbibe water to thereby create an osmotic pressure gradient across the barrier surrounding the coating. Useful typical osmogens include magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, sodium carbonate, sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate, mannitol, xylitol, urea, sorbitol, inositol, raffinose, sucrose, glucose, fructose, lactose, citric acid, succinic acid, tartaric acid and mixtures thereof. Particularly preferred osmogens are glucose, lactose, sucrose, mannitol, xylitol and sodium chloride.

OTHER COMPONENTS OF THE NUCLEUS Finally, the solid dispersion core can include a wide variety of excipient additives that enhance the solubility of the drug or that promote stability, tablet preparation or dispersion processing. Such additives and excipients include tableting aids, surfactants, water soluble polymers, pH modifiers, fillers, binders, pigments, disintegrants, antioxidants, lubricants and flavorings. Examples of such 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; esters of fatty acids such as glyceryl mono- and di-stearates, triglycerides, glyceryl ester (palmitic-stearic) ester, sorbitan monostearate, sucrose monostearate, sucrose monopalmitate and sodium stearyl fumarate; alkyl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; polymers such as polyethylene glycols, polyoxyethylene glycols and polytetrafluoroethylene; and inorganic materials such as talc and dicalcium phosphate; sugars such as lactose and xylitol; and sodium starch glycolate. The core may also include solubility enhancing agents that promote the water solubility of the drug, present in an amount ranging from about 5 to about 50% by weight. Examples of suitable solubility-enhancing agents include surfactants; agents for pH control such as buffers, salts of organic acids and inorganic acids and organic and inorganic bases; glycerides; partial glycerides; glyceride derivatives; polyoxyethylene and polyoxypropylene ethers and their copolymers; sorbitan esters; polyoxyethylene sorbitan esters; carbonate salts; alkylsulfonates; and cyclodextrins. All of the additives to improve the solubility and the other types mentioned above can be added directly to the spray-dried solution so that the additive is dissolved or suspended in the solution as a suspension. Alternatively, such additives may be added after the spray drying process to help form the final dosage form.

THE COATING The fundamental limitations of the coating are that it is permeable in water, that it has at least one hole for drug release and that it does not dissolve or erode during the release of the drug formulation, so that the drug is substantially completely released through the orifice or delivery holes or pores, as opposed to the release primarily by permeation through the coating material itself. "Release hole" refers to any passage opening, perforation or pore, made by practicing the orifice mechanically or by laser, by forming a pore during the coating process or in situ during use, or by rupture during use. The coating will be present in an amount ranging from about 5 to 30% by weight, preferably from 10 to 20% by weight, based on the weight of the core. A preferred form of coating is a semipermeable polymer membrane having the orifice or holes formed therein before or during use. The thickness of said polymeric membrane can vary from about 20 to 800 μm and preferably varies in the range from 100 to 500 μm. The orifice or orifice of release will generally vary from 0.1 to 3000 μm in diameter or greater, preferably in the order of 50 to 3000 μm in diameter. Such orifice or holes may be formed after the coating by practicing the orifice mechanically or by laser, or may be formed in situ by rupture of the coatings; said breaking can be controlled by intentionally incorporating a relatively weak portion in the coating. The release orifices can also be formed in situ by erosion of a plug of water-soluble material or by rupture of a thinner portion of coating on a groove in the core. In addition, the release holes may be formed during coating, as in the case of asymmetric membrane coatings of the type described in U.S. Patent Nos. 5,612,059 and 5,698,220, the disclosures of which are incorporated herein by reference. memory as reference. When the release orifice is formed in situ by rupture of the coating, a particularly preferred embodiment is a series of microspheres that can be virtually identical or of a variable composition. The drug is released primarily from such microspheres after the coating ruptures and, after rupture, said release may be gradual or relatively sudden. When the array of microspheres has a variable composition, the composition can be chosen such that the microspheres are broken at different times after administration, resulting in the total release of the drug being sustained for a desired period. The coatings can be compact, microporous or "asymmetric" with a region supported by a compact porous region as described in U.S. Patent Nos. 5,612,059 and 5,698,220. When the coating is compact, the coating is formed by a water-permeable material. When the coating is porous, it may be formed of a permeable or water impermeable material. When the coating is formed of a porous material impermeable to water, water penetrates through the pores of the coating as liquid or as steam. Examples of osmotic devices using such compact coatings include those of U.S. Patent Nos. 3,995,631 and 3,845,770, the disclosures of which are incorporated herein by reference. Such compact coatings are permeable to external fluid such as water and can be composed of any of the materials cited in these patents, as well as other water-permeable polymers known in the art. The membranes can also be porous as described in U.S. Patent Nos. 5,654,005 and 5,458,887 or even be formed of water-resistant polymers. U.S. Patent No. 5,120,548 describes another suitable process for forming coatings from a mixture of water insoluble polymer and a leachable water soluble additive., whose pertinent descriptions are incorporated herein by reference. The porous membranes can also be formed by the addition of pore formers as described in U.S. Patent No. 4,612,008, the pertinent description of which is incorporated herein by reference. In addition, vapor permeable coatings can be formed even from extremely hydrophobic materials such as polyethylene or poly (vinylidene fluoride) which, when compact, are basically waterproof, provided such coatings are porous. Useful materials for forming the coating include various grades of acrylic, vinyl, ether, polyamide, polyester and cellulose derivatives that are water permeable and water-insoluble at relevant physiological pH, or can become insoluble in water by such a chemical alteration. as crosslinking. Specific examples of suitable polymers (or crosslinked versions) useful for forming the coating include, in its unplasticized, plasticized or reinforced form, cellulose acetate (CA), cellulose diacetate, cellulose triacetate, cellulose acetate propionate, cellulose nitrate , cellulose acetate butyrate (CAB), cellulose acetate ethylcarbamate, CAP, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose trimellitate acetate (CAT), cellulose acetate dimethylaminoacetate, cellulose acetate ethylcarbonate, cellulose acetate chloroacetate, acetate cellulose ethyl oxalate, cellulose acetate methylsulfonate, cellulose acetate butylsulphonate, cellulose acetate p-toluenesulfonate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethylacetate, locust bean gum triacetate, ethylene hydroxylated vinylacetate, EC, PEG, PPG, copolymers of PEG / PPG, PVP, HEC, HPC, CMC, CMEC, H PMC, HPMCP, HPMCAS, HPMACT, po! I (acrylic acids and esters) and poly (methacrylic acids and esters) and copolymers thereof, starch, dextran, dextrin, chitosan, collagen, gelatin, polyalkenes, polyethers, polysulfones, polyethersulfones , polystyrenes, poly (vinyl halides), poly (esters and vinyl ethers), natural waxes and synthetic waxes. A preferred coating composition comprises a cellulosic polymer, in particular cellulose ethers, cellulose esters and cellulose ester ethers, ie, cellulose derivatives having ester and ether substituents, such as HPMCP. Another preferred class of coating materials are poly (acrylic acids and esters), poly (methacrylic acids and esters) and their copolymers. A particularly preferred coating composition comprises cellulose acetate. An even more preferred coating includes a cellulosic polymer and PEG. A more preferred coating comprises cellulose acetate and PEG. The coating is performed in a conventional manner, typically by dissolving the coating material in a solvent and then coating by immersion, spray coating or preferably, by tray coating. A preferred coating solution contains from 5 to 15% by weight of polymer. Typical solvents useful with the cellulosic polymers mentioned above include acetone, methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methylpropyl ketone, ethylene glycol monoethyl ether, ethylene glycol monoethyl acetate, methylene dichloride, dichloride ethylene, propylene dichloride, nitroethane, nitropropane, tetrachloroethane, 1,4-dioxane, tetrahydrofuran, diglyme and mixtures thereof. Pore formers and non-solvent media (such as water, glycerol and ethanol) or plasticizers (such as diethyl phthalate) can also be added in any amount as long as the polymer remains soluble at the spray temperature. Pore formers and their use in the manufacture of coatings are described in U.S. Patent No. 5,612,059, whose pertinent description is incorporated herein by reference. The coatings can also be hydrophobic microporous layers in which the pores are substantially filled with a gas and are not wetted by the aqueous medium but are permeable to water vapor, as described in U.S. Patent No. 5,798. 119, whose pertinent description is incorporated herein by reference. Such hydrophobic but water vapor permeable coatings are typically formed by hydrophobic polymers such as polyalkenes, poly (acrylic acid) derivatives, polyethers, polysulfones, polyethersulfones, polystyrenes, poly (vinyl halides), poly (esters and vinyl ethers) ), natural waxes and synthetic waxes. Especially preferred hydrophobic microporous coating materials include polystyrene, polysulfones, polyethersulfones, polyethylene, polypropylene, polyvinyl chloride, polyvinylidene fluoride and polytetrafluoroethylene. Such hydrophobic coatings can be prepared by known phase inversion methods using any of the thermal vapor extinction or liquid extinguishing processes by leaching the soluble material from the coating or by sintering the coating particles. In thermal processes, a polymer solution in a latent solvent is carried to a liquid-liquid phase separation in a cooling step. If evaporation of the solvent is not avoided, the resulting membrane will typically be porous. Such coating processes can be carried out by the methods described in U.S. Patent Nos. 4,247,498; 4,490,431 and 4,744,906, the disclosures of which are incorporated herein by reference. Another embodiment of sustained release osmotic dosage forms of this invention comprises a tablet containing an osmotic drug that is surrounded by an asymmetric membrane, said asymmetric membrane arranging one or more thinner compact regions in addition to less compact porous regions. This type of membrane, similar to those used in the reverse osmosis industry, generally allows greater osmotic water flows than can be obtained with a compact membrane. When applied to a drug formulation, eg, a tablet, said asymmetric membrane allows high drug flows and sustained release of the well-controlled drug. This asymmetric membrane comprises a semipermeable polymeric material, i.e., a material that is permeable to water and substantially impermeable to organic salts and solutes such as drugs. Useful materials for forming such semipermeable asymmetric membranes include polyamides, polyesters and cellulose derivatives. The ethers and esters of cellulose are preferred. CA, CAB and EC are especially preferred. Especially useful materials include those that spontaneously form one or more exit openings, either during manufacture or when placed in an environment of use. These preferred materials comprise porous polymers, whose pores are formed by phase inversion during manufacture, as described above, or by dissolution of a water-soluble component present in the membrane. The asymmetric membrane is formed by a phase inversion process. The coating polymer, e.g., EC or CA, is dissolved in a mixed solvent system comprising a mixture of solvents (e.g., acetone) and non-solvents (e.g., water) for the polymer. The components of the mixed solvent are chosen such that the solvent (eg, acetone) is more volatile than the non-solvent (e.g., water). When a tablet is contacted with said solution and dried, the solvent component of the solvent mixture evaporates more rapidly than the non-solvent component. This change in the composition of the solvent during drying causes the separation of the solution into two phases such that, when solidified, the tablet polymer is a porous solid with a thin outer compact region. This outer region has several pores through which the drug can be released as a solution or suspension of drug particles, which crystalline, amorphous particles or a drug / polymer dispersion can be. In a preferred embodiment of a tablet coated with an asymmetric membrane, the polymer / solvent / non-solvent mixture is sprayed onto a bed of tablets in a tablet coating apparatus such as a Freund HCT-60 tablet coater. In this process, the tablet is coated with thick porous regions and with a final thin outer compact region. In the use environment such as the Gl tract, water is imbibed through the asymmetric semi-permeable membrane into the core of the tablet. When the soluble material in the core of the tablet dissolves, a gradient of osmotic pressure is generated across the membrane. When the hydrostatic pressure in the membrane surrounding the core exceeds the pressure of the environment of use, the solution containing the drug is "pumped" out of the dosage form through the orifice or orifices through the semi-permeable membrane . In addition, hydrostatic pressure can cause the formation of even larger pores or pores by rupturing a portion of the coating. The difference in relatively constant osmotic pressure across the membrane causes a well-controlled drug release to the environment of use. A portion of the drug dissolved in the tablet also exits by diffusion. In this embodiment of tablet coated by an asymmetric membrane, the drug can be incorporated into the dispersion in its neutral form or as a salt. It is often desirable to include one or more solubilizing excipients, such as ascorbic acid, erythorbic acid, citric acid, tartaric acid, glutamic acid, aspartic acid, glycerides, partial glycerides, glyceride derivatives, PEG, PEG ethers, PPG esters, esters of polyhydric alcohols, polyoxyethylene ethers, sorbitan esters, polyoxyethylene sorbitan esters, saccharide esters, phospholipids, block copolymers of poly (ethylene oxide) -poly (propylene oxide). Most preferred are the solubilizing excipients ascorbic acid, aspartic acid, citric acid, tartaric acid, glyceryl monocaprylate, glyceryl monostearate, glycerol monolaurate and C8-C10 partial glycerides.

USE AND MANUFACTURE In use, the solid dispersion core imbibes water through the coating from the environment of use such as the Gl tract so that the pressure inside the core increases. The difference in pressure between the core and the exterior of the device drives the release of core content. Since the coating remains intact, the drug formulation is expelled out of the core through the orifice or delivery holes to the environment of use, either primarily as a drug solution or as a drug suspension; when released as a suspension, the drug formulation is subsequently dissolved in the Gl tract. A preferred embodiment of the osmotic delivery device consists of a drug layer containing the substantially amorphous drug / polymer dispersion and a swelling layer comprising a water swellable polymer, with a coating surrounding the drug layer and the layer of swelling. Each layer may contain other excipients such as tablet preparation aids, osmagents, surfactants, water-soluble polymers and water-swellable polymers. Such osmotic delivery devices can be manufactured with various geometries including that of two layers, wherein the core comprises a layer of drug and a swelling layer adjacent to each other; that of three layers, in which the core comprises a layer of swelling "interposed" between two layers of drug; and the concentric, in which the core comprises a central swelling composition surrounded by the drug layer. The coating of said tablet comprises a membrane permeable to water but essentially impermeable to the drug and the excipients contained therein. The coating contains one or more exit passage openings or exit ports in communication with the layer or layers containing the drug to release the drug dispersion composition. The layer or layers containing the core drug contains the drug dispersion composition (including the optional osmagents and the hydrophilic water soluble polymers), while the swelling layer comprises an expandable hydrogel, with or without additional osmotic agents. Said release devices are exemplified in Figure 4 and Example 3 (three layers), in Figure 2 and Example 4 (two layers) and in Figure 3 and Example 5 (concentric). When placed in an aqueous medium, the tablet imbibes water through the membrane, causing the composition to form a dispensable aqueous composition, and causing the hydrogel layer to expand and push the composition containing the drug dispersion, forcing to the composition to exit through the exit passage opening. The composition can swell, helping to push the drug through the through opening. The drug can be released from this type of release system dissolved or dispersed in the composition that is expelled from the outlet passage opening. The rate of drug release is controlled by factors such as the permeability and thickness of the coating, the osmotic pressure of the drug-containing layer, the degree of hydrophilicity of the hydrogel layer and the surface area of the device. Those skilled in the art will appreciate that increasing the thickness of the coating will reduce the rate of release, while any of the following factors will increase the rate of release: increase the permeability of the coating; increase the hydrophilicity of the hydrogel layer; increase the osmotic pressure of the layer containing the drug; or increase the surface area of the device. Useful example materials for forming the composition containing the drug dispersion, in addition to the drug dispersion itself, include HPMC, PEO and PVP and other pharmaceutically acceptable carriers. In addition, osmagents such as sugars or salts can be added, especially sucrose, lactose, xylitol, mannitol or sodium chloride. Materials that are useful for forming the hydrogel layer include sodium CMC, PEO, po (i) (acrylic acid), poly (sodium acrylate), croscarmellose sodium, sodium starch glycolate, PVP, cross-linked PVP and other hydrophilic high molecular weight materials . Particularly useful are PEO polymers having an average molecular weight of from about 5,000,000 to about 7,500,000 daltons. In general, the dosage form provides a maximum drug concentration (MDC) in an environment of use that is at least 1.2 times that of an equivalent control dosage form, except that the drug is in undispersed form. When the dosage form contains homogeneous dispersions (which are preferred), the MDC value obtained when dosing a larger amount of drug may be higher for such dispersions with respect to dispersions for which at least a portion of the drug is present. as a drug-rich amorphous phase or as a crystalline phase. Alternatively, the dosage form of the present invention, when tested in vitro in a physiologically relevant aqueous solution, for dissolution times of 90 to 1200 minutes, provides an AUC value of at least 1.25 times that measured for an equivalent dosage form containing an equivalent amount of undispersed drug. Preferably, when administered in an environment of use, the dosage form also provides, for dissolution times of 90 to 1200 minutes, an AUC value that is at least 1.25 times that observed when dosing an equivalent amount. of drug not dispersed. In the case of a two-layer geometry, the delivery orifice or holes, or the exit opening or openings may be located on the face of the tablet containing the drug composition or may be on both sides of the tablet or even on the edge of the tablet so as to connect both the drug layer and the swelling layer to the exterior of the device. The exit opening apertures can be produced by practicing by mechanical means or with a laser, or by creating a difficult region to be coated on the tablet using a special press during compression of the tablet or by other means. The rate of drug release from the device can be optimized by providing a method for releasing the drug to a mammal to obtain the optimal therapeutic effect. Osmotic systems can also be prepared with a homogeneous core surrounded by a semi-permeable membrane coating. The drug dispersions can be incorporated into a tablet core so that it also contains other excipients that provide sufficient osmotic motive power and optionally, solubilizing excipients such as acids or compounds of the surfactant type. A semipermeable membrane coating can be applied by conventional tablet coating techniques such as using a tray coater. A drug release passage opening in this coating can be formed by making a hole in the coating, using a laser or other mechanical means. Alternatively, the through opening may be formed by breaking a portion of the coating or creating a region in the tablet that is difficult to coat, as described above. Another embodiment of sustained release osmotic dosage forms of the invention include multiparticulates containing drug dispersion coated with a water permeable membrane; the polymer can be compact, porous or asymmetric, as described above. Such multiparticulates are prepared, for example, by freezing a melt on a rotating disk, by extrusion / spheronization or by fluid bed granulation, or coating the coating matrix cores with a drug mixture and a water soluble polymer as described before. Multiparticulates containing drug can be homogeneous or stratified with a drug dispersion surrounding the matrix nucleus. After being formed, such multiparticulates are then coated by spraying with a substantially water permeable coating comprising a solution of a polymer in a mixture of a solvent and, depending on the type of coating desired, a non-solvent medium, as described above . This spray coating operation is carried out in a fluid bed coating apparatus, for example, a Glatt GPCG-5 fluid bed coater (Glatt Air, Ramsey, New Jersey). The polymer used to form the semipermeable membrane is chosen as described above. Osmotic capsules can be prepared using the same or similar components as described above for osmotic and multiparticulate tablets. The shell of the capsule or the shell portion of the capsule may be semipermeable and be made of the materials described above. The capsule can then be filled with a powder or a liquid comprising the drug dispersion, excipients that imbibe the water to provide the osmotic potential and / or a water swellable polymer, and optionally, soluzing excipients. The core of the capsule can also be made in such a way that it has a two-layer or multi-layer composition analogous to the two-layer, three-layered or concentric geometries described above. Another class of sustained release dosage forms useful in this invention comprises coated and multiparticulate inflatable tablets, such as those described in EP 378 404, incorporated herein by reference. The coated inflatable tablets comprise a tablet core comprising the drug dispersion and an inflatable material, preferably a hydrophilic polymer, coated with a membrane containing orifices or pores through which the hydrophilic polymer can exit and carry the composition of drug to an aqueous environment of use. Alternatively, the membrane may contain polymeric or water-soluble low molecular weight "porogens" that dissolve in the aqueous environment of use, causing pores through which the hydrophilic polymer and the drug may exit. Examples of porogens are water soluble polymers such as HPMC and low molecular weight compounds such as glycerol, sucrose, glucose and sodium chloride. In addition, pores can be formed in the coating by making holes in the coating using a laser or other mechanical means. In this class of sustained release dosage forms, the membrane material can comprise any film-forming polymer, provided that the membrane deposited on the core of the tablet is porous or contains water-soluble porogens or has a macroscopic orifice for the entry of water and the release of drug. Similarly, multiparticulates (or microspheres) can be prepared with a drug dispersion core / swellable material, coated with a porous membrane or containing porogens. Embodiments of this class of sustained release dosage forms can also be multi-stratified, as described in EP 378404 A2. For any of the sustained or controlled release dosage forms cited above, the dosage form may further comprise an intermediate release layer of the same or a different drug in crystalline, amorphous or dispersed form. The dosage forms of the present invention are useful in the treatment of various disorders and diseases including those exemplified herein, by administering the dosage forms described herein to a patient or person in need of such treatment.

EXAMPLE 1 Exemplary dosage forms of the present invention were prepared comprising a solid dispersion ("SD") load of 10% by weight poorly soluble drug and 90% by weight polymer by mixing the drug [R- (R * S *) ] -5-chloro-N- [2-hydroxy-3- [methoxymethylamino] -3-1- (phenylmethyl) propyl] propyl] -1H-indole-2-carboxamide (an inhibitor of glycogen phosphorylase) (in which successively named "Drug 1") having a solubility in water of 1 μg / ml, in acetone as a solvent, together with HPMCAS of "good medium" (MF) quality (AQUOT, Shinetsu, Tokyo, Japan) forming a solution. The solution comprised Drug 1 at 0.27% by weight, polymer at 2.43% by weight and 97.3% by weight of solvent. This solution was spray dried by directing an atomization spray from a rotary atomizer at 12.4 x 104 Pa and 100 g / min of feed rate in a stainless steel chamber of a Niro mobile spray dryer maintained at 120 ° C in the entrance and at 68 ° C at the exit. The portions of the dispersion were retained and subjected to powder X-ray diffraction analysis and thus it was verified that the drug was in an essentially non-crystalline amorphous state. The resulting solid particles had an average diameter of 5 to 20 μm. The particles were then mixed with 15% by weight of tablet preparation aid and microcrystalline cellulose (PROSOLV, Edward Mendell Co., Patterson, New York), 30% by weight of PEO hydrogel having an average MW of 600,000 Daltons, % by weight of adjuvant for the preparation of tablets and HPC (KLUCEL LXF, Hercules, Wilmington Delaware), 20% by weight of the lactose solute, osmotically effective and 1% by weight of the magnesium stearate lubricant and mixed for 40 minutes to make the homogeneous mixture. The homogeneous core mixture thus formed contained 30% by weight of solid dispersion, so that the core mixture contained 3% by weight of Drug 1. This homogenous core mixture was formed into tablet cores in a tablet press at about 17.79 x103 N of compression force using a die of 33.02 / 81, 28 cm. The tablet cores were then coated with CA (Eastman Fine Chemicals, CA 398-10, Kingsport, Tennessee) by tray coating them in a coating composition comprising 7 wt% CA, 3% PEG weight with an average MW of 3350 Daltons in a mixture of acetone / water (68% by weight / 22% by weight) and then drying it in a convection oven at 50 ° C. This coating was examined by SEM (scanning electron microscopy) and was shown to contain alternate regions of (1) coarse and porous and (2) compact and thin, generally having the morphology shown in U.S. Patent No. 5,612,059. The final weight of the core was 500 mg, while the dry coating weight was 79 mg (15.8% by weight). Twelve holes of 0.9 μm diameter were then mechanically machined into the coating on each side of the tablet providing 24 release holes per tablet. A coated and perforated core having the same composition in all aspects was prepared as the first control (Control A) except that HPMCAS was not present and the drug was in crystalline form. A second control (Control B) was prepared comprising only the identical solid dispersion. A model Duodenum Fasting (MFD) solution was prepared to emulate the chemical environment of the small intestine, the solution comprising a phosphate-buffered saline solution containing 14.7 mM sodium taurocholic acid and 2.8 mM 1-palmitoyl-2 -oleil-sn-glycero-3-phosphocholine with a pH of 6.5. The in vitro solution of the drug was studied from three dosage forms by adding each of the following dosage forms to separate 50 ml aliquots of the MFD solution at 37 ° C; (1) a coated solid dispersion tablet of the invention ("Coated SD"); (2) one Control A tablet; and (3) 150 mg of solid dispersion of Control B.

In all three cases, the total amount of Drug 1 present was 15 mg. Thus, if all the drug of each form is dissolved, the maximum drug concentration in each one of the test solutions would be approximately 300 μg / ml. The drug concentration was determined over time by periodically extracting samples from each of the three solutions, filtering the samples to eliminate the undissolved drug, analyzing the samples by High Resolution Liquid Chromatography (HPLC) and calculating from them the drug concentrations. The results are presented in Table 1 and Figure 5. As is evident, the dosage form of the present invention showed considerably higher drug concentrations over time, as well as an approximately 10-fold increase in the AUC when compared with Control A.

TABLE 1 "• μg / ml" * min- μg / ml The mechanism of drug delivery from the coated SD of the present invention (Example 1) was studied by periodic visual inspection of the tablet during drug release and revealed an entry of water into the drug. the core that gradually caused a swelling of the core, followed by an almost constant expulsion of "elongated" sections of core material swollen by water through the release holes, leaving the rest of the coating intact, indicating that no dissolution occurred or erosion of the coating.

EXAMPLE 2 An amorphous solid dispersion comprising 33% by weight of a different glycogen phosphorylase inhibitor, namely [1 (S) -benzyl-3 - ((3R, 4S), was prepared in substantially the same manner as in Example 1. 5-Chloro-1 H-indole-2-carboxylic acid (dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] amide ("Drug 2") having a solubility in water of 80 μg / ml and 66.7% HPMCAS of the same quality used in Example 1, with the following differences: the concentrations of drug and polymer in the spray solution were 2.5% by weight and 5.0% by weight, respectively; the inlet temperature was 179 ° C and the outlet temperature was 70 ° C; the feed rate was 200 g / min and a two fluid nozzle was used. The solid dispersion thus formed was mixed with the remaining tablet preparation excipients as in Example 1 so that the final composition was a solid dispersion of 28% by weight drug, 22% by weight of xylitol containing 1.5% by weight of CMC (XILITAB 200, American Xyrofin, Shaumberg, Illinois), 29% by weight of PEO with an average MW of 600,000 Daltons, 20% by weight of sodium starch glycolate osmopolymer (EXPLO , Edward Mendell Co., Patterson, New York) and 1% by weight of magnesium stearate. The tablets for this homogenous core mixture were prepared as in Example 1, each core having a weight of 500 mg. The substantially amorphous state of the drug in the dispersion was confirmed by powder X-ray diffraction analysis.

These cores were coated as in Example 1 with CA from a coating solution comprising 7% by weight of CA, 3% by weight of PEG with an average MW of 3350 daltons, 5% by weight of water and 85% by weight of acetone, the dry coating weight being 57.5 mg (11.5% by weight of the core of the tablet). The resulting coating was compact and substantially non-porous. Five holes of 0.9 ml in diameter were made in the coating as in Example 1, to a total of 10 release holes for each tablet. For a comparative dissolution study, Controls C and D were prepared. Control C comprised 280 mg of the identical amorphous solid drug dispersion without excipients of tablet preparation and without coating, while Control D comprised a physical mixture of 93 mg of crystalline drug and 186 mg of HPMCAS-MF. To simulate the dissolution of the drug in vivo, two tablets of the invention and Controls C and D were first placed in 40 ml of simulated buffered gastric solution for 30 minutes at 37 ° C and stirred, then 10 ml of MFD solution and enough sodium hydroxide solution were added to adjust the pH of the resulting solution to 6.5. The resulting MFD solution had the same composition as in Example 1, except that the concentrations of taurocholic acid and phosphocholine ester were 73.5 mM and 14 mM, respectively. The concentration of drug over time was determined as in Example 1, and the results are shown in Table 2 and in the graph of Figure 6. The data shows that about 25% drug was released in about 8 hours. 52% in 20 hours. This demonstrates that the dosage form of the present invention exhibits a true sustained release of the drug when compared to the uncoated solid drug dispersion, since the uncoated dispersion (Control C) releases practically all of the drug in less than one hour, generally considered as undesirable "transient and short-term" drug dosage. In addition, the concentration of drug achieved by the device of the present invention (967 μg / ml) exceeds by two times the maximum solubility of the crystalline drug (Control D) (482 μg / ml).

TABLE 2 * μg / ml ** min.μg / ml The release mechanism of the coated solid dispersion of the invention was studied as in Example 1 and it was confirmed that the coating did not dissolve or erode, while the solid dispersion in the The core was expelled as a solid dispersion which was then dissolved in the combined gastric / MFD solution.

EXAMPLE 3 This example illustrates the release of the invention of Drug 2, except that the core of the tablet was a "three layer" design of the type shown in Figure 4. The core comprised two compositions; a swelling layer between two essentially identical drug layers. The drug was in the form of a solid dispersion of identical composition to that of Example 2. The drug layers were composed of 26.25% by weight of solid dispersion, 35% by weight of XILITAB 200, 32.5% by weight of PEO with an average MW of 600,000 daltons, 5.0% by weight of EXPLOTAB and 1.25% by weight of magnesium stearate. The swelling layer was composed of 74% by weight of EXPLO , 25% by weight of PROSOLV 90 and 1% by weight of magnesium stearate. The tablets were formed by first mechanically mixing the ingredients of the above drug layer to homogeneity, compressing to a hardness of 4 kp and then milling to a size of 800 μm or less. 200 mg of the drug layer mixture was then placed in the bottom of a conventional 7.62 / 20.56 cm die and lightly compacted. Next, 100 mg of the mixture of the swelling layer in the die was placed on top of the drug layer and lightly compacted. Finally, another 200 mg of the drug layer mixture was placed in the die above the swelling layer. The tablet was then pressed to a hardness of 10 to 14 kp with the device described in Example 1. The resulting three-ply core thus had a total weight of 500 mg and contained 105 mg of solid dispersion, 35 mg of which were Drug 2. The three-layer core was then coated and holes were made as in Example 2, except that the coating weight was 11.8 wt.% Based on the weight of the core. For a comparative dissolution study, the Control was prepared E, formed by 35 g of Drug 2 crystalline. The drug solution was studied by placing two of the three-layer tablets and Control E in 35 ml of a phosphate-buffered saline solution (PBS) consisting of 6 mM KH 2 PO 4, 5 mM NaOH, 60 mM KCl and 30 mM NaCl. The drug concentration was determined over time as in Example 1 and the results are shown in Table 3. The data for the three-layer tablet is the average of the values for the two tablets tested. The data show that the drug was released gradually from the three-layer tablet, reaching a maximum concentration after about eight hours and demonstrating the sustained release of the drug. In addition, the MDC achieved by the three-layer tablet was 510 μg / ml, almost three times the 171 μg / ml observed for the pure crystalline drug.

TABLE 3 * μg / ml EXAMPLE 4 This example illustrates a process for preparing a dosage form of the present invention with a core geometry with two layers of the type shown in Figure 2. The two-layer core consists of a drug layer and a swelling layer. To form the drug layer, the following materials can be mixed and wet granulated in a mixer: from 50 g to 200 g of the drug dispersion of Example 2; from 250 to 325 g of a PEO having an average MW of approximately 200,000 daltons; from 10 to 30 g of an HPMC having an average MW of about 11,300; and from 0 to 10 g of magnesium stearate. The swelling layer can be formed by wet granulation of the following materials: from 110 g to 140 g of PEO having an average MW of about 5,000,000 to 7,500,000 daltons; from 5 to 25 g of an HPMC having a MW of approximately 11,300 daltons; from 40 g to 70 g of sucrose; and from 0 to 10 g of magnesium stearate. The two-layer core is formed by initially placing 50 mg to 300 mg of the granulation of the swelling layer at the bottom of a 7.62 / 20.56 cm die and then compacting the material slightly. 50 mg to 300 mg of the granulate of the drug layer was then placed on top of this swelling layer. The tablet was pressed to a hardness of 6 to 15 kp. The resulting two-layer cores are then coated with a semipermeable coating composed of 50% to 98% CA having an acetyl content of about 32 to 40% by weight and 2 to 50% of PEG with an average MW of approximately 3350 daltons. In the coating, at least one outlet passage opening of 500 to 2000 μm in diameter is formed on the face of the drug layer.

EXAMPLE 5 This example illustrates the manufacture of the dosage form of the invention except that the core of the device has a concentric design of the type shown in Figure 3. The core comprises a central core with a swelling composition surrounded by the drug composition. To form the central core, 100 to 200 mg of the wet granulation swelling of Example 3 is placed on the bottom of a 2.54 / 10.16 cm die and compressed to a hardness of about 4 to 6 kp. 200 to 300 mg of the composition containing the drug of Example 3 are then placed in the bottom of a die of 33.02 / 81, 28 cm and filled by hand using a spatula. The previously formed core is then placed on top of the drug-containing composition layer at its center and another 200 to 300 mg of the same composition is placed on top of it, around the central core. The material is then compressed to a hardness of 10 to 14 kp forming a tablet core of concentric design, which is then coated with a semipermeable coating as described in Example 3. Finally, at least one outlet passage opening is formed. from 500 to 2,000 μm in diameter on each side of the coated tablet.

EXAMPLE 6 This example illustrates the release of a SD of Drug 1 and HPMCAS-MF of a tablet in which the core has a three-layer design represented in Figure 4. The core was constituted by two compositions: a swelling layer between two layers of essentially identical drugs, each drug layer comprising an SD prepared as in Example 1, except that the SD contained 67% by weight of Drug 1 and 33% by weight of HPMCAS-MF. The drug layers comprised 9.56% by weight of SD, 38.4% by weight of XYLITAB 200, 37.3% by weight of PEO with an average MW of 600,000 daltons, 13.5% by weight of EXPLOTAB and 1. , 24% by weight of magnesium stearate. The swelling layer was composed of 74.5% by weight of EXPLO , 25% by weight of microcrystalline cellulose (AVICEL PH 200, FMC Corporation, Philadelphia, Pennsilvania) and 0.5% by weight of magnesium stearate. The tablets were formed by mechanical mixing of the ingredients of the drug layer to homogeneity. The ingredients of the swelling layer were then mixed until homogeneous. Tablets were formed by initially placing 200 mg of the drug layer mixture in a conventional 33.02 / 81, 28 cm die and compacted lightly. Next, 100 mg of the swelling layer mixture in the same die was placed on top of the first drug layer, followed by 200 mg of a second drug layer and compressed to a hardness of 10 kp. The resulting three-ply core thus had a total weight of 500 mg and contained 38.25 mg of SD. It was determined that the SD had an activity and a pharmacological potency of Drug 1 of 65.4% and 90.5%, respectively. Thus, the three layer core contained 122.6 mg of Drug 1. The three layer core was then coated and holes were made as in Example 2, except that the weight of the coating was 12.9% based on the weight of the core. . For a comparative dissolution study, a Control F composed of 22.64 mg of Crystalline Drug 1 was prepared. The drug solution was studied by placing two tablets of three layers and two of Control F preparation containing an equal amount of Drug 1 in 50 ml of the MFD solution of Example 1. The drug concentration was determined over time as in Example 1 and the results are shown in table 4. The data for the three-layer tablet is the average of the values for the two tablets tested. The data show that the drug was released gradually from the three-layer tablet, reaching a maximum concentration after about 8 hours. In addition, the MDC obtained by the three-layer tablet was 151 μg / ml, almost 10 times higher than the observed of 16 μg / ml for the pure crystalline drug.

TABLE 4 μg / ml EXAMPLE 7 This example illustrates the release of Drug 2 from a tablet in which the core has a two-layer design shown in Figure 2. The core comprises a swelling layer and a drug layer. The drug layer was in the form of an SD formed by 50% by weight of Drug 2 with a solubility in water of 80 μg / ml and 50% of HPMCAS-MF. The SD was prepared basically in the same manner as in Example 1, except that the spray solution comprised 7.5 wt.% Of Drug 2, 7.5 wt.% Of polymer and 85 wt.% Of acetone: water. :5. This solution was spray dried using a two fluid atomizer with external mixture with a spray gas feed rate of 460 g / min and a solution feed rate of 200 g / min with an inlet temperature of 195 ° C and a outlet temperature of 70 ° C. The resulting solid particles had an average diameter of about 50 μm. The drug layer comprised 44.4% by weight of SD, 26.1% by weight of XYLITAB 200, 25.2% by weight of PEO with an average MW of 600,000 daltons, 3.5% by weight of EXPLO , and 0.8 wt% of magnesium stearate. The swelling layer was 74.5% by weight of EXPLO , 25% by weight of PROSOLV 90 and 0.5% by weight of magnesium stearate. The tablets were formed by initially mechanically mixing the ingredients of the drug layer to homogeneity, compressing it into slightly compacted tablets and grinding the resulting tablets to particles less than 16 mesh in size. The ingredients of the swelling layer were then mixed until homogeneous. Tablets were formed by initially placing 450 mg of the drug layer mixture in a conventional 38.1 / 81.28 cm die, then placing 150 mg of the swelling layer mixture in the die at the top of the die. the drug layer and compressing to a hardness of 15 kp. The resulting two-layer core thus had a total weight of 600 mg and contained 199.8 mg of SD, 99.9 mg of which were Drug 2. This core was then coated and holes were made as in Example 2, except because the coating weight was 8.9% of the core weight and five 900 μm holes were made only on the drug face. For a comparative dissolution study, a Control G was prepared, consisting of 100 mg of Crystalline Drug 2. The drug solution was studied by placing a two-layer and a Control G preparation tablet containing an equal amount of Drug 2 in 50 ml of phosphate buffered solution of Example 3 (pH 7.2, osmotic pressure 5.37 x 105 Pa) to simulate the intestinal environment of use. The drug concentration was determined over time as in Example 1, and the results are shown in Table 5. The data shows that the drug was gradually released from the two-layer tablet, reaching an MDC after about 8 hours and demonstrating a sustained release of the drug. In addition, the MDC achieved by the two-layer tablet was 608 μg / ml, almost eight times higher than the 77 μg / ml observed for the pure crystalline drug.

TABLE 5 μg / ml EXAMPLE 8 Exemplary dosage forms of the present invention were prepared for sertraline (a drug that inhibits the reuptake of low solubility serotonin) with a core geometry with two layers of the type depicted in Figure 2. The two-layer core comprised a layer of a composition containing sertraline and a layer of a water swellable composition. The composition containing sertraline was in the form of a solid dispersion formed by 50% by weight of drug and 50% by weight of HPMCP-55. The solid dispersion was prepared basically in the same manner as in Example 1, except for the following: the solution comprised 2.5% by weight of drug, 2.5% by weight of polymer, 47.5% by weight of methane ! and 47.5% by weight of acetone. This solution was spray dried using a two fluid nozzle with a spray pressure of 1, 5 x 105 Pa and 193 g / min of feed flow. The inlet temperature was maintained at 230 ° C and the outlet temperature was 72 ° C. The drug layer was formed by 41, 15% by weight of solid dispersion, 26.75% by weight of XYLITAB 200, 26.75% by weight of PEO with an average MW of 600,000 daltons, 4.33% by weight of EXPLOTAB and 1. 02% by weight of magnesium stearate. The swelling layer was formed by 74.66% by weight of EXPLO , 24.73% by weight of PROSOLV 90, 0.47% by weight of magnesium stearate and 0.14% by weight of Red Lake # 40. The tablets were formed by initially combining the ingredients of the above drug layer, by pre-compren and milling in a mill at 1100 rpm (0.19 cm mesh size). The ingredients of the swelling layer were combined without the magnesium stearate, mixed for 20 minutes in a Turbula mixer, then mixed again for 4 minutes with magnesium stearate. Each tablet was prepared using 550 mg of drug layer and 150 mg of swelling layer and compressed to a hardness of 11.5 kp. The resulting two-layer core had a total weight of 700 mg and contained 226.3 mg of solid dispersion, 113.2 of which were sertraline. The two-layer core was then coated and holes were made as described above, except that the coating weight was 9.3% of the core weight and an orifice of 700 μm was made. For a comparative dissolution study, Control H, composed of 111.4 mg of crystalline drug, was used. The drug solution was studied by placing the two-layer tablet and Control H each in 40 ml of MFD solution. The drug concentration was determined over time as in Example 1 and the results are shown in table 6.

TABLE 6 * μg / ml ** min.μg / ml The data show that the drug was released gradually from the two-layer tablet, reaching a maximum concentration after about 6 hours and demonstrating a sustained release of the drug. The MDC achieved by the two-layer tablet was 566 μg / ml, higher than the MDC of 401 μg / ml observed for the pure crystalline drug. At 14 hours, the AUC for the two-layer tablet was 1.8 times the AUC for the control.

EXAMPLE 9 Multiparticulates that provide controlled release of a drug formed as an amorphous solid dispersion can be prepared by preparing drug-containing cores by a melt-freezing process and then applying a water-permeable coating around these cores. To prepare the drug-containing cores, a drug dispersion made as in Example 1 is mixed with glyceryl behenate (COMPRITOL 888 ATOP, Gattefosse Corporation, Westwood, New Jersey) and PEO with an average MW of 600,000 daltons. This mixture consists of 50% by weight of COMPRITOL, 25% by weight of PEO and 25% by weight of drug dispersion and is mixed in a stirred and heated vessel. The mixture is heated to 85 ° C, the COMPR1TOL is melted and a PEO suspension and the drug dispersion are formed. This suspension is pumped into a rotary atomizer to form droplets that solidify upon cooling, forming microspheres containing drug dispersion. The suspension is pumped to the rotating disc of the atomizer at a flow rate of approximately 1 kg / hr and a rotational speed of approximately 3600 rpm. The solidified microspheres are collected and sieved to separate the fines and any large particles or agglomerates. A water permeable coating is then applied to these microspheres by a conventional coating process in a fluid bed. A coating solution consisting of 7% by weight of CA 389-10, PEG 3350 and 18% by weight of water dissolved in acetone is prepared in a stirred vessel. The coating solution sprays the microspheres in a fluidized bed coater with a lower spray, equipped with an inserted Wurster device. The coating solution is applied until a coating weight of approximately 15% by weight (based on the weight of the core) is achieved. Drug-release orifices are formed in the environment of use by imbibing water into the nuclei of the microspheres, causing swelling of the core material and rupture of the coating. The core material is then expelled to the exterior through the rupture of the coating, providing a controlled release of the drug dispersion.

EXAMPLE 10 Multiparticulates that provide controlled release of a drug formed as an amorphous solid dispersion can be prepared by preparing drug-containing cores by a spray coating process and then applying a water permeable coating around these cores. To prepare the drug-containing cores, a drug solution on matrix cores is spray coated by a conventional fluidized bed coating method. The drug solution consists of 1% by weight of drug, 1% by weight of PEO with an average MW of 600,000 daltons and 3% by weight of HPMCAS dissolved in acetone. This drug solution is coated on microcrystalline cellulose spheres (CELPHERE CP-507, FMC Corporation, Philadelphia, Pennsylvania) with a nominal diameter of 600 μm in a fluid bed coater equipped with an inserted Wurster device. The coating is applied to the cores until a coating weight is obtained is approximately 100%, compared to the original weight of the cores. An amorphous drug dispersion is formed by this spray coating process which also forms drug-containing microspheres. A water permeable coating is then applied to these microspheres by a conventional coating process in a fluid bed. A coating solution consisting of 7% by weight of CA 389-10 is prepared in a stirred vessel., PEG 3350 and 18% by weight of water dissolved in acetone. The coating solution sprays the microspheres in a fluidized bed coater with a lower spray, equipped with an inserted Wurster device. The coating solution is applied until a coating weight of approximately 15% by weight compared to the original weight of the microspheres is achieved. Drug release orifices are formed in these coatings in the environment of use by imbibing water into the nuclei of the microspheres, causing swelling of the core material and rupture of the coating. The core material is then expelled to the exterior through the rupture of the coating, providing a controlled release of the drug dispersion. The terms and expressions that have been used in the above description are used herein as descriptive and non-limiting terms and, with the use of such terms and expressions, it is not intended to exclude equivalences of the characteristics shown and described or portions thereof. the same, recognizing that the scope of the invention is defined and limited only by the following claims.

Claims (47)

NOVELTY OF THE INVENTION CLAIMS

1. A controlled release dosage form comprising: (a) a core comprising an osmotic agent and a drug of low solubility in the form of solid dispersion of said drug in a dispersion polymer, with at least a majority portion of said drug being amorphous and (b) a substantially water permeable coating around said core having at least one release orifice, said coating controlling the entry of water to said core from an aqueous environment of use, so as to cause the extrusion of at least one portion of said core through at least not said release orifices to said aqueous environment of use, said coating being non-soluble and non-erodible during the release of said drug.

2. The dosage form according to claim 1, wherein substantially all of said drug is amorphous.

3. Dosage form according to claim 1, wherein essentially all of said drug is amorphous.

4. The dosage form according to claim 1, wherein said coating is a polymeric membrane.

5. The dosage form according to claim 4, wherein said polymer membrane is semipermeable.

6. - Dosage form according to claim 4, wherein said polymeric membrane is porous.

7. The dosage form according to claim 4, wherein said polymeric membrane comprises at least one asymmetric membrane.

8. Dosage form according to claim 7, wherein at least one of said release orifices comprises pores in said coating.

9. Dosage form according to claim 1, wherein at least one of said release orifices is formed by practicing the holes by laser.

10. Dosage form according to claim 1, wherein at least one of said orifices is formed in said environment of use.

11. The dosage form according to claim 10, wherein at least one of said release orifices is formed by the erosion of a plug of water-soluble material.

12. Dosage form according to claim 10, wherein said coating can be broken forming at least one of said release holes.

13. The dosage form according to claim 12, wherein at least one of said release orifices is formed by rupture of a relatively small portion of said coating.

14. Dosage form according to claim 13, wherein said rupture takes place in a thinner portion of said coating on a slit in said core.

15. Dosage form according to claim 4, wherein said coating is constituted by a polymer selected from the group consisting of poly (acids and acrylic esters); poly (methacrylic acids and esters); copolymers of poly (acids and acrylic and methacrylic esters); cellulose esters; cellulose ethers; and ester / ethers of cellulose.

16. The dosage form according to claim 4, wherein said coating is constituted by a polymer selected from the group consisting of polyethylene glycol, polypropylene glycol, copolymers of polyethylene glycol and polypropylene glycol, polyvinylpyrrolidone, ethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, starch, dextran, dextrin, chitosan, collagen, gelatin, bromelain, cellulose acetate, unplasticized cellulose acetate, plasticized cellulose acetate, reinforced cellulose acetate, cellulose acetate phthalate, cellulose trimellitate acetate, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, acetate succinate of hydroxypropylmethylcellulose, acetate trimellitate of hydroxypropylmethylcellulose, cellulose nitrate, cellulose diacetate, cellulose triacetate, agar acetate, amylose triacetate, beta-glucan acetate, beta-glucan triacetate, acetaldehyde dimethylacetate, cellulose acetate ethylcarbamate, cellulose acetate phthalate, cellulose acetate methylcarbamate, cellulose acetate succinate, cellulose acetate dimethamino acetate, cellulose acetate ethylcarbonate, cellulose acetate chloroacetate, cellulose acetate ethyl oxalate, cellulose acetate methylsulfonate, acetate butylsulphonate cellulose, cellulose acetate propionate, cellulose acetate p-toluenesulfonate, locust bean gum triacetate, cellulose acetate with acetylated hydroxyethylcellulose, hydroxylated ethylene vinylacetate, cellulose acetate butyrate, polyalkenes, polyethers, polysulfones, polyethersulfones, 5 polystyrenes, poly ( vinyl halides), poly (vinyl esters and ethers), natural waxes and synthetic waxes.

17. Dosage form according to claim 1, in a form selected from the group consisting of a tablet, a capsule, a microsphere and a group of at least two types of microspheres with different io drug release properties and wherein the Use environment is the gastrointestinal tract of a human being.

18. The dosage form according to claim 1, wherein said osmotic agent is selected from the group consisting of an osmotically effective solute and a hydrophilic polymer swellable in water.

19. The dosage form according to claim 18, wherein said osmotic agent is water swellable and is substantially segregated from said solid dispersion.

20. Dosage form according to claim 19, wherein said osmotic agent and said solid dispersion are in respective layers 2 or discrete.

21. The dosage form according to claim 20, wherein said osmotic agent is in a first layer and said solid dispersion is in a second layer.

22. - Dosage form according to claim 21, which includes a solid dispersion in a third layer, said osmotic agent being between said first layer and said second layer.

23. The dosage form according to claim 19, wherein said solid dispersion surrounds said osmotic agent.

24. Dosage form according to claim 1, wherein said osmotic agent and said dispersion polymer are equal.

25. The dosage form according to claim 18, wherein said hydrophilic water swellable polymer is selected from the group consisting of hydrophilic vinyl and acrylic polymers, polysaccharide alginates, poly (ethylene oxide), polyethylene glycol, propylene glycol, poly (methacrylate), 2-hydroxyethyl), poIi (acrylic acid), poly (methacrylic acid), polyvinylpyrrolidone, crosslinked polyvinylpyrrolidone, polyvinyl alcohol, polyvinylpyrrolidone / polyvinyl alcohol copolymers, vinyl acetate, hydrophilic polyurethanes containing large blocks of poly (ethylene oxide), carrageenan, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, sodium alginate, polycarbophil, gelatin, xanthan gum, croscarmellose sodium and sodium starch glycolate.

26.- Dosage form according to claim 25, wherein said hydrophilic water swellable polymer is selected from the group consisting of poly (ethylene oxide), polyethylene glycol, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylmethylcellulose, poly (acrylic acid), poly (acid) acrylic) crosslinked, croscarmellose sodium and sodium glycolate starch.

27. - Dosage form according to claim 1, wherein said core further comprises a solubility enhancing agent.

28. Dosage form according to claim 27, wherein said solubility-enhancing agent is selected from the group consisting of salts of organic acids and inorganic acids; partial glycerides; glycerides; glyceride derivatives; polyethylene glycol esters; polypropylene glycol esters; esters of polyhydric alcohols; polyoxyethylene ethers; sorbitan esters; polyoxyethylene sorbitan esters; carbonate salts; and cyclodextrins.

29. Dosage form according to claim 1, wherein i or said solid dispersion is formed by spray drying.

30. Dosage form according to claim 1, wherein said dispersion polymer is selected from the group consisting of: (a) ionizable cellulosic polymers; (b) nonionizable cellulosic polymers; and (c) vinyl polymers and copolymers having substituents selected from 15 hydroxyl group, alkylacyloxy and cycloamido.

31.- Dosage form according to claim 30, wherein said dispersion polymer comprises hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinylpyrrolidone, poly ( vinyl alcohol) and copolymers of polyvinylpyrrolidone and polyvinyl alcohol.

32. Dosage form according to claim 29, wherein, before the formation of said solid dispersion, said drug is amorphous.

33. - Dosage form according to claim 29, wherein, prior to the formation of said solid dispersion, said drug is crystalline.

34. Dosage form according to claim 1, wherein said core further comprises excipients. 35.- Dosage form according to claim 34, wherein said excipients are selected from the group consisting of surfactants, water-soluble polymers, pH modifiers, fillers, binders, colorants, lubricants, antioxidants and flavorings. 36.- Dosage form according to claim 1, wherein said dosage form provides a maximum concentration of said drug in the environment of use that is at least 1, 2 times that of a control dosage form comprising an identical dosage form containing an equivalent amount of undispersed drug. 37.- Dosage form according to claim 1, wherein said dosage form provides an AUC in the environment of use that is at least 1.25 times that of a control dosage form comprising an identical dosage form that contains an equivalent amount of undispersed drug. 38.- Dosage form according to claim 1, wherein said dosage form is orally dosed to a mammal and provides an AUC of the concentration of drug in the blood that is at least 1.25 times that of a dosage form of control comprising an identical dosage form containing an equivalent amount of undispersed drug. 39.- Dosage form according to claim 38, wherein said dosage form provides a maximum concentration of drug in the blood at a tmax that is at least 30 minutes higher, although not higher than 24 hours, than the tmax observed for said control dosage form. 40.- Dosage form according to claim 1, wherein said drug is selected from the group consisting of an antihypertensive, an anxiolytic, an anticoagulant agent, an agent to reduce the blood glucose level, a decongestant, an antihistamine, a antitussive, an anti-inflammatory, an anti-atherosclerotic agent, an antipsychotic agent, a cognitive enhancer, an agent for lowering cholesterol, an anti-obesity agent, an agent for autoimmune disorders, a hypnotic agent, an anti-Parkinson's agent, an antibiotic, a antiviral, an agent against impotence, an antineoplastic, 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, an anti-infective agent, a coronary vasodilator, an inhibitor of carbonic anhydrase, an antifungal agent, an antiprotozoa or, a gastrointestinal agent, a dopaminergic agent, an agent against Alzheimer's disease, an antiulcer agent, a platelet inhibitor and an inhibitor of glycogen phosphorylase. 41.- Dosage form according to claim 40, wherein said drug is an antihypertensive agent selected from the group consisting of prazosin, nifedipine, trimazosin and doxazosin. 42.- Dosage form according to claim 40, wherein said drug is the ziprasidone antipsychotic agent. 43.- The dosage form according to claim 40, wherein said drug is the glipizide blood glucose reducing agent. 44.- Dosage form according to claim 40, wherein said drug is an agent against the impotence selected from the group formed by sildenafil and its pharmaceutically acceptable salts. 45.- Dosage form according to claim 40, wherein said drug is the anti-inflammatory agent (+) - N-. { 4- [3- (4-fluorophenoxy) phenoxy] -2-cyclopenten-1-yl} -N-hydroxycarbamide. 46.- The dosage form according to claim 40, wherein said drug is an antidepressant agent selected from the group consisting of fluoxetine, paroxetine, venlafaxine, sertraline, [3,6-dimethyl-2- (2,4,6-trimethyl) -phenoxy) -pyridin-4-yl] - (1-ethylpropyl) -amine and Sd-dimethyl-ISS-pentoxy-1'-e'-trimethylphenoxy) pyridine. 47.- The dosage form according to claim 40, 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) -dihydroxy) rrolin-1-yl) - (2R) -hydroxy-3-oxpropyl] amide of 5-chloro-1H-indole-2-carboxylic acid.