PHARMACEUTICAL FORMULATIONS CONTAINING SOLUBLE DRUGS

INTRODUCTION

Aspects of the present disclosure relate to pharmaceutical compositions providing modified release of water-soluble drugs. In embodiments,

pharmaceutical compositions of the present disclosure are in the form of hydrogel matrix-based drug delivery systems.

Due to rapid drug diffusion through polymer matrices, it has been difficult to achieve modified release formulations for soluble drugs. Thus, there is a need for new formulations and processes that are capable of reducing drug diffusion rates and initial burst effects of water-soluble drugs, and extend the duration of drug release.

Administration of drugs by conventional oral and intravenous methods can severely limit the effectiveness of many drugs. Instead of maintaining drug plasma levels within therapeutic windows, these methods can cause an initial, rapid rise in plasma concentration levels, followed by a rapid decline below minimum

therapeutic levels as the drugs are metabolized by the body. Therefore, repeated doses are necessary to maintain drug levels at therapeutic levels for a sufficient period of time to achieve a therapeutic effect. To address this problem, numerous controlled release preparations have been developed to reduce the initial burst effect and allow drug to be released at more consistent rates.

Polymeric formulations have been used to achieve extended drug release, for example, see R. Langer, "Drug Delivery and Targeting," Nature, 392 (Supp), 5- 10, 1998. Various successful polymeric sustained release preparations have been developed for release of drugs with different physical properties. Such

preparations have been effective for increasing release times for relatively hydrophobic and water-insoluble drugs.

However, the release mechanism is predominantly by initial drug erosion followed by slow diffusion through the polymer matrices. It has been difficult to achieve extended release for highly soluble drugs using current hydrophilic matrix technologies. Thus, there is a need for new formulations and processes which are capable of reducing initial drug erosion and thus eliminating initial burst effect of highly water-soluble drugs, such that the drug release can be prolonged for extended duration.

Hydrogels are three-dimensional networks composed of homopolymers or copolymers that are capable of absorbing large amounts of water or biological fluids. A characteristic of hydrogels is that they swell in water without dissolving. Their high water content and soft consistency make hydrogels similar to natural living tissue, more than other classes of synthetic biomaterials. Thus, hydrogels have found numerous applications especially in medical and pharmaceutical sectors. Hydrogels have been investigated widely as drug carriers due to their adjustable swelling capacities, which permit flexible control of drug release rates.

U.S. Patent Nos. 6,403,120 and 6,419,958, and U.S. Patent Application Publication No. 2006/0073201 , describe spheroids comprising venlafaxine hydrochloride, microcrystalline cellulose, and optionally hydroxypropyl

methylcellulose, coated with a mixture of ethyl cellulose and hydroxypropyl methylcellulose.

U.S. Patent Nos. 4,966,768 and 4,389,393 disclose sustained release therapeutic compressed solid unit dose forms having an active ingredient plus a carrier base comprised of a high molecular weight hydroxypropyl methylcellulose, methyl cellulose, sodium carboxymethylcellulose, and/or other cellulose ethers.

International Application Publication No. WO 99/22724 discloses encapsulated venlafaxine hydrochloride extended release dosage forms, wherein spheroids are substantially free of HPMC.

U.S. Patent No. 6,703,044 and U.S. Patent Application Publication No. 2006/0057204 disclose formulations comprising a burst release a core containing a swellable material, covered by a coating that includes a water insoluble hydrophobic carrier.

U.S. Patent No. 6,994,871 discloses a controlled release pharmaceutical formulation comprising a compressed matrix core for the controlled release of a decongestant and an immediate release coating for the immediate release of an antihistamine.

U.S. Patent Nos. 5,840,321 and 5,731 ,365 relate to hydrophilic, highly swellable hydrogels that are coated with nonreactive, water-insoluble waxes in quantities from about 0.05 to about 2% by weight, based on uncoated hydrogel. U.S. Patent No. 5,419,917 is directed to a method for the modification of the rate of release of a drug from a hydrogel which is based on the use of an effective amount of a pharmaceutically acceptable ionizable compound that is capable of providing a substantially zero-order release rate of drug from the hydrogel.

U.S. Patent Application Publication Nos. 201 1/0165236 and 2008/0075785 provide pharmaceutical formulations comprising a therapeutically effective amount of a hydrophobic drug, an adjustable ratio of a non-cross linked hydrogel polymer, and a non-gelling insoluble polymer.

U.S. Patent Application Publication No. 2010/0144807 discloses a pharmaceutical composition for modified release, comprising at least one additive that ensures penetration of water and a hydrogel-forming polymer.

U.S. Patent Application Publication No. 2009/01 10727 relates to osmotic extended release formulations of proton pump inhibitors, comprising a hydrogel and a polymer.

U.S. Patent Application Publication No. 2003/0099710 discloses a once-a- day matrix tablet that contains granules of naproxen and an organic acid, a hydrogel forming polymer; and an immediate release coating.

U.S. Patent Nos. 6,717,015 and 6,696,496 disclose pharmaceutical compositions comprising low water-soluble venlafaxine salts, such as venlafaxine besylate and venlafaxine maleate, using hydrogel extended release tablets.

U.S. Patent No. 6,274,171 and related European Patent Application 0 797 991 A1 disclose encapsulated once-daily extended release formulations for venlafaxine hydrochloride, comprising spheroids of venlafaxine hydrochloride, microcrystalline cellulose, and HPMC, further coated with a mixture of ethyl cellulose and HPMC. These documents also state that forming an extended release dosage form of venlafaxine hydrochloride was difficult, in part due to the high water solubility of the hydrochloride salt. In fact, these documents disclose that "[n]umerous attempts to produce extended release tablets by hydrogel technology proved to be fruitless because the compressed tablets were either physically unstable (poor compressibility or capping problems) or dissolved too rapidly in dissolution studies." Unlike the encapsulated extended release formulations described in these patents, a hydrogel extended release venlafaxine hydrochloride tablet is taught to typically exhibit a dissolution profile wherein 40- 50% is released by 2 hours, 60-70% is released by 4 hours, and 85-100% is released by 8 hours.

There remains a need for extended release pharmaceutical formulations comprising highly water soluble drugs that provide effective plasma

concentrations of the active agent, and also which are easy to manufacture.

SUMMARY

Aspects of the present disclosure relate to hydrogel matrix based drug delivery systems, for obtaining modified release of highly water soluble drugs.

In embodiments, the present disclosure relates to extended release pharmaceutical formulations comprising high solubility active agents such as venlafaxine, propranolol, metoprolol, pseudoephedrine, minocycline, galantamine, metformin, donepezil, including pharmaceutically acceptable salts thereof.

In embodiments, the present disclosure relates to extended release pharmaceutical formulations comprising active agents in amorphous or crystalline form or mixtures thereof, together with one or more excipients.

In embodiments, extended release pharmaceutical formulations of the present disclosure comprise at least one hydrophilic rate controlling substance.

In embodiments, a hydrophilic rate controlling substance used in the formulations of the present disclosure has a viscosity in the range of about 1000 mPa-s to about 150000 mPa-s.

In embodiments, a hydrophilic rate controlling substance used in the formulations of the present disclosure has a specific gravity in the range of about 1 to about 2.5.

In embodiments, extended release pharmaceutical formulations are in the form of hydrogel matrix systems comprising a water soluble active agent, at least one hydrophilic rate controlling substance and at least one disintegrant in weight ratios about 1 :0.01 to about 1 :10, and one or more excipients. In embodiments, the formulations are devoid of a functional coating, and an initial burst release of the active agent from the hydrogel matrix is substantially prevented, thus providing an uniform drug release of the water soluble active agent for a prolonged duration.

In embodiments, extended release pharmaceutical formulations are in the form of a hydrogel matrix systems comprising a water soluble active agent, at least one hydrophilic rate controlling substance and at least one disintegrant in weight ratios about 1 :0.01 to about 1 :10, and one or more excipients including a non-functional coating agent. In embodiments, the formulations are devoid of a functional coating, and an initial burst release of the active agent from the hydrogel matrix is substantially prevented, thus providing a uniform drug release of the water soluble active agent for a prolonged duration.

In embodiments, extended release pharmaceutical formulations of the present disclosure comprise an active agent and a hydrophilic rate controlling substance such as any one or more of hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl celluloses, polyvinylpyrrolidones, carboxymethyl starches, carboxymethyl celluloses, polyethylene glycols, sodium alginate, xanthan gum, gaur gum, polyethylene oxide, gelatin, and their derivatives.

In embodiments, weight ratios of active agent to hydrophilic rate controlling substance range from about 1 :0.1 to about 1 :20.

In embodiments, a disintegrant used in the formulations of the present disclosure has a density in the range of about 0.1 g/cm ³ to about 2.5 g/cm ³ .

In embodiments, a disintegrant used in the formulations of the present disclosure has a specific surface area in the range of about 0.05 m ² /g to about 3 m ² /g.

In embodiments, weight ratios of active agent to hydrophilic rate controlling substance range from about 1 :0.1 to about 1 :10, or from about 1 :0.5 to about 1 :5.

In embodiments, weight ratios of active agent to a disintegrant range from about 1 :0.1 to about 1 :10, or from about 1 :0.5 to about 1 :5.

In embodiments, extended release pharmaceutical formulations of the present application include a disintegrant such as carmellose calcium,

carboxymethyl starch sodium, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcelluloses, sodium starch glycolate, colloidal silicon dioxide, starches, their derivatives, and any mixtures of two or more thereof.

In embodiments, a hydrophilic rate controlling substance and a disintegrant are present in weight ratios of about 1 :0.01 to about 1 :10, respectively.

In embodiments, an active agent, hydrophilic rate controlling substance, and a disintegrant are present in weight ratios of about 1 :0.1 :0.1 to about 1 :10:10, respectively. In embodiments, pharmaceutical formulations of the present application comprise a hydroxypropyl methylcellulose as a hydrophilic rate controlling substance and a carboxymethyl cellulose calcium as a disintegrant.

In embodiments, a hydroxypropyl methylcellulose and a carboxymethyl cellulose calcium are present in weight ratios of about 1 :0.01 to about 1 :10, respectively.

In embodiments, an active agent, a hydroxypropyl methylcellulose, and a carboxymethyl cellulose calcium are present in weight ratios of about 1 :0.1 :0.1 to about 1 :10:10, respectively.

In embodiments, formulations of the present disclosure are in the form of matrix tablets.

In embodiments, formulations of the present disclosure are in the form of hydrogel based matrix tablets.

In embodiments, hydrogel based matrix formulations of the present disclosure, upon contact with aqueous media, exhibit a swelling index of less than about 100 at 1 hour and less than about 500 at 10 hours.

In embodiments, hydrogel based matrix formulations of the present disclosure, upon contact with aqueous media, exhibit a percentage swelling of less than about 20% at 1 hour and less than about 150% at 6 hours.

In embodiments, pharmaceutical formulations of the present application comprising a release rate controlling substance show the work of penetration more than about 60 kg/mm at 1 hour and less than about 50 kg/mm at 24 hours in an aqueous medium.

In embodiments, pharmaceutical formulations of the present application comprising a combination of at least one release rate controlling substance and at least one disintegrant show the work of penetration less than about 100 kg/mm at 1 hour and more than about 40 kg/mm at 24 hours in an aqueous medium.

In embodiments, hydrogel based matrix formulations of the present disclosure provide in-vitro drug release as a combination of diffusion, swelling, and erosion mechanisms.

In embodiments, the present disclosure includes extended release formulations comprising an active ingredient, which is released from dosage forms in amounts not less than about 30% of the contained drug within about 2 hours after immersion in an aqueous medium. In embodiments, the present disclosure includes extended release formulations comprising an active ingredient, which is released from dosage forms in amounts greater than about 50%, or greater than about 80%, of the contained active ingredient, within about 24 hours after immersion into an aqueous medium.

In embodiments, the present disclosure includes extended release formulations exhibiting in vitro drug release wherein an initial immediate release is followed by extended release of the active agent.

In embodiments, the disclosure includes modified release pharmaceutical compositions comprising an active agent, optionally together with one or more pharmaceutically acceptable excipients, wherein said compositions are in multiparticulate form. In various embodiments, 'multi-particulates' according to the present disclosure may be in the forms of powders, granules, pellets, spheroids, extrudates, mini-tablets, and the like.

In embodiments the powder blends of the formulations of the present disclosure are characterized for parameters such as Hausner's ratio,

compressibility index, bulk and tapped density, and bulk particle sizes. Powders having bulk and tapped densities less than about 2 g/cm ³ and Hausner's ratios less than about 1 show excellent flowability.

In embodiments, formulations of the present disclosure have

compressibility index values between about 10% and about 30%.

In embodiments, formulations of the present disclosure have bulk particle sizes such that 100% of the particles pass through a 24 mesh ASTM sieve and not more than 10% of the particles pass through a 120 mesh ASTM sieve.

In embodiments, tablet formulations of the present disclosure have hardness values between about 8 Kp and about 40 Kp.

In embodiments, tablets formulations of the present disclosure have friability less than about 2%, or less than about 1 %.

In embodiments, the disclosure provides processes for preparation of pharmaceutical compositions of the present disclosure.

In embodiments, pharmaceutical formulations of the present disclosure are prepared using any of direct compression, dry granulation, and wet granulation methods. In embodiments, the disclosure provides methods of using pharmaceutical formulations of the present disclosure for treating conditions and disease states in a subject in need thereof.

BRIEF DESCRIPTION OF THE DRAWING

Fig. 1 shows powder X-ray diffraction ("PXRD") patterns of tablets prepared Example 1 .

DETAILED DESCRIPTION

"Modified release" herein is intended to mean altering the release of a drug substance from a dosage form that is immersed in an aqueous fluid, such as a physiologically relevant medium used for dissolution testing, through techniques such as incorporating a polymer into particles that contain the drug. The term includes "controlled release" (CR) where the rate of drug release is altered, "extended release" (ER) where the time required to deliver a desired dose of the drug is prolonged, and "delayed release" (DR) where the commencement of drug release occurs after some time elapses. These are compared with "immediate release" (IR) where a dosage form begins to disintegrate essentially immediately upon entering an aqueous environment and drug dissolution from the produced fragments is not inhibited. Any combinations of two or more of IR, CR, ER, and DR can be useful for delivering particular drugs, depending of their

pharmacological properties. In some instances, it may be desired to deliver the contained drug in more than one mode, for example with an initial or delayed pulse of dissolution, followed by another pulse after some time and/or an extended release of the remaining quantity of the drug.

The term "hydrogel" is used in its conventional sense to refer to water- swellable polymeric substances that absorb a substantial amount of water to form elastic gel matrices, wherein "matrices" are three-dimensional networks of macromolecules held together by covalent or non-covalent cross-linkage. Upon entering an aqueous environment, dry hydrogels swell to the extent allowed by the degree of cross-linking.

A hydrophilic matrix, controlled-release system is a dynamic one involving polymer wetting, polymer hydration, gel formation, swelling, and polymer dissolution. At the same time, other soluble excipients or drugs can also wet, dissolve, and diffuse out of the matrix while insoluble materials will be held in place until the surrounding polymer/excipient/drug complex erodes or dissolves away. The mechanisms by which drug release is controlled in matrix tablets are dependent on many variables. A main principle is that the water-soluble polymer, present throughout a dosage form such as a tablet, hydrates on the outer tablet surface to form a gel layer. Throughout the lifetime of an ingested tablet, the rate of soluble drug release is determined by diffusion through the gel and by the rate of tablet erosion. Drug release from hydrophilic matrices a complex interaction involving swelling, diffusion, and erosion mechanisms.

The hydrophilic matrix comprises a hydrogel, which undergoes molecular relaxation when passing from the anhydrous to the hydrate state, thus inducing increases in the system volume, hindrance, and weight, due to the coordination of a large number of water molecules by the polar groups in the polymer chain. Examples of hydrogels that can be used in this disclosure include, but are not limited to, substances such as acrylic or methacrylic polymers or copolymers, alkylvinyl polymers, hydroxyalkyl celluloses, hydroxyalkyl alkylcelluloses, carboxyalkyl celluloses, polysaccharides, alginates, pectins, starches and derivatives thereof, natural and synthetic gums, polycarbophils, and chitosans.

Hydroxyalkylcellulose compounds include, without limitation thereto, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, and hydroxybutyl celluloses. Hydroxyalkyl alkylcellulose compounds include, without limitation thereto, hydroxypropyl methylcelluloses.

"Matrix tablets" are tablet dosage forms, in which a drug is substantially homogenously dispersed in a polymer in association with excipients.

A pharmaceutically active agent that is "water soluble," or that is "highly soluble," "highly water soluble", etc., refers to a pharmaceutically active agent (in its free base, free acid, salt, or ester form) having solubility in water in excess of about 10 mg/mL at room temperature (20-25°C). In certain embodiments, a pharmaceutically active agent of the present disclosure has a water solubility of at least about 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, or 250 mg/mL, at room temperature.

Examples of drugs having high water solubility and one or both of short half-life and high dose, and which are useful to make the present compositions, include, but are not limited to: verapamil HCI, potassium chloride, cefdinir, propafenone HCI, hydroxyurea, hydrocodone bitartrate, delavirdine mesylate, nelfinavir meslyate, pentosan polysulfate sodium, tocainide HCI, quetiapine fumarate, fexofenadine HCI, carafate, rifampin, moxifloxacin HCI, praziquantel, ciprofloxacin, phosphate sodium potassium, methenamine mandelate, sotalol HCI, cefprozil, cefadroxil, metformin HCI, irbesartan, nefazodone HCI, gatifloxacin, didanosine, modafinil, efavirenz, metaxalone, amantadine HCI, morphine sulfate, mefenamic acid, diltiazem HCI, sevelamer HCI, albendazole, amoxicillin, clavulanate potassium, lithium carbonate, lamivudine, sumatriptan succinate, nabumetone, zidovudine, cimetidine, chlorpromazine HCI, valacyclovir HCI, bupropion HCI, ranitidine, abacavir sulfate, acyclovir, aminobenzoate potassium, pyridostigmine bromide, potassium chloride, isosorbide mononitrate, niacin, demeclocycline HCI, cefixime, naproxen sodium, tetratcycline HCI, cefuroxime axetil, propoxyphene napsylate, pyrazinamide, flecainide acetate, simethicone, mebendazole, methyldopa, chlorathiazide, indinavir, penicillamine, metyrosine, losartan potassium, thiobendazole, norfloxacin, procainamide, entacapone, valsartan, terbinafine HCI, metaprolol tartrate, ofloxacin, levofloxacin,

chlorzoxazone, tolmetin sodium, tramadol HCI, bepridil HCI, phenytoin sodium, atorvastatin calcium, gabapentin, celecoxib, fluconazole, doxepine HCI,

trovafloxacin mesylate, azithromycin, sertraline HCI, rifabutin, cefpodoxime proxetil, mesalamine, etidronate disodium, nitrofurantoin, choline magnesium trisalicylate, theophylline, nizatidine, pancreatin, quinidine sulfate, methocarbamol, mycophenolate mofetil, ganciclovir, saquinavir mesylate, tolcapne, ticlopidine HCI, valganciclovir HCI, capecitabine, orlistat, colsevelam HCI, irbesartan, succimer, meperidine HCI, hydroxychloroquine sulfate, guaifenesine, eprosartan mesylate, aminodarone HCI, felbamate, pseudoephedrine sulfate, carisoprodol, venlafaxine, propranolol HCI, metoprolol succinate, etodolac, acebutolol, chondrotin, pyruvate, water soluble vitamins, creatinine, isoflavone, betaine HCI, psyllium, pantothenic acid, zinc chloride, zinc gluconate, zinc sulfate, phytoestrogen, pycnogenol, proanthocyanidin, suntheanine, methylsulfonyl-methane, L- glutamine,

colostrums, biotin, acetyl-L-carnitine, inositol, L-tyrosine, s-adenosyl methionine, bromelain, 2-dimethylaminoethanol, chromium picolinate, and combinations thereof. Specific salts, esters, etc. recited for a drug compound is merely exemplary, as any other forms are also useful. Additional examples of drugs having high water solubility, and one or both of short half-life and high dose, include, but are not limited to, amino acids, sugars, carbohydrates, proteins, saccharides, phospholipids, ginkgo biloba, standardized St. John's wort, standardized Echinacea, yeasts, enzymes, bacteria, and combinations thereof.

In embodiments, the present disclosure relates to extended release pharmaceutical formulations comprising active agents in amorphous or crystalline form, or mixtures thereof, together with one or more excipients.

In embodiments, pharmaceutical formulations of the present disclosure include highly soluble drugs in unit doses ranging from about 10 mg to about 1000 mg.

In this disclosure, the pharmaceutically active agents venlafaxine, propranolol, metoprolol, pseudoephedrine, minocycline, galantamine, metformin, and donepezil are used to illustrate certain specific embodiments. However, the scope of the disclosure is not to be construed as limited to only the use of these specific drugs.

Extended release is release of a drug from its dosage form (e.g., a tablet or capsule) at such a rate that blood levels of the drug are maintained within the therapeutic range, i.e., at or above a minimum effective concentration (MEC) but below toxic concentrations over an extended period of time, e.g., about 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 hours, or longer. The extended release property of a dosage form is typically measured using an in vitro dissolution method and confirmed by an in vivo blood concentration-time profile (i.e., a pharmacokinetic profile).

Hydrogels have a network structure of cross-linked polymer chains, which allow smaller molecules to diffuse through the structure. However, it has been surprisingly found that by adding a disintegrant, including super-disintegrants, the diffusion path is lengthened and initial burst releases of highly soluble drugs from the hydrogel matrix can be controlled.

Hydrogels in tablets, etc. can swell upon hydration from moisture in the digestive system, thereby limiting exposure of the active ingredient to moisture. As the hydrogels are gradually leached away by moisture, water more deeply penetrates the gel matrix and the active ingredient slowly dissolves and diffuses through the gel, making it available for absorption by the body. While this disclosure is not to be bound to any particular theories of operation, this is a possible mechanism for explaining the observed effects.

"Functional coating" refers to a coating over a hydrogel matrix formulation that includes a rate controlling substance as defined herein forth.

"Non-functional coating" refers to a coating over a hydrogel matrix formulation that does not include a rate controlling substance as defined herein forth.

The term "rate controlling substance" as used herein refers to any substance which is present in such an amount that can alter or modify the drug release time, rate, and extent from a composition or formulation in any manner, such as, for example to control, sustain, modify, prolong, or delay the rate of drug release.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, such as a filler, diluent, carrier, etc. The excipients that are useful in preparing the

pharmaceutical composition are generally safe, non- toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. An "excipient" or "pharmaceutically acceptable excipient" as used in the specification includes both one and more than one such excipient.

The term "stability" as used in the description includes both physical and chemical stability. The term "physical stability" refers to maintenance of the form of an active agent such as crystalline or amorphous or mixtures thereof, and term "chemical stability" refers to maintenance of impurity contents at acceptable levels.

Aspects of the present disclosure provide improved compositions, wherein the compositions are simple, cost-effective, do not involve toxic and hazardous solvents, and also are easy to make on a commercial scale.

In embodiments, the active ingredients used to make the compositions or contained in the compositions are in the form of amorphous, crystalline, or mixtures thereof.

In embodiments, extended release pharmaceutical formulations are in the form of hydrogel matrix systems comprising a water soluble active agent, at least one hydrophilic rate controlling substance and at least one disintegrant in weight ratios about 1 :0.01 to about 1 :10, and one or more excipients. In embodiments, the formulations are devoid of a functional coating, and an initial burst release of the active agent from the hydrogel matrix is substantially prevented, thus providing an uniform drug release of the water soluble active agent for a prolonged duration.

In embodiments, extended release pharmaceutical formulations are in the form of a hydrogel matrix systems comprising a water soluble active agent, at least one hydrophilic rate controlling substance and at least one disintegrant in weight ratios about 1 :0.01 to about 1 :10, and one or more excipients including a non-functional coating agent. In embodiments, the formulations are devoid of a functional coating, and an initial burst release of the active agent from the hydrogel matrix is substantially prevented, thus providing a uniform drug release of the water soluble active agent for a prolonged duration.

In embodiments, the present disclosure relates to modified release pharmaceutical formulations comprising a rate controlling substance such as any one or more of hydroxypropyl methylcelluloses, hydroxypropyl celluloses, hydroxyethyl celluloses, polyvinylpyrrolidones, carboxymethyl starches,

polyethylene glycols, sodium alginate, xanthan gum, gaur gum, polyethylene oxides, and gelatin.

In embodiments, a hydrophilic rate controlling substance used in the formulations of the present disclosure has a viscosity in the range of about 100 mPa-s to about 150000 mPa-s. Viscosity can be determined by preparing a 2% w/v of aqueous solution of the hydrophilic rate controlling substance and

measuring the viscosity at 20°C using Ubbelohde viscometer.

In embodiments, a weight ratio of active agent to hydrophilic rate controlling substance ranges from about 1 :0.1 to about 1 :50.

In embodiments, pharmaceutical formulations of the present application comprising a combination of a release rate controlling substance and at least one disintegrant have improved control of drug release wherein drug release is uniform and extended over prolonged time, as compared to those formulations having a release rate controlling substance alone. It has been found that the initial burst release can be substantially avoided by using combinations of at least one release rate controlling substance and at least one disintegrant. Further, it is also found that use of a disintegrant in combination with a hydrophilic release rate controlling substance aids in controlling the drug release of a water soluble drug, which is contrary to what is reasonably expected, i.e., it will generally be expected by a person skilled in art that incorporation of a disintegrant may hasten the drug release of a water soluble drug from a hydrophilic polymer matrix.

In embodiments, a disintegrant used in the formulations of the present disclosure has a density in the range of about 0.1 g/cm ³ to about 2.5 g/cm ³ .

In embodiments, a disintegrant used in the formulations of the present disclosure has a specific surface area in the range of about 0.05 m ² /g to about 3 m ² /g.

In embodiments, weight ratios of active agent to hydrophilic rate controlling substance range from about 1 :0.1 to about 1 :10, or from about 1 :0.5 to about 1 :5.

In embodiments, weight ratios of active agent to disintegrant range from about 1 :0.1 to about 1 :10, or from about 1 :0.5 to about 1 :5.

In embodiments, extended release pharmaceutical formulations of the present disclosure include a disintegrant such as a carmellose calcium, carboxymethyl starch sodium, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone, low-substituted hydroxypropylcellulose, sodium starch glycolate, colloidal silicon dioxide, starch, any of their derivatives, and any mixtures of two or more thereof.

In embodiments, extended release pharmaceutical formulations of the present disclosure include two or more disintegrants.

In embodiments, a hydrophilic rate controlling substance and a disintegrant are present in weight ratios of about 1 :0.01 to about 1 :50, or about 1 :0.1 to about 1 :10.

In embodiments, an active agent, hydrophilic rate controlling substance, and a disintegrant are present in weight ratios of about 1 :0.1 :0.1 to about 1 :10:10.

In embodiments, pharmaceutical formulations of the present disclosure comprise a hydroxypropyl methylcellulose as a hydrophilic rate controlling substance and a carboxymethyl cellulose calcium as a disintegrant.

In embodiments, the pharmaceutical formulations of the present disclosure comprise a hydroxypropyl methylcellulose as a hydrophilic rate controlling substance, and a combination of a carboxymethyl cellulose calcium with a croscarmellose sodium, crospovidone, or sodium starch glycolate as a

disintegrant. In embodiments, a hydroxypropyl methylcellulose and a carboxymethyl cellulose calcium are present in weight ratios of about 1 :0.01 to about 1 :50, or about 1 :0.1 to about 1 :10.

In embodiments, an active agent, hydroxypropyl methylcellulose, and carboxymethyl cellulose calcium are present in weight ratios of about 1 :0.1 :0.1 to about 1 :10:10.

In embodiments, the formulations comprise an active agent, hydroxypropyl methylcellulose, and carboxymethyl cellulose calcium, wherein the carboxymethyl cellulose calcium is present in amounts greater than about 10% by weight of the formulation.

In embodiments, the formulations comprise an active agent, a

hydroxypropyl methylcellulose, and a carboxymethyl cellulose calcium, wherein the carboxymethyl cellulose calcium is present in amounts greater than about 15% by weight of the composition.

In embodiments, formulations of the present disclosure are in the form of tablets.

In embodiments, formulations of the present disclosure are in the form of matrix tablets.

In embodiments, formulations of the present disclosure are in the form of hydrogel-based matrix tablets.

In aspects, the present disclosure provides extended release formulations comprising an active agent or pharmaceutically acceptable salts, etc. thereof, wherein dosage forms release more than about 50%, or more than about 80%, of their contained active agent, within about 24 hours following immersion into 900 ml_ of an aqueous dissolution medium, using type 1 apparatus according to the procedure of Test 71 1 "Dissolution" in United States Pharmacopeia 29, United States Pharmacopeial Convention, Inc., Rockville, Maryland, 2005 ("USP").

In aspects, the disclosure includes modified release pharmaceutical compositions comprising an active agent, optionally together with one or more pharmaceutically acceptable excipients, wherein said compositions are in multiparticulate form. In embodiments, the "multi-particulates" according to the present disclosure may be in the form of powders, granules, pellets, spheroids,

extrudates, mini-tablets, and the like. In embodiments, multi-particulates of the present disclosure are

compressed to form tablets or are filled into capsules.

In embodiments, tablet formulations can optionally be coated using film- forming polymers.

In aspects, the disclosure includes modified release pharmaceutical formulations comprising cores containing an active agent, optionally together with one or more pharmaceutically acceptable excipients, and a coating comprising one or more polymers, wherein the formulations are in multi-particulate form.

In embodiments, modified release multi-particulates comprise non-pariel cores such as sugar, cellulose, or similar substances, upon which an active agent is coated, optionally together with one or more pharmaceutically acceptable excipients, using any of techniques such as powder layering, solution spraying, suspension spraying, or any other techniques known in the art.

In embodiments, the disclosure includes pharmaceutical compositions comprising modified release multi-particulates having an active agent in cores and a coating applied thereto comprising one or more polymers, and optionally having one or more further coatings.

Multi-particulate formulations of the disclosure can be prepared using any of the techniques described herein, as well as other methods known to those having skill in the art.

In embodiments, portions of multi-particulates comprising an active agent are coated with different amounts and/or types of polymers, giving portions having different drug release profiles, and these can be combined to form a

pharmaceutical composition or dosage form to achieve desired modified release profiles.

In embodiments, portions of multi-particulates comprising an active agent are coated with different amounts and/or types of polymers, such as enteric polymers (pH dependent polymers) or modified release polymers (pH independent polymers), giving different release profiles, and these can be combined to form a pharmaceutical composition or dosage form to achieve desired modified release profiles.

In embodiments, multi-particulates comprising an active agent can be combined with pharmaceutically acceptable excipients, and compounded to form a pharmaceutical composition, which can be compressed into tablets or placed into suitable capsules, using techniques known to those having skill in the art. In embodiments, compositions of the present disclosure are filled into hard gelatin capsules, wherein the empty hard gelatin capsule shells can comprise one or more of hydroxymethyl cellulose, carrageenan, potassium chloride, polyvinyl polymers such as polyvinyl acetate and polyvinyl alcohol, and the like.

In embodiments, the disclosure includes rate controlling substances useful for making extended release formulations, such as, but not limited to, hydrophilic substances, hydrophobic substances, lipophilic substances, pH dependent polymers, pH independent polymers, swelling polymers, non-swelling polymers, gelling polymers, water soluble polymers, water insoluble polymers, gums, waxes, oily substances, polyethylene glycol glycerides such as Gelucire® products, hydrogenated vegetable oils, alginic acid and alginates, acrylic and/or methacrylic acid polymers or copolymers, and the like, and any combinations thereof.

Examples of useful polymers include, without limitation thereto, cellulose ethers, e.g., hydroxypropyl methylcelluloses (hypromellose or HPMC),

hydroxypropyl celluloses (HPC), hydroxyethyl celluloses, ethylcelluloses, polyvinylpyrrolidones (PVP or povidone), including non-crossl inked

polyvinylpyrrolidones, carboxymethyl starches, polyethylene glycols,

polyoxyethylenes, poloxamers (polyoxyethylene-polyoxypropylene copolymers), polyvinyl alcohols, glucanes (glucans), carrageenans, scleroglucanes

(scleroglucans), mannans, galactomannans, gellans, alginic acid and derivatives thereof (e.g., sodium or calcium alginate, propylene glycol alginate),

polyaminoacids (e.g. gelatin), methyl vinyl ether/maleic anhydride copolymers, polysaccharides (e.g. carageenan, guar gum, xanthan gum, tragacanth and ceratonia), alpha-, beta- or gamma-cyclodextrins, dextrin derivatives (e.g. dextrin), polymethacrylates (e.g. copolymers of acrylic and methacrylic acid esters containing quaternary ammonium groups), acrylic acid polymers (e.g.,

carbomers), shellac and derivatives thereof, cellulose acetate, cellulose butyrate, cellulose diacetate, cellulose triacetate, cellulose propionate, cellulose acetate butyrate and other acetylated cellulose derivatives, and the like, and any mixtures of two or more thereof.

Examples of lipophilic/hydrophobic substances that can be used in the present disclosure include, without limitation thereto, waxes (e.g., carnauba wax, microcrystalline wax, beeswax, and polyethoxylated beeswax), natural fats (coconut, soya, cocoa) including modified forms such as totally or partially hydrogenated castor oil, hydrogenated vegetable oil, and fatty acid derivatives such as mono-, bi- and tri-substituted glycerides, phospholipids,

glycerophospholipids, glyceryl palmitostearate, glyceryl behenate, glyceryl monostearate, diethyleneglycol palmitostearate, polyethyleneglycol stearate, polyethyleneglycol palmitostearate, polyoxyethylene-glycol palmitostearate, glyceryl monopalmitostearate, cetyl palmitate, fatty alcohols associated with polyethoxylated fatty alcohols, cetyl alcohol, stearic acid, saturated or unsaturated fatty acids and their hydrogenated derivatives, lecithin, cephalins, chitosan and derivatives thereof, sphingolipids, sterols such as cholesterol and its substituted derivatives, etc.

Various useful disintegrants include, but are not limited to, carmellose calcium (Gotoku Yakuhin Co., Ltd.), carboxymethylcellulose calcium,

carboxymethylcellulose sodium (Matsutani Kagaku Co., Ltd., Kimura Sangyo Co., Ltd., etc.), croscarmellose sodium (Ac-di-sol™ from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including, but not limited to, crosslinked povidone, Kollidon™ CL from BASF (Germany), Polyplasdone™ XL, XI-10, and INF-10 from ISP Inc. (USA), and low-substituted hydroxypropyl celluloses. Examples of low-substituted hydroxypropylcelluloses include but are not limited to low-substituted

hydroxypropylcellulose LH1 1 , LH21 , LH31 , LH22, LH32, LH20, LH30, LH32 and LH33 (all manufactured by Shin-Etsu Chemical Co., Ltd.). Other useful

disintegrants include sodium starch glycolate, colloidal silicon dioxide, and various starches.

Compositions of the disclosure can be processed into various

pharmaceutical dosage forms, or can be combined with one or more

pharmaceutically acceptable excipients. The different pharmaceutical dosage forms that comprise pharmaceutical compositions of the present disclosure include solid oral dosage forms such as, but not limited to, powders, granules, pellets, tablets, and capsules. Modified release compositions may comprise hydrophilic, lipophilic, or hydrophobic release controlling substances, or their combinations to form matrix or reservoir, or combinations of matrix and reservoir, systems. Certain compositions may be prepared by extrusion and spheronization, or by using a melt granulation technique. Compositions may be presented as uncoated, film coated, sugar coated, compression-coated, powder coated, enteric coated, or modified release coated forms.

In embodiments, cores contain one or more release modifying polymers in admixture with an active agent, to form a matrix. In certain embodiments, a modified release matrix is further coated with pH dependent polymers, pH independent polymers, or combinations thereof.

The pharmaceutical formulations of the present disclosure can be characterized for swelling index, texture analysis, drug release kinetics, and other properties.

The swelling behavior of the formulations can be investigated through textural analysis of swollen tablets. Tablets are placed in the dissolution vessels under conditions related to those described in the USP for dissolution testing. The hydrated tablets are removed at intervals, patted lightly with tissue paper, and subjected to textural profiling to determine gel layer thickness, movement of the erosion and swelling fronts and total work of probe penetration into the entire matrix. Measurements can be carried out in triplicate for each time point.

In specific embodiments, textural analysis is performed using a TA.XT2i texture analyzer equipped with a 5 kg load cell and Texture Expert software (Texture Technologies Corp. Scarsdale, NY/Stable Micro Systems, Godalming, UK). The force-displacement-time profiles associated with the penetration of a 2 mm round-tipped steel probe into the swollen matrices are monitored at a data acquisition rate of 200 points per second. The probe approaches the sample at a pretest speed of 1 .0 mm/second. Once a trigger force of 0.005 N is detected (upon contact of the probe with the tablet) the probe is advanced into the sample at a test speed of 0.5 mm/second until a maximum force of 20N is reached.

Swollen thickness is determined by measuring the total probe displacement value recorded, and by the observation of textural profiles. Total work of penetration, which is a measure of gel strength and resistance to probe penetration, is also determined from the textural profiles.

The total work of penetration calculated as the area under the force- displacement curve indicates matrix stiffness or rigidity and is expressed by the equation:

Total work of penetration = W = J FdD where W is work done by the probe, F the force applied, and dD is the total probe displacement.

Work of penetration of extended release matrix tablets by texture analysis depicts the change in work of penetration with time as the exposure to swelling medium is extended and hydration is increased.

In embodiments, formulations of the present disclosure show sharp decreases in work of penetration from 0 hours (dry tablet) to 4 hours, which reflects the initial high rate of hydration of tablets. Between 4 hours and 24 hours lower values for work of penetration are observed, a result which is attributed to the soluble nature of drug in providing for greater water penetration and subsequently weakening of the gel structure. The inward movement of the fully hydrated region as well as increases in total thickness of swollen tablets for each time point is apparent in texture analysis profiles.

In embodiments, pharmaceutical formulations of the present disclosure comprising a release rate controlling substance have work of penetration more than about 60 mg/mm at 1 hour, and less than about 50 kg/mm at 24 hours.

In embodiments, the pharmaceutical formulations of the present disclosure comprising a combination of a release rate controlling substance and at least one disintegrant show the work of penetration less than about 100 mg/mm at 1 hour and more than about 40 Kg/mm at 24 hours.

In embodiments, pharmaceutical formulations of the present disclosure comprising a combination of a release rate controlling substance and at least one disintegrant have improved control of drug release wherein drug release is uniform and extended over prolonged time, as compared to formulations having a release rate controlling substance alone. Initial burst release can be avoided by using combination of a release rate controlling substance and at least one disintegrant.

The swelling index of tablets of the present disclosure can be determined after immersion into water at room temperature. The swollen weight of the tablets is determined at different time intervals. The swelling index is calculated using the following equation:

Swelling index = (Wt - W0) ÷ W0

where W0 is the initial weight of the tablet, and Wt is the weight of the tablet at time t. The initial diameter of the tablet and swollen diameter of the tablet is determined at different time intervals. The difference in the diameter is recorded as percentage axial swelling.

A direct relationship is observed between swelling index and gel concentration. It has been observed that the cumulative percent drug release decreases with increasing concentration of gel and swelling index. This slower release is because of the formation of a thick gel structure that delays the drug release from the matrix tablets, where hydration of individual particles results in extensive swelling. This results in a continuous visco-elastic matrix that fills the interstices, maintaining the integrity of the tablet, and retarding further penetration of the dissolution medium.

In embodiments, hydrogel based matrix formulations of the present disclosure, upon exposure to aqueous media, have a swelling index less than about 100 at 1 hour, and about 500 at 10 hours.

In embodiments, hydrogel based matrix formulations of the present disclosure, upon exposure to aqueous media, have a percentage swelling of less than about 10% at 1 hour, and about 100% at 6 hours.

Different dissolution models can be applied in order to evaluate the release mechanism and release kinetics. A criteria for selecting the most appropriate model is based on linearity (coefficient and correlation). The drug release data fit well to the Higuchi expression. In embodiments, the drug release mechanism is found as a complex mixture of diffusion, swelling and erosion. The combination of a release rate controlling substance and a disintegrant can be extended to formulations of any highly soluble drugs.

To determine mechanism of drug release, first 60% drug release data of venlafaxine hydrochloride is fitted in a Korsmeyer-Peppas mathematical model. The Korsmeyer derives a simple relationship which describes drug release from a polymeric system according to the following equation:

Mt/M°° = k tn.

where Mt/M∞ is the fraction of drug released at time t, k is the rate constant, and n is the release exponent. The magnitude of the drug release exponent 'n' indicates the release mechanism.

In embodiments, pharmaceutical formulations of the present disclosure result in drug release such that the 'n' value ranges from 0.517-0.721 , which appears to indicate a coupling of diffusion and erosion mechanism, so-called "anomalous diffusion."

Further, in the case of combinations of a release rate controlling substance and a disintegrant the drug release rate is nearly constant and the release process is slower, compared to that of matrices containing a release rate controlling substance alone. The formulations containing combinations of a hydroxypropyl methylcellulose and a carboxymethyl cellulose calcium exhibit a well controlled effect by the use of the synergistic interaction between two cellulose polymers to produce a strong and elastic gel around the core of the matrices in the presence of a ternary component by controlling the drug release from the matrices.

In aspects, the disclosure provides methods for preparing pharmaceutical compositions of the present disclosure.

An aspect of the disclosure provides preparation processes for hydrogel matrix pharmaceutical compositions, embodiments comprising:

(a) Combining an active agent, a release rate controlling substance, and a disintegrant.

(b) Dissolving a binder in a solvent and granulating the blend of (a) with the solution.

(c) Mixing a filler and colloidal silicon dioxide with the granules of (b).

(d) Mixing a lubricant with the blend of (c).

(d) Compressing the blend of (d) into tablets or filling into capsules. In embodiments, pharmaceutical compositions of the present disclosure are prepared using any one or more of direct compression, dry granulation, and wet granulation methods.

Equipment suitable for processing pharmaceutical compositions of the present disclosure include any one or more of rapid mixer granulators, planetary mixers, mass mixers, ribbon mixers, fluid bed processors, mechanical sifters, blenders, roller compactors, extruder-spheronizers, compression machines, capsule filling machines, rotating bowls or coating pans, tray dryers, fluid bed dryers, rotary cone vacuum dryers, and the like, multimills, fluid energy mills, ball mills, colloid mills, roller mills, hammer mills, and the like, equipped with a suitable screen. In embodiments, powder blends for preparing formulations of the present disclosure are characterized for Hausner ratio, compressibility index, bulk and tapped density, and particle sizes. Bulk and tapped density less than about 1 g/cm ³ and Hausner's ratio of less than 1 confirm excellent flowability properties of the powders.

In embodiments, particulate compositions of the present disclosure have compressibility index values between about 10% and about 30%.

In embodiments, particulate compositions of the present disclosure have particle sizes such that 100% of the particles pass through a 24 mesh ASTM sieve and not more than about 10% of the particles pass through a 120 mesh ASTM sieve.

In embodiments, tablet formulations of the present disclosure are

characterized for properties such as hardness, friability, moisture content, pH and dimensions.

In embodiments, tablets formulations of the present disclosure have hardness values between about 8 Kp (kiloponds) and about 40 Kp.

In embodiments, tablet formulations of the present disclosure have friability less than about 2%.

Pharmaceutically acceptable excipients according to the present disclosure include, for example, any one or more of diluents-binders, stabilizers, lubricants, glidants, non-functional coating agents, and other additives that are useful in solid pharmaceutical dosage form preparations.

Various useful fillers or diluents according to the present disclosure include, but are not limited to, starches, lactose, cellulose derivatives, confectioner's sugar, and the like. Different grades of lactose include, but are not limited to, lactose monohydrate, lactose DT (direct tableting), lactose anhydrous, Flowlac™

(available from Meggle Products), Pharmatose™ (available from DMV), and others. Useful starches include, but are not limited to, maize starch, potato starch, rice starch, wheat starch, pregelatinized starch (commercially available as PCS PC10 from Signet Chemical Corporation), pregelatinized starch , pregelatinized starch LM grade (low moisture content grade) from Colorcon, fully pregelatinized starches (commercially available as National 78-1551 from Essex Grain

Products), and others. Different cellulose compounds that can be used include crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to Ceolus™ KG801 , Avicel™ PH101 , PH102, PH301 , PH302 and PH-F20, PH-1 12, microcrystalline cellulose 1 14, and microcrystalline cellulose 1 12. Other useful diluents include, but are not limited to, carmellose, sugar alcohols such as mannitol (e.g., Pearlitol™ SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.

Various useful binders according to the present disclosure include, but are not limited to, hydroxypropylcelluloses (e.g., Klucel™ LF and Klucel™ EXF) and useful in various grades, hydroxypropyl methylcelluloses (e.g., Methocel™ products) and useful in various grades, polyvinylpyrrolidones (such as grades K25, K29, K30, and K90), copovidones (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products),

methylcelluloses, polymethacrylates, and starches.

Useful lubricants include magnesium stearate, glyceryl monostearates, palmitic acid, talc, carnauba wax, calcium stearate sodium, sodium or magnesium lauryl sulfate, calcium soaps, zinc stearate, polyoxyethylene monostearates, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and any combinations thereof.

One or more glidant materials, which improve the flow of powder blends, pellets, or mini-tablets, and minimize dosage form weight variations, can be used. Useful glidants include, but are not limited to, silicon dioxide, talc, and

combinations thereof.

Various non-functional coating agents include film formers such as

Opadry® products (manufactured by Colorcon), other hydrophilic or hydrophobic substances, and mixtures thereof. Useful additives for coating include, but are not limited to, plasticizers, anti-adherents, opacifiers, solvents, and optionally colorants, lubricants, pigments, antifoam agents, and polishing agents.

Various solvents can be used in the processes of preparation of

pharmaceutical compositions of the present disclosure, including, but not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, Ν,Ν-dimethylformamide, tetrahydrofuran, and various mixtures of two or more thereof.

The foregoing descriptions of excipients are illustrative and are not intended to be exhaustive. Those skilled in the art will be aware of many other substances that are useful in the practice of the disclosure, and the use of such substances is specifically included in this disclosure.

The pharmaceutical dosage forms of the present disclosure are intended for oral administration to a patient in need thereof.

The following examples will further describe certain specific aspects and embodiments of this disclosure. The examples are provided solely for the purpose of illustration, and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLE 1 : Venlafaxine hydrogel matrix tablets.

* Evaporates during processing.

Manufacturing procedure:

1 . Sift together venlafaxine HCI, HPMC K100 M, and CMC Ca through a #40 mesh sieve, and blend. 2. Dissolve povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 and sift the dried granules through a #24 mesh sieve.

4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets.

In vitro dissolution studies are performed for the tablet formulations and the commercially available product EFFEXOR XR 150 mg capsules, using the conditions below, and results are in the following table.

Dissolution medium: 900 ml_ of water.

Apparatus: USP type 1 .

Rotation speed: 100 rpm.

Tablets of 1 B are stored in closed containers at 40°C and 75% relative humidity for three months. The in vitro dissolution profile of stored tablets is determined using the same conditions as above. The data are in the following table, showing no significant change in the drug release profile from the storage.

Hours 1 2 4 8 12 16 20 24

Cumulative % of 21 28 42 61 74 83 89 94 Drug Released Tablets of 1 B are analyzed for impurities, initially and after storage in closed containers, and results are shown in the following table. Values are percentages of the label venlafaxine content.

Fig. 1 shows PXRD patterns of: (A) venlafaxine hydrochloride crystalline

Form A which is used to prepare the formulations of Example 1 ; (B) tablets as prepared in Example 1 B; (C) tablets of Example 1 B after storage in a closed container for three months at 40°C and 75% relative humidity; and (D) a placebo formulation prepared similarly to the tablets of Example 1 B, but omitting the venlafaxine hydrochloride. The patterns all are generated using copper Ka radiation. EXAMPLE 2: Venlafaxine hydrogel matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together venlafaxine HCI, HPMC K100 M, and crospovidone or CMC Ca or SSG, or pregelatinized starch through a #40 mesh sieve, and blend.

2. Dissolve Povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 at 50°C for 45 minutes and sift the dried granules through a #24 mesh sieve.

4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets.

In vitro dissolution profiles are determined for formulations 2A-2E and a commercially available capsule product, using the conditions described in

Example 1 . The results are shown in the following table. Hours Cumulative % of Drug Released

Example Effexor

2A 2B 2C 2D 2E XR

1 35 24 31 16 27 8

2 47 34 41 26 36 19

4 66 46 57 45 55 44

8 83 61 76 65 69 72

12 91 72 90 80 73 83

16 96 81 94 88 77 89

24 100 96 100 98 82 97

EXAMPLE 3: Venlafaxine hydrogel matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together venlafaxine HCI, HPMC K100 M, and CMC Ca through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in water (for 3A) or isopropyl alcohol (for other examples) and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 at 50°C for 60 minutes and sift the dried granules through a #24 mesh sieve. 4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets.

In vitro dissolution profiles for the tablet formulations, and a commercially available capsule product, are determined using the conditions described in Example 1 . The results are shown in the following table.

The swelling index of tablets of Examples 3B, 3C, 3F and 3G is shown in the following table.

Hours Example

3B 3C 3F 3G

1 69.9 83.87 73.30 72.89

2 104.4 134.40 123.40 1 18.54

3 125.6 147.15 140.03 137.65

4 139.2 163.28 155.06 148.35

5 165.64 191 .70 180.36 177.53

6 172.5 194.00 187.20 180.23

7 166.41 195.39 193.86 190.32

8 166.87 196.01 194.06 191 .54 9 164.8 196.27 195.87 192.36

10 163.3 196.31 196.28 193.10

Axial swelling is expressed as percentage difference between initial diameter in millimeters of a tablet and the diameter after immersion in an aqueous environment. The axial swelling values are shown in the following table.

EXAMPLE 4: Venlafaxine hydrogel matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

Examples 4A and 4C

1 . Sift together venlafaxine HCI, HPMC K100 M, and CMC Ca through #40 mesh sieve, and blend.

2. Dissolve Povidone K 30 in 1 :1 mixture of purified water or isopropyl alcohol and use the solution to granulate the blend of 1 . 3. Dry the granules of 2 at 50°C for 60 minutes and sift the dried granules through a #24 mesh sieve.

4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3 in a double cone blender.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets.

Example 4B

1 . Sift together venlafaxine HCI, HPMC K100 M, CMC Ca and polyvinylpyrrolidone through a #40 mesh sieve, blend, and subject to slugging.

2. De-slug the material of 1 and mix thoroughly.

3. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 2.

4. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 3.

5. Compress the blend of 4 to form tablets.

In vitro drug release profiles for the tablets and a commercial capsule product are determined using conditions described in Example 1 . The results shown in the following table.

Hours Cumulative % of Drug Released

Example Effexor

4A 4B 4C XR

1 0 0 0 0

2 17 17 21 10

4 28 27 33 19

8 40 41 46 45

12 62 60 61 72

16 70 71 68 83

20 82 74 77 89

24 91 88 84 98 EXAMPLE 5: Propranolol hydrogel matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together propranolol HCI, HPMC K100 M or sodium alginate, and CMC Ca through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 at 50°C for 40 minutes and sift the dried granules through a #24 mesh sieve.

4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets.

In vitro dissolution profiles for tablet formulations 5A and 5B, and the commercially available capsule product INDERAL® LA 160 mg, are determined using the conditions below, and the results are shown in the following table.

Dissolution medium: 900 mL of pH 1 .2 buffer solution for 1 .5 hours, followed by 900 mL of pH 6.8 phosphate buffer solution.

Apparatus: USP type 1 .

Rotation speed: 100 rpm. Hours Cumulative % of Drug Released

Examples Inderal LA

5A 5B

1 .5 23 25 19

4 45 49 46

8 66 71 70

14 88 86 85

24 108 102 93

EXAMPLE 6: Metoprolol hydrogel matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together metoprolol succinate, HPMC K100 M, and CMC Ca through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 at 50°C for 60 minutes and sift the dried granules through a #24 mesh sieve.

4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets. In vitro dissolution profiles for tablet formulations 6A and 6B are determined using the following conditions, and the results are shown in the following table.

Dissolution medium: 500 ml_ of pH 6.8 phosphate buffer solution.

Apparatus: USP type 2.

Rotation speed: 50 rpm.

EXAMPLE 7: Venlafaxine hydrogel matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together venlafaxine HCI, HPMC K100 M, and CMC Ca through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 at 50°C for 60 minutes and sift the dried granules through a #24 mesh sieve.

4. Sift DCP and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3. 5. Sift magnesium stearate through #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form tablets.

In vitro dissolution profiles are determined for the tablet formulations, using the conditions described in Example 1 , and results are shown in the following table.

EXAMPLE 8: Venlafaxine hydrogel matrix mini-tablets.

^* Evaporates during processing.

Manufacturing process: 1 . Sift together venlafaxine HCI, HPMC K100 M, and CMC Ca through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 and sift dried granules through a #35 mesh sieve.

4. Sift Avicel PH102, Aerosil 200, and talc through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 to form mini-tablets.

EXAMPLE 9: Propranolol hydrogel matrix mini-tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together propranolol HCI, HPMC K100 M, and CMC Ca through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in isopropyl alcohol and use the solution to granulate the blend of 1 .

3. Dry the granules of 2 and sift dried granules through a #35 mesh sieve. 4. Sift Avicel 102, Aerosil 200, and talc through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of step 5 to form mini-tablets.

EXAMPLE 10: Venlafaxine hydrogel matrix spheroid formulations.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together venlafaxine HCI, HPMC K100 M, CMC Ca, and Avicel PH101 through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in water and use the solution to granulate the blend of 1 .

3. Pass the wet mass through an extruder, and process in a

spheronizer.

4. Dry the spheroids for 1 hour at 50°C.

5. Sift the spheroids through a sieve and collect the desired size fraction.

6. Fill the spheroids into capsules.

EXAMPLE 1 1 : Propranolol hydrogel matrix spheroid formulations.

Ingredient mg/Capsule

11A 11 B

Propranolol hydrochloride 160 160

HPMC K100M 43 - Ca CMC 43 86

Povidone K30 20 20

Microcrystalline cellulose (Avicel PH101 ) 84 84

Water ^* q.s. q.s.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift together propranolol HCI, HPMC K100 M, CMC Ca, and Avicel PH101 through a #40 mesh sieve, and blend.

2. Dissolve povidone K30 in water and use the solution to granulate the blend of 1 .

3. Pass the wet mass through an extruder and process in a

spheronizer.

4. Dry the spheroids for 1 hour at 50°C.

5. Sift the spheroids through a sieve and collect the desired size fraction.

6. Fill the spheroids into capsules.

EXAMPLE 12: Pseudoephedrine hydrogel matrix tablets.

Ingredient mg/Tablet

12A 12B

Core

Pseduephedrine HCI 180 180

HPMC K100M 180 90

Ca CMC 180 270

PVP K 30 62.5 62.5

Isopropyl alcohol ^* q.s. q.s.

Dicalcium phosphate dihydrate 65 49.5

Aerosil 200 1 .5 2

Magnesium stearate 6 6

Coating

Pseduephedrine HCI 60 60 Opadry II 85F18422† 30 30

Water ^* q.s. q.s.

^* Evaporates during processing.

† Opadry II 85F18422, a product of Colorcon, is a polyvinyl alcohol based polymer containing PEG 3350,

Manufacturing procedure:

1 . Sift pseduephedrine HCI, HPMC K100M, and Ca CMC through a

#40 mesh sieve, and blend.

2. Dissolve PVP K30 in isopropyl alcohol and use to granulate the blend of 1 in a rapid mixer granulator to get a dough-like consistency.

3. Dry the granules of 2 for 30 minutes at 55°C and sift the granules through a #24 mesh sieve.

4. Sift dicalcium phosphate dihydrate and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 into tablets.

7. Dissolve pseduephedrine HCI in water.

8. Disperse Opadry II 85F18422 in the solution of 7.

9. Spray the dispersion onto the tablets of 6 in a coating pan, then dry.

EXAMPLE 13: Venlafaxine extended release matrix tablets

Ingredient mg/Tablet

13A 13B

Venlafaxine HCI 172.2 172.2

HPMC K100M 172.2 172.2

Ca CMC 172.2 172.2

PVP K30 62.5 62.5

Isopropyl alcohol ^* q.s. q.s.

Dicalcium phosphate dihydrate 45 19.7

Lactose monohydrate (Flowlac 100) 19.7 45 Aerosil 200 1 .2 1 .2

Magnesium stearate 5 5

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift venlafaxine HCI, HPMC K100M, and Ca CMC through a #40 mesh sieve, and blend.

2. Dissolve PVP K30 in isopropyl alcohol and use to granulate the blend of 1 .

3. Dry the granules of 2 for 30 minutes at 55°C and sift the granules through a #24 mesh sieve.

4. Sift dicalcium phosphate dihydrate, lactose monohydrate, and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 into tablets. EXAMPLE 14: Propranolol extended release matrix tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift propranolol HCI, HPMC K100M, and Ca CMC through a #40 mesh sieve, and blend. 2. Dissolve PVP K30 in isopropyl alcohol and use to granulate the blend of 1 .

3. Dry the granules of 2 for 30 minutes at 55°C and sift the granules through a #24 mesh sieve.

4. Sift dicalcium phosphate dihydrate, lactose monohydrate, and Aerosil 200 through a #40 mesh sieve and mix with granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 into tablets.

EXAMPLE 15: Minocycline extended release tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift minocycline HCI, HPMC K100M or xanthan gum, Ca CMC or sodium starch glycolate, and dicalcium phosphate dihydrate through a #40 mesh sieve, and blend.

2. Dissolve PVP K30 in a mixture of isopropyl alcohol and water (90:10 by volume) and use to granulate the blend of 1 . 3. Dry the granules for 30 minutes at 55°C and sift the granules through a #24 mesh sieve.

4. Sift Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 into tablets. EXAMPLE 16: Galantamine extended release tablets

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift galantamine HBr, HPMC K100M or polyethylene oxide, Ca CMC or crospovidone, and DCP through a #40 mesh sieve, and blend.

2. Dissolve PVP K30 in a mixture of isopropyl alcohol and water (70:30 by volume) and use to granulate the blend of 1 .

3. Dry the granules for 30 minutes at 55°C and sift the granules through a #30 mesh sieve.

4. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 3.

5. Compress the blend of 4 into tablets. EXAMPLE 17: Metformin extended release tablets.

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift metformin HCI, HPMC K100M, Ca CMC, and microcrystalline cellulose through a #40 mesh sieve, and blend.

2. Dissolve PVP K30 in a mixture of isopropyl alcohol and water (70:30 by volume) and use to granulate the blend of 1 .

3. Dry the granules of 2 for 30 minutes at 55°C and sift the granules through a #24 mesh sieve.

4. Sift Aerosil 200 through a #40 mesh sieve and mix with the blend of

3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 into tablets.

EXAMPLE 18: Donepezil extended release tablets

Ingredient mg/Tablet

Donepezil hydrochloride 23

HPMC K100M 11 .5

Ca CMC (E.C.G-505) 5.7

PVP K30 8

Isopropyl alcohol ^* q.s. Dicalcium phosphate dihydrate 98.8

Aerosil 200 2

Magnesiunn stearate 1

^* Evaporates during processing.

Manufacturing procedure:

1 . Sift donepezil HCI, HPMC K100M, and Ca CMC through a #40 mesh sieve, and blend.

2. Dissolve PVP K30 in isopropyl alcohol and use to granulate the blend of 1 .

3. Dry the granules of 3 for 30 minutes at 55°C and sift the granules through a #24 mesh sieve.

4. Sift dicalcium phosphate dihydrate and Aerosil 200 through a #40 mesh sieve and mix with the granules of 3.

5. Sift magnesium stearate through a #60 mesh sieve and mix with the blend of 4.

6. Compress the blend of 5 into tablets.

An in-vitro dissolution study of the tablets is carried out using the following conditions, and the results are shown in the following table.

Dissolution medium: 900 ml_ of 0.05 M Phosphate buffer pH 6.8.

Apparatus: USP Type 1 .

Speed: 50 rpm.

Hours Cumulative % of

Drug Released

1 32

2 46

3 54

4 59

6 70

8 80

10 85

12 88

16 90