WO2012068076A2 - Formulations pharmaceutiques contenant des médicaments solubles - Google Patents

Formulations pharmaceutiques contenant des médicaments solubles Download PDF

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Publication number
WO2012068076A2
WO2012068076A2 PCT/US2011/060742 US2011060742W WO2012068076A2 WO 2012068076 A2 WO2012068076 A2 WO 2012068076A2 US 2011060742 W US2011060742 W US 2011060742W WO 2012068076 A2 WO2012068076 A2 WO 2012068076A2
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WIPO (PCT)
Prior art keywords
pharmaceutical formulation
solid pharmaceutical
disintegrant
rate controlling
drug
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PCT/US2011/060742
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English (en)
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WO2012068076A3 (fr
Inventor
Sanjay Chhagan Wagh
Suryakumar Jayanthi
Sabyasachi Banerjee
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Dr. Reddy's Laboratories Ltd.
Dr. Reddy's Laboratories, Inc.
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Publication of WO2012068076A2 publication Critical patent/WO2012068076A2/fr
Publication of WO2012068076A3 publication Critical patent/WO2012068076A3/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/65—Tetracyclines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin

Definitions

  • compositions providing modified release of water-soluble drugs.
  • compositions of the present disclosure are in the form of hydrogel matrix-based drug delivery systems.
  • 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.
  • 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.
  • 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.
  • concentrations of the active agent and also which are easy to manufacture.
  • aspects of the present disclosure relate to hydrogel matrix based drug delivery systems, for obtaining modified release of highly water soluble drugs.
  • 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.
  • high solubility active agents such as venlafaxine, propranolol, metoprolol, pseudoephedrine, minocycline, galantamine, metformin, donepezil, including pharmaceutically acceptable salts thereof.
  • 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.
  • extended release pharmaceutical formulations of the present disclosure comprise at least one hydrophilic rate controlling substance.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • weight ratios of active agent to hydrophilic rate controlling substance range from about 1 :0.1 to about 1 :20.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • a hydrophilic rate controlling substance and a disintegrant are present in weight ratios of about 1 :0.01 to about 1 :10, respectively.
  • 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.
  • pharmaceutical formulations of the present application comprise a hydroxypropyl methylcellulose as a hydrophilic rate controlling substance and a carboxymethyl cellulose calcium as a disintegrant.
  • a hydroxypropyl methylcellulose and a carboxymethyl cellulose calcium are present in weight ratios of about 1 :0.01 to about 1 :10, respectively.
  • 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.
  • formulations of the present disclosure are in the form of matrix tablets.
  • formulations of the present disclosure are in the form of hydrogel based matrix tablets.
  • 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.
  • 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.
  • 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.
  • 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.
  • hydrogel based matrix formulations of the present disclosure provide in-vitro drug release as a combination of diffusion, swelling, and erosion mechanisms.
  • 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.
  • 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.
  • 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.
  • 'multi-particulates' according to the present disclosure may be in the forms of powders, granules, pellets, spheroids, extrudates, mini-tablets, and the like.
  • the powder blends of the formulations of the present disclosure are characterized for parameters such as Hausner's ratio,
  • Powders having bulk and tapped densities less than about 2 g/cm 3 and Hausner's ratios less than about 1 show excellent flowability.
  • formulations of the present disclosure have
  • compressibility index values between about 10% and about 30%.
  • 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.
  • tablet formulations of the present disclosure have hardness values between about 8 Kp and about 40 Kp.
  • tablets formulations of the present disclosure have friability less than about 2%, or less than about 1 %.
  • the disclosure provides processes for preparation of pharmaceutical compositions of the present disclosure.
  • pharmaceutical formulations of the present disclosure are prepared using any of direct compression, dry granulation, and wet granulation methods.
  • the disclosure provides methods of using pharmaceutical formulations of the present disclosure for treating conditions and disease states in a subject in need thereof.
  • Fig. 1 shows powder X-ray diffraction ("PXRD") patterns of tablets prepared Example 1 .
  • 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.
  • CR controlled release
  • ER extended release
  • DR delayed release
  • IR immediate release
  • Any combinations of two or more of IR, CR, ER, and DR can be useful for delivering particular drugs, depending of their
  • pharmacological properties 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.
  • 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.
  • 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.
  • 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.
  • Microx 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).
  • 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.
  • drugs having high water solubility and one or both of short half-life and high dose 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, me
  • 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, prop
  • 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.
  • 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.
  • pharmaceutical formulations of the present disclosure include highly soluble drugs in unit doses ranging from about 10 mg to about 1000 mg.
  • the pharmaceutically active agents venlafaxine, propranolol, metoprolol, pseudoephedrine, minocycline, galantamine, metformin, and donepezil are used to illustrate certain specific embodiments.
  • 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.
  • MEC minimum effective concentration
  • 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.
  • 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.
  • rate controlling substance 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.
  • 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.
  • excipients that are useful in preparing the composition
  • compositions 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.
  • 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.
  • 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.
  • the active ingredients used to make the compositions or contained in the compositions are in the form of amorphous, crystalline, or mixtures thereof.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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,
  • 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.
  • 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
  • a weight ratio of active agent to hydrophilic rate controlling substance ranges from about 1 :0.1 to about 1 :50.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • extended release pharmaceutical formulations of the present disclosure include two or more disintegrants.
  • 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.
  • 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.
  • pharmaceutical formulations of the present disclosure comprise a hydroxypropyl methylcellulose as a hydrophilic rate controlling substance and a carboxymethyl cellulose calcium as a disintegrant.
  • 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
  • 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.
  • 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.
  • 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.
  • the formulations comprise an active agent, a
  • carboxymethyl cellulose calcium wherein the carboxymethyl cellulose calcium is present in amounts greater than about 15% by weight of the composition.
  • formulations of the present disclosure are in the form of tablets.
  • formulations of the present disclosure are in the form of matrix tablets.
  • formulations of the present disclosure are in the form of hydrogel-based matrix tablets.
  • 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").
  • 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.
  • the "multi-particulates" according to the present disclosure may be in the form of powders, granules, pellets, spheroids,
  • multi-particulates of the present disclosure are
  • tablet formulations can optionally be coated using film- forming polymers.
  • 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.
  • 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.
  • 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.
  • 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
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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, alg
  • cellulose ethers e.g., hydroxypropyl methylcelluloses (hypromellose or HPMC)
  • HPC hydroxypropyl celluloses
  • PVP polyvinylpyrrolidones
  • polyvinylpyrrolidones carboxymethyl starches, polyethylene glycols,
  • polyoxyethylenes 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 such as 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.
  • lipophilic/hydrophobic substances examples 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,
  • waxes e.g., carnauba wax, microcrystalline wax, beeswax, and polyethoxylated beeswax
  • natural fats coconut, soya, cocoa
  • 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-solTM from FMC-Asahi Chemical Industry Co., Ltd.), crospovidones, examples of commercially available crospovidone products including, but not limited to, crosslinked povidone, KollidonTM CL from BASF (Germany), PolyplasdoneTM 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 combinations
  • 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.
  • cores contain one or more release modifying polymers in admixture with an active agent, to form a matrix.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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:
  • W0 is the initial weight of the tablet
  • 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.
  • 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.
  • 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.
  • 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.
  • Mt/M ⁇ is the fraction of drug released at time t
  • k is the rate constant
  • n is the release exponent.
  • the magnitude of the drug release exponent 'n' indicates the release mechanism.
  • 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.”
  • 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.
  • 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:
  • 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.
  • 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.
  • particulate compositions of the present disclosure have compressibility index values between about 10% and about 30%.
  • 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.
  • tablet formulations of the present disclosure are provided.
  • tablets formulations of the present disclosure have hardness values between about 8 Kp (kiloponds) and about 40 Kp.
  • tablet formulations of the present disclosure have friability less than about 2%.
  • compositions 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 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, FlowlacTM
  • 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
  • cellulose compounds that can be used include crystalline cellulose and powdered cellulose.
  • crystalline cellulose products include but are not limited to CeolusTM KG801 , AvicelTM 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., PearlitolTM SD200), sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
  • binders include, but are not limited to, hydroxypropylcelluloses (e.g., KlucelTM LF and KlucelTM EXF) and useful in various grades, hydroxypropyl methylcelluloses (e.g., MethocelTM products) and useful in various grades, polyvinylpyrrolidones (such as grades K25, K29, K30, and K90), copovidones (e.g., PlasdoneTM S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products),
  • hydroxypropylcelluloses e.g., KlucelTM LF and KlucelTM EXF
  • hydroxypropyl methylcelluloses e.g., MethocelTM products
  • polyvinylpyrrolidones such as grades K25, K29, K30, and K90
  • copovidones e.g., PlasdoneTM S 630
  • methylcelluloses 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.
  • 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
  • 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.
  • 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, ⁇ , ⁇ -dimethylformamide, tetrahydrofuran, and various mixtures of two or more thereof.
  • the pharmaceutical dosage forms of the present disclosure are intended for oral administration to a patient in need thereof.
  • EXAMPLE 1 Venlafaxine hydrogel matrix tablets.
  • Dissolution medium 900 ml_ of water.
  • 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.
  • 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.
  • Example 1 The results are shown in the following table. Hours Cumulative % of Drug Released
  • EXAMPLE 3 Venlafaxine hydrogel matrix tablets.
  • 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.
  • 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.
  • Rotation speed 100 rpm. Hours Cumulative % of Drug Released
  • Dissolution medium 500 ml_ of pH 6.8 phosphate buffer solution.
  • Rotation speed 50 rpm.
  • EXAMPLE 7 Venlafaxine hydrogel matrix tablets.
  • EXAMPLE 8 Venlafaxine hydrogel matrix mini-tablets.
  • step 5 Compress the blend of step 5 to form mini-tablets.
  • EXAMPLE 10 Venlafaxine hydrogel matrix spheroid formulations.
  • EXAMPLE 1 1 Propranolol hydrogel matrix spheroid formulations.
  • EXAMPLE 12 Pseudoephedrine hydrogel matrix tablets.
  • Opadry II 85F18422 a product of Colorcon, is a polyvinyl alcohol based polymer containing PEG 3350,
  • Lactose monohydrate (Flowlac 100) 19.7 45 Aerosil 200 1 .2 1 .2
  • Dissolution medium 900 ml_ of 0.05 M Phosphate buffer pH 6.8.

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Abstract

L'invention concerne des compositions pharmaceutiques à libération modifiée de médicaments solubles dans l'eau. Dans des mode de réalisation, un médicament, une substance de régulation de la vitesse de libération hydrophile, et un désintégrant sont conjointement réduits en granules qui sont utilisés pour préparer des formes de dosage en comprimés ou en capsules.
PCT/US2011/060742 2010-11-15 2011-11-15 Formulations pharmaceutiques contenant des médicaments solubles WO2012068076A2 (fr)

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WO2016088041A1 (fr) * 2014-12-01 2016-06-09 Sun Pharmaceutical Industries Limited Composition de cefpodoxime proxétil à libération prolongée
WO2019075229A1 (fr) * 2017-10-13 2019-04-18 Research Triangle Institute Formulations de sulfate d'hydroxychloroquine et leurs procédés de préparation et d'utilisation
CN112176011A (zh) * 2020-10-26 2021-01-05 辰欣药业股份有限公司 一种酶催化制备盐酸伐昔洛韦的方法

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US5602182A (en) * 1995-01-30 1997-02-11 American Home Products Corporation Taste masking pseudoephedrine HCL containing liquids
US20030190351A1 (en) * 2002-03-28 2003-10-09 Synthon Bv Extended release venlafaxine formulations
US6703044B1 (en) * 2002-10-25 2004-03-09 Dexcel Pharma Tech, Ltd Venlafaxine formulations
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WO2007025182A2 (fr) * 2005-08-26 2007-03-01 Bpsi Holdings, Inc. Compositions de medicament renfermant des matrices d'hypermellose a liberation commandee
US20100221335A1 (en) * 2007-08-31 2010-09-02 Daiichi Sankyo Company, Limited Sustained-release preparation and method for producing the same

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US5602182A (en) * 1995-01-30 1997-02-11 American Home Products Corporation Taste masking pseudoephedrine HCL containing liquids
US20030190351A1 (en) * 2002-03-28 2003-10-09 Synthon Bv Extended release venlafaxine formulations
US6703044B1 (en) * 2002-10-25 2004-03-09 Dexcel Pharma Tech, Ltd Venlafaxine formulations
US20050191349A1 (en) * 2003-12-31 2005-09-01 Garth Boehm Galantamine formulations
WO2007025182A2 (fr) * 2005-08-26 2007-03-01 Bpsi Holdings, Inc. Compositions de medicament renfermant des matrices d'hypermellose a liberation commandee
US20100221335A1 (en) * 2007-08-31 2010-09-02 Daiichi Sankyo Company, Limited Sustained-release preparation and method for producing the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016088041A1 (fr) * 2014-12-01 2016-06-09 Sun Pharmaceutical Industries Limited Composition de cefpodoxime proxétil à libération prolongée
WO2019075229A1 (fr) * 2017-10-13 2019-04-18 Research Triangle Institute Formulations de sulfate d'hydroxychloroquine et leurs procédés de préparation et d'utilisation
US20200297636A1 (en) * 2017-10-13 2020-09-24 Research Triangle Institute Hydroxychloroquine sulfate formulations and methods for preparation and use thereof
US11648202B2 (en) 2017-10-13 2023-05-16 Research Triangle Institute Hydroxychloroquine sulfate formulations and methods for preparation and use thereof
CN112176011A (zh) * 2020-10-26 2021-01-05 辰欣药业股份有限公司 一种酶催化制备盐酸伐昔洛韦的方法
CN112176011B (zh) * 2020-10-26 2022-10-18 辰欣药业股份有限公司 一种酶催化制备盐酸伐昔洛韦的方法

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