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WO2012035409A1 - Compositions d'agents anti-alzheimer à libération prolongée - Google Patents

Compositions d'agents anti-alzheimer à libération prolongée Download PDF

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Publication number
WO2012035409A1
WO2012035409A1 PCT/IB2011/002133 IB2011002133W WO2012035409A1 WO 2012035409 A1 WO2012035409 A1 WO 2012035409A1 IB 2011002133 W IB2011002133 W IB 2011002133W WO 2012035409 A1 WO2012035409 A1 WO 2012035409A1
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Prior art keywords
composition
alzheimer
copolymer
phthalate
cellulose
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Ceased
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PCT/IB2011/002133
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Inventor
Pratibha Sudhir Pilgaonkar
Maharukh Tehmasp Rustomjee
Anilkumar Surendrakumar Gandhi
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Rubicon Research Pvt Ltd
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Rubicon Research Pvt Ltd
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    • 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
    • A61K31/13—Amines
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A61K38/09—Luteinising hormone-releasing hormone [LHRH], i.e. Gonadotropin-releasing hormone [GnRH]; Related peptides
    • 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
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    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5015—Organic compounds, e.g. fats, sugars
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention relates to sustained release compositions of anti-Alzheimer's agents.
  • the present invention relates to sustained release compositions comprising one or more anti-Alzheimer's agents, at least one heat sensitive release retardant and at least one enteric polymer.
  • AD Alzheimer's disease
  • AD is a progressive neurological disease of the brain characterized by irreversible loss of neurons and the loss of intellectual abilities, including memory and reasoning that become severe enough to impede social or occupational functioning. Alzheimer's disease is the most common form of dementia.
  • Clinically, Alzheimer's disease (AD) is characterized by beta-amyloid plaque depositions, tau pathology, inflammation, cerebrovascular damage, and cell death of cholinergic neurons.
  • the lack of cortical acetylcholine results in deficient cholinergic functions in cortex and hippocampus causing cognitive impairment.
  • the average duration of the disease is 10 years, during which afflicted persons progress from mild memory loss to the need for 24-hour supervision to total dependency and death.
  • anti-Alzheimer's drugs are designed to treat and manage its symptoms.
  • anti-Alzheimer's agents used for management of Alzheimer's include donepezil, rivastigmine, galantamine, tacrine and memantine.
  • Donepezil hydrochloride is a centrally acting reversible acetylcholinesterase inhibitor used in the treatment of Alzheimer's disease. It is postulated to exert its therapeutic effect by enhancing cholinergic function.
  • Donepezil hydrochloride is available as ARICEPT ® from Eisai, Inc in the form of immediate release tablets.
  • the immediate release of cholinesterase inhibitor such as donepezil hydrochloride results in a spike in the patient's blood plasma levels within 2 to 5 hours after administration of the drug.
  • the initial spike in blood plasma levels at tmax may cause undesirable side effects in patients, such as anxiety, nightmares, insomnia, and/or gastrointestinal problems such as nausea, emesis and/or diarrhoea.
  • a sustained release formulation containing a physiologically active drug allows blood concentrations of the drug to be maintained for a long time or above the therapeutic concentration. Accordingly, by achieving the sustained- release characteristics of a drug it may be possible to reduce the number of dosings while providing the same or better therapeutic effects— potentially improving compliance. With the sustained release properties of the drug, it may also be possible to avoid a rapid increase in blood plasma concentration levels immediately after administration of the drug, thus potentially reducing or eliminating adverse side effects. There is thus a need for sustained release compositions to treat Alzheimer's disease that overcome the side effects of immediate release formulations or provide other benefits over immediate release formulations.
  • U.S Patent Application 2005/0232990 discloses a dosage formulation, comprising: amorphous donepezil or an amorphous pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable polymeric carrier such as hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, cellulose acetate phthalate, cellulose acetate butyrate, hydroxyethyl cellulose, ethyl cellulose, polyvinyl alcohol, polypropylene, polyvinyl chloride, polyvinyl acetate, ethylene vinyl acetate, lectins, carbopols, silicon elastomers, polyacrylic polymers, maltodextrins, polyethylene glycol, crosslinked polyvinylpyrrolidone, or a combination thereof, wherein the polymeric carrier maintains the active agent in substantially amorphous form.
  • a pharmaceutically acceptable polymeric carrier such as hydroxypropyl cellulose, methyl cellulose, carboxymethyl cellulose, sodium carboxymethyl
  • U.S Patent Application 2006/0159753 A1 provides a matrix type sustained-release preparation comprising a basic drug or a salt thereof which has higher solubility in a 0.1 N hydrochloric acid solution and a neutral aqueous solution, pH 6.0 than in a basic aqueous solution, pH 8.0; a water-insoluble polymer and at least one enteric polymer.
  • a matrix type sustained release preparation is said to inhibit unexpected increases in blood concentrations associated with the rapid dissolution of the basic drug from the preparation in the stomach and is also said to offer a decreased risk of reduced bioavailability associated with the sustained-release characteristics.
  • U.S Patent Application 2008/0213368 A1 provides a pharmaceutical matrix type sustained-release composition containing an anti-dementia drug, particularly donepezil and a high molecular basic substance such as ethyl cellulose in which a high molecular weight acidic substance such as an enteric polymer is contained for stabilizing the anti- dementia drug. That degradation products derived from donepezil hydrochloride are produced in such matrix type sustained-release preparation containing donepezil hydrochloride and ethyl cellulose, a high molecular weight basic substance as a sustained- release base; a high molecular weight acidic substance is included to effectively prevent or inhibit formation of such degradation products produced.
  • PCT Publication WO2011/069076 provides sustained release formulations of donepezil and at least one release rate controlling excipient including hydrophilic polymers.
  • anti-Alzheimer's agents such as donepezil
  • the various sustained release compositions discussed above tend to result in the formation of degradation products and need incorporation of special agents or excipients to avoid the formation of degradative products.
  • a need thus exists to provide sustained release compositions of anti-Alzheimer's agents that are stable and prevent or minimize the formation of any degradation products of the actives.
  • Anti-dementia drugs tend to form degradation products on contact with high molecular basic substances for e.g.
  • water-insoluble polymers such as ethylcellulose, aminoalkyl methacrylate copolymer (Eudragit RL, Eudragit RS) and ethyl acrylate-methyl methacrylate copolymer (Eudragit NE).
  • Eudragit RL, Eudragit RS aminoalkyl methacrylate copolymer
  • Eudragit NE ethyl acrylate-methyl methacrylate copolymer
  • insoluble polymers such as ethyl cellulose and enteric polymers as matrix forming agents would not achieve desired control of burst release.
  • compositions comprising one or more anti-Alzheimer's agents, at least one heat sensitive release retardant and at least one enteric polymer provide the desired sustained release properties and stability profile.
  • the present inventors have found that the use of at least one heat sensitive release retardant and at least one enteric polymer with anti-Alzheimer's agents to develop sustained release compositions provides compositions which achieve desired control of release and also degradation of the anti- Alzheimer's actives is prevented or minimized to provide stable compositions that provide the desired in-vitro profile as well as bioavailability.
  • the present invention relates to sustained release compositions comprising one or more anti-Alzheimer's agents, at least one heat sensitive release retardant and at least one enteric polymer.
  • the present invention relates to sustained release compositions and particularly the present invention relates to sustained release compositions of anti-Alzheimer's agents.
  • the sustained release compositions of the present invention comprise one or more anti- Alzheimer's agents, at least one heat sensitive release retardant and at least one enteric polymer.
  • anti-Alzheimer's agent or "anti-Alzheimer agent”, as employed herein refers to any compound that can be employed for the treatment of Alzheimer's disease and other dementias; such as, but not limited to, modulators of cholinesterase, acetylcholine synthesis modulators, acetylcholine storage modulators, acetylcholine release modulators, N-methyl- D-aspartate receptor (NMDA) receptor antagonists, ⁇ inhibitors, ⁇ plaque removal agents, inhibitors of ⁇ plaque formation, inhibitors of amyloid precursor protein processing enzymes, ⁇ -amyloid converting enzyme inhibitors, ⁇ -secretase inhibitors, ⁇ -secretase modulators, nerve growth factor agonists, hormone receptor blockade agents, neurotransmission modulators, and combinations thereof.
  • modulators of cholinesterase such as, but not limited to, modulators of cholinesterase, acetylcholine synthesis modulators, acetylcholine storage modulators,
  • the anti- Alzheimer's agent is an inhibitor of cholinesterase.
  • the modulator of cholinesterase includes, but is not limited to, donepezil, tacrine, rivastigmine, galantamine, physostigmine, neostigmine, Huperzine A, icopezil (CP-118954, 5,7-dihydro-3-[2-[1- (phenylmethyl)-4-piperidinyl]ethyl]-6H-pyrrolo-[4,5-f]-1 ,2-benzisoxazol-6-one maleate), ER- 127528 (4-[(5,6-dimethoxy-2-fluoro-1-indanon)-2-yl]methyl-1-(3-fluorobenzyl) piperidine hydrochloride), zanapezil (TAK-147; 3-[1-(phenylmethyl)piperidin-4-yl]-1-(2,3,4,5-tetrahydro- 1 H-1 H-1
  • the anti-Alzheimer's agent is an NMDA receptor antagonist.
  • the NMDA receptor antagonist includes, but is not limited to, memantine, neramexane (1 , 3, 3, 5, 5-pentamethylcyclohexan-l-amine), and/or combinations thereof.
  • the anti-Alzheimer's agent is an ⁇ inhibitor, ⁇ plaque removal agents, inhibitors of ⁇ plaque formation, inhibitors of amyloid precursor protein processing enzymes, ⁇ -amyloid converting enzyme inhibitors, ⁇ -secretase inhibitors, ⁇ -secretase modulators.
  • the ⁇ inhibitor includes, but is not limited to, tarenflurbil, tramiprosate, clioquinol, PBT-2 and other 8-hydroxyquinilone derivatives, ⁇ plaque removal agents, inhibitors of ⁇ plaque formation, inhibitors of amyloid precursor protein processing enzymes, ⁇ -amyloid converting enzyme inhibitors, ⁇ -secretase inhibitors, ⁇ -secretase modulators (LY450139; N— [N-(3,5-difluorophenacetyl)-L-alanyl)-S- phenylglycine t-butyl ester), and combinations thereof.
  • the anti- Alzheimer's agent is a nerve growth factor agonist.
  • the nerve growth factor agonist is, but not limited to, xaliproden or brain derived neurotrophic factor or nerve growth factor.
  • the anti-Alzheimer's agent is a hormone receptor blockade agent.
  • the hormone receptor blockade agent is, but not limited to, leuproelide or a derivative thereof.
  • the anti- Alzheimer's agent is a neurotransmission modulator.
  • the neurotransmission modulator is, but not limited to, ispronicline.
  • the anti- Alzheimer's agent is donepezil, tacrine, rivastigmine, galantamine, physostigmine, neostigmine, icopezil, zanapezil, metrifonate, xaliproden, leuproelide, memantine or neramexane.
  • the anti-Alzheimer's agent is donepezil.
  • the anti-Alzheimer agent employed in the compositions of the present invention may be in the form of free base or pharmaceutically acceptable salts, prodrugs, active metabolites, polymorphs, solvates, hydrates, enantiomers, optical isomers, tautomers or racemic mixtures thereof.
  • Suitable salts include, but are not limited to, acid addition salts, such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic pyruvic, malonic, succinic, maleic, fumaric, maleic, tartaric, citric, benzoic, carbonic cinnamic, mandelic, methanesulfonic, ethanesulfonic, benezenesulfonic, hydroxyethanesulfonic, p-toluene sulfonic, cyclohexanesulfamic, salicyclic, p- aminosalicylic, 2-phenoxybenzoic, and 2-acetoxy benzoic acid.
  • acid addition salts such as those made with hydrochloric, hydrobromic, hydroiodic, methylsulfonic, perchloric, sulfuric, ni
  • the anti-Alzheimer's agent employed in the present invention is donepezil in the form of free base or its pharmaceutically acceptable salts, prodrugs, polymorphs, solvates, hydrates, active metabolites, enantiomers, optical isomers, tautomers or racemic mixtures.
  • the anti-Alzheimer's agent employed in the compositions of the present invention is donepezil hydrochloride.
  • Pharmaceutically effective amount of anti-Alzheimer's agent is employed in the composition of the present invention.
  • the term "effective amount" refers to an amount effective to achieve desired preventive, therapeutic and/or beneficial effect.
  • the amount of anti-Alzheimer's agent in the composition can vary from about 0.01 weight % to about 85 weight %, based on the total weight of the composition. In another embodiment the amount of anti-Alzheimer's agent in the composition can vary from about 0.02 weight % to about 75 weight %, based on the total weight of the composition. In still another embodiment, the amount of anti-Alzheimer's agent in the composition can vary from about 0.05 weight % to about 60 weight %, based on the total weight of the composition. In one embodiment the compositions of the present invention may be administered at a dose of about 0.01 mg to about 300 mg of anti-Alzheimer's agent.
  • compositions of the present invention may be administered at a dose of about 0.1 mg to about 250 mg of anti-Alzheimer's agent. In still another embodiment the compositions of the present invention may be administered at a dose of about 0.5 mg to about 200 mg of anti- Alzheimer's agent. In one embodiment the compositions of the present invention may be administered at a dose of about 1 mg to about 100 mg of donepezil hydrochloride. In a most preferred embodiment the dose of donepezil hydrochloride is 23 mg.
  • the anti-Alzheimer's agent may be in the form of, but not limited to, powder, granules, pellets, beads, minitablets or the like.
  • Anti-Alzheimer's agent granules may be prepared by methods such as, but not limited to, wet granulation, melt granulation, dry granulation or roll compaction or the like.
  • pellets of anti-Alzheimer's agent may be prepared using extrusion spheronization.
  • anti-Alzheimer's agent can be loaded on an inert carrier.
  • the inert carrier can be selected from, but not limited to, beads, pellets, spheres or similar particles that do not contain an active ingredient.
  • Non-limiting examples of inert carriers include microcrystalline cellulose, sugar or silicon dioxide.
  • anti-Alzheimer's agent, in the powder form may be employed in the compositions of the present invention.
  • compositions of the present invention comprising anti-Alzheimer's agent, comprise at least one heat sensitive release retardant and at least one enteric polymer.
  • compositions of the present invention comprising one or more anti-Alzheimer's agents further comprise at least one heat sensitive release retardant.
  • heat sensitive release retardant used herein intends to encompass substances that lose their consistency or physical state when exposed to higher temperatures. On exposure to heat these substances either melt to a liquid state or soften to a semisolid state. These substances exhibit heat sensitivity in the temperature range of 30° C- 200° C.
  • the heat sensitive release retardants are polymeric substances which soften or liquefy on application of heat.
  • the heat sensitive release retardant is a lipophilic non-polymeric agent. Lipophilic non-polymeric agents are those release retardants that do not comprise repeating units of monomers and are insoluble or partially soluble or dispersible or partially dispersible in water.
  • Lipophilic non-polymeric agents employed for the purpose of the present invention include, but are not limited to, fats, oils, waxes, fatty acids, fatty acid esters, long chain monohydric alcohols and their esters, phospholipids, terpenes or combinations thereof.
  • Waxes are esters of fatty acids with long chain monohydric alcohols. Natural waxes are often mixtures of such esters, and may also contain hydrocarbons.
  • Waxes employed in the present invention include, but are not limited to, natural waxes, such as animal waxes, vegetable waxes, and petroleum waxes (i.e., paraffin waxes, microcrystalline waxes, petrolatum waxes, mineral waxes), and synthetic waxes.
  • Specific examples include but are not limited to spermaceti wax, carnauba wax, Japan wax, bayberry wax, flax wax, beeswax, yellow wax, Chinese wax, shellac wax, lanolin wax, sugarcane wax, candelilia wax, castor wax paraffin wax, microcrystalline wax, petrolatum wax, carbowax, and the like, and mixtures thereof.
  • Waxes are also monoglyceryl esters, diglyceryl esters, or triglyceryl esters (glycerides) and derivatives thereof formed from a fatty acid having from about 10 to about 22 carbon atoms and glycerol, wherein one or more of the hydroxyl groups of glycerol are substituted by a fatty acid.
  • Glycerides employed in the present invention include, but are not limited to, glyceryl monostearate, glyceryl distearate, glyceryl tristearate, glyceryl dipalmitate, glyceryl tripalmitate, glyceryl monopalmitate, glyceryl palmitostearate, glyceryl dilaurate, glyceryl trilaurate, glyceryl monolaurate, glyceryl didocosanoate, glyceryl tridocosanoate, glyceryl monodocosanoate, glyceryl monocaproate, glyceryl dicaproate, glyceryl tricaproate, glyceryl monomyristate, glyceryl dimyristate, glyceryl trimyristate, glyceryl monodecenoate, glyceryl didecenoate, glyceryl tridecen
  • Fatty acids employed in the present invention include, but are not limited to, hydrogenated palm kernel oil, hydrogenated peanut oil, hydrogenated palm oil, hydrogenated rapeseed oil, hydrogenated rice bran oil, hydrogenated soybean oil, hydrogenated sunflower oil, hydrogenated castor oil, hydrogenated cottonseed oil, and mixtures thereof.
  • Other fatty acids include, but are not limited to, decenoic acid, docosanoic acid, stearic acid, palmitic acid, lauric acid, myristic acid, and the like, and mixtures thereof.
  • the fatty acids employed include, but not limited to, hydrogenated palm oil, hydrogenated castor oil, stearic acid, hydrogenated cottonseed oil, palmitic acid, and mixtures thereof.
  • Long chain monohydric alcohols include, but are not limited to, cetyl alcohol, and stearyl alcohol and mixtures thereof.
  • the lipophilic non-polymeric agents employed in the compositions of the present invention include, but not limited to, Cutina® (hydrogenated castor oil), Hydrobase® (hydrogenated soybean oil), Castorwax® (hydrogenated castor oil), Croduret® (hydrogenated castor oil), Carbowax®, Compritol® (glyceryl behenate), Sterotex® (hydrogenated cottonseed oil), Lubritab® (hydrogenated cottonseed oil), Apifil® (wax yellow), Akofine® (hydrogenated cottonseed oil), Softisan® (hydrogenated palm oil), Hydrocote® (hydrogenated soybean oil), Corona® (Lanolin), Gelucire® (macrogolglycerides Lauriques), Precirol® (glyceryl palmitostearate), EmulcireTM (cetyl alcohol), Plurol® diisostearique (polyglyceryl diisostearate), Geleol® (glyceryl stea
  • the lipophilic non-polymeric agents employed in compositions of the present invention are hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, hydrogenated soybean oil, carnauba wax, candelilla wax, spermaceti, beeswax, montan wax, microcrystalline wax, lecithin, hydrogenated tallow, paraffin wax, shellac wax, petrolatum, glyceryl behenate, cetyl alcohol, cetostearyl alcohol, precirol, stearic acid or synthetic wax, or a combination thereof.
  • the lipophilic non-polymeric agents employed in compositions of the present invention are hydrogenated vegetable oil, hydrogenated cottonseed oil, hydrogenated castor oil, glyceryl behenate or combinations thereof.
  • lipids or waxes can also be employed in the form of an aqueous dispersion stabilized by surfactants and suitable stabilizers.
  • the amount of heat sensitive release retardant that may be employed in the compositions of the present invention is from about 1% to about 95% by weight of the composition. In one embodiment the amount of heat sensitive release retardant that may be employed in the compositions of the present invention is from about 2% to about 90% by weight of the composition. In another embodiment the amount of heat sensitive release retardant that may be employed in the compositions of the present invention is from about 5% to about 85% by weight of the composition.
  • the active ingredient may be physically mixed or blended with these heat sensitive release retardants or is partially or completely coated with these excipients by any of the techniques known in the art, such as microencapsulation, hot melt granulation, hot melt extrusion, fluid bed coating, wet granulation, spray drying, solvent treatment, dry granulation or roll compaction. In one embodiment, the lipophilic non-polymeric agent may be incorporarated in the present invention in the form of physical blend, solid dispersion, solid solution, complex with the active or as a partial or complete coat on the active.
  • compositions of the present invention further comprise at least one enteric polymer.
  • the enteric polymer employed is the one that is acid insoluble or acid resistant. Particularly the enteric polymers dissolve in aqueous buffer solutions at a pH of about 3 or more.
  • the enteric polymer employed in the composition of the present invention includes, but is not limited to, polyacrylic acid, polymethacrylic acid polymer, cellulose polymer, maleic acid copolymer, polyvinyl polymer, or derivative or a combination thereof.
  • the cellulose polymer or derivative thereof employed in the composition of the present invention as an enteric polymer includes, but is not limited to, cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, cellulose acetate trimellitate, ethylhydroxycellulose phthalate, carboxymethyl ethyl cellulose, hydroxymethylethylcellulose phthalate, cellulose acetate maleate, cellulose benzoate phthalate, cellulose propionate phthalate, or a combination thereof.
  • the maleic copolymer or derivative thereof employed in the composition of the present invention as an enteric polymer includes, but is not limited to, vinylacetate maleic acid anhydride copolymer, styrene ' maleic acid anhydride copolymer, styrene ' maleic acid monoester copolymer, vinylmethylether ' maleic acid anhydride copolymer, ethylene ' maleic acid anhydride copolymer, vinylbutylether ' maleic acid anhydride copolymer, acrylonitrile ' methyl acrylate maleic acid anhydride copolymer, butyl acrylatestyrene maleic acid anhydride copolymer, or a combination thereof.
  • the polyvinyl polymer or derivative thereof employed in the composition of the present invention as an enteric polymer includes, but is not limited to, polyvinyl alcohol phthalate, polyvinylacetal phthalate, polyvinylbutyrate acetate, polyvinylacetate phthalate, polyvinyl butylate phthalate, polyvinylacetoacetal phthalate, or a combination thereof.
  • the acrylic acid or polymethacrylic acid polymer or derivative thereof employed in the composition of the present invention as an enteric polymer includes, but is not limited to, styrene ' acrylic acid copolymer, methyl acrylate acrylic acid copolymer, methyl acrylate methacrylic acid copolymer, butyl acrylate styrene acrylic acid copolymer, methacrylic acid methyl methacrylate copolymer, methacrylic acid ' ethyl acrylate copolymer, methyl acrylate ' methacrylic acidoctyl acrylate copolymer or a combination thereof.
  • enteric coating materials are pharmaceutically acceptable methacrylic acid copolymers based on methacrylic acid and methyl methacrylate/ethyl acrylate such as poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit® S), poly(methacrylic acid, methyl methacrylate) 1 :1 (Eudragit® L), poly (methacrylic acid, ethyl acrylate) (Eudragit L100-55, Eudragit L30D-55).
  • methacrylic acid copolymers based on methacrylic acid and methyl methacrylate/ethyl acrylate such as poly(methacrylic acid, methyl methacrylate) 1 :2 (Eudragit® S), poly(methacrylic acid, methyl methacrylate) 1 :1 (Eudragit® L), poly (methacrylic acid, ethyl acrylate) (Eudragit L100-55, Eudragit L30
  • the amount of enteric polymer that may be employed in the compositions of the present invention is from about 5% to about 95% by weight of the composition. In one embodiment, the amount of enteric polymer that may be employed in the compositions of the present invention is from about 10% to about 85% by weight of the composition. In another embodiment, the amount of enteric polymer that may be employed in the compositions of the present invention is from about 12% to about 80% by weight of the composition. In one embodiment the enteric polymer employed in the compositions of the present invention is non-swelling. The enteric polymer may be employed in the compositions of the present invention in powder form or in the form of an aqueous suspension or an organic solvent solution.
  • composition of the present invention may further include at least one pharmaceutically acceptable excipient to ease the manufacturing process as well as to improve the performance of the dosage form.
  • pharmaceutically acceptable excipients include, but are not limited to, diluents, lubricants, binders, colorants, flavorants, surfactants, pH adjusters, anti-adherents, gildants, disintegrant and the like
  • the present invention may include one or more diluents including, but not limited to, lactose, lactose monohydrate, sugar, dextrate, dextrate hydrated, dextrins, fructose, lactitol, corn starch, modified corn starch, mannitol, sorbitol, inorganic salts such as calcium carbonate, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate and/or cellulose derivatives such as wood cellulose and microcrystalline cellulose, or mixtures thereof in an amount within the range of from about 0 to about 90% by weight.
  • the diluent may be present in an amount of about 1 % to about 80% by weight.
  • Binders employed in the dosage form include, but are not limited to, starch, microcrystalline cellulose, highly dispersed silica, mannitol, lactose, polyethylene glycol, polyvinylpyrrolidone, vinyl copolymers, copovidone, polymethacrylic acid derivative, ethyl cellulose, cross-linked carboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxypropylcellulose, natural or synthetic gums and the like or mixtures thereof.
  • the binders employed in the compositions of the present invention is hydroxyl propyl cellulose, polyvinyl pyrrolidone or copovidone, or combinations thereof.
  • Binders may be incorporated into the system in an amount of about 0.1% to about 30% by weight of the dosage form. In another embodiment, the binder may be incorporated in an amount of about 1 % to about 20% by weight of dosage form. In a further embodiment, the binder may be present in an amount of about 2% to about 15% by weight of the dosage form. In a further embodiment, the binder may be present in an amount of about 0.5% to about 10% by weight of the dosage form. In a further embodiment, the binder may be present in an amount of about 0.1 % to about 7.5% by weight of the dosage form.
  • Lubricants employed in the dosage form include, but are not limited to, magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, polyethylene glycol, colloidal silicon dioxide, sodium stearyl fumarate, carnauba wax and the like and mixtures thereof. Lubricants may be employed in an amount of from about 0.2 to about 10% by weight of the dosage form. In another embodiment, lubricants may be employed in an amount of from about 0.5 to about 5% by weight of the dosage form. Compositions of the present invention may optionally also include a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
  • a glidant such as, but not limited to, colloidal silica, silica gel, precipitated silica, or combinations thereof.
  • Anti-adherents employed in the dosage form include, but are not limited to, talc, magnesium stearate or finely divided silica, or combinations thereof.
  • Disintegrants that may be employed include, but are not limited to natural, modified or pregelatinized starch, crospovidone, croscarmellose sodium, sodium starch glycolate, low-substituted hydroxypropyl cellulose and calcium silicate.
  • surfactants include, but are not limited to, sodium docusate, glyceryl monooleate, polyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, sorbic acid, sorbitan fatty acid ester, and mixtures thereof.
  • pH adjusters include, but are not limited to, sodium citrate, magnesium oxide, citric acid or combinations thereof.
  • flavorants employed include but are not limited to, mint flavor, orange flavor, lemon flavors, strawberry aroma, vanilla flavor, raspberry aroma, cherry flavor, tutty frutty flavor, magnasweet 135, key lime flavor, grape flavor, trusil art 511815, and fruit extracts.
  • colorants employed include, but are not limited to, titanium dioxide, dyes, lake pigments or natural colors.
  • the dosage form of present invention is a solid dosage form such as, but not limited to, tablet, granule, spheroid, bead, pellet or capsule.
  • the solid dosage form is a tablet which may vary in shape such as oval, triangle, almond, peanut, parallelogram, pentagonal, hexagonal, and trapezoidal.
  • the tablet dosage form may be monolithic or multilayered.
  • the tablet dosage form may be matrix type or multiparticulate type.
  • the dosage form may be optionally coated.
  • Surface coating may be employed for aesthetic purposes or for dimensionally stabilizing the compressed dosage form.
  • the coating may be carried out using any conventional technique employing conventional ingredients suitable for oral use.
  • a surface coating can, for example, be in the form of a film using conventional polymers including, but not limited to, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, polyvinyl alcohol, polymethacrylates and the like, and combinations thereof.
  • the composition may be optionally coated with a functional coat.
  • the functional coat may be applied using coating agents including, but not limited to, hydrophilic polymers, hydrophobic polymers, waxes, and the like, or mixtures thereof, either alone or in combination, along with plasticizers, colorants, opacifiers etc.
  • the functional coat may help provide the desired drug release profile.
  • Sustained release composition according to the present invention is one which achieves release of anti-Alzheimer's agent over an extended period of time, thereby extending the duration of drug action over that achieved by conventional delivery.
  • composition of the present invention maintains drug concentration in the blood within the therapeutic range for up to about 4 hours or more.
  • composition of the present invention releases anti-Alzheimer's agent for over a period of up to about 4 hours or more.
  • composition of the present invention releases anti-Alzheimer's agent or a pharmaceutically acceptable salt thereof for over a period of up to about 6 hours or more.
  • composition of the present invention provides in-vitro drug release for over a period of about 4 hours or more.
  • composition of the present invention provides in-vitro drug release for over a period of about 6 hours or more. In a further embodiment, composition of the present invention provides in- vitro drug release for over a period of up to about 8 hours. In one embodiment, composition of the present invention provides in-vitro drug release for over a period of up to about 12 hours. In another embodiment, composition of the present invention provides in-vitro drug release for over a period of up to about 24 hours.
  • sustained release compositions of the present invention are formulated for extended release of donepezil hydrochloride following oral administration, with the in vitro release rate corresponding to the following % rate of active agent released as shown in Table A:
  • the sustained release dosage form has an in vitro release rate corresponding to the following % rate of donepezil hydrochloride released as shown in Table B: TABLE B
  • the sustained release composition of the present invention has an in vitro release rate corresponding to the following % rate of donepezil hydrochloride released as shown in Table C:
  • the sustained release dosage form in accordance with the invention has an in vitro release rate corresponding to the following % rate of donepezil hydrochloride released as shown in Table D: TABLE D
  • compositions of the present invention do not comprise swelling release retardant/s.
  • swelling release retardants such as, but not limited to, polyethylene oxide, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, methyl cellulose, xanthan gum, or mixture thereof, are not present in the compositions of the present invention.
  • at least one swelling release retardant or combinations thereof are not present in the compositions of the present invention in an amount more than 30% by weight of the composition.
  • At least one swelling release retardant or combinations thereof are not present in the compositions of the present invention in an amount more than 20% by weight of the composition. In another embodiment, at least one swelling release retardant or combinations thereof are not present in the compositions of the present invention in an amount more than 10% by weight of the composition. In a still another embodiment the dosage form of the present invention is a non-swelling dosage form.
  • the dosage form of the present invention can be prepared by various methods such as, but not limited to, direct compression or granulation techniques.
  • direct compression technique involves compression of active agent, at least one heat sensitive release retardant and at least one enteric polymer after mixing them for a definite time period with other excipients.
  • Granulation is any process of size enlargement whereby small particles are gathered together into larger, permanent aggregates to render them into a free flowing state. Methods such as but not limiting to wet granulation, dry granulation, melt granulation or hot melt extrusion methods can be used.
  • the heat sensitive release retardant is melted and the active agent is added and mixed with the molten mass effectively, allowed to solidify and thus producing drug granules which are either blended or coated completely or partially with at least one enteric polymer.
  • the active agent is granulated using a molten heat sensitive release retardant. Drug granules thus obtained are blended or coated partially or completely with enteric polymers before incorporation into a dosage form.
  • active agent is blended with a binder and granulation is carried out using a solvent.
  • a blend of active agent and other inactive excipients is granulated using a binder solution.
  • Such granules are then blended and/or coated with at least one heat sensitive agent and at least one enteric polymer.
  • the active, at least one heat sensitive agent and at least one enteric polymer along with at least one pharmaceutically acceptable excipient are blended and granulated using a binder solution. Dry granulation process employs a roller compaction process.
  • the method of preparing sustained release dosage form of anti- Alzheimer's agent comprises the steps of:
  • step (b) blending the drug granules of step (a) with at least one enteric polymer and at least one pharmaceutically acceptable excipient to form a blend;
  • step (c) lubricating and compressing the blend of step (b) to form monolithic tablets.
  • the method of preparing sustained release dosage form of anti- Alzheimer's agent comprises the steps of:
  • step (b) coating the drug granules of step (a) with at least one enteric polymer to form coated drug granules;
  • step (c) blending the coated drug granules of step (b) with at least one pharmaceutically acceptable excipient to form a blend; and (d) lubricating and compressing the blend of step (c) to form monolithic tablets.
  • the method of preparing sustained release dosage form of anti- Alzheimer's agent comprises the steps of:
  • step (a) blending the active agent with at least one heat sensitive release retardant, at least one enteric polymer and at least one pharmaceutically acceptable excipient to form a blend; and (b) lubricating and compressing the blend of step (a) to form monolithic tablets.
  • the method of preparing sustained release dosage form of anti- Alzheimer's agent comprises the steps of:
  • the preparation of the sustained release composition of the present invention is simple and non-demanding with respect to energy and time.
  • the method of preparation and choice of pharmaceutical excipients employed in the compositions of the present invention, described herein, also ensure very good stability and the desired physical properties of the dosage form as well as the required dissolution profile.
  • sustained release compositions of the present invention for the manufacture of a medicament for the treatment of Alzheimer's disease or other dementias.
  • a method of treating Alzheimer's disease or other dementias comprises administering to the subject in need thereof sustained release composition of the present invention.
  • sustained release compositions of the present invention may be adapted to deliver one or more active agents either in an immediate or a sustained release manner in addition to anti-Alzheimer's agent.
  • sustained release compositions of the present invention comprising anti-Alzheimer's agent may be co-administered with compositions of other active agents.
  • the active agent that may be combined with the anti-Alzheimer's agent includes, but is not limited to, pimavanserin, benzoxazinone-derived sulfonamide compounds, rosiglitazone, mirtazapine, mianserin, amantadine, rimantadine, ketamine, eliprodil, ifenprodil, dizocilpine, remacemide, iamotrigine, riluzole, aptiganel, phencyclidine, flupirtine, celfotel, felbamate, neramexane, spermine, spermidine, levemopamil, dextromethorphan or dextrorphan.
  • Example 1 Sustained release tablets of donepezil hydrochloride
  • the sustained release tablets of donepezil hydrochloride were prepared as per the following composition
  • the drug was dry mixed with glyceryl behenate and other excipients except lubricant to get a uniform blend that was lubricated and compressed to form tablets.
  • the sustained release tablets of donepezil was prepared as per the composition is described below
  • Coating solution of table 4 was prepared by melting hydrogenated vegetable oil in water bath and adding glyceryl stearate to it. Hydroxy propyl methyl cellulose was dissolved in water and this aqueous phase was added to oily phase. Talc was added to the emulsion, homogenized well and cooled to room temperature.
  • Drug granules were coated with coating composition using top spray assembly to weight gain of 30 %.
  • the core was formed by mixing the drug with dextrate hydrated and adding it to molten glyceryl monostearate. The resulting mixture was cooled to obtain a granular mass.
  • Donepezil hydrochloride was blended with microcrystalline cellulose and granulated using methacrylic acid copolymer dispersion. The granules formed were further blended with lactose monohydrate and hydrogenated vegetable oil. This final blend was lubricated and compressed into tablets.
  • Methacrylic acid copolymer, Type C, USPNF 62 Methacrylic acid copolymer, Type C, USPNF 62

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Abstract

La présente invention concerne des compositions d'agents anti-Alzheimer à libération prolongée. La présente invention concerne notamment des compositions à libération prolongée comprenant un ou plusieurs d'agents anti-Alzheimer, au moins un agent retardant la libération thermosensible et au moins un polymère gastro-résistant.
PCT/IB2011/002133 2010-09-14 2011-09-14 Compositions d'agents anti-alzheimer à libération prolongée Ceased WO2012035409A1 (fr)

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WO2014132218A1 (fr) * 2013-02-28 2014-09-04 Lupin Limited Compositions pharmaceutiques de donépézil présentant un profil de dissolution in vitro ou des paramètres pharmacocinétiques spécifiques
WO2014132215A1 (fr) * 2013-02-28 2014-09-04 Lupin Limited Compositions pharmaceutiques de donépézil présentant un profil de dissolution in vitro ou des paramètres pharmacocinétiques spécifiques
WO2015037019A3 (fr) * 2013-09-15 2015-06-04 Rubicon Research Private Limited Formulations pharmaceutiques à libération modifiée

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CN1456151A (zh) * 2003-05-27 2003-11-19 解健博 石杉碱缓释制剂的制备方法
US20090220611A1 (en) * 2005-09-30 2009-09-03 Frederic Dargelas Microparticles With Modified Release of At Least One Active Principle and Oral Pharmaceutical Form Comprising Same
CN1861056A (zh) * 2006-06-05 2006-11-15 沈阳药科大学 天麻素缓释制剂
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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014132218A1 (fr) * 2013-02-28 2014-09-04 Lupin Limited Compositions pharmaceutiques de donépézil présentant un profil de dissolution in vitro ou des paramètres pharmacocinétiques spécifiques
WO2014132215A1 (fr) * 2013-02-28 2014-09-04 Lupin Limited Compositions pharmaceutiques de donépézil présentant un profil de dissolution in vitro ou des paramètres pharmacocinétiques spécifiques
US20160015698A1 (en) * 2013-02-28 2016-01-21 Lupin Limited Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
JP2016510021A (ja) * 2013-02-28 2016-04-04 ルピン・リミテッドＬｕｐｉｎ Ｌｉｍｉｔｅｄ 特異的なインビトロ溶出プロファイルまたは薬物動態パラメーターを有するドネペジル医薬組成物
JP2016513133A (ja) * 2013-02-28 2016-05-12 ルピン・リミテッドＬｕｐｉｎ Ｌｉｍｉｔｅｄ 特異的なインビトロ溶出プロファイルまたは薬物動態パラメーターを有するドネペジル医薬組成物
US10278963B2 (en) 2013-02-28 2019-05-07 Lupin Limited Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
AU2018278967B2 (en) * 2013-02-28 2020-07-30 Lupin Limited Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
AU2018282448B2 (en) * 2013-02-28 2020-07-30 Lupin Limited Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
WO2015037019A3 (fr) * 2013-09-15 2015-06-04 Rubicon Research Private Limited Formulations pharmaceutiques à libération modifiée

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