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WO2012129759A1 - Formulations pharmaceutiques orales contenant à la fois des médicaments à libération immédiate et à libération prolongée pour traiter des troubles neurodégénératifs - Google Patents

Formulations pharmaceutiques orales contenant à la fois des médicaments à libération immédiate et à libération prolongée pour traiter des troubles neurodégénératifs Download PDF

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Publication number
WO2012129759A1
WO2012129759A1 PCT/CN2011/072158 CN2011072158W WO2012129759A1 WO 2012129759 A1 WO2012129759 A1 WO 2012129759A1 CN 2011072158 W CN2011072158 W CN 2011072158W WO 2012129759 A1 WO2012129759 A1 WO 2012129759A1
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Prior art keywords
compound
max
formulation
release
sustained
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PCT/CN2011/072158
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English (en)
Inventor
Guang-Tzuu Shane
Chien-Fen Chen
Chuen-Lin Din
Hui-Ling Tsai
Pei-Chen Tsai
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CENTER LABORATORIES Inc
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CENTER LABORATORIES Inc
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Priority to PCT/CN2011/072158 priority Critical patent/WO2012129759A1/fr
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Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K31/33—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
    • 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
    • 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
    • A61P25/26—Psychostimulants, e.g. nicotine, cocaine
    • 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
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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 disclosure in general relates to methods for treating neurodegenerative disorders. More particularly, the disclosure invention relates to methods for treating neurodegenerative disorders with an oral dosage formulation that contains both immediate-release and sustained-release drugs.
  • Neurodegenerative disorders are conditions in which cells of the brain and spinal cord are lost, which may eventually lead to central nervous system (CNS) -related dysfunction, which includes, for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, etc.
  • CNS central nervous system
  • 1-aminocyclohexane derivatives and AChEI are known to cause side effects such as dizziness, headache, fatigue, asthenia, somnolence, chills, insensible sweats, anorexia, gastrointestinal discomfort, nausea, and/or vomiting.
  • side effects such as dizziness, headache, fatigue, asthenia, somnolence, chills, insensible sweats, anorexia, gastrointestinal discomfort, nausea, and/or vomiting.
  • disclosure herein features a novel method useful for treating disorders related to central nervous system (CNS) in a subject, particularly, the human with a CNS disorder such as dementia, Alzheimer's disease, Parkinson's disease, Huntington's disease and the like.
  • CNS central nervous system
  • the present disclosure is directed to methods for treating a patient suffering from a CNS disorder with an oral dosage formulation comprising a sustained-release portion of a first compound and an immediate-release portion of a second compound.
  • the oral dosage formulation may be formulated to meet the steady state blood levels required for the treatment of the CNS disorder while ameliorating the side effects experienced by the patient.
  • the formulation provides an average blood level C max of the first compound in a range of about 10-24 ng/niL during an average T max of about 10-45 hours, and an average blood level C max of the second compound in a range of about 12-38 ng/mL during an average T max of less than about 4 hours.
  • the first compound is memantine, a salt, a solvate, or a mixture thereof and is present in an amount of about 1-80 mg in the formulation
  • the second compound is an acetylcholinesterase inhibitor (AChEI) and is present in an amount of about 1-160 mg in the formulation.
  • the formulation may exhibit an AUC 0 . t of the first compound in a range of about
  • the oral dosage formulation may be administered once a day or once every two days, which is advantageous at least in terms of patient compliance.
  • the sustained-release portion is in the form of pellets having sustained-release films coated thereon, and the immediate-release portion is in the form of granules.
  • the sustained-release portion and the immediate-release portion are mixed with at least one binder and then compressed to form tablets or caplets.
  • the first compound is present in an amount of about 5-60 mg, and the second compound is present in an amount of about 5-30 mg. In some example, the first compound is present in an amount of about 16-24 mg and the second compound is present in an amount of about 8-12 mg. In one specific example, the first compound is present in an amount of about 20 mg and the second compound is present in an amount of about 10 mg.
  • the first compound is memantine. In another specific example, the first compound is memantine hydrochloride.
  • the second compound or AChEI useful for the described purpose is any of galantamine, tacrine, donepezil, rivastigmine, huperzine A, zanapezil, ganstigmine, phenserine, phenethylnorcymserine, cymserine, thiacymserine, SPH 1371, ER 127528, RS 1259, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof.
  • AChEI is donepezil.
  • AChEI is donepezil hydrochloride.
  • the present oral dosage formulation By administering a patient the present oral dosage formulation on a daily (once per day) or bi-daily (once every two days) basis, the course of a treatment for a subject with a CNS disorder such as dementia or Alzheimer's disease is greatly simplified thereby enhancing the patient compliance.
  • the number of tablets the subject required to take daily may be substantially reduce to a significantly low number of one or even less than one, such as half a tablet per day or one tablet for every two days, in accordance with some examples of this disclosure.
  • C max refers to the maximum concentration of an active compound or drug (e.g., memantine or AchEI) in the blood plasma
  • T max means the time to achieve the maximum plasma concentration of said active compound or drug.
  • AUC 0 . t refers to an area under the curve from zero to the last measured time point of a measurable drug concentration.
  • the oral dosage formulation provides an average blood level C max of the first compound in a range of about 10-24 ng/niL during an average T max of about 10-45 hours, and an average blood level C max of the second compound in a range of about 12-38 ng/niL during an average T max of less than about 4 hours.
  • the first compound is memantine, a salt, a solvate, or a mixture thereof and is present in an amount of about 1-80 mg in the formulation
  • the second compound is an acetylcholinesterase inhibitor (AChEI) and is present in an amount of about 1-160 mg in the formulation.
  • the average blood level C max of the first compound is in a range of about 11-22 ng/mL during the average T max of about 12-42 hours, and the average blood level C max of the second compound is in a range of about 14-35 ng/mL during the average T max of less than about 3 hours.
  • the average blood level C max of the first compound is in a range of about 15-20 ng/mL during the average T max of about 20-24 hours, and the average blood level C max of the second compound is in a range of about 18-31 ng/mL during the average T max of less than about 2 hours.
  • the blood level of the active compound is last measured at 156 hours after the ingestion of the oral dosage formulation.
  • the formulation may provide an AUC 0 - t of the first compound in a range of about 1300-1800 ng-h/mL and an AUCo-t of the second compound in a range of about 700-1000 ng-h mL, respectively measured for a period of 156 hrs.
  • Memantine hydrochloride is currently sold under various brand names including EBIXA® and NAMENDA®. For daily dosage containing more than 5 mg of memantine hydrochloride, it is generally advised that the formulation shall be administered twice daily. For example, if the patient is prescribed to take 15 mg of memantine hydrochloride daily, he/she is advised to take a dose of 10 mg in the morning and a dose of 5 mg in the afternoon. According to embodiments of this disclosure, total daily dosage of memantine hydrochloride may be 5, 10, 15 or 20 mg/day.
  • the oral dosage formulation is administered once a day or once every two days according to the present methods.
  • the method according to embodiments of the present disclosure may advantageously simplify the course of the treatment while reduce the occurrence and/or severity of at least one of the side effects.
  • salt refers herein as a salt which is formed by the interaction of a base (such as memantine or donepezil in this disclosure) with an acid, including organic or inorganic types of acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, perchloric acid, methylsulfonic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, pyruvic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, carbonic acid, cinnamic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, cyclohexanesulfamic acid, salicyclic acid, p-aminosalicyclic acid, 2-phenoxy
  • the salt is memantine hydrochloride.
  • the salt is donepezil hydrochloride.
  • solvate herein refers to a complex formed by the interaction of a compound (such as memantine or donepezil in this disclosure) with surrounding solvent molecules, such as water, ethanol, and etc.
  • the solvate of a first compound is a memantine hydrate.
  • acetylcholinesterase inhibitor refers herein to a drug that enhances the functions of cholinergic neurons by inhibiting the activity of acetylcholinesterase (AChE).
  • AChEI useful for the described purpose is any of galantamine, tacrine, donepezil, rivastigmine, huperzine A, zanapezil, ganstigmine, phenserine, phenethylnorcymserine, cymserine, thiacymserine, SPH 1371, ER 127528, RS 1259, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof.
  • Suitable salts of AChEI may be formed by the interaction of any AChEI compound with an acid, such as the acids described above.
  • AChEI is donepezil hydrochloride ((R, S)-l-benzyl-4-[(5, 6-dimethoxy-l-indanone) -2 -yl] -methyl -piperidine hydrochloride).
  • sustained-release herein refers to the release of the therapeutic compound occurs over an extended period of time leading to lower peak plasma concentrations and/or is directed to a prolonged T max as compared with "immediate-release” portion containing the same compound.
  • the sustained-release portion of the dosage formulation is designed to deliver memantine, a salt, or a solvate thereof to the digestive system of a subject continuously over a period of time for at least an hour and preferably more than several hours.
  • the dissolution rate is slow enough that at least about 60% of memantine, a salt or a solvate thereof remains unreleased after two hours and more preferably at least about 70% of memantine, a salt or a solvate thereof remains unreleased after two hours.
  • the memantine, a salt, or a solvate thereof will be at least 80% released within 12 hours, and will be at least 90% released within 24 hours.
  • the memantine, a salt or a solvate thereof in the sustained-release portion of the formulation is retained in a matrix that is composed by at least one polymer that includes, but is not limited to, methylcellulose (MC), ethyl cellulose (EC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), carboxyl methylcellulose (CMC), microcrystalline cellulose, cellulose acetate, cellulose propionate, cellulose acetate propionate, cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, polymethyl methacrylate, polyethyl methacrylate, polyvinyl alcohol, polyvinyl acetate, polyvinyl alcohol-ethylene glycol, carbomer, polyethylene glycol (PEG) and a combination thereof.
  • MC methylcellulose
  • EC ethyl cellulose
  • HPMC hydroxypropyl methylcellulose
  • CMC carboxyl methyl
  • Suitable polymer(s) for producing the matrix are those sold under the trademark that includes, but is not limited to, CELPHERE® CP708, EUDRAGIT®, OPADRY®, ACRYL-EZE®, SURELEASE®, METHOCEL®, ETHOCEL®, or SURETERIC®.
  • the sustained-release (SR) portion may be prepared by mixing memantine, a salt, a solvate, or a mixture thereof with the matrix polymer described above and suitable binders, then directly compressing the mixture into SR tablets.
  • the sustained-release portion may contain sustained-release fine particles or pellets that are produced by any known method such as wet granulation or dry granulation method.
  • the sustained-release fine particles or pellets are produced by wet granulation, particularly, fluid bed granulation.
  • Wet granulation generally involves the steps of mixing the drug, at least one of the matrix polymer as described above and a binder solution; drying the moist granules; and screening through a suitable sieve to produce particles with desired sizes.
  • Useful binders include, but are not limited to, acacia, tragacanth, alginic acid, sodium alginate, carbomer, carboxymethylcellulose sodium, carrageenan, cellulose acetate phthalate, ceratonia, copovidone, dextrates, dextrin, dextrose, methylcellulose, ethylcellulose, carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hydroxypropyl starch; hypromellose, gelatin, starch, sucrose, lactose, magnesium aluminum silicate, maltodextrin, maltose, microcrystalline cellulose, polyvinyl pyrrolidone, polyacrylamide, povidone and pregelatinized starch.
  • the sustained-release portion is prepared by mixing memantine, a salt, a solvate or a mixture thereof with a sugar sphere made of microcrystalhne cellulose (e.g., CELPHERE® CP708), and at least one other matrix polymer as described above, to form granules or pellets that contain memantine. Then, each of the memantine containing granules or pellets is coated with a sustained-release film to produce the sustained-release portion or the SR portion.
  • the sustained-release film contains at least a matrix polymer described above (e.g., EUDRAGIT® NE30D and HPMC), and a diluent (e.g., talc). In other examples, the sustained-release film contains at least EUDRAGIT® NE30D, SURELEASE®, HPMC, and titanium dioxides.
  • Other useful diluents include, but are not limited to, ammonium alginate, calcium carbonate, calcium phosphate dibasic, calcium phosphate tribasic, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol; ethylcellulose, fructose, fumaric acid, glyceryl palmitostearate, lactitol, lactose, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, microcrystalline cellulose, polydextrose, polymethacrylates, sodium chloride, sorbitol, starch, sucrose, sugar spheres, ARBOCEL A300®; LUDIPRESS®; and SUPER TAB®.
  • the SR portion (such as the SR tablets, SR pellets and the SR granules) may be further coated with a protective coating to delay the release of the active ingredient therein.
  • the protective coating may comprise at least one of the matrix polymers as described above.
  • the protective coating comprises hydroxymethyl cellulose and polyethylene glycol (PEG).
  • the protective coating comprises triethyl citrate (TEC) and talc.
  • the SR coating and the protective coating may be applied as a film respectively deposited over the sustained-release pellets and the sustained-release portion, by any known techniques such as spraying, dipping, or pan-coating.
  • the immediate-release portion of the dosage formulation is designed to rapidly disintegrate upon contacting a fluid such as water and allow fast leaching out of AChEI to the environment continuously over a short period of time, such as several minutes or in an hour.
  • the dissolution rate is fast enough that at least 80% of AChEI is released within the first 60 minutes. In general, at least 90% of AChEI will be released within 2 hours.
  • the AChEI in the immediate-release portion is in a form of an immediate-release particle or granule which could be mixed with the SR portion (such as the SR pellets and SR granules) and at least one binder, and then compressed into tablets or caplets.
  • the AChEI may be applied as a thin film deposited over the outer surface of the sustained release portion (such as the SR tablets).
  • the oral dosage formulation could be a tablet constructed in two or more layers with at least one layer being the IR portion while one of the other layers thereof being the SR portion.
  • the immediate-release particles may be produced by any known method, such as dry or wet granulation method as described above.
  • AChEI is mixed with disintegrants and/or binders, and adsorbents and then the mixture is subjected to either fluid bed granulation or spray drying to produce particles with desired immediate-release property.
  • disintegrants include, but are not limited to, cross-linked polyvinyl pyrrolidone or crospovidone, starch derivatives such as carboxymethyl cellulose and cellulose derivatives; calcium alginate; carboxymethylcellulose calcium; carboxymethylcellulose sodium; croscarmellose sodium; docusate sodium; hydroxypropyl cellulose; magnesium aluminum silicate; methylcellulose; polacrilin potassium; sodium alginate; sodium starch glycolate and pregelatinized starch.
  • starch derivatives such as carboxymethyl cellulose and cellulose derivatives
  • calcium alginate carboxymethylcellulose calcium; carboxymethylcellulose sodium; croscarmellose sodium; docusate sodium; hydroxypropyl cellulose; magnesium aluminum silicate; methylcellulose; polacrilin potassium; sodium alginate; sodium starch glycolate and pregelatinized starch.
  • adsorbents include, but are not limited to, aluminum hydroxide adjuvant; aluminum oxide; aluminum phosphate adjuvant; attapulgite; bentonite; powdered cellulose; colloidal silicon dioxide; hectorite; kaolin; magnesium aluminum silicate; magnesium carbonate; microcrystalline cellulose; pectin; polycarbophil; and saponite.
  • At least 50% of the immediate-release particles thus prepared have a size that may pass an 80-mesh sieve; preferably, a 60-mesh sieve; more preferably, a 40-mesh sieve; and most preferably, a 20-mesh sieve.
  • the sustained-release portion and the immediate-release portion respectively prepared by steps as described above are combined with binders (such as those described above) and lubricants to form the oral dosage formulation of this disclosure.
  • Suitable lubricants include, but are not limited to, calcium stearate; glyceryl behenate; glyceryl palmitostearate; magnesium lauryl sulfate; magnesium stearate; polyethylene glycol; potassium benzoate; sodium lauryl sulfate; sodium stearyl fumarate; stearic acid; talc and zinc stearate.
  • the dosage formulation may also contain at least one suitable glidant; examples of which include, but are not limited to, calcium phosphate, tribasic; calcium silicate; cellulose, powdered; colloidal silicon dioxide; magnesium silicate; magnesium trisilicate; silicon dioxide; starch and talc. Still optionally, the dosage formulation may additionally contain suitable pigments such as titanium dioxide.
  • suitable glidant examples of which include, but are not limited to, calcium phosphate, tribasic; calcium silicate; cellulose, powdered; colloidal silicon dioxide; magnesium silicate; magnesium trisilicate; silicon dioxide; starch and talc.
  • the dosage formulation may additionally contain suitable pigments such as titanium dioxide.
  • the oral dosage formulation of this disclosure may be in a form of tablets, caplets, bi-layer tablets, film-coated tablets, pills, capsules, or the like. Tablets in accordance with this disclosure can be prepared by any mixing and tabletting techniques that are well known in the pharmaceutical formulation industry.
  • the dosage formulation is fabricated by direct compressing the respectively prepared sustained-release portion and the immediate-release portion by punches and dies fitted to a rotary tabletting press, ejection or compression molding or granulation followed by compression.
  • the dosage form is a single layer tablet containing therein both the sustained-release and the immediate-release portions.
  • the dosage form is a tablet containing two layers, with one layer being the immediate-release portion and the other layer being the sustained-release portion.
  • the dosage form is a film-coated tablet having a sustained-release portion and a thin film of the immediate-release portion deposited over the outer surface of the sustained-release portion.
  • the immediate-release portion may be applied as a coating over the sustained-release portion by any known techniques such as spraying, dipping, or pan-coating, or as an additional layer by tabletting or compressing in the same manner as the sustained-release portion.
  • the tablet is a scoring tablet having a score line at the center of the tablet for breaking the tablet into two equal halves when necessary.
  • the oral dosage formulation is in a form of capsule containing therein both the sustained-release particles or pellets of the first compound (i.e., memantine, a salt, a solvate, or a mixture thereof) and the immediate-release particles or pellets of the second compound (i.e., AChEI, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof).
  • the sustained-release particles or pellets of the first compound i.e., memantine, a salt, a solvate, or a mixture thereof
  • the immediate-release particles or pellets of the second compound i.e., AChEI, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof.
  • SR portions e.g., SR pellets, in which each pellet contains a SR film coated thereon
  • IR granules are mixed with polyvinyl pyrrolidone (PVRPXL-10®) and magnesium stearate, and then the mixture is compressed to obtain a single layer tablet containing therein both the sustained-release and the immediate-release portions.
  • PVRPXL-10® polyvinyl pyrrolidone
  • the oral dosage formulations described herein are administered to a patient at therapeutically effective doses, preferably, with minimal toxicity.
  • Specific examples of the oral dosage formulation of this disclosure include about 1-80 mg of memantine, a salt, a solvate or a mixture thereof, such as 5-60 mg, or 16-24 mg of memantine, a solvate or a mixture thereof; and about 1-160 mg of AChEI, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof, such as 5-30 mg, or 8-12 mg of AChEI, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof.
  • memantine, a solvate or a mixture thereof is present in an amount of about 20 mg/dosage formulation
  • AChEI, a salt or a solvate thereof, an enantiomer thereof, a salt or a solvate of the enantiomer or a mixture thereof is present in an amount of about 10 mg/dosage formulation.
  • the sustained-release (SR) portion and the immediate-release (IR) portion were separately produced in accordance with steps and conditions described in examples 1.1 and 1.2.
  • the tablet containing both the IR and SR portions (or the IR/SR Tablet), was subsequently made by compressing the IR and SR portions together in accordance with the conditions set forth in Examples 1.3 and 1.4.
  • the SR portion was produced by forming a memantine pellet first; then followed by coating the thus made memantine pellet with a sustained release film (i.e., SR film) outside each pellet.
  • the memantine pellets were produced by mixing the ingredients listed in the SR pellet formulation in Table 1 in a fluid bed machine under processing parameters set as follows:
  • SR-coating formulation- 1 and SR-coating formulation-2 respectively listed in Table 1 and Table 2, and thereby producing SR portions 1 and 2.
  • the processing parameters for coating SR-coating formulation- 1 and SR-coating formulation-2 respectively onto the memantine pellets to form the respective SR portions are respectively set as follows:
  • the IR portions were prepared by mixing the ingredients listed in the IR granule formulation in Table 1 or 2 in accordance with steps as described below. Briefly, donepezil and microcrystalline cellulose (i.e., MCC KG802) were mixed in equal amount to form a mixture that passed an 80-mesh sieve. Then, the remaining microcrystalline cellulose, other excipient(s) including non-soluble pregelatinized starch (i.e., PC-10) were added thereto, followed by the addition of water to form wet granule that passed a 20-mesh sieve. The granules were subsequently dried at 50°C for 3 hours.
  • CELPHERE® CP305 300-500 ⁇
  • MCC CEOLUS® KG802 were purchased from Asahi Kasei Chemicals Corporation, (Tokyo, Japan)
  • EUDRAIGIT® NE30D was purchased from Evonik Rohm GmbH (Darmstadt, Germany).
  • HPMC hydroxypropyl methyl cellulose
  • PEG 400 polyethylene glycol 400
  • MCC microcrystalline cellulose
  • PVPP XL- 10 polyvinyl polypyrrolidone, Copovidone
  • IR/SR tablet-2 were produced in accordance with similar steps described in Example 1.3, except SR portion 2 of example 1.1 was used in this example; and tablets (about 310 mg) having a hardness of 5-6 Kg were produced.
  • the unit dose formulation of IR/SR tablet-2 is given in Table 2.
  • CELPHERE® CP305 300-500 ⁇
  • MCC CEOLUS® KG802 were purchased from Asahi Kasei Chemicals Corporation, (Tokyo, Japan)
  • EUDRAIGIT® NE30D was purchased from Evonik Rohm GmbH (Darmstadt, Germany).
  • SURELEASE® aqueous ethylcellulose dispersion
  • HPMC hydroxypropyl methyl cellulose
  • PEG 400 polyethylene glycol 400
  • MCC microcrystalline cellulose
  • PVPP XL-10 polyvinyl polypyrrolidone, Copovidone
  • Tablet-1 5 kg Tablet-1, 6 kg Tablet-1, 8 kg Tablet-2 Mean Diss, Mean Diss, Mean Diss,
  • Tablet-1 5 kg Tablet-1, 6 kg Tablet-1, 8 kg Tablet-2
  • IR/SR tablets- 1 having a hardness of 5 and 6 kg the data in Table 4 demonstrated about 40% of memantine was released after contacting simulated gastric condition for 2 hours, and over 90% of memantine were released after 6 hours. In contrast, for IR/SR tablet having a hardness of 8 kg, about 70% of memantine was released after 2 hours. As to IR/SR tablet-2, more than about 70% of memantine remained in the SR coating after 2 hours, and over 90% of memantine were released after 12 hours.
  • the compression pressure used for manufacturing the IR/SR tablet may affect the release behavior of memantine. As such, it is preferable in some embodiments that the compression pressure remained lower than 8 kg.
  • Pilot PK study was carried out in Chinese subjects, each receiving a single-dose medication, either positive control formulation or the respective IR/SR formulations of Example 1.3 and 1.4; PK properties of memantine and donepezil in each test subjects were then measured and recorded, as well as incidences and severities of undesirable side effects associated therewith.
  • Age 18-40 years old, and the age differences among subjects in the same study group is less than 10;
  • Physical condition without prior histories of any heart, liver, kidney, gastrointestinal (GI) tract, neurologic, mental, or metabolism disorders; tested normal in physical examination, which includes electrocardiogram, blood pressure, heart rate, and respiratory pattern examination; and routine laboratory examination, which includes urine, blood, liver function, and kidney tests.
  • GI gastrointestinal
  • the enrolled subjects have not taken any drugs for at least two weeks prior to the administration of the first dose of study drug, which is either the IR/SR formulation of this disclosure or the control formulation; and are forbidden from ingestion of any tobacco- or nicotine-containing products, alcohol- and caffeine-containing beverages of foods and juices during the course of the study
  • Exclusion Criteria • History and/or physical findings of cardiac disorders, including bradycardia, conduction disturbance, sinus node syndrome, heart failure, hypertension, cardionosis, etc.
  • the enrolled subjects were randomly allocated to three groups according to a computer-generated randomization schedule.
  • Each subjects in Group 1 receive a positive control medicine (i.e., the immediate-release formulation of memantine and donepezil); whereas each subjects in Groups 2 and 3 respectively receive the IR/SR tablet- 1 of Example 1.3 and IR/SR tablet-2 of Example 1.4. All subjects were required to fast for at least 10 hours prior to the administration of the medication so as to avoid any effects that might have been caused by food intake on the PK properties.
  • Two subjects did not complete this study; specifically, subject No. 1 withdrew due to severe adverse responses to the administered medication, and subject No. 18 withdrew before the commencement of this study.
  • EBIXA® containing 10 mg of memantine HC1, from Lundbeck
  • ARICEPT® containing 10 mg of donepezil HC1, from Eisai
  • IR/SR tablet- 1 of Example 1.3 and IR/SR tablet-2 of Example 1.4 were orally administered to each subjects in Groups 2 and 3, respectively.
  • Blood samples were drawn from each subject at pre-designated time points and plasma concentrations of memantine and donepezil were determined by HPLC-MS/MS.
  • PK properties including maximal plasma concentration (0 ⁇ 3 ⁇ ), time to reach the peak concentration (T max ), time required for the plasma drug concentration to decrease by one half (T 1 2 ), apparent first order elimination or terminal rate constant (K or K d ), the area under the plasma concentration verses time curve from zero to the last measured time point (AUC 0 . t ), and the area under the plasma concentration verses time curve from zero to infinity (AUC 0- ⁇ ) were assessed immediately before (0 hour) and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 24, 36, 60, 84, 108, and 156 hours after drug administration. Blood samples were collected at two extra time points, i.e., 12.5 and 20 hrs, respectively for subjects in Group 1.
  • C max and T max were obtained directly by the visual inspection of each subjects' plasma concentration-time profile.
  • the slope of the terminal log-linear portion of the concentration-time profile was determined by least-squares regression analysis and used as the elimination rate constant (K).
  • the AUC 0 . t from time zero to the last measured time point i.e., 156 hours after the initial administration
  • AUC 0 - ⁇ the extrapolated AUC from the last measured time point to infinity
  • C t the elimination rate constant.
  • the area under the plasma concentration-time from zero to infinity (AUC 0 - ⁇ ) was calculated as the sum of the AUC 0 . t plus the ratio of C/K.
  • Subject no. 1 did not take the second dose of EBIXA® (10 mg) due to severe side effects; hence, the data of subject no. 1 regarding PK properties of memantine is excluded.
  • the T max of memantine derived from Group 1 is statistically different from that derived from both Groups 2 and 3. It is inferred that the reduced maximal plasma concentration in connection with the extended time to reach the peak concentration may be advantageous in ameliorating the undesired side effects.
  • PK properties of donepezil do not differ significantly among the three groups. Assuming that the data distribution is approximately normal, then about 68% of the data values are within one standard deviation of the mean (mathematically, ⁇ ⁇ ⁇ , where ⁇ is the arithmetic mean and ⁇ is one standard deviation).
  • the " ⁇ ⁇ ⁇ " of C max of donepezil derived from Groups 1, 2 and 3 subjects are respectively 21.25 ⁇ 5.52 (15.73-26.77), 24.37 ⁇ 4.37 (20-28.74) and 18.36 ⁇ 2.45 (15.91-20.81), and these ranges substantially overlap with one another indicating that at least the PK properties for the immediate-release portion of the IR/SR formulation of this invention is comparable to the control medicine, which is also a fast-release formulation.
  • the AUC 0 - t and AUC 0 - ⁇ of donepezil in these three groups are also comparable to one another.

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Abstract

La présente invention concerne des formulations pharmaceutiques orales contenant à la fois des médicaments à libération immédiate et à libération prolongée pour traiter des patients souffrant de troubles du système nerveux central. Ledit médicament à libération prolongée est la mémantine et le médicament à libération immédiate est un inhibiteur d'acétylcholinestérase (AChEL), de préférence, le chlorhydrate de donépézil.
PCT/CN2011/072158 2011-03-25 2011-03-25 Formulations pharmaceutiques orales contenant à la fois des médicaments à libération immédiate et à libération prolongée pour traiter des troubles neurodégénératifs Ceased WO2012129759A1 (fr)

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CN109381431A (zh) * 2017-08-10 2019-02-26 广州中大南沙科技创新产业园有限公司 石杉碱甲缓释微丸及其制备方法
CN112804992A (zh) * 2018-11-19 2021-05-14 苏佩努斯制药公司 较高剂量的改良释放石杉碱制剂的用途
US12311060B2 (en) 2017-05-19 2025-05-27 Biscayne Neurotherapeutics, Inc. Modified release pharmaceutical compositions of huperzine and methods of using the same

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CN101166543A (zh) * 2005-04-28 2008-04-23 卫材R&D管理有限公司 含抗痴呆药物的组合物
US20110006408A1 (en) * 2009-07-13 2011-01-13 Advanced Semiconductor Engineering, Inc. Chip package and manufacturing method thereof

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CN101166543A (zh) * 2005-04-28 2008-04-23 卫材R&D管理有限公司 含抗痴呆药物的组合物
US20110006408A1 (en) * 2009-07-13 2011-01-13 Advanced Semiconductor Engineering, Inc. Chip package and manufacturing method thereof

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12311060B2 (en) 2017-05-19 2025-05-27 Biscayne Neurotherapeutics, Inc. Modified release pharmaceutical compositions of huperzine and methods of using the same
CN109381431A (zh) * 2017-08-10 2019-02-26 广州中大南沙科技创新产业园有限公司 石杉碱甲缓释微丸及其制备方法
CN109381431B (zh) * 2017-08-10 2020-11-13 广州中大南沙科技创新产业园有限公司 石杉碱甲缓释微丸及其制备方法
CN112804992A (zh) * 2018-11-19 2021-05-14 苏佩努斯制药公司 较高剂量的改良释放石杉碱制剂的用途
US11351120B2 (en) * 2018-11-19 2022-06-07 Supernus Pharmaceuticals, Inc. Use of higher doses of modified release huperzine formulations
US20230090653A1 (en) * 2018-11-19 2023-03-23 Supernus Pharmaceuticals, Inc. Use of higher doses of modified release huperzine formulations

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