EP1729740A2 - FORMES GALENIQUES PHARMACEUTIQUES A LIBERATION IMMEDIATE ET/OU CONTROLEE RENFERMANT UN AGONISTE DU RECEPTEUR GABA<SB>B</SB> - Google Patents

FORMES GALENIQUES PHARMACEUTIQUES A LIBERATION IMMEDIATE ET/OU CONTROLEE RENFERMANT UN AGONISTE DU RECEPTEUR GABA<SB>B</SB>

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Publication number
EP1729740A2
EP1729740A2 EP05733181A EP05733181A EP1729740A2 EP 1729740 A2 EP1729740 A2 EP 1729740A2 EP 05733181 A EP05733181 A EP 05733181A EP 05733181 A EP05733181 A EP 05733181A EP 1729740 A2 EP1729740 A2 EP 1729740A2
Authority
EP
European Patent Office
Prior art keywords
dosage form
gaba
pharmaceutical dosage
agonist
hours
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP05733181A
Other languages
German (de)
English (en)
Inventor
Chien-Hsuan Han
Ann Hsu
Larry Hsu
Charles Hsiao
Ching-Ling Diana Teng
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Impax Laboratories LLC
Original Assignee
Impax Laboratories LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US10/815,929 external-priority patent/US20050220864A1/en
Priority claimed from US10/815,930 external-priority patent/US20050220874A1/en
Priority claimed from US10/815,926 external-priority patent/US20050220873A1/en
Priority claimed from US10/815,924 external-priority patent/US20050220863A1/en
Application filed by Impax Laboratories LLC filed Critical Impax Laboratories LLC
Publication of EP1729740A2 publication Critical patent/EP1729740A2/fr
Withdrawn legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of 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
    • A61K9/48—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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078—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 having two or more different coatings optionally including drug-containing subcoatings with drug-free core
    • 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
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • 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
    • A61K9/5073—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 having two or more different coatings optionally including drug-containing subcoatings

Definitions

  • the present invention relates generally to pharmaceutical dosage forms having immediate release and controlled release properties that contain a ⁇ -aminobutyric acid (GABA B ) receptor agonist, e.g., baclofen, for the treatment of medical conditions, which include spasms, cramping, tightness of muscles, or spasticity associated with ailments such as multiple sclerosis, spinal cord diseases or certain spinal injuries.
  • GABA B ⁇ -aminobutyric acid
  • baclofen ⁇ -aminobutyric acid
  • the GABA B agonist baclofen can be used to treat these symptoms.
  • Baclofen can also facilitate adjunct medical treatment, such as physical therapy, to improve the condition of a patient with multiple sclerosis or certain spinal injuries. Baclofen is also used to reduce the number and severity of attacks of trigeminal neuralgia in patients who are not able to tolerate, or who have become refractory to, the effects of carbamazepine. Baclofen, or 4-amino-3-(4-chlorophenyl)-butanoic acid, is a muscle relaxant and antispastic. Its mechanism of action appears unclear.
  • Baclofen seems capable of inhibiting both monosynaptic and polysynaptic reflexes at the spinal level, possibly by hyperpolarization of afferent terminals, although actions at supraspinal sites may also occur and contribute to its clinical effect.
  • baclofen has been shown to have general central nervous system (CNS) depressant properties as indicated by the production of sedation with tolerance, somnolence, ataxia, and respiratory and cardiovascular depression.
  • CNS central nervous system
  • the absorption of baclofen is site specific. Baclofen is primarily absorbed in the upper gastrointestinal (Gl) tract, with the extent of absorption of baclofen substantially reduced in the lower Gl tract. Baclofen is rapidly and extensively absorbed.
  • Absorption may be dose- dependent, being reduced with increasing doses.
  • An improved method of administering baclofen to a patient would include the delivery of effective amounts of the drug to the upper Gl tract for an extended period.
  • side effects are possibly associated with the administration of baclofen to mammals. These problems include nausea, vomiting, diarrhea, dizziness, daytime sedation, and less frequently, psychotic states such as depressive mood disorder.
  • patient compliance with a dosing regimen can be suboptimal where frequent doses are required, such as the need for administering a dosage form three or four times a day.
  • baclofen pharmaceutical formulations including Baclofen Tablet, 10/20 mg (Watson Pharmaceuticals, Inc., Corona, CA) and the orally disintegrating tablet marketed as KEMSTROTM (Schwarz Pharma, Monheim, Germany), are marketed commercially, but do not provide controlled release of baclofen. For example, following a single 20 mg oral dose of KEMSTROTM, the peak plasma concentration is reached about l f- hours after administration. Baclofen has a serum half-life of 2.5 to 4 hours.
  • the present invention relates generally to pharmaceutical dosage forms having controlled release properties that contain a GABA B receptor agonist, such as baclofen. These dosage forms can be used in the treatment of medical conditions, lik& spasms, cramping, and tightness of muscles, which are associated with ailments such as multiple sclerosis or certain spinal injuries.
  • the pharmaceutical dosage forms of the present invention may involve a controlled release dosage form, where the controlled release dosage f-orm includes a GABA B agonist and a pharmaceutically acceptable excipient, and the dosage form exhibits an in vitro dissolution profile in simulated intestinal fluid medium comprising lesss than about 70% GABA B agonist release after 1 hour, at least about 20% GABA B agonist release after 4 hours, and at least about 30% GABA B agonist release after 6 hours.
  • the controlled release dosage form exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (1 hour switchover) medium comprising less than about 80% GABA B agonist release after 1 hour, at least about 30% GABA B agonist release after 4 hours, and at least about 40% GABA B agonist release after 6 hours.
  • the controlled release dosage form including the GABA B agonist and pharmaceutically acceptable excipient exhibits an in vitro dissolution profile in simulated intestinal fluid medium comprising less than about 50% G-ABA B agonist release after 1 hour, at least about 40% GABA B agonist release after 4 hours, and at least about 50% GABA B agonist release after 6 hours.
  • the controlled-release GABA B agonist dosage form is combined with an immediate release GABA B agonist component.
  • the immediate release component exhibits an in vitro dissolution profile Ln simulated gastric fluid comprising at least about 80% GABA B agonist release after 1 hour.
  • the ratio of the immediate-release component to the controlled-release component will be from about 1:10 to about 10:1, preferably from about 1:4 to about 4:1, more preferably from about 1:3 to about 3:1, and most preferably from about 1:2 to about 2:1.
  • the pharmaceutical dosage forms of the present invention contain an enteric-coated controlled release component, where the enteric-coated controlled release component includes a GABA B agonist and a pharmaceutically acceptable excipient, and the enteric-coated controlled release component exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) maxim_m comprising less than about 10% GABA B agonist release after 2 hours, at least about 40% GABA B agonist release after 3 hours, and at least about 70% GABA B agonist release after S hours.
  • the enteric-coated controlled release component exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 10% GABA B agonist release after 2 hours, at least about 50% GABA B agonist release after 3 hours, and at least about 80% GABA B agonist release after 6.
  • the enteric-coated controlled release component exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hoxir switchover) medium comprising less than about 10% GABA B agonist release after 2 hoxirs, at least about 60% GABA B agonist release after 3 hours, and at least about 90% GABA B agonist release after 6 hours.
  • the dosage form also contains an immediate release component, in combination with the enteric-coated controlled release component.
  • the GABA B agonist may be formulated as a combination of immediate-release beads and controlled-release beads, compressed into a tablet or contained in a capsule dosage form.
  • the ratio of the immediate-release component to the controlled-release component will be from about 1:10 to about 10:1, preferably from about 1:4 to about 4:1, more preferably from about 1:3 to about 3:1, and most preferably from about 1:2 to about 2: 1.
  • the present invention includes pharmaceutical dosage forms having both immediate release and extended release properties.
  • the pharmaceutical dosage form comprising a GABA B agonist and a pharmaceutically acceptable excipient exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 75% GABA B agonist release after 2 hours, and at least about 80% GABA B agonist release after 3 hours.
  • the pharmaceutical dosage form exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 65% GABA B agonist release after- 2 hours, and at least about 90% GABA B agonist release after 3 hours
  • the pharmaceutical dosage forms of the present invention are adapted to be administered twice daily in patients requiring chronic baclofen therapy. As such, the in.
  • vivo absorption is prolonged as compared to immediate release baclofen formulations, such that the median time period at which at least 80% of said baclofen is absorbed, in vivo, under fasting conditions, is greater than 2.5 hours.
  • the dosage forms of the present invention will typically exhibit an in vivo plasma profile comprising mean maximum baclofen levels CG m a ⁇ ) from about 30 minutes to about 7 hours after administration to a fasting patient, often between 2.5 and 5.5 hours after administration.
  • Figure 1 A is a graph of the in vitro dissolution profile of a baclofen tablet formulation, 20 mg, prepared according to Example 8, according to measurements under the USP paddle method of 50 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37°C.
  • Figure IB is a graph of the in vitro dissolution profile of a baclofen tablet formulation, 20 mg, prepared according to Example 11, according to measurements under the USP paddle method of 50 rpm in 900 ml simulated intestinal fluid (pH 6.8) at 37°C.
  • Figure 2 is a graph of the in vitro dissolution profiles of baclofen tablet formulations, 20 mg, prepared according to Example 11, according to measurements under the USP paddle method of 50 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37°C for 1 hour with a switchover to simulated intestinal fluid (pH 6.8).
  • Figure 3 is a graph of the in vitro dissolution profile of a baclofen capsule formulation, 20 mg, prepared according to Example 2, according to measurements under the USP paddle method of 75 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37°C.
  • Figure 4 is a graph of the in vitro dissolution profiles of baclofen capsule formulations, 20 mg, prepared according to Example 12, according to measurements under the USP paddle method of 75 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37°C for 2 hours with a switchover to simulated intestinal fluid (pH 6.8).
  • Figure 5 is a graph of the in vitro dissolution profiles of baclofen capsule formulations, 30 mg, prepared according to Examples 13 and 14, according to measurements under the USP paddle method of 75 rpm in 900 ml simulated gastric fluid (pH 1.2) at 37°C for 2 hours with a switchover to simulated intestinal fluid (pH 6.8).
  • Figure 6 is a graph of the in vivo plasma profiles of baclofen tablet formulations, determined as described in Example 16.
  • Figure 7 is a graph simulating steady-state baclofen plasma levels determined as described in Example 17, where (C) represents the 40 mg dosage form of the present invention and (D) represents the reference 20 mg immediate-release dosage form.
  • the present invention relates to pharmaceutical dosage forms comprising a controlled-release GABA B agonist (preferably baclofen, a baclofen prodrug, a baclofen analog, or a mixture thereof, as well as a racemic baclofen mixture or a substantially pure L- baclofen enantiomeric product) formulation.
  • the controlled-release GABA B agonist formulation may be in the form of an enteric-coated controlled-release formulation.
  • the controlled-release GABA B agonist formulations, including enteric-coated controlled-release formulations may be combined with immediate release GABA B agonist formulations in the final pharmaceutical dosage forms.
  • the formulations of the present invention allow for less frequent dosing as compare to existing immediate release formulations. For example, for patients requiring chronic GABA B agonist therapy, twice daily administration of the formulations of the present invention is bioequivalent to three times daily administration of an existing immediate release formulation. This reduced dosing frequency is more convenient for patients, and typically leads to better patient compliance. In addition, it reduces the number of plasma peaks and troughs, which is typically associated with improved efficacy and reduced side effects.
  • the singular forms "a,” “an,” and “the” include the plural reference unless the context clearly indicates otherwise. Thus, for example, the reference to a profile is a reference to one or more such profiles, including equivalents thereof known to those skilled in the art.
  • the baclofen also known as butanoic acid or 4-amino-3-(4-chlorophenyl) butanoic acid
  • the baclofen includes racemic baclofen, enantiomerically pure L-baclofen, and analogs, derivatives, prodrugs, metabolites thereof, and any pharmaceutically acceptable salts thereof.
  • Baclofen is a GABA B receptor agonist, and thus other GABA B receptor agonists are envisioned within the scope of the invention.
  • A 4-aminobutanoic acid
  • 3-aminopropyl)methylphosphinic acid 4-amino-3-phenylbutanoic acid; 4-amino-3- hydroxybutanoic acid; 4-amino-3-(4-chlorophenyl)-3-hydroxyphenylbutanoic acid; 4-amino- 3-(thien-2-yl)butanoic acid; 4-amino-3-(5-chlorothien-2-yl)butanoic acid; 4-amino-3-(5- bromothien-2-yl)butanoic acid; 4-amino-3-(5-methylthien-2-yl)butanoic acid; 4-amino-3-(2- imidazolyl)butanoic acid; 4-guanidino-3-(4-chlorophenyl)butanoic acid; 3-amino-2-(4- chlorophenyl)-l-nitropropane; (3-aminopropyl)methylphos
  • analog means a compound which comprises a chemically modified form of a specific compound or class thereof, and which maintains the pharmaceutical and/or pharmacological activities characteristic of said compound or class.
  • baclofen analogs include 3-thienyl- and 3-furylaminobutyric acids.
  • derivative means a chemically modified compound wherein the modification is considered routine by the ordinary skilled chemist, such as an ester or an amide of an acid, protecting groups, such as a benzyl group for an alcohol or thiol, and tert- butoxycarbonyl group for an amine.
  • prodrug includes any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a patient. Because prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (i.e., solubility, bioavailability, manufacturing, etc.) the compounds of the present invention may be delivered in prodrug form. Prodrugs of the present invention may be prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound.
  • the transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
  • Prodrugs within the scope of the present invention include compounds wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively.
  • Functional groups that may be rapidly transformed, by metabolic cleavage, in vivo form a class of groups reactive with the carboxyl group of the compounds of this invention.
  • alkanoyl such as acetyl, propionyl, butyryl, and the like
  • unsubstituted and substitoted aroyl such as benzoyl and substitoted benzoyl
  • alkoxycarbonyl such as ethoxycarbonyl
  • trialkysilyl such as trimethyl- and triethysilyl
  • monoesters formed with dicarboxylic acids such as succinyl
  • the compounds bearing the metabolically cleavable groups have the advantage that they may exhibit improved bioavailability as a result of enhanced solubility and/or rate of absorption conferred upon the parent compound by virtue of the presence of the metabolically cleavable group.
  • a discussion of prodrugs is provided in the following: DESIGN OF PRODRUGS, H. Bundgaard, ed. (Elsevier, 1985); METHODS IN ENZYMOLOGY, K. Widder etal, eds., vol. 42, 309-96 (Academic Press 1985); A TEXTBOOK OF DRUG DESIGN AND DEVELOPMENT, Krogsgaard-Larsen & H.
  • Bundgaard ed., Chapter 5; Design and Applications of Prodrugs, 113-91 (1991); H. Bundgard, Advanced Drug Delivery Reviews, 1-38 (1992); 8 J. PHARM. SCIENCES 285 (1988); N. Nakeya et al, 32 CHEM. PHARM. BULL. 692 (1984); T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, 14 A.C.S. SYMPOSIUM SERIES: BIOREVERSIBLE CARRIERS IN DRUG DESIGN, Edward B. Roche, ed. (Am. Pharm. Assoc. & Pergamon Press 1987), each of which is incorporated herein by reference.
  • the present invention contemplates the use of prodrugs of GABA B receptor agonists (including baclofen), methods of delivering the same, and compositions containing the same.
  • GABA B receptor agonists including baclofen
  • baclofen prodrugs have been described in Leisen et al, Lipophilicities of Baclofen Ester Prodrugs Correlate with Affinities to the ATP -dependent Efflux Pump P-glycoprotein, 20 PHARM. RES. 772-78 (2003).
  • metabolite refers to a form of a compound obtained in a human or animal body by action of the body on the administered form of the compound, for example a de- methylated analog of a compound bearing a methyl group which is obtained in the body after administration of the methylated compound as a result of action by the body on the methylated compound. Metabolites may themselves have biological activity.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the specified compound is converted to an acid or base salt thereof.
  • Such pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluensulfonic, methanesulfonic, ethane dislfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, mal
  • controlled release refers to part or all of a dosage form that can release one or more active pharmaceutical agents over a prolonged period of time (i.e., over a period of more than 1 hour), or delays the release of active agent for a prolonged period of time.
  • the characteristic of controlled release (CR) may also be referred to as sustained release (SR), prolonged release (PR), modified release (MR), delayed release (DR) or extended release (ER).
  • sustained release SR
  • PR prolonged release
  • MR modified release
  • DR delayed release
  • extended release ER
  • controlled release refers to that portion of a dosage form according to the present invention that delivers active agent over a period of time greater than 1 hour.
  • immediate release refers to part or all of a dosage form that releases active agent substantially immediately upon contact with gastric juices and that results in substantially complete dissolution within about 1 hour.
  • the characteristic of immediate release (IR) may also be referred to as instant release (IR).
  • immediate release refers to that portion of a dosage form according to the present invention that delivers active agent over a period of time less than 1 hour.
  • C M A X is the peak blood plasma concentration exhibited by the compositions of the present invention.
  • T A X refers to the time that CM AX occurs in the plasma concentration-time profile.
  • C MIN is the minimum plasma concentration.
  • C is shorthand for concentration, "T” for time, “max” for maximum, and “min” for minimum.
  • Initial peak plasma level refers to the first rise in blood plasma level of the active agent and may be followed by one or more additional peaks, one of which may be CMA X -
  • “mean maximum GABA B agonist level” refers to the mean GABA B agonist C MAX -
  • the blood plasma concentrations described herein are typically determined across a population of at least 12 subjects.
  • the blood plasma concentrations described above may refer to plasma levels after a single oral administration of the dosage form, or may refer to levels obtained at steady state.
  • steady state blood plasma concentrations refers to the plasma levels obtained upon the repeated dosing of a drug until it reaches a stable level of absorption and elimination such that the amount of drug in the body is substantially constant.
  • patient means any mammal including humans.
  • effective amount means an amount of a compound composition according to the present invention effective in producing the desired therapeutic effect.
  • excipients refer to pharmacologically inert ingredients that are not active in the body. See HANDBOOK OF PHARMACEUTICAL EXCIPIENTS (Am. Pharm. Ass'n 1986).
  • the active ingredients of the present invention may be mixed with pharmaceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preserving agents, fillers, polymers, disintegrating agents, glidants, wetting agents, emulsifying agents, suspending agents, sweetening agents, flavoring agents, perfuming agents, lubricating agents, acidifying agents, and dispensing agents, depending on the nature of the mode of administration and dosage forms.
  • Such ingredients, including pharmaceutically acceptable carriers and excipients may be used to formulate oral dosage forms.
  • Pharmaceutically acceptable carriers include water, ethanol, polyols, vegetable oils, fats, waxes polymers, including gel forming and non-gel forming polymers, and suitable mixtures thereof.
  • excipients include starch, pregelatinized starch, Avicel, lactose, milk sugar, sodium citrate, calcium carbonate, dicalcium phosphate, and lake blend.
  • disintegrating agents include starch, alginic acids, and certain complex silicates.
  • examples of lubricants include magnesium stearate, sodium lauryl sulphate, talc, as well as high molecular weight polyethylene glycols.
  • Dosing under fasting conditions is defined as when the dosage is administered orally with 240 ml of room temperature water after subjects are fasted overnight for at least 10 hours. No fluid, except that given with drug administration, will be allowed from 1 hour prior to dose administration until 1 hour after dosing. At 2 hours post-dose, subjects may consume 240 ml of room temperature water.
  • the pharmaceutical dosage forms of the present invention may involve a controlled release dosage form, where the controlled release dosage form includes a GABA B agonist and a pharmaceutically acceptable excipient, and the dosage form exhibits an in vitro dissolution profile in simulated intestinal fluid medium comprising less than about 70% GABA B agonist release after 1 hour, at least about 20% GABA B agonist release after 4 hours, and at least about 30% GABA B agonist release after 6 hours.
  • the controlled release dosage form exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (1 hour switchover) medium comprising less than about 80% GABAB agonist release after 1 hour, at least about 30% GABA B agonist release after 4 hours, and at least about 40% GABA B agonist release after 6 hours.
  • the controlled release dosage form exhibits an in vitro dissolution profile in simulated intestinal fluid medium comprising less than about 50% GABA B agonist release after 1 hour, at least about 40% GABA B agonist release after 4 hours, and at least about 50% GABA B agonist release after 6 hours.
  • the controlled release dosage form exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (1 hour switchover) medium comprising less than about 70% GABA B agonist release after 1 hour, at least about 40% GABA B agonist release after 4 hours, and at least about 50% GABA B agonist release after 6 hours
  • the controlled-release GABAB agonist dosage form is combined with an immediate release GABA B agonist component.
  • the immediate release component exhibits an in vitro dissolution profile in simulated gastric fluid comprising at least about 80% GABA B agonist release after 1 hour.
  • the pharmaceutical dosage forms of the present invention contain an enteric-coated controlled release component, where the enteric-coated controlled release component includes a GABA B agonist and a pharmaceutically acceptable excipient, and the enteric -coated controlled release component exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 10% GABA B agonist release after 2 hours, at least about 40% GABA B agonist release after 3 hours, and at least about 70% GABA B agonist release after 6 hours.
  • the enteric-coated controlled release component exhibits an in vitro dissolution profile in simulated gastric fluid simulated intestinal fluid (2 hour switchover) medium comprising less than about 10% GABA B agonist release after 2 hours, at least about 50% GABA B agonist release after 3 hours, and at least about 80% GABA B agonist release after 6.
  • the enteric-coated controlled release component exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 10% GABAB agonist release after 2 hours, at least about 60% GABA B agonist release after 3 hours, and at least about 90% GABA B agonist release after 6 hours.
  • the dosage form also contains an immediate release component, in combination with the enteric-coated controlled release component.
  • the present invention includes pharmaceutical dosage forms having both immediate release and extended release properties.
  • the pharmaceutical dosage form comprising a GABA B agonist and a pharmaceutically acceptable excipient exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 75% GABAB agonist release after 2 hours, and at least about 80% GABA B agonist release after 3 hours.
  • the pharmaceutical dosage form exhibits an in vitro dissolution profile in simulated gastric fluid/simulated intestinal fluid (2 hour switchover) medium comprising less than about 65% GABAB agonist release after 2 hours, and at least about 90% GABA B agonist release after 3 hours
  • in vitro dissolution testing methods for the dosage forms of the present invention are known to those of skill in the art and include those described in the Examples herein.
  • the USP paddle method refers to the Paddle and Basket Method as described in United States Pharmacopoeia, Edition XXII (1990).
  • the USP paddle method of 50 rpm or 75 rpm in 900 ml simulated gastric fluid (SGF) (pH 1.2) or simulated intestinal fluid (SIF) (pH 6.8) at 37°C may be used to determine the in vitro dissolution profiles according to the present invention.
  • the dosage forms of the present invention include a controlled release component, including enteric-coated controlled release, as well as an immediate release component
  • the ratio of the immediate release component to the controlled release component is from about 1:10 to about 10:1, preferably about 1:4 to about 4:1, more preferably from about 1:3 to about 3:1, and most preferably from about 1:2 to about 2:1.
  • the pharmaceutical dosage forms of the present invention are adapted to allow prolonged absorption of the active agent, which allows less frequent administration as compared to existing immediate-release formulations.
  • "prolonged absorption” means that the active agent is absorbed in vivo, under fasting conditions, over an extended period of time.
  • the time period over which the majority (i.e., 80-90%) of the absorption occurs extends to about 7 or 8 hours after administration of the dosage form.
  • the median time period at which at least 80% of the active agent is absorbed from the dosage forms of the present invention is greater than 2.5 hours after administration, typically three to 4.5 hours after administration.
  • the median time period at which at least 80% of the active agent is absorbed from existing immediate- release formulations is 1.5 to two hours after administration.
  • the period over which an active agent is absorbed from a dosage form can be calculated by deconvolution, using mathematical methods known to those of skill in the art.
  • the dosage forms of the present invention will exhibit an in vivo plasma profile comprising mean maximum GABA B agonist levels from about 30 minutes to about 7 hours, often from about 2.5 hours to about 5.5 hours, after administration of a single dose to a fasting patient.
  • the pharmaceutical dosage forms of the present invention will reach a C MIN comparable to that obtained at steady-state from an immediate-release dosage form at a later time point, which will allow less frequent dosing.
  • a 40 mg dosage form of the present invention when administered twice daily, will deliver mean steady-state area under the plasma concentration-time curve (AUC), maximum plasma concentration (C MAX ), and minimum plasma concentration (C MIN ) similar to that of an immediate-release tablet formulation administered three times daily.
  • These dosage forms preferably a tablet or capsule, which may contain beads, granules, particles, or a mixture thereof
  • Total daily dosages of the compounds useful according to this invention administered to a host in single or divided doses are generally in amounts of from about 0.01 mg/kg to about 100 mg/kg body weight daily, and preferably from about 0.05 mg/kg to about 50 mg/kg body weight daily. It should be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including body weight, general health, gender, diet, time and route of administration, rates of absorption and excretion, combination with other drugs, and the severity of the particular disease being treated. Actual dosage levels of active ingredient in the compositions of the present invention may be varied so as to obtain an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • Total daily dose of the compounds useful according to this invention administered to a host in single or divided doses may be in amounts, for example, of from about 0.01 mg/kg to about 20 mg/kg body weight daily and preferably 0.02 to 10 mg/kg/day.
  • the preferred dosage range of baclofen is between 2.5 mg and 100 mg per dosage form.
  • Dosage forms according to the present invention may contain such amounts or fractions thereof as may be used to make up the daily dose.
  • Preferred dosage strengths for the formulations of the present invention include those having 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg baclofen.
  • the optimal dosage for a patient will be determined by titration, whereby the patient is initially given small doses, which are then gradually increased until the patient reaches the dosage level that achieves maximum therapeutic efficacy with minimum side effects.
  • One embodiment of the present invention provides a controlled release solid oral dosage form in which there is immediate release of baclofen and delayed or delayed- sustained release of baclofen.
  • Dosages according to the present invention may include an immediate release component and a delayed or delayed-sustained release component. The combination of these two components can release the drug in a pulsed release fashion or a continuous fashion upon oral administration of the dosage form.
  • the invention relates to a controlled release baclofen solid oral dosage form comprising an immediate release baclofen component and a delayed or delayed- sustained, or sustained release baclofen component.
  • the immediate release baclofen component comprises baclofen formulated with one or more pharmaceutically acceptable excipients that allow for immediate release of the baclofen
  • the delayed, or delayed- sustained, or sustained release baclofen component comprises baclofen formulated with one or more excipients that allow for delayed, or delayed-sustained, or sustained release of the baclofen.
  • U.S. Patent No. 6,372,254 refers to formulations, such as tablets, having both an immediate release component and an extended release component.
  • the solid oral dosage form according to the present invention may be a tablet formulation, or a discrete unit-filled capsule formulation, or a sachet formulation.
  • the discrete units of the present invention include beads, granules, pellets, spheroids, particles, tablets, pills, etc.
  • the immediate release, delayed release, delayed-sustained release, and sustained release components of the dosage form can take any form known to a skilled pharmaceutical formulator, including one component of a multi-component tablet such as described in U.S. Patent 6,372,254, issued Apr. 16, 2002, pending U.S. Patent Application Serial No. 10/241,837, filed Sept. 12, 2002, and published International Patent Application No.
  • the controlled release baclofen dosages according to the present invention may be in the form of cores comprising baclofen. Dosage forms can be made according to known methods in the art. Some preferred methods are described below. Matrix Dosage Forms.
  • the term matrix refers to a solid material having an active agent incorporated therein. Upon exposure to a dissolution media, channels are formed in the solid material so that the active agent can escape.
  • Dosage forms according to the present invention may be in the form of coated or uncoated matrices. A coating, for example may contain immediate release baclofen, or in the alternative, and the matrix itself can contain controlled release baclofen.
  • Drug release from the delayed or delayed-sustained, or sustained release component can be immediate or sustained, for example within 7 hours after oral administration of the oral dosage form to ensure effective absorption of the drug.
  • the controlled release baclofen component may be comprised of baclofen coated with at least one delayed release layer.
  • the delayed-sustained release baclofen component may be comprised of sustained-release-coated baclofen coated with at least one delayed release layer.
  • the sustained release baclofen component may be comprised of baclofen coated with at least one sustained-release polymer, or a matrix-controlled release polymer.
  • the matrix material can be chosen from a wide variety of materials that can provide the desired dissolution profiles.
  • Materials can include, for example, one or more gel forming polymers such as polyvinyl alcohol, cellulose ethers including, for example, hydroxyl propyl alkyl, celluloses such as hydroxypropyl methyl cellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose, natural or synthetic gums such as guar gum, xanthum gum, and alginates, as well as, ethyl cellulose, polyethylene oxide, polyvinyl pyrrolidone, fats, waxes, polycarboxylic acids or esters such as the Carbopol® series of polymers, methacrylic acid copolymers, and methacrylate polymers.
  • gel forming polymers such as polyvinyl alcohol, cellulose ethers including, for example, hydroxyl propyl alkyl, celluloses such as hydroxypropyl methyl cellulose, hydroxy alkyl celluloses such as hydroxy propyl cellulose, natural or synthetic gums such as guar gum,
  • Methods of making matrix dosages are known in the art and any such method that can yield the desired dissolution profiles and/or plasma profiles may be relied upon according to the present invention.
  • One such method involves baclofen with a solid polymeric material and one or more pharmaceutically acceptable excipients that are then blended and compressed in controlled release tablet cores.
  • controlled release tablet cores can be used for further processing as bilayer tablets, press coated tablets, or film coated tablets.
  • a coating containing the immediate release baclofen can be added to the outside of the controlled release tablet cores to produce a final dosage form.
  • Such a coating can be prepared by mixing baclofen with polyvinylpyrrolidone (PNP) 29/32 or hydroxypropyl methylcellulose (HPMC) and water/isopropyl alcohol and triethyl acetate.
  • PNP polyvinylpyrrolidone
  • HPMC hydroxypropyl methylcellulose
  • Such an immediate release coating can be spray coated onto the tablet cores.
  • the immediate release coating may also be applied using a press-coating process with a blend consisting of 80% by weight baclofen and 20% by weight of lactose and hydroxypropyl methylcellulose type 2910. Press coating techniques are known in the art and are described in U.S. Patent No. 6,372,254 (Ting et al), incorporated herein by reference in its entirety.
  • the formulation of respective release components can occur by appropriate granulation methods as is well known in the art.
  • wet granulation solutions of the binding agent (polymer) are added with stirring to the mixed powders.
  • the powder mass is wetted with the binding solution until the mass has the consistency of damp snow or brown sugar.
  • the wet granulated material is forced through a sieving device.
  • Moist material from the milling step is dried by placing it in a temperature controlled container. After drying, the granulated material is reduced in particle size by passing it through a sieving device.
  • Lubricant is added, and the final blend is then compressed into a matrix dosage form.
  • fluid-bed granulation particles of inert material and/or active agent are suspended in a vertical column with a rising air stream.
  • the dosage forms can include immediate release particles in combination with controlled release particles in a ratio sufficient to dehver the desired release of active agents.
  • the controlled release particles can be produced by coating the immediate release particles.
  • the term "particle” as used herein means a granule having a diameter of between about 0.01 mm and about 5.0 mm, preferably between about 0.1 mm and about 2.5 mm, and more preferably between about 0.5 mm and about 2 mm.
  • particles according to the present invention can be any geometrical shape within this size range and so long as the mean for a statistical distribution of particles falls within the particle sizes enumerated above, they will be considered to fall within the contemplated scope of the present invention.
  • Particles can assume any standard structure known in the pharmaceutical arts.
  • Such structures include, for example, matrix particles, nonpareil cores having a drug layer and active or inactive cores having multiple layers thereon.
  • a controlled release coating can be added to any of these structures to create a controlled release particle.
  • the particles can be produced according to any of a number of known methods for making particles.
  • the immediate release particles comprise the active agent combination and a disintegrant. Suitable disintegrants include, for example, starch, low-substitution hydroxypropyl cellulose, croscarmellose sodium, calcium carboxymethyl cellulose, hydroxypropyl starch, sodium starch glycolate, and microcrys-alline cellulose.
  • the matrix may also contain suitable quantities of other materials, for example, diluents, lubricants, binders, granulating aids, colorants, flavorants, and glidants that are conventional in the pharmaceutical arts.
  • suitable quantities of these additional materials are sufficient to provide the desired effect to the desired formulation.
  • a matrix incorporating particles may also contain suitable quantities of these other materials such as diluents, lubricants, binders, granulating aids, colorants, flavorants, and glidants that are conventional in the pharmaceutical arts in amounts up to about 75% by weight of the particulate, if desired.
  • oral dosage forms are prepared to include an effective amount of particles as described above within a capsule.
  • melt-extruded particles may be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid.
  • a suitable amount of the particles are compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin), and pills are also described in REMINGTON'S PHARMACEUTICAL SCIENCES, Arthur Osol, ed., 1553-93 (1980), incorporated herein by reference.
  • the particles can be made by mixing the relevant ingredients and granulating the mixture. The resulting particles are dried and screened, and the particles having the desired size are used for drug formulation. Controlled Release Particles.
  • the controlled release particles of the present invention slowly release baclofen when ingested and exposed to gastric fluids, and then to intestinal fluids.
  • the controlled release profile of the formulations of the invention can be altered, for example, by increasing or decreasing the thickness of the retardant coating, i.e., by varying the amount of overcoating.
  • the resultant solid controlled release particles may thereafter be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid, intestinal fluid or dissolution media.
  • the particles may be overcoated with an aqueous dispersion of a hydrophobic or hydrophilic material to modify the release profile.
  • the aqueous dispersion of hydrophobic material preferably further includes an effective amount of plasticizer, e.g. triethyl citrate.
  • plasticizer e.g. triethyl citrate.
  • the release of the therapeutically active agent from the controlled release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents.
  • the release-modifying agent may be organic or inorganic and include materials that can be dissolved, extracted, or leached from the coating in the environment of use.
  • the pore-formers may comprise one or more hydrophilic materials such as hydroxypropyl methylcellulose.
  • the release-modifying agent may also comprise a semi-permeable polymer. In certain preferred embodiments, the release- modifying agent is selected from hydroxypropyl methylcellulose, lactose, metal stearates, and mixtures thereof.
  • the controlled-release component may also include a combination of hydrophilic and hydrophobic polymers. In this embodiment, once administered, the hydrophilic polymer dissolves away to weaken the structure of the controlled-release component, and the hydrophobic polymer retards the water penetration and helps to maintain the shape of the drug delivery system.
  • the hydrophobic material may be selected from the group consisting of alkylcellulose, acrylic and methacrylic acid polymers and copolymers, shellac, zein, hydrogenated castor oil, hydrogenated vegetable oil, or mixtures thereof.
  • the hydrophobic material is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine copolymer, poly(methyl methacrylate), poly(methacrylic acid anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • the hydrophobic material is selected from materials such as one or more hydroxyalkyl celluloses such as hydroxypropyl methylcellulose.
  • the hydroxyalkyl cellulose is preferably a hydroxy ( to C 6 ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose, or preferably hydroxyethylcellulose.
  • the amount of the hydroxyalkyl cellulose in the present oral dosage form is determined, inter alia, by the precise rate of active agents desired and may vary from about 1% to about 80%.
  • the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic polymer can further improve the physical properties of the film.
  • a plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 percent to about 50 percent by weight of the film-former.
  • plasticizer Concentration of the plasticizer, however, is preferably determined after careful experimentation with the particular coating solution and method of application.
  • suitable plasticizers for ethylcellulose include water-insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tributyl citrate, and triacetin, although other water-insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used.
  • Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention.
  • plasticizers for the acrylic polymers of the present invention include, but are not limited to, citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2-propylene glycol.
  • Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit® RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin.
  • Triethyl citrate is an especially preferred plasticizer for aqueous dispersions of ethyl cellulose.
  • talc reduces the tendency of the aqueous dispersion to stick during processing and acts a polishing agent.
  • aqueous dispersion of ethylcellulose is Aquacoat® which is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the ethylcellulose in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated into the pseudolatex during the manufacturing phase. Thus, prior to using the pseudolatex as a coating, the Aquacoat® is mixed with a suitable plasticizer.
  • aqueous dispersion of ethylcellulose is commercially available as Surelease ⁇ (Colorcon, Inc., West Point, PA, US-A).
  • This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process.
  • a hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture which is then diluted with an alkahne solution to obtain an aqueous dispersion which can be applied directly onto substrates.
  • the acrylic coating is an acrylic resin lacquer used in the form of an aqueous dispersion, such as that which is commercially available from Rohm Pharma under the trade name Eudragit®.
  • the acrylic coating comprises a mixtore of two acrylic resin lacquers commercially available from Rohm Pharma under the trade names Eudragit® RL 30 D and Eudragit® RS 30 D.
  • Eudragit® RL 30 D and Eudragit® RS 30 D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit® RL 30 D and 1:40 in Eudragit® RS 30 D.
  • the mean molecular weight is about 150,000 Daltons.
  • the code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents.
  • Eudragit ⁇ RL/RS mixtures are insoluble in water and in digestive fluids, however, coatings formed from them are swellable and permeable in aqueous solutions and digestive fluids.
  • the Eudragit® RL/RS dispersions may be mixed together in any desired ratio in order to ultimately obtain a controlled release formulation having a desirable dissolution profile. Desirable controlled release formulations may be obtained, for instance, from a retardant coating derived from one of a variety of coating combinations, such as 100% Eudragit® RL; 50% Eudragit® RL and 50% Eudragit® RS; or 10% Eudragit® RL and 90% Eudragit® RS.
  • a retardant coating derived from one of a variety of coating combinations, such as 100% Eudragit® RL; 50% Eudragit® RL and 50% Eudragit® RS; or 10% Eudragit® RL and 90% Eudragit® RS.
  • acrylic polymers may also be used, for example, Eudragit® L.
  • the dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the retardant coating.
  • the stabilized product is obtained by subjecting the coated substrate to oven curing at a temperature above the T g of the plasticized acrylic polymer for the required time period, the optimum values for temperature and time for the particular formulation being determined experimentally.
  • the stabilized product is obtained via an oven curing conducted at a temperature of about 45°C for a time period from about 1 to about 48 hours.
  • certain products coated with the controlled release coating of the present invention may require a curing time longer than 24 to 48 hours, e.g., from about 48 to about 60 hours or more.
  • the coating solutions preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead of, or in addition to the aqueous dispersion of hydrophobic material.
  • color may be added to Aquacoat® via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide >y adding color with shear to the water soluble polymer solution and then using low shear to the plasticized Aquacoat®.
  • any suitable method of providing color to the formulations of the present invention may be used.
  • Suitable ingredients for providing color to the formulation when an aqueous dispersion of an acrylic polymer is used include titanium dioxide and color pigments, such as iron oxide pigments. The incorporation, of pigments, may, however, increase the retardant effect of the coating.
  • Spheroids or beads coated with the therapeutically active agents can be prepared, for example, by dissolving the therapeutically active agents in water and then spraying the solution onto a substrate, for example, non pareil 18/20 beads, using a Wuster insert.
  • additional ingredients are also added prior to coating the beads in order to assist the binding of the active agents to the beads, and/or to color the solution, etc.
  • a product that includes hydroxypropyl methylcellulose with- or without colorant e.g., Opadry®, commercially available from Colorcon, Inc.
  • the resultant coated substrate, beads in this example may then be optionally overcoated with a barrier agent to separate the therapeutically active agent from the hydrophobic controlled release coating.
  • a suitable barrier agent is one th-at comprises hydroxypropylmethylcellulose.
  • any film-former known in the art may be used.
  • baclofen is administered via a press coated, pulsatile drug delivery system suitable for oral administration with a controlled release component, which contains a compressed blend of an active agent and one or more polymers, substantially enveloped by an immediate release component, which contains a compressed blend of the active agent and hydrophilic and hydrophobic polymers.
  • the immediate release component preferably comprises a compressed blend of active agent and one or more polymers with disintegration characteristics such that the polymers disintegrate rapidly upon exposure to the aqueous medium.
  • the controlled release component preferably comprises a combination of hydrophilic and hydrophobic polymers.
  • the hydrophilic polymer dissolves away to weaken the structure of the controlled release component, and the hydrophobic polymer retards the water penetration and l ⁇ elps to maintain the shape of the drug delivery system.
  • the term "polymer” includes single or multiple polymeric substances, which can swell, gel, degrade or erode on contact with an aqueous environment (e.g., water).
  • Examples include alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, colloidal silicon dioxide, croscarmellose sodium, crospovidone, guar gum, magnesium aluminum silicate, methylcellulose, microcrystalline cellulose, polacrilin potassium, powdered cellulose, pregelatinized starch, sodium alginate, sodium starch glycolate, starch, ethylcellulose, gelatin, tiydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polymethacrylates, povidone, pregelatinized starch, shellac, zein, and combinations thereof.
  • hydrophilic polymers includes one or more of carboxymethylcellulose, natural gums such as guar gum- or gum acacia, gum tragacanth, or gum xanthan, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, and povidone, of which hydroxypropyl methylcellulose is further preferred.
  • hydrophilic polymers can also include sodium carboxymethycellulose, hydroxymethyl cellulose, polyethelene oxide, -hydroxyethyl methyl cellulose, carboxypolymethylene, polyethelene glycol, alginic acid, gelatin, polyvinyl alcohol, polyvinylpyrrolidones, polyacrylamides, polymethacrylamides, polyphosphazines, polyoxazohdines, poly(hydroxyalkylcarboxylic acids), an alkali metal or alkaline earth metal, carageenate alginates, ammonium alginate, sodium alganate, or mixtures thereof.
  • the "hydrophobic polymer" of the drug delivery system can be any hydrophobic polymer which will achieve the goals of the present invention including, but not limited to, one or more polymers selected from carbomer, carnauba wax, ethylcellulose, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil type 1, microcrystalline wax, polacrilin potassium, polyethylene oxide, polymethacrylates, or stearic acid, of which hydrogenated vegetable oil type 1 is preferred.
  • Hydrophobic polymers can include, for example, a pharmaceutically acceptable acrylic polymer, including, but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copc-lymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, poly(methyl methacrylate), poly(methyl methacrylate) copolymer, polyacrylamide, -aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers.
  • a pharmaceutically acceptable acrylic polymer including, but not limited to, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino
  • the acrylic polymers may be cationic, anionic, or non-ionic polymers and may be acrylates, methacrylates, formed of methacrylic acid or methacrylic acid esters.
  • the polymers may also be pH dependent. Enteric Coated Controlled Release.
  • the delayed or delayed- sustained release coating is an enteric coating. All commercially available pH-sensitive polymers may be used to form the enteric coating.
  • the drug coated wit-h the enteric coating is minimally or not released in the acidic stomach environment of approximately below pH 4.5. The drug should become available when the enteric layer dissolves at tt e higher pH present in the intestine; after a suitable delayed time; or after the unit passes through the stomach.
  • Enteric polymers include cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerized methacrylic acid/methacarylic acid methyl esters such as, for instance, materials known under the trade name Eudragit® L12.5, Eudragit® L100, or Eudragit® S12.5, S100 (Rohm GmbH, Darmstadt, Germany) or similar compounds used to obtain enteric coatings.
  • Aqueous colloidal polymer dispersions or re- dispersions can be also applied, e.g., Eudragit® L 30D-55, Eudragit® L100-55, Eudragit® S100, Eudragit® preparation 4110D c; Aquateric®, Aquacoat® CPD 30 (FMC Corp.); Kollicoat MAE® 30D and Kollicoat MAE® 30DP (BASF); Eastacryl® 30D (Eastman Chemical, Kingsport, TN).
  • the enteric polymers used in this invention can be modified by mixing with other known coating products that are not pH sensitive.
  • Such coating products include the neutral methacrylic acid esters with a small portion of trimethylammonioethyl methacrylate chloride, sold currently under the trade names E Eudragit®, Eudragit® RL, Eudragit® RS; a neutral ester dispersion without any functional groups, sold under the trade names Eudragit® NE30D and Eudragit® NE30; and other pH independent coating products.
  • the enteric coating will substantially envelop the controlled-release component.
  • the term "substantially envelop" is intended to define the total or near-total enclosure of: a component. Such an enclosure includes, preferably, at least about 80% enclosure, more preferably at least about 90% enclosure, and even more preferably at least about 99*-% enclosure.
  • An embodiment of the present invention provides for a free flowing formulation comprising baclofen.
  • free flowing means dosage forms t-hat pass through a patient' s digestive system without impediment or mechanism to slow passage.
  • the term “free flowing” would exclude gastric raft type dosage forms, which are designed to reside in the stomach for extended periods as in, e.g., U.S. Patent No. 5,651,985.
  • Dosage forms according to the present invention can also include a combination of baclofen and at least one additional active agent, such as tizanidine, dantrolene, nonsteroidal anti-inflammatory agents (NSAIDs), opioids, and COX-2 inhibitors.
  • NSAIDs nonsteroidal anti-inflammatory agents
  • the other active agents can be co-formulated in the immediate-release or delayed-release, delayed-sustained release, or sustained-release components to provide desirable therapeutic effects.
  • Dosage forms according to the present invention can also apply to pure racer ⁇ iic, L- baclofen, and other GABA related active agents as referred to in U.S. Patent 6,350,769, issued February 26, 2002 to Kaufman et al.
  • Dosage levels of baclofen (racemic or L-baclofen), as well as any active agent that is to be used in combination with baclofen, in the compositions may be varied so as to obtain an amount of baclofen, and, when used as a combination product, an amount of active ingredient that is effective to obtain a desired therapeutic response for a particular composition and method of administration.
  • Bioavailability refers to the degree to which the therapeutically active medicament becomes available in the body after administration. Typically, bioavailability is measured in patients who fasted overnight before being dosed with the test preparation. Plasma samples are then taken and analyzed for the plasma concentration of the parent compound and or its active metabolite. These data may be expressed as C MAX . the maximum amount of active ingredient found in the plasma, or as AUC, the area under the plasma concentration time curve.
  • C MAX the maximum amount of active ingredient found in the plasma, or as AUC, the area under the plasma concentration time curve.
  • baclofen formulations may be used in a comparative bioavailability study in subjects. Subjects fast over night prior to drug administration. Plasma samples are then taken at dosing, and every hour for twelve hours after dosing, and then at sixteen and twenty-four hours after dosing, and analyzed for the ng/ml concentration of baclofen or a baclofen metabolite. Without further elaboration, one skilled in the art having the benefit of the preceding description can utilize the present invention to the fullest extent. The following examples are illustrative only and do not limit the remainder of the disclosure in any way.
  • Povidone (Plasdone K-29/32®) is added to purified water and mixed until the povidone is fully dissolved. Baclofen is mixed in the above solution until uniformly dispersed. A fluidized bed coating apparatus is then used to coat the sugar spheres with the baclofen suspension to produce active coated seeds.
  • Hypromellose, Type 2910' , USP (Pharmacoat 606, 6cps) is added to a suitable amount of purified water and mixed until the Hypromellose is fully dissolved. Baclofen is mixed in the above solution until uniformly dispersed. A fluidized bed coating apparatus is then used to coat the sugar spheres with the baclofen suspension to produce active coated seeds. The dissolution profile of this formulation is shown in Figure 3. Example 3. Active baclofen-containing granules.
  • Example 4 Enteric-coated seeds containing baclofen.
  • Example 5 Enteric-coated seeds containing baclofen.
  • Example 6 Composition containing baclofen active coated and enteric-coated seeds.
  • Designated portions of active coated seeds and enteric-coated seeds are mixed together to form dosage forms.
  • the seeds are mixed and added to gelatin capsules.
  • the seeds are compressed to form a tablet.
  • the seed are mixed and filled into the pouch.
  • Example 7 Enteric-coated seeds containing baclofen.
  • Pharmacoat 606 is dissolved in purified water and baclofen is then dispersed into this aqueous solution to make an aqueous suspension.
  • a fluidized bed coating equipment is used to coat the sugar sphere with the baclofen suspension to produce active coated seeds.
  • Eudragit® RL 100, RS 100, and dibutyl sebacate are dissolved in a mixture of acetone and isopropyl alcohol.
  • Talc and magnesium stearate are then dispersed into the solution.
  • a fluidized bed coating equipment is used to coat the active coated seeds with the above suspension to produce sustained-release coated seeds.
  • HPMCP and triethyl citrate are dissolved in a mixture of acetone and purified water.
  • a fluidized bed coating equipment is used to coat the sustained-release coated seeds with the above solution to produce enteric-coated seeds.
  • Example 8 Baclofen tablets.
  • baclofen, sodium starch glycolate, dicalcium phosphate anhydrous, and lactose anhydrous in a high-shear granulator Wet granulate the mixtore with purified water and dry the granulate in an oven at a temperature of 60°C for at least 16 hours. Screen the granules using a #25 mesh screen. Mill the oversized granules by a Fitzpatric comminuting machine equipped with a #18 mesh screen. Blend the screened and milled granules with magnesium stearate and compress the blend into tablets using a rotary tablet press.
  • Example 9 Baclofen tablets.
  • baclofen, hydroxypropyl methylcellulose, lactose monohydrate or mannitol, and microcrystalline cellulose in a high-shear granulator.
  • Example 10 Composition containing baclofen active coated and enteric-coated seeds.
  • Hypromellose, Type 2910, USP is added to a suitable amount of purified water and mixed until the hypromellose is fully dissolved. Baclofen is then mixed in the above solution until uniformly dispersed. The suspension is passed through a #40 mesh sieve into a stainless steel container. Sugar spheres are charged into a fluid-bed coater equipped with a Wurster insert and heated until exhaust air temperature reaches 50 ⁇ 5°C. The active suspension from above is sprayed to coat the sugar spheres, which are then dried at a temperature of 60 ⁇ 10°C for 5 minutes. The IR seeds are passed through a #16 mesh stainless steel screen. Acceptable IR seeds are collected and mixed with talc, USP in a slant cone blender for one minute.
  • An enteric solution is prepared by mixing purified water and acetone. Triethyl citrate and methacrylic acid copolymer, type C, are stirred into the mixture until completely dissolved. Talc is mixed in the above solution until completely dispersed. A fluidized bed coating apparatus is then used to coat IR seeds prepared as above with the enteric solution to produce enteric-coated seeds. The enteric-coated seeds are passed through a #14 mesh stainless steel screen. Acceptable enteric-coated seeds are collected and mixed with talc, USP in a slant cone blender for one minute. An appropriate amount of IR seeds plus the appropriate amount of enteric-coated seeds are encapsulated to yield Baclofen ER capsules. Example 11. Baclofen Tablets Tablets having the following compositions were prepared according to the process described in Example 9.
  • Baclofen ER Capsules Baclofen extended release capsules (20 mg) were prepared having the following formulations, using the process described in Example 7.
  • Baclofen ER Capsules Baclofen ER capsules having the following formulations were prepared according to the process described in Example 10.
  • Baclofen ER Capsules Baclofen ER capsules of the following compositions were prepared according to the process described in Example 10, with the exception that the enteric materials are Acetyltributyl Citrate and Hydromellose Phthalate instead of Triethyl Citrate and Methacrylic Acid Copolymer, type C.
  • Example 15 Baclofen ER Capsules. Baclofen ER capsules having the following composition were prepared according to the method described in Example 10. Capsules were prepared having 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg and 40 mg baclofen, with the different dosage strengths being directly proportional.
  • Example 16 Determining plasma profiles for baclofen-containing formulations.
  • a bioavailability study was done in 20 healthy volunteers comparing a 36mg baclofen formulation prepared according to Example 15, with the exception that the immediate-release component contained 12mg baclofen and the enteric-coated controlled release component contained 24mg baclofen, and the remaining excipients were adjusted dose proportionally.
  • the formulation was compared with a 20mg immediate release reference tablet (Watson Laboratories, Inc.) under fasting conditions. Test samples were administered orally with 240 ml of room temperature water after subjects are fasted overnight for at least 10 hours. No fluid, except that given with drug administration, is allowed from 1 hour prior to dose administration until 1 hour after dosing.

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Abstract

La présente invention concerne d'une manière générale des formes galéniques pharmaceutiques à libération immédiate et contrôlée qui renferment un agoniste du récepteur de l'acide η-aminobutyrique (GABAB), tel que le baclofène, et qui servent au traitement d'états pathologiques tels que les spasmes, les crampes et la raideur musculaire associés à des affections telles que la sclérose en plaques ou certains traumatismes spinaux.
EP05733181A 2004-04-02 2005-04-01 FORMES GALENIQUES PHARMACEUTIQUES A LIBERATION IMMEDIATE ET/OU CONTROLEE RENFERMANT UN AGONISTE DU RECEPTEUR GABA<SB>B</SB> Withdrawn EP1729740A2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US10/815,929 US20050220864A1 (en) 2004-04-02 2004-04-02 Pharmaceutical dosage forms having controlled release properties that contain a GABAB receptor agonist
US10/815,930 US20050220874A1 (en) 2004-04-02 2004-04-02 Pharmaceutical dosage forms having immediate release and controlled release properties that contain a GABAB receptor agonist
US10/815,926 US20050220873A1 (en) 2004-04-02 2004-04-02 Pharmaceutical dosage forms having immediate and controlled release properties that contain a GABAB receptor agonist
US10/815,924 US20050220863A1 (en) 2004-04-02 2004-04-02 Pharmaceutical dosage forms having controlled release properties that contain a GABAB receptor agonist
PCT/US2005/011032 WO2005097079A2 (fr) 2004-04-02 2005-04-01 Formes galeniques pharmaceutiques a liberation immediate et/ou controlee renfermant un agoniste du recepteur gabab

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BR (1) BRPI0509399A (fr)
CA (1) CA2560995A1 (fr)
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ATE511392T1 (de) * 2007-01-11 2011-06-15 Xenoport Inc Verzögert freigesetzte orale dosierungsformen eines prodrugs von r-baclofen und behandlungsverfahren damit
WO2009096985A1 (fr) * 2008-02-01 2009-08-06 Xenoport, Inc. Formes posologiques orales particulaires à libération soustenue de promédicaments de (r)-baclofène et procédés de traitement correspondants
CA2753057C (fr) 2009-03-03 2018-09-11 Xenoport, Inc. Formes posologiques orales a liberation entretenue d'un promedicament de r-baclofene
RU2672884C1 (ru) * 2017-11-07 2018-11-20 Федеральное государственное бюджетное образовательное учреждение высшего образования "Российский государственный педагогический университет им. А.И. Герцена" (РГПУ им. А.И. Герцена) Средство, сохраняющее популяцию ГАМК-ергических нейронов после острой перинатальной гипоксии
WO2019146642A1 (fr) * 2018-01-24 2019-08-01 大原薬品工業株式会社 MÉTHODE D'AMÉLIORATION DE LA STABILITÉ CHIMIQUE D'UN COMPRIMÉ CONTENANT UN DÉRIVÉ D'ACIDE γ-AMINOBUTYRIQUE
CN119970650A (zh) * 2020-10-05 2025-05-13 凯瑞康宁生物工程有限公司 γ-羟基丁酸衍生物的修饰释放组合物
CN115919806A (zh) * 2022-12-22 2023-04-07 南京乐韬生物科技有限公司 一种gaba缓释胶囊的制备方法

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IL155704A0 (en) * 2000-11-30 2003-11-23 Pfizer Prod Inc Combination of gaba agonists and sorbitol dehydrogenase inhibitors

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CA2560995A1 (fr) 2005-10-20
JP2007531727A (ja) 2007-11-08
TW200536523A (en) 2005-11-16
MXPA06011322A (es) 2007-02-21
IL178296A0 (en) 2007-02-11
KR20070020022A (ko) 2007-02-16
NO20065013L (no) 2007-01-02
BRPI0509399A (pt) 2007-09-18
WO2005097079A3 (fr) 2006-01-05
WO2005097079A2 (fr) 2005-10-20

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