Classifications

• • 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
  • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
• • 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
  • A61K9/2072—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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
  • A61P25/10—Antiepileptics; Anticonvulsants for petit-mal
• • 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
  • A61P25/08—Antiepileptics; Anticonvulsants
  • A61P25/12—Antiepileptics; Anticonvulsants for grand-mal
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

• the present invention relates to a pharmaceutical composition containing gabapentin.
• Gabapentin is the common name of the 1-aminomethyl-cyclohexane-acetic acid, a known drug with anti-epileptic activity.
• additives which have to be avoided in the composition because they favour the formation of lactam, is listed as well. They are: modified cornstarch, croscarmellose sodium, glyceric esters of behenic acid, copolymers of metacrylic acid (type A and C), anion-exchange resins, titanium dioxide, silica gel and PEG with low molecular weight.
• the stabilizers belong to the following classes: volatile alcohols, non-volatile alcohols, non-volatile liquids, water miscible solids or liquids, immiscible solids or liquids, liquid or solid surface active agents, antioxidants, ketones or aldehydes.
• gabapentin is proposed with different dosages and in two pharmaceutical forms for oral use: capsules and tablets.
• a gabapentin granulate obtained by granulating gabapentin with PEG having a melting point comprised between 50 and 80° C.
• the so-obtained granulate can be used as such for preparing tablets or it can be supplemented with other additives and then compressed.
• glydants or disgregants additives useful for the subsequent compression or for the disgregation of the tablet
• additives useful for the subsequent compression or for the disgregation of the tablet such as glydants or disgregants, specific examples being the silica gel, the pregelatiniaed starch and the croscarmellose sodium.
• a gabapentin granulate obtained by granulating the gabapentin with PEG having the melting point comprised between 50 and 80° C. and additives chosen among glydants, disgregants and diluents.
• the granulate will contain a high quantity of gabapentin, for example higher than 80% by weight or even higher than 90% by weight and it can reach even 98% by weight, the remaining 2% being the PEG.
• the usable PEG is the one commonly used in the pharmaceutical field and it is not necessary using particular pure PEGs. If desired, PEG mixtures with different average molecular weight can be used so that the melting point of the mixture is comprised between 50 and 80° C.
• a single PEG or a PEG mixture having the melting point comprised between 50 and 80° C. will be designated indifferently.
• the granulate can be prepared by using rotogranulators available on the market, such as, for example, the fast rotogranulators (high shear mixer) produced by the Zanchetta firm, Rotojunion 10 model, or similar devices such as Glatt, Collette, Diosna.,
• compositions in tablets can be prepared by direct compression of the granulate or by adding to the granulate, before the compression, additives of typical pharmaceutical use which give to the tablet properties useful both in the industrial preparation and in the regular therapeutic effect of the drug administered therewith.
• additives are disgregants, lubricants and glydants.
• composition of the tablet resulting from the mixture compression will be comprised within the following values:
• gabapentin tablets containing between 70 and 100% by weight of a granulate as described above and between 0 and 30% by weight, prefcrably bctwccn 0 and 20% of additives for pharmaceutical use.
• the granulate of the invention does not cause the degradation of the active principle and since one of the gabapentin pharmaceutical forms for oral use is constituted by capsules containing it, the granulate itself can be used successfully for the preparation of capsules.
• a mixture of powders constituted by gabapentin, PEG and, in case, other additives is charged in a Zanchetta rotogranulator, Rotojunior 10 model.
• the total amount of powders which can be charged in the apparatus mentioned above is comprised between 0.8 and 3 kg and 1-2 kg are preferably charged.
• the powders are mixed in the rotogranulator for 5 minutes at 25° C., the blade speed being 100 rpm.
• the mixture under stifling is heated until the PEG melting point (between 50 and 80° C.) with the blade speed comprised between 150 and 400 rpm, preferably 300 rpm, and the crusher speed comprised between 600 and 1200 rpm, preferably, 1000 rpm. It is left for a time comprised between 30 and 60 minutes, preferably 45 minutes.
• the mixture is then cooled at 25° C. by keeping it under stirring with the blade speed of 100 rpm and the crusher speed of 1000 rpm.
• the so-obtained granulated is discharged which, independently from the quantity of the introduced materials, can have a composition comprised within the following values:
• the so-produced granulates have optimum sliding and compressibility properties (rest angle 30-35% and Carr index 10-18%); the appearance of gabapentin degradtion products is not found and, from the FT-Raman analysis, the gabapentin keeps its original crystalline form.
• the granulates according to the invention can be used for obtaining pharmaceutical tablets by using usual compressors.
• Co 1 Gr 1 granulate 70-100% by weight additives 0-30% by weight
• Co 1 Gr 1 granulate (see example 2) 85% pregelatinized starch 13.5% colloidal silica 0.5% stearate magnesium 0.5% titanium dioxide 0.5%
• Co 2 Gr 3 granulate 87% croscarmellose sodium 11.5% colloidal silica 0.5% stearate magnesium 0.5% titanium dioxide 0.5%
• Co 2 Gr 2 granulate 85% copolymer of the metacrylic acid (type C) 10% stearate magnesium 0.5% titanium dioxide 0.5% glyceric esters of the behenic acid 4%
• the Gr 1 granulate described in the example 2 is compressed without adding additional additives to obtain tablets.
• Co 5 Gr 1 granulate 99% colloidal silica 0.5% stearate magnesium 0.5%
• Co 6 Gr 3 granulate 85% PEG 4000 5% copolymer of the metacrylic acid (type A) 10%
• the so-obtained tablets show technological properties suitable for a pharmaceutical use (hardness 10-12 Kn, friability ⁇ 0.1%, disgegation time comprised between 10 and 25′, usually ⁇ 15′) and do not show degradation of the active principle or variations of the crystalline form. They are also suitable for a subsequent possible coating.

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• Health & Medical Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Chemical & Material Sciences (AREA)
• Engineering & Computer Science (AREA)
• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Pharmacology & Pharmacy (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Pain & Pain Management (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

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Citations (13)

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• 2003
  • 2003-12-09 IT IT002399A patent/ITMI20032399A1/it unknown
• 2004
  • 2004-12-02 SI SI200431665T patent/SI1699438T1/sl unknown
  • 2004-12-02 PL PL04804655T patent/PL1699438T3/pl unknown
  • 2004-12-02 WO PCT/EP2004/053233 patent/WO2005055993A2/en active Application Filing
  • 2004-12-02 AT AT04804655T patent/ATE506052T1/de active
  • 2004-12-02 EP EP04804655A patent/EP1699438B1/en active Active
  • 2004-12-02 ES ES04804655T patent/ES2363503T3/es active Active
  • 2004-12-02 BR BRPI0417420-8A patent/BRPI0417420B1/pt active IP Right Grant
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  • 2004-12-02 DK DK04804655.1T patent/DK1699438T3/da active
  • 2004-12-02 CN CNB2004800366347A patent/CN100508966C/zh active Active
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  • 2004-12-02 US US10/581,367 patent/US20080194687A1/en not_active Abandoned
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• 2011
  • 2011-04-06 US US13/081,036 patent/US8927017B2/en active Active
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