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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0007—Effervescent
• • 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
  • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7135—Compounds containing heavy metals
  • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • 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
  • A61K9/1682—Processes
• • 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
  • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/08—Antiepileptics; Anticonvulsants

Definitions

• the present invention relates to pharmaceutical formulations comprising pregabalin that shall be used in the treatment of epilepsy, central nervous system disorders, Parkinson's disease; Huntington's disease; tardive dyskinesia; spasticity; cerebral ischemia; postherpetic neuralgia; social phobia; fibromyalgia and spinal cord injury induced chronic pains; neuropathic pains associated with diabetic peripheral neuropathy and common anxiety disorder.
• Pregabalin was first disclosed in the application numbered EP 0641330 Bl. In said document, it was disclosed that use of pregabalin is effective in the treatment of central nervous system disorders, epilepsy, Parkinson's disease; Huntington's disease; tardive dyskinesia; spasticity; cerebral ischemia.
• Pregabalin is available in 25mg, 50mg, 75mg, lOOmg, 150mg, 200mg, 225mg and 300mg capsule, oral forms on the market.
• the present invention relates to pharmaceutical formulations comprising pregabalin and methods for preparation of these formulations.
• at least one excipient and optionally a second active agent is in the range of 300 - 2500 ⁇ , preferably in the range of 350 - 2000 ⁇ , more preferably in the range of 500 - 1750 ⁇ are formed into any solid dosage form, their relative standard deviation is low, a homogeneous pharmaceutical composition is obtained and weight and content uniformity are provided by preventing weight changes.
• average particle size of the granules comprising pregabalin, at least one excipient and optionally the second active agent is in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ in preparation of the formulations comprising pregabalin.
• average particle size refers to average particle size by volume and it is also shown with dso in short. In this sense, the term dso signifies that half of the said substance by volume has a particle size over the value stated with dso and the other half of the substance by volume has a particle size below the value stated with d 50
• Dso value can be measured by one of the known measuring devices, for instance by a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.). r , . , maybe,
• the present invention relates to a process that shall be usea in production oi the granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ and comprising pregabalin, at least one excipient and optionally the second active agent characterized in that said granules having an average particle size in the range of 300-2500 ⁇ , preferably in the range of 350-2000 ⁇ , more preferably in the range of 500-1750 ⁇ are obtained by
• pulverization is performed by the impact of rotating blades in the device.
• pulverization is performed by the impact of rotating hammers in the device.
• pulverization is performed by providing collision of the particles with each other with the help of high-pressured and high-speed airstream.
• the pharmaceutical formulation according to the present invention can be obtained by a method comprising
• T e mvCTwrs ⁇ o serve re at ve stan ar ev at on o we g t y cha c particle size values of the granules in order to find the effect of the average particle size of the granules sieved after granulation and drying processes on weight changes and therefore on weight uniformity in the solid dosage form obtained.
• the average particle size values of the granules obtained after the sieving process and the relative standard deviation values (RSD %) observed according to these values are given in Table 1.
• Table 1 Average particle sizes of the granules and relative standard deviation values according to these particle sizes.
• the parameters such as drying temperature and moisture ratio of the obtained granules are important in order to attain optimum values of hardness, fragility and stability characteristics of the granules obtained and the end product in solid form prepared by using said granules during preparation of the formulations comprising pregabalin and therefore important for preventing possible problems that may be encountered during quality control and use phases.
• the inventors have surprisingly seen that the granules obtained according to the process of the present invention by being dried at 10-120°C, preferably at 20-100°C and more preferably at 25-70°C show proper flow characteristics and the solid forms prepared with these granules have desired hardness and fragility.
• the present invention relates to drying the granules comprising pregabalin, at least one excipient and optionally the second active agent at a temperature in the range of 10-120°C, preferably at a temperature in the range of 20-100°C and more preferably at a temperature in the range of 25-70°C in preparation of the formulations comprising pregabalin.
• the present invention relates to drying the granules comprising pregabalin, at least one excipient and optionally the second active agent to have a moisture ratio less than 1% by weight, preferably in the range of 0.1-0.9% by weight in preparation of the formulations comprising pregabalin.
• Pregabalin comprised in the pharmaceutical formulations prepared according to the process of the present invention is in the form of its free base or pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomers or combinations; in amorphous form or crystalline form or a combination thereof in terms of polymorphic structure.
• compositions prepared according to the process of the present invention and comprising pregabalin can be prepared in any solid dosage form such as tablet, ⁇ , w ,
• effervescent tablet effervescent granule, effervescent dry powder
• film coated tablet enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet.
• the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin are preferably in the form of effervescent tablet or tablet, more preferably in effervescent tablet form.
• the pharmaceutical formulation obtained according to the present invention can be formed into any abovementioned dosage forms.
• the obtained tablets can be treated with film coating agents for instance, sugar based coating agents, water soluble film coating agents, enterically coating agents, delayed release coating agents or coating compositions comprising a combination thereof.
• Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
• the water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
• the enterically coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or the combinations thereof.
• the delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion or combinations thereof.
• compositions prepared according to the process of the present invention and comprising pregabalin can comprise various excipients in addition to the active agent pregabalin. ,. ,
• the pharmaceutical formulations prepared accordmg to the process of the present invention and comprismg pregabalin comprise at least one excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent pregabalin and lubricant.
• excipient selected from a group comprising disintegrant, diluent, lubricant, glidant, binder, effervescent couple comprising at least one acidic agent and at least one basic agent, colouring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavouring agent in addition to the active agent pregabalin and lubricant.
• the disintegrant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from a group comprising carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycolate.
• the diluent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
• the glidant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
• the binder that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
• the acidic agent composing the effervescent couple comprising at least one acidic agent and at least one basic agent that can be used in the pharmaceutical compositions of the present invention comprising pregabalin selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid; and the basic agent can be selected from a group comprising agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
• the pH regulating agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from citrate, phosphate, carbonate, tartrate, fumarate, acetate and amino acid salts.
• the surfactant that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from sodium lauryl sulphate, polysorbate, polyoxyethylene, polyoxypropylene glycol and similar agents.
• the stabilizing agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from a group comprising tocopherol, tetrasodium edetate, nicotinamide, cyclodextrin.
• the sweetener and or taste regulating agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from a group comprising acesulfame, aspartame, dextrose, fructose, maltitol, maltose, mannitol, saccharine, saccharine sodium, sodium cyclamate, sorbitol, sucralose, sucrose, xylitol, sodium chloride.
• the flavouring agent that can be used in the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can be selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
• the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can comprise pregabalin in the range of 0.1 to 99.9 % by weight, preferably in the range of 1 to 99% by weight, more preferably in the range of 5 to 95% by weight.
• the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin can optionally comprise a second active agent in addition to pregabalin.
• the second active agent can be selected from antacid, anticholinergic, antispasmodic, antiemetic, antidiabetic, antipropulsive, antiallergic, antidiarrheal, antiobesity, antithrombotic, antifibrinolytic, antianemic, antihypertensive, antifungal, antipruritic, antipsoriatic, antibiotic, antiseptic, antiacne, antibacterial, antimycotic, antiviral, antineoplastic, antiarrhythmic, antiadrenergic, antiepileptic, anti-parkinson, antiprotozoal, anthelmintic, anti-inflammatory, diuretic, laxative, sulphonamide, imidazole, corticosteroid, thiazolidinedione, biguanide, immunostimulant, immunosup
• the pharmaceutical formulations prepared according to the process of the present invention and comprising pregabalin preferably comprise a vitamin; more preferably comprise vitamin B 12 as the second active agent in addition to pregabalin.
• the pharmaceutical formulations prepared according to the process of the present invention and comprising a second active agent in addition to pregabalin can be prepared in any solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet in the case that two active agents are comprised in the same formulation; in dosage forms such as layered tablet, capsule in the case that the two active agents are in different formulations but in the same dosage form; in treatment package form comprising a combination of the solid dosage forms such as tablet, effervescent tablet, effervescent granule, effervescent dry powder, film coated tablet, enterically coated tablet, dry powder, granule, capsule, prolonged release tablet, modified release tablet, delayed release tablet or in the form of capsule comprising micro tablet and/or micropellet in the case that the two active agents are in different formulations and dosage forms.
• any solid dosage forms such as
• the pharmaceutical formulation according to the present invention can be used in the prevention and treatment of epilepsy, central nervous system disorders, Parkinson's disease; Huntington's disease; tardive dyskinesia; spasticity; cerebral ischemia; postherpetic neuralgia; social phobia; fibromyalgia and spinal cord injury induced chronic pains; neuropathic pains associated with diabetic peripheral neuropathy and common anxiety disorder.
• Pregabalin and the diluent are mixed.
• the mixture is granulated with the granulation solution comprising the binder.
• the granules obtained are dried, mixed with the disintegrant and other excipients.
• the final mixture obtained is compressed in tablet compression machine and coated with the film coating agent.
• the formulation comprising pregabalin and excipients is granulated with the granulation solution comprising a pharmaceutically acceptable binder.
• the granulation solution used herein can comprise any solvent in addition to the binder.
• the granules are dried and sieved.
• the sweetener, the flavouring agent and the lubricant are added and the formulation is finalised.
• Optionally tablet compression is performed.

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Cited By (3)

Citations (7)

• 2012
  • 2012-12-19 WO PCT/TR2012/000221 patent/WO2013100873A1/fr not_active Ceased

Patent Citations (7)

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