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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
• • 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
  • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
• • 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
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
  • A61K9/1605—Excipients; Inactive ingredients
  • A61K9/1629—Organic macromolecular compounds
  • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—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

Definitions

• the present invention relates to a sustained release composition of ibuprofen or pharmaceutically acceptable salt thereof, comprising high drug load of active ingredient and its method of preparation.
• Ibuprofen is 2-(4-isobutylphenyl) propionic acid known as ibuprofen, is a non-steroidal anti-inflammatory compound (NSAID), which exhibits high levels of anti-inflammatory, analgesic and antipyretic activities necessary for the effective treatment of rheumatoid arthritis and osteo-arthritis and other inflammatory conditions. It is available in both prescription and OTC dosages. Compared with other non-steroidal anti-inflammatory products, ibuprofen is distinguished by inter alia, being well tolerated by the stomach.
• NSAID non-steroidal anti-inflammatory compound
• dosage forms of ibuprofen are immediate release dosage forms that provide rapid onset of therapeutic action, then rapidly declining levels of active ingredient, necessitating repeated dosing. They do not maintain therapeutic levels from one treatment over an extended period of time. Repeat dosing is thus required at intervals of four to six hours.
• the recommended dose for the treatment of, in particular, rheumatoid arthritis and osteoarthritis is 1200 mg-3200 mg daily (400 mg, 600 mg or 800 mg tid or qid).
• a dose of 400 mg of ibuprofen in every 4 to 6 hours is necessary for relief of pain and a dose of 400 mg every 4 hours is necessary for the treatment of dysmenorrhea.
• US patent application No. 20060068009 describes a solid dosage form for modified oral administration of ibuprofen comprising a hydrophilic polymer, 10% to 35% by weight of the ibuprofen and a dissolution additive.
• European Patent application No. 061217 describes a product with delayed release of the active compound, which is composed of hard gelatin capsules containing 300 mg of ibuprofen. The production is carried out in a coating pan. Ibuprofen in the form of a powder is bound, by means of low-viscosity polyvinylpyrrolidone, over a spherical core composed of sugar and starch, the spheroids are then coated with a high-viscosity polyvinylpyrrolidone and the final spheroids are encapsulated. Ibuprofen has a low melting point (75°-77°C) which is reduced further on mixing with customary excipients.
• ibuprofen is having very low melting point, there is a particularly disadvantageous effect in the preparation of controlled-release products which frequently contain fatty compositions or similar low melting auxiliaries like lipids such as hydrogenated oils or paraffins according to JP No. 84-122,425 A.
• any process of preparation of ibuprofen dosage form using temperature higher than the melting point of active ingredient causes instability of the active ingredient.
• sustained release composition of ibuprofen is the most suitable dosage form considering its pharmacokinetic profile
• the known sustained release dosage forms in the art are having so many drawbacks like higher dosage size; complex, time consuming and costly method of preparation; stability problem. So there is a need to develop a sustained release composition which will solve most of the problems of the current composition.
• one of the objects of the present invention to provide a sustained release pharmaceutical composition with high drug loading comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more, preferably about 85% in the weight of the active ingredient based on the total weight of the composition.
• Another object of the present invention to provide a sustained release pharmaceutical composition
• a sustained release pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof prepared by hot melt extrusion method using processing temperature below the melting point of active ingredient.
• another object of the present invention to provide a sustained release pharmaceutical composition
• a sustained release pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of 80% or more in the weight of the active ingredient based on the total weight of the composition prepared by hot melt extrusion method.
• Another object of the present invention to provide a sustained release pharmaceutical composition
• a sustained release pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof prepared by hot melt extrusion method using processing temperature below 70°C.
• another object of the present invention to provide a sustained release pharmaceutical composition
• a sustained release pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of 80% or more in the weight of the active ingredient based on the total weight of the composition prepared by hot melt extrusion method using processing temperature below the melting point of active ingredient.
• another object of the present invention to provide a sustained release pharmaceutical composition
• a sustained release pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of 80% or more in the weight of the active ingredient based on the total weight of the composition prepared by hot melt extrusion method using processing temperature below 70°C.
• Another object of the present invention to provide a process of preparation of a pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of 80% or more in the weight of the active ingredient based on the total weight of the composition.
• Another object of the present invention to provide to a process of preparation of a pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of 80% or more in the weight of the active ingredient based on the total weight of the composition by hot melt extrusion method.
• Another object of the present invention to provide a process of preparation of a pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof by hot melt extrusion method using processing temperature below the melting point of active ingredient.
• Another object of the present invention to provide a process of preparation of a pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof by hot melt extrusion method using processing temperature below 70°C.
• the present invention relates to a sustained release composition of ibuprofen or pharmaceutically acceptable salt thereof.
• the present invention relates to a sustained release composition of ibuprofen or pharmaceutically acceptable salt thereof, comprising high drug load of active ingredient.
• the sustained release pharmaceutical composition with high drug loading comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more, preferably about 85% in the weight of the active ingredient based on the total weight of the composition.
• the present invention relates to a sustained release pharmaceutical composition comprising ibuprofen or a pharmaceutically acceptable salt thereof prepared by hot melt extrusion method using processing temperature below the melting point of active ingredient.
• ibuprofen includes various forms of ibuprofen such as hydrates, solvates, polymorphs, isomers, stereoisomers, enantiomers, racemates, esters, prodrugs, complexes or mixture thereof and all other forms known in the art.
• Ibuprofen can be present in different physical forms, e.g. in an amorphous form, in one or several crystal form (s) (e.g. anhydrous, solvated or hydrated forms), in the form of mixture of different crystal forms (e.g. anhydrous, solvated or hydrated forms) or as a mixture of an amorphous form and crystal form (s) (e.g. anhydrous, solvated or hydrated forms).
• pharmaceutical composition refers to a solid dosage form suitable for administration, such as a tablet, capsule, caplets, powders, pellets, beads, microspheres, granules, pill, etc.
• pharmaceutically acceptable salt means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime).
• Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids.
• the active ingredient, active agent and drug herein can be interchangeably used.
• % refers to the weight percent of a substance as it relates to the overall composition unless otherwise indicated.
• the term “comprising”, which is synonymous with “including”, “containing”, or “characterized by” here is defined as being inclusive or open-ended, and does not exclude additional, unrecited elements or method steps, unless the context clearly requires otherwise.
• Sustained release rate of an active agent is the rate of release of the active agent other than that of an immediate release formulation as per USP.
• sustained release includes but not limited to slow release, controlled release, prolonged release, extended release, timed release etc., which terms are generally known in the art and to the extent they mean a release other than an immediate release.
• the sustained release composition of ibuprofen or pharmaceutically acceptable salt thereof comprising high drug load of active ingredient is relatively small size and accommodate more drug in the dosage form.
• the sustained release pharmaceutical composition with high drug loading comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more, preferably about 85% in the weight of the active ingredient based on the total weight of the composition.
• the remaining of the dosage form is release rate controlling agents and optionally one or more excipients required for the dosage form preparation.
• Release rate controlling agents are defined as hydrophilic or hydrophobic agents, which can be polymeric or non-polymeric and which are capable of controlling the release rate of an active agent, preferably the rate controlling agent is a hydrophilic agent.
• the release controlling agents may be natural, semi-synthetic and synthetic agents or mixtures thereof.
• the release controlling agent can be used in the concentration ranges from about 1 to about 20 % w/w of the total composition, preferably from about 1 to about 15 % w/w of the total composition.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition, mixed with at least one hydrophilic release rate controlling agent.
• the hydrophilic release rate controlling agents preferably, hydrophilic polymers gel and dissolve slowly in gastrointestinal track thereby allowing ibuprofen to diffuse from the gel for sustained action.
• hydrophilic release rate controlling agents suitable for use in the sustained release pharmaceutical composition include: one or more natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum, celluloses and cellulose derivatives such as methylecllulose, hydroxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, carboxyethylcellulose, hydroxybutylmethyl cellulose, sodium carboxymethyl cellulose, polycarbonates, polyalkylenes, polyalkylene glycols such as poly(ethylene glycol), polyalkylene oxides, polyalkylene terephthalates, polyvinyl alcohols (PVA), polyvinyl phenol, polyvinyl ethers, polyvinyl esters, polyvinyl halides, polyvinylpyrrolidone (PVP), polyglycolides, polysiloxanes, polyure thanes
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition, mixed with at least one hydrophobic release rate controlling agent.
• hydrophobic release rate controlling agents includes but are not limited to hydrogenated vegetable oil, but other suitable agents include purified grades of beeswax; fatty acids; long chain fatty alcohols, such as cetyl alcohol, myristyl alcohol, and stearyl alcohol; glycerides such as glyceryl esters of fatty acids like glyceryl monostearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like, or acetylated glycerides; ethyl cellulose, stearic acid, paraffin, carnauba wax, talc; and the stearate salt(s) such as calcium, magnesium, zinc, cellulose derivatives like ethylcellulose and other materials known to the person skilled in the art; preferably ethylcellulose and stearic acid.
• fatty acids such as cetyl alcohol, myristyl alcohol, and stearyl alcohol
• a type of low viscosity polyvinylpyrrolidone is for instance that available on the market under the trademark Kollidon ® 30 and a high viscosity polyvinylpyrrolidone is for instance that available on the market under the trademark Kollidon ® 90 and Kollidon ® SR of the company BASF AKTIENGESELL-SCHAFT of Ludwigshafen, Federal Republic of Germany.
• Ethylcellulose is for instance that available on the market under the trademark Ethocel of Dow Chemicals Ltd is used in the composition.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition, mixed with at least one hydrophilic release rate controlling agent and at least one hydrophobic release rate controlling agent.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof prepared by hot melt extrusion method using processing temperature below the melting point of the active ingredient (i.e. below 75°C), preferably below 70°C.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition prepared by hot melt extrusion method using processing temperature below the melting point of the active ingredient (i.e. below 75°C), preferably below 70°C.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition, mixed with at least one hydrophilic release rate controlling agent, prepared by hot melt extrusion method using processing temperature below the melting point of the active ingredient (i.e. below 75°C), preferably below 70°C.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition, mixed with at least one hydrophobic release rate controlling agent, prepared by hot melt extrusion method using processing temperature below the melting point of the active ingredient (i.e. below 75°C), preferably below 70°C.
• a sustained release composition comprises ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition, mixed with at least one hydrophilic release rate controlling agent and at least one hydrophobic release rate controlling agent, prepared by hot melt extrusion method using processing temperature below the melting point of the active ingredient (i.e. below 75°C), preferably below 70°C.
• a) sieving and mixing active ingredient and a release rate controlling agent b) heating the mixture in a hot melt extrusion to prepare a solid dispersion, c) cooling the solid dispersion to room temperature, milling to achieve suitable d) optionally filling into a capsule or compressing into a tablet.
• compositions can be in the form of a tablet, capsule, caplets, powders, pellets, beads, microspheres, granules, pill, etc.
• the preferred dosage form is capsule and tablet.
• the dosage form is preferably suitable for oral application.
• a sustained release pharmaceutical composition with high drug loading comprising ibuprofen or a pharmaceutically acceptable salt thereof in an amount of about 80% or more in the weight of the active ingredient based on the total weight of the composition and one or more excipients such as binders, diluents, lubricants/glidants, disintegrating agents, surfactants, solvents, and coloring agents.
• Excipients such as diluents, lubricants and glidants commonly used in pharmaceutical composition may be used and reference is made to the extensive literature on suitable substances [see in particular "Handbook of Pharmaceutical Excipients” edited by Raymond C Rowe, Paul J Sheskey & Sian C Owen (2006)] the content of which is incorporated herein by reference.
• excipients are also used in the preparation of the pharmaceutical composition like diluents such as microcrystalline cellulose, powdered cellulose, lactose (anhydrous or monohydrate), compressible sugar, fructose, dextranes, other sugars such as mannitol, sorbitol, lactitol, saccharose or a mixture thereof, siliconised microcrystalline cellulose, calcium hydrogen phosphate, calcium carbonate, calcium lactate or mixtures thereof.
• a further preferred diluent that also causes reduced sticking properties of tablets to the equipment used for tabletting is silica, preferably colloidal or fumed silica.
• the excipients include at least one diluent selected from microcrystalline cellulose and lactose monohydrate.
• Non-limiting examples of binders include one or more of gum acacia, cholesterol, tragacanth, stearic acid, gelatin, casein, lecithin (phosphatides), carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcelluloses, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose phthalates, microcrystalline celluloses, noncrystalline celluloses, polyvinylpyrrolidones (povidones or PVP), cetostearyl alcohol, cetyl alcohol, cetyl esters wax, dextrates, dextrin, lactose, dextrose, glyceryl monooleate, glyceryl monostearate, glyceryl palmitostearate, polyoxyethylene alkyl ethers, polyethylene glycols, polyoxyethylene castor oil derivatives, polyoxyethylene stearates, polyvinylalcohols, and mixtures thereof.
• binders include one or more of gum a
• Non-limiting examples of disintegrants include starches, modified starches, croscarmellose sodium, crospovidones, and sodium starch glycolate.
• the composition according to the invention can also comprise lubricants, such as stearic acid, magnesium stearate, calcium stearate, sodium lauryl sulphate, hydrogenated vegetable oil, hydrogenated castor oil, sodium stearyl fumarate, macrogols, or mixtures thereof. It is preferred that the excipients include at least one lubricant, selected from stearic acid, magnesium stearate, calcium stearate and sodium lauryl sulphate, more preferably from stearic acid, magnesium stearate and calcium stearate.
• the composition can also comprises glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
• glidants such as colloidal silica (e. g. Aerosil®), magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate.
• Useful coloring agents include FDA approved colorants and examples are iron oxides, lake of tartrazine, allura red, lake of quinoline yellow, and lake of erythrosine.
• compositions prepared can be packaged using appropriate packaging materials such as containers and closures composed of polyethylene (high density polyethylene or low density polyethylene), polypropylene, glass, stainless steel, etc.
• PVC/PVDC polyvinylidene dichloride
• the In vitro dissolution test was performed at 30 rpm with USP apparatus I (Basket), using pH 6.0 phosphate buffer as a dissolution media.
• the dissolution medium used was 900 ml; maintained at 37 ⁇ 0.5°C.
• the dissolution profiles of various formulations tested are as below:

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• 2013
  • 2013-12-27 IN IN5549CH2012 patent/IN2012CH05549A/en unknown
  • 2013-12-27 WO PCT/IB2013/061370 patent/WO2014102745A1/en active Application Filing

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