WO2012153313A1 - Pharmaceutical composition of febuxostat - Google Patents

Pharmaceutical composition of febuxostat Download PDF

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Publication number
WO2012153313A1
WO2012153313A1 PCT/IB2012/052371 IB2012052371W WO2012153313A1 WO 2012153313 A1 WO2012153313 A1 WO 2012153313A1 IB 2012052371 W IB2012052371 W IB 2012052371W WO 2012153313 A1 WO2012153313 A1 WO 2012153313A1
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WO
WIPO (PCT)
Prior art keywords
febuxostat
immediate
composition
release
release febuxostat
Prior art date
Application number
PCT/IB2012/052371
Other languages
French (fr)
Inventor
Ajay K. SINGLA
Mukesh Garg
Amit Gupta
Prakash A. JADHAV
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Ranbaxy Laboratories Limited
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Publication date
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Publication of WO2012153313A1 publication Critical patent/WO2012153313A1/en

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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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • 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

Definitions

  • the present invention relates to an immediate-release febuxostat composition and process of preparation for the same.
  • Febuxostat is chemically known as 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5- thiazolecarboxylic acid. (U.S. Patent Nos. 5,614,520 and 6,225,474).
  • Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It works by non-competitively blocking the channel leading to the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat is a useful therapeutic agent for gout and hyperuricemia. In a comparative study between febuxostat and allopurinol, it was found that more individuals treated with febuxostat had decreased levels of uric acid. For treatment of hyperuricemia in patients with gout, febuxostat is recommended at 40 mg or 80 mg once daily. No dose adjustment is necessary when administering febuxostat in patients with mild to moderate renal and hepatic impairment.
  • Febuxostat is commercially available as an immediate-release formulation in the form of tablets.
  • febuxostat is classified as a Class 2 compound (low solubility, high permeability). It suffers from the disadvantage of being poorly soluble in an aqueous medium, thus having an insufficient dissolution profile and, consequently, poor bioavailability within the organism following oral administration. The therapeutic dose required to be administered must thus be increased in order to obviate this disadvantage.
  • U.S. Patent No. 6,225,474 assigned to Teijin Limited discloses six crystal polymorphs of febuxostat designated as crystal A, B, C, D, E and G.
  • U.S. Patent No. 7,361,676 discloses a pharmaceutical preparation containing crystal A with average particle diameter from 12.9 ⁇ to 26.2 ⁇ .
  • CN 101966163 discloses dispersible tablets of febuxostat.
  • CN 101953814 discloses a solid preparation prepared from febuxostat and medicinal adjuvants.
  • CN 101940562 discloses a solid preparation composed of nano-capsules of febuxostat or its medicinal salt and drug accessories.
  • the present invention relates to an immediate-release febuxostat composition
  • an immediate-release febuxostat composition comprising:
  • micronized form having an average particle size less than 50 um, a hydrophilic polymer and, optionally, a surfactant;
  • composition of present invention can optionally have one or more film coatings.
  • the present invention relates to a process for preparing an immediate-release febuxostat composition
  • a process for preparing an immediate-release febuxostat composition comprising:
  • step b) applying the suspension from step a) to an inert carrier;
  • Step b) is preferably carried out in a fluidized-bed granulator.
  • the method can comprise a step in which products obtained from step b) or c) are compressed, with or without additional excipients.
  • the compositions according to the invention can additionally contain any excipient conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as diluents, binders, disintegrants, lubricants, glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents and combinations thereof.
  • the invention also provides a solution or suspension of febuxostat in micronized form having an average particle size less than 50 ⁇ , in a solution of hydrophilic polymer and, optionally, surfactant.
  • hyperuricemia by administering to a person in need thereof an immediate-release febuxostat composition
  • an immediate-release febuxostat composition comprising:
  • micronized form having an average particle size less than 50 ⁇ ⁇ , a hydrophilic polymer and, optionally, a surfactant;
  • composition of febuxostat described herein may be administered in combination with other therapeutic agents.
  • the present invention relates to an immediate-release febuxostat composition
  • an immediate-release febuxostat composition comprising:
  • an inert carrier covered with at least one layer containing febuxostat in a micronized form having an average particle size less than 50 ⁇ , a hydrophilic polymer and, optionally, a surfactant;
  • micronized form in this invention means a substance in a particulate form, wherein the average particle size being less than 50 ⁇ .
  • carrier includes any excipient, pharmaceutically inert, crystalline or amorphous, in a particulate form, not leading to a chemical reaction under the operating conditions employed.
  • the inert carrier may be hydrosoluble or hydroinsoluble.
  • inert carriers comprise sucrose, lactose, maltodextrin, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, celphere and non-pareils.
  • the carriers may be of any geometric shape, though spheres are particularly used for the case of uniform coating.
  • the individual particle size of the inert carrier can be, for example, between 50 ⁇ and 500 um.
  • Febuxostat used herein, encompasses all the polymorphic crystals, solvates, hydrates, co-crystals as well as amorphous forms of febuxostat, i.e., Crystal A, B, C, D, G as disclosed in U.S. Patent No. 6,225,474 or any other stable form of febuxostat.
  • hydrophilic polymers used in the invention include, but are not limited to, one or more of cellulose derivatives such as hydroxypropylmethylcellulose,
  • alginates such as ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid; polyvinyl alcohol; povidone; crosslinked polyacrylic acid polymers such as carbomer, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, co-povidone, polysaccharide, polyalkylene oxides, polyalkyleneglycol, starch and derivatives; and mixtures thereof.
  • surfactant used in the composition may be amphoteric, non-ionic, cationic or anionic. Examples include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of
  • polyoxyethylene sorbitane sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, and mixtures thereof.
  • DOSS sodium dioctylsulfosuccinate
  • lecithin lecithin
  • stearylic alcohol cetostearylic alcohol
  • cholesterol polyoxyethylene ricin oil
  • polyoxyethylene fatty acid glycerides polyoxyethylene fatty acid glycerides
  • poloxamer poloxamer
  • the expression "outer phase or layer” should be taken to mean any coating on the element (a) with the active ingredient forming a "core". Indeed, it can be useful to have available one or several phase(s) or layer(s) on top of the coated core.
  • the invention thus covers a single core with one layer, but also several cores in a phase, as is the case of tablets which are formed from “cores” mixed with a phase.
  • compositions according to the invention can additionally contain any excipient conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as diluents, binders, disintegrants, lubricants/glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents, and combinations thereof.
  • solvents used for preparing a solution or suspension of the febuxostat include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, methylethylketone, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 0.1M NaOH, and mixtures thereof.
  • the solvents used in the composition include, but are not limited to, water, methylethylketone, acetone, DMSO, ethanol, 0.1M NaOH, m
  • fillers or diluents include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized.
  • the fillers comprise lactose, microcrystalline cellulose, calcium hydrogen phosphate dehydrate, or a mixture thereof.
  • binders include, but are not limited to, povidones, starches, corn starch, pregelatinized starch, microcrystalline celluloses (MCC), silicified MCC (e.g.,
  • ProsolvTMHD 90 microfine celluloses, lactose, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, stearic acid, gums, hydroxypropyl methylcelluloses or hypromelloses (e.g., KlucelTMEF, MethocelTME5 premium) and other pharmaceutically acceptable substances with cohesive properties.
  • hypromelloses e.g., KlucelTMEF, MethocelTME5 premium
  • disintegrants include, but are not limited to, cross-linked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, agar-agar, calcium carbonate, sodium carbonate, alginic acids, cross-carmellose sodium, sodium starch glycolate, microcrystalline cellulose, and mixtures thereof.
  • lubricants and glidants examples include, but are not limited to, colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, solid polyethylene glycols, sodium stearyl fumarate, silica gel and mixtures thereof and other substances with lubricating or gliding properties.
  • colloidal silicon dioxide such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, solid polyethylene glycols, sodium stearyl fumarate, silica gel and mixtures thereof and other substances with lubricating or gliding properties.
  • buffers examples include, but are not limited to, phosphate, acetate, citrate, succinate and histidine buffers.
  • wetting agents examples include, but are not limited to, ammonium lauryl sulfate and sodium lauryl sulfate.
  • the coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
  • compositions according to the invention comprise, in general, based on the total composition weight an inert carrier making up from 10% to 80% by weight, preferably 30% to 60% by weight, the febuxostat representing from 5% to 50% by weight, preferably from 15% to 35% by weight, the hydrophilic polymer representing from 1% to 50% by weight, preferably 5% to 40% by weight, the surfactant making up from 0% to 10% by weight, preferably 0.1% to 3% by weight.
  • the outer layer or phase if present, can make up to 80% by weight of the total weight, preferably up to 50% by weight.
  • the composition according to the invention takes the form of tablets.
  • This tablet preferably results from the compression of elements (a) (under the form of granules) together with an outer phase.
  • composition of the invention takes the form of granules enclosed inside a capsule, for example, in gelatin, or inside a bag.
  • compositions of the invention are particularly suitable for administering active ingredients by oral route.
  • composition according to the invention is prepared by a process comprising spraying a solution or suspension of the active ingredient in a micronized form in a solution of a hydrophilic polymer and, optionally, a surfactant, onto the inert cores.
  • the method according to the invention consists in using the fluidized-bed granulation principle, but with specific starting materials, in order to arrive at an improved dissolution profile and thus, at elevated bioavailability.
  • the invention employs a suspension or solution of the micronized active ingredient in a solution of a hydrophylic polymer and, optionally, a surfactant.
  • the fluidized-bed granulation technique is widely used in the pharmaceutical industry for preparing capsules or tablets.
  • a powder or a mixture of powders (active ingredient+excipients) is put into suspension in the fluidized bed in a granulator, and a solution containing a binder and, optionally, a surfactant, is sprayed onto this bed to form granules.
  • the fluidized-bed granulation technique is well known to those skilled in the art.
  • the invention comprises spraying a solution or suspension of an active ingredient micronized with a hydrophilic polymer onto an inert carrier.
  • the granulate formed consists of crystals of, for example, lactose, which are isolated (or possibly agglomerated together by the spray solution) and particles of active ingredient and PVP adhering to the crystal surface.
  • the granulate could similarly be constituted of coated crystals which are agglomerated, or even of such an agglomerate having received a coating.
  • the granulates thus obtained can, if desired, be provided with an outer coating or compressed into tablets, or form agglomerates.
  • the outer layer or layer is/are applied using conventional coating techniques such as coating in a pan or fluidized bed coater.
  • this step can be implemented using any conventional technique which is suitable, for example, using an alternating or rotating compressing equipment.
  • the tablets may further be film coated. Additional excipients such as film-forming polymers, solvents, plasticizers, antiadherents, opacifiers and optionally colorants, pigments, antifoam agents, and polishing agents can be used in coatings.
  • film-forming agents include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as
  • methylcelluloses hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc.; insoluble cellulose derivatives such as ethylcelluloses and the like; dextrins; starches and starch derivatives; polymers based on carbohydrates and derivatives thereof; natural gums such as gum Arabic; xanthans; alginates; polyacrylic acids; polyvinyl alcohols; polyvinyl acetates; polyvinylpyrrolidones; polymethacrylates and derivatives thereof (Eudragit® products), chitosan and derivatives thereof; shellac and derivatives thereof; waxes and fat substances.
  • insoluble cellulose derivatives such as ethylcelluloses and the like
  • dextrins such as ethylcelluloses and the like
  • starches and starch derivatives polymers based on carbohydrates and derivative
  • the coating can also be performed using any commercially available ready-to-coat preparations such as Opadry® AMB, Opadry® White, Opadry® Clear, Opadry® II, etc.
  • Opadry® formulations generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate.
  • OPADRY® products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures.
  • excipients are used as adjuvants to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like.
  • plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof.
  • An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.
  • Antiadhesives are frequently used in the film coating process to avoid sticking effects during film formation and drying.
  • An example of an antiadhesive for this purpose is talc.
  • polishing agents include, but are not limited to, polyethylene glycols of various molecular weights, or mixtures thereof, talc, surfactants (e.g., glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).
  • surfactants e.g., glycerol monostearate and poloxamers
  • fatty alcohols e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol
  • waxes e.g., carnauba wax, candelilla wax and white wax.
  • the present invention also encompasses suspension of the active ingredient.
  • This suspension is prepared by putting the micronized active ingredient into suspension in a solution comprising the hydrophylic polymer and, optionally, a surfactant, in solution in a solvent. If a surfactant is employed, it is put into solution in the solvent.
  • the hydrophylic polymer is dispersed, while stirring, in the solution previously obtained. Depending on polymer solubility, this either dissolves in the solution or forms a gel or a suspension having varying degrees of thickness.
  • the micronized active ingredient is dispersed in the form of a fine shower into the above solution or suspension, to form a homogeneous suspension.
  • the order of these steps can be reversed.
  • the solvent employed can be aqueous or organic (for example, ethanol).
  • demineralized water can be used.
  • composition of the invention may be used in treating conditions such as gout and hyperuricemia.
  • the pharmaceutical composition of febuxostat may be administered in combination with other therapeutic agents.
  • Polyvinylpyrrolidone was dissolved in purified water and febuxostat was dispersed under continuous stirring. Drug dispersion was passed through a colloid mill.
  • step 3 Pregelatinised starch of step 3 was coated with the dispersion of step 2 in a fluid bed processor.
  • the granules were dried to achieve desired LOD and passed through suitable mesh.
  • Microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sifted through suitable mesh and blended with granules of step 5 in suitable blender. 7.
  • Sodium stearyl fumarate was sifted through suitable mesh and blended with the blend of step 6.
  • step 7 The blend of step 7 was compressed.
  • the film coating suspension was prepared and step 8 core tablets were coated.

Abstract

The present invention relates to an immediate-release febuxostat composition and process of preparation for the same. It also relates to a method of treating gout and hyperuricemia using the composition of the present invention.

Description

PHARMACEUTICAL COMPOSITION OF FEBUXOSTAT
Field of the Invention
The present invention relates to an immediate-release febuxostat composition and process of preparation for the same.
Background of the Invention
Febuxostat is chemically known as 2-(3-cyano-4-isobutyloxyphenyl)-4-methyl-5- thiazolecarboxylic acid. (U.S. Patent Nos. 5,614,520 and 6,225,474).
Febuxostat is a non-purine selective inhibitor of xanthine oxidase. It works by non-competitively blocking the channel leading to the active site on xanthine oxidase. Xanthine oxidase is needed to successively oxidize both hypoxanthine and xanthine to uric acid. Febuxostat inhibits xanthine oxidase, therefore reducing production of uric acid. Febuxostat is a useful therapeutic agent for gout and hyperuricemia. In a comparative study between febuxostat and allopurinol, it was found that more individuals treated with febuxostat had decreased levels of uric acid. For treatment of hyperuricemia in patients with gout, febuxostat is recommended at 40 mg or 80 mg once daily. No dose adjustment is necessary when administering febuxostat in patients with mild to moderate renal and hepatic impairment.
Febuxostat is commercially available as an immediate-release formulation in the form of tablets.
According to the Biopharmaceutics Classification System, febuxostat is classified as a Class 2 compound (low solubility, high permeability). It suffers from the disadvantage of being poorly soluble in an aqueous medium, thus having an insufficient dissolution profile and, consequently, poor bioavailability within the organism following oral administration. The therapeutic dose required to be administered must thus be increased in order to obviate this disadvantage.
Hence, there exists a need in the art to develop a formulation of febuxostat having improved dissolution profile and bioavailability.
U.S. Patent No. 6,225,474 assigned to Teijin Limited discloses six crystal polymorphs of febuxostat designated as crystal A, B, C, D, E and G. U.S. Patent No. 7,361,676 discloses a pharmaceutical preparation containing crystal A with average particle diameter from 12.9 μπι to 26.2 μπι.
CN 101966163 discloses dispersible tablets of febuxostat.
CN 101953814 discloses a solid preparation prepared from febuxostat and medicinal adjuvants.
CN 101940562 discloses a solid preparation composed of nano-capsules of febuxostat or its medicinal salt and drug accessories.
Summary of the invention
In one aspect, the present invention relates to an immediate-release febuxostat composition comprising:
(a) an inert carrier covered with at least one layer containing febuxostat in a
micronized form having an average particle size less than 50 um, a hydrophilic polymer and, optionally, a surfactant; and
(b) optionally one or several outer phase(s) or layer(s).
In one embodiment, the composition of present invention can optionally have one or more film coatings.
In another aspect, the present invention relates to a process for preparing an immediate-release febuxostat composition comprising:
a) preparing febuxostat solution or suspension in micronized form with an
average particle size less than 50 um, in a solution of hydrophilic polymer and, optionally a surfactant;
b) applying the suspension from step a) to an inert carrier;
c) optionally coating granules thus obtained with one or several phase(s) or
layer(s).
Step b) is preferably carried out in a fluidized-bed granulator. The method can comprise a step in which products obtained from step b) or c) are compressed, with or without additional excipients. The compositions according to the invention can additionally contain any excipient conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as diluents, binders, disintegrants, lubricants, glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents and combinations thereof.
The invention also provides a solution or suspension of febuxostat in micronized form having an average particle size less than 50 μτη, in a solution of hydrophilic polymer and, optionally, surfactant.
In yet another aspect, there is provided a method of treating gout and
hyperuricemia by administering to a person in need thereof an immediate-release febuxostat composition comprising:
a) an inert carrier covered with at least one layer containing febuxostat in a
micronized form having an average particle size less than 50 μτη, a hydrophilic polymer and, optionally, a surfactant; and
b) optionally one or several outer phase(s) or layer(s).
The pharmaceutical composition of febuxostat described herein may be administered in combination with other therapeutic agents.
The details of one or more embodiments of the inventions are set forth in the description below. Other features and objects of the invention will be apparent from the description and examples.
Detailed Description of the Invention
The present invention relates to an immediate-release febuxostat composition comprising:
a) an inert carrier covered with at least one layer containing febuxostat in a micronized form having an average particle size less than 50 μπι, a hydrophilic polymer and, optionally, a surfactant; and
b) optionally one or several outer phase(s) or layer(s).
The expression "in a micronized form" in this invention means a substance in a particulate form, wherein the average particle size being less than 50 μπι. The term "carrier", as used herein, includes any excipient, pharmaceutically inert, crystalline or amorphous, in a particulate form, not leading to a chemical reaction under the operating conditions employed.
The inert carrier may be hydrosoluble or hydroinsoluble. Examples of inert carriers comprise sucrose, lactose, maltodextrin, microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, celphere and non-pareils. The carriers may be of any geometric shape, though spheres are particularly used for the case of uniform coating. The individual particle size of the inert carrier can be, for example, between 50 μπι and 500 um.
Febuxostat, used herein, encompasses all the polymorphic crystals, solvates, hydrates, co-crystals as well as amorphous forms of febuxostat, i.e., Crystal A, B, C, D, G as disclosed in U.S. Patent No. 6,225,474 or any other stable form of febuxostat.
The hydrophilic polymers used in the invention include, but are not limited to, one or more of cellulose derivatives such as hydroxypropylmethylcellulose,
hydroxypropylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium or combinations thereof; alginates such as ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid; polyvinyl alcohol; povidone; crosslinked polyacrylic acid polymers such as carbomer, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, co-povidone, polysaccharide, polyalkylene oxides, polyalkyleneglycol, starch and derivatives; and mixtures thereof.
The term "surfactant" used in the composition may be amphoteric, non-ionic, cationic or anionic. Examples include, but are not limited to, sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of
polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, and mixtures thereof.
Here, the expression "outer phase or layer" should be taken to mean any coating on the element (a) with the active ingredient forming a "core". Indeed, it can be useful to have available one or several phase(s) or layer(s) on top of the coated core. The invention thus covers a single core with one layer, but also several cores in a phase, as is the case of tablets which are formed from "cores" mixed with a phase.
This outer layer or phase comprises conventional excipients. The compositions according to the invention can additionally contain any excipient conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as diluents, binders, disintegrants, lubricants/glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents, and combinations thereof.
Examples of solvents used for preparing a solution or suspension of the febuxostat include, but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, oils, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulphoxide, methylethylketone, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 0.1M NaOH, and mixtures thereof. Preferably, the solvents used in the composition include, but are not limited to, water, methylethylketone, acetone, DMSO, ethanol, 0.1M NaOH, methanol, acetonitrile, or mixtures thereof.
Examples of fillers or diluents include, but are not limited to, corn starch, lactose, white sugar, sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium dihydrogen phosphate dihydrates, calcium phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose, kaolin, lactitol, mannitol, starch and starch pregelatinized. Particularly, the fillers comprise lactose, microcrystalline cellulose, calcium hydrogen phosphate dehydrate, or a mixture thereof.
Examples of binders include, but are not limited to, povidones, starches, corn starch, pregelatinized starch, microcrystalline celluloses (MCC), silicified MCC (e.g.,
Prosolv™HD 90), microfine celluloses, lactose, calcium carbonate, calcium sulfate, sugar, mannitol, sorbitol, dextrates, dextrin, maltodextrin, dextrose, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, stearic acid, gums, hydroxypropyl methylcelluloses or hypromelloses (e.g., Klucel™EF, Methocel™E5 premium) and other pharmaceutically acceptable substances with cohesive properties. Examples of disintegrants include, but are not limited to, cross-linked polyvinyl pyrrolidone, corn starch, potato starch, maize starch and modified starches, agar-agar, calcium carbonate, sodium carbonate, alginic acids, cross-carmellose sodium, sodium starch glycolate, microcrystalline cellulose, and mixtures thereof.
Examples of lubricants and glidants that can be used in the present invention include, but are not limited to, colloidal silicon dioxide, such as Aerosil® 200, talc, stearic acid, magnesium stearate, calcium stearate, solid polyethylene glycols, sodium stearyl fumarate, silica gel and mixtures thereof and other substances with lubricating or gliding properties.
Examples of buffers that can be used in the present invention include, but are not limited to, phosphate, acetate, citrate, succinate and histidine buffers.
Examples of wetting agents that can be used in the present invention include, but are not limited to, ammonium lauryl sulfate and sodium lauryl sulfate.
The coloring agents and flavoring agents of the present invention may be selected from any FDA approved colors and flavors for oral use.
The compositions according to the invention comprise, in general, based on the total composition weight an inert carrier making up from 10% to 80% by weight, preferably 30% to 60% by weight, the febuxostat representing from 5% to 50% by weight, preferably from 15% to 35% by weight, the hydrophilic polymer representing from 1% to 50% by weight, preferably 5% to 40% by weight, the surfactant making up from 0% to 10% by weight, preferably 0.1% to 3% by weight.
The outer layer or phase, if present, can make up to 80% by weight of the total weight, preferably up to 50% by weight.
In one embodiment, the composition according to the invention takes the form of tablets. This tablet preferably results from the compression of elements (a) (under the form of granules) together with an outer phase.
In another embodiment, the composition of the invention takes the form of granules enclosed inside a capsule, for example, in gelatin, or inside a bag. The compositions of the invention are particularly suitable for administering active ingredients by oral route.
The composition according to the invention is prepared by a process comprising spraying a solution or suspension of the active ingredient in a micronized form in a solution of a hydrophilic polymer and, optionally, a surfactant, onto the inert cores. The method according to the invention consists in using the fluidized-bed granulation principle, but with specific starting materials, in order to arrive at an improved dissolution profile and thus, at elevated bioavailability. In particular, the invention employs a suspension or solution of the micronized active ingredient in a solution of a hydrophylic polymer and, optionally, a surfactant.
The fluidized-bed granulation technique is widely used in the pharmaceutical industry for preparing capsules or tablets. Conventionally, according to the prior art, a powder or a mixture of powders (active ingredient+excipients) is put into suspension in the fluidized bed in a granulator, and a solution containing a binder and, optionally, a surfactant, is sprayed onto this bed to form granules. The fluidized-bed granulation technique is well known to those skilled in the art.
The invention, as has been indicated, comprises spraying a solution or suspension of an active ingredient micronized with a hydrophilic polymer onto an inert carrier.
Following granulation, the granulate formed consists of crystals of, for example, lactose, which are isolated (or possibly agglomerated together by the spray solution) and particles of active ingredient and PVP adhering to the crystal surface. The granulate could similarly be constituted of coated crystals which are agglomerated, or even of such an agglomerate having received a coating.
The granulates thus obtained can, if desired, be provided with an outer coating or compressed into tablets, or form agglomerates.
The outer layer or layer is/are applied using conventional coating techniques such as coating in a pan or fluidized bed coater.
When the granulate obtained (whether subsequently coated or not) is compressed to form tablets, this step can be implemented using any conventional technique which is suitable, for example, using an alternating or rotating compressing equipment. The tablets may further be film coated. Additional excipients such as film-forming polymers, solvents, plasticizers, antiadherents, opacifiers and optionally colorants, pigments, antifoam agents, and polishing agents can be used in coatings.
Examples of film-forming agents include, but are not limited to, cellulose derivatives such as soluble alkyl- or hydroalkyl-cellulose derivatives such as
methylcelluloses, hydroxymethyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxymethylethyl celluloses, hydroxypropyl methylcelluloses, sodium carboxymethyl celluloses, etc.; insoluble cellulose derivatives such as ethylcelluloses and the like; dextrins; starches and starch derivatives; polymers based on carbohydrates and derivatives thereof; natural gums such as gum Arabic; xanthans; alginates; polyacrylic acids; polyvinyl alcohols; polyvinyl acetates; polyvinylpyrrolidones; polymethacrylates and derivatives thereof (Eudragit® products), chitosan and derivatives thereof; shellac and derivatives thereof; waxes and fat substances.
The coating can also be performed using any commercially available ready-to-coat preparations such as Opadry® AMB, Opadry® White, Opadry® Clear, Opadry® II, etc. Opadry® formulations generally comprise polymer, plasticizer and, if desired, pigment in a dry concentrate. OPADRY® products produce attractive, elegant coatings on a variety of tablet cores and can be used in both aqueous and organic coating procedures.
Some of the excipients are used as adjuvants to the coating process, including excipients such as plasticizers, opacifiers, antiadhesives, polishing agents, and the like.
Examples of plasticizers include, but are not limited to, castor oil, diacetylated monoglycerides, dibutyl sebacate, diethyl phthalate, glycerin, polyethylene glycols, propylene glycols, triacetin, triethyl citrate, and mixtures thereof. An opacifier like titanium dioxide may also be present in an amount ranging from about 10% (w/w) to about 20% (w/w) based on the total weight of the coating.
Antiadhesives are frequently used in the film coating process to avoid sticking effects during film formation and drying. An example of an antiadhesive for this purpose is talc.
Examples of polishing agents include, but are not limited to, polyethylene glycols of various molecular weights, or mixtures thereof, talc, surfactants (e.g., glycerol monostearate and poloxamers), fatty alcohols (e.g., stearyl alcohol, cetyl alcohol, lauryl alcohol and myristyl alcohol) and waxes (e.g., carnauba wax, candelilla wax and white wax).
The present invention also encompasses suspension of the active ingredient. This suspension is prepared by putting the micronized active ingredient into suspension in a solution comprising the hydrophylic polymer and, optionally, a surfactant, in solution in a solvent. If a surfactant is employed, it is put into solution in the solvent. Next, the hydrophylic polymer is dispersed, while stirring, in the solution previously obtained. Depending on polymer solubility, this either dissolves in the solution or forms a gel or a suspension having varying degrees of thickness. While still stirring, the micronized active ingredient is dispersed in the form of a fine shower into the above solution or suspension, to form a homogeneous suspension. The order of these steps can be reversed. The solvent employed can be aqueous or organic (for example, ethanol). For example, demineralized water can be used.
The composition of the invention may be used in treating conditions such as gout and hyperuricemia. The pharmaceutical composition of febuxostat may be administered in combination with other therapeutic agents.
The present invention is illustrated below by reference to the following example. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention.
Example:
Figure imgf000011_0001
* Includes 10% extra to compensate the losses during coating process.
# Average particle size <50.00 micron
Procedure:
1. Polyvinylpyrrolidone was dissolved in purified water and febuxostat was dispersed under continuous stirring. Drug dispersion was passed through a colloid mill.
2. Sodium lauryl sulphate was dissolved in purified water and transferred to dispersion of step 1.
3. Pregelatinized starch was sifted through suitable mesh.
4. Pregelatinised starch of step 3 was coated with the dispersion of step 2 in a fluid bed processor.
5. The granules were dried to achieve desired LOD and passed through suitable mesh.
6. Microcrystalline cellulose, crospovidone and colloidal silicon dioxide were sifted through suitable mesh and blended with granules of step 5 in suitable blender. 7. Sodium stearyl fumarate was sifted through suitable mesh and blended with the blend of step 6.
8. The blend of step 7 was compressed.
9. The film coating suspension was prepared and step 8 core tablets were coated.
10. Tablets were packed in HDPE and blister pack.
While several particular forms of the invention have been illustrated and described, it will be apparent that various modifications and combinations of the invention detailed in the text can be made without departing from the spirit and scope of the invention.

Claims

We claim:
1. An immediate-release febuxostat composition comprising an inert carrier covered with at least one layer containing febuxostat in a micronized form having an average particle size less than 50 μπι, a hydrophilic polymer and, optionally, a surfactant.
2. A composition according to claim 1 further comprising at least one outer phase or layer.
3. An immediate-release febuxostat composition according to claim 1, wherein the inert carrier is hydrosoluble or hydroinsoluble.
4. An immediate-release febuxostat composition according to claim 1, wherein the inert carrier comprises one or more of sucrose, lactose, maltodextrin,
microcrystalline cellulose, pregelatinized starch, dicalcium phosphate, celphere or non-pareils.
5. An immediate-release febuxostat composition according to claim 1, wherein the hydrophilic polymer comprises one or more of cellulose derivatives; alginates, polyvinyl alcohol, povidone, crosslinked polyacrylic acid polymers, xanthan gum, guar gum, locust bean gum, potassium pectate, potassium pectinate, co-povidone, polysaccharide, polyalkylene oxides , polyalkyleneglycol, starch and derivatives; and mixtures thereof.
6. An immediate-release febuxostat composition according to claim 1, wherein the surfactant used in the composition is amphoteric, non-ionic, cationic or anionic.
7. An immediate-release febuxostat composition according to claim 2, wherein the outer layer or phase comprises conventional excipients such as diluents, binders, dis integrants, lubricants/glidants, surfactants, buffers, wetting agents, coloring agents, flavoring agents and combinations thereof.
8. A process for preparing an immediate-release febuxostat composition comprising: a) preparing febuxostat solution or suspension in micronized form with an
average particle size less than 50 μπι, in a solution of hydrophilic polymer and, optionally a surfactant; b) applying the suspension from step a) to an inert carrier.
A process according to claim 8, further comprising the step of coating the granules obtained in step b) with at least one phase or layer.
A method of treating gout and hyperuricemia by administering to a person in need thereof an immediate-release febuxostat composition comprising an inert carrier covered with at least one layer containing febuxostat in a micronized form having an average particle size less than 50 um, a hydrophilic polymer and, optionally, a surfactant.
A method of treating gout and hyperuricemia according to claim 10, wherein the immediate-release febuxostat composition further comprises at least one outer phase or layer.
A method of treating gout and hyperuricemia according to claim 10, wherein the immediate-release febuxostat composition is administered in combination with other therapeutic agents.
PCT/IB2012/052371 2011-05-11 2012-05-11 Pharmaceutical composition of febuxostat WO2012153313A1 (en)

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