+

WO2013030789A1 - Forme pharmaceutique orale solide contenant un inhibiteur pde-iv faiblement soluble dans l'eau - Google Patents

Forme pharmaceutique orale solide contenant un inhibiteur pde-iv faiblement soluble dans l'eau Download PDF

Info

Publication number
WO2013030789A1
WO2013030789A1 PCT/IB2012/054476 IB2012054476W WO2013030789A1 WO 2013030789 A1 WO2013030789 A1 WO 2013030789A1 IB 2012054476 W IB2012054476 W IB 2012054476W WO 2013030789 A1 WO2013030789 A1 WO 2013030789A1
Authority
WO
WIPO (PCT)
Prior art keywords
dosage form
inhibitor
pde
pharmaceutical
poorly water
Prior art date
Application number
PCT/IB2012/054476
Other languages
English (en)
Inventor
Vikas Batra
Sumit Gupta
Anupam Trehan
Vinod Kumar Arora
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2013030789A1 publication Critical patent/WO2013030789A1/fr

Links

Classifications

    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/08—Bronchodilators

Definitions

  • the present invention relates to a pharmaceutical solid oral dosage form of a poorly water-soluble phosphodiesterase 4 selective inhibitor (PDE-IV inhibitor) as an active ingredient, in particular roflumilast, and processes of preparation thereof.
  • PDE-IV inhibitor poorly water-soluble phosphodiesterase 4 selective inhibitor
  • Phosphodiesterase inhibitors are the drugs that block one or more of the five subtypes of the enzyme phosphodiesterase (PDE) and prevent the inactivation of the intracellular second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype.
  • PDE-IV is the major cAMP-metabolizing enzyme found in inflammatory and immune cells. This has generated great interest in PDE-IV as a potential target to treat lung inflammatory diseases.
  • PDE-IV inhibitors have proven potential as anti-inflammatory drugs, especially in inflammatory pulmonary diseases such as asthma, chronic obstructive pulmonary disease (COPD), and rhinitis. The selective targeting of PDE-IV has been actively pushed as a novel
  • U.S. Patent No. 6,677,362 assigned to Warner-Lambert Company, discloses a solid dispersion of water-insoluble drugs and the process for its preparation in which water-insoluble drugs were combined with a carrier polymer such as polyvinylpyrrolidone (PVP) without the need of any organic solvents and/or high fusion temperatures.
  • a carrier polymer such as polyvinylpyrrolidone (PVP)
  • U.S. Patent No. 7,407,670 assigned to Janssen Pharmaceutica, N.V., also discloses solid dispersions of bioactive compounds for enhancing dissolution and solubility of the bioactive compounds by using various carrier polymers.
  • U.S. Patent No. 7,951,397 assigned to Nycomed GmbH, discloses a process for producing solid oral dosage forms of poorly water-soluble PDE-IV inhibitors having improved solubility and dissolution.
  • the process comprises granulating the active compound with an aqueous solution of polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the present invention provides a pharmaceutical solid oral dosage form of a poorly water-soluble PDE-IV inhibitor, comprising:
  • binder is selected from a group consisting of a saccharide, protein or synthetic polymer.
  • Embodiments of the invention may include one or more of the following features.
  • the poorly water-soluble PDE-IV inhibitor may be roflumilast.
  • the PDE-IV inhibitor may be present in an amount of from about 0.1% to about 10% by weight of the solid dosage form.
  • the poorly water-soluble PDE-IV inhibitor and the binder may be present in a weight ratio of from about 1 : 1 to about 1 :20.
  • the binder may be a saccharide such as sucrose, lactose, starches, microcrystalline cellulose, low- viscosity hydroxypropyl cellulose and/or a hydroxypropylmethyl cellulose.
  • the low- viscosity hydroxypropyl cellulose may have a viscosity of less than about 1000 cPs.
  • the protein may be a gelatin and the synthetic polymer may be one or more of polyethylene glycol, polyvinyl acetate, polyvinyl alcohol and propylene glycol.
  • the binder may be present in an amount of from about 0.1% to about 10% by weight of the solid dosage form.
  • the pharmaceutically acceptable excipient may include diluents, disintegrants, lubricants, surfactants, coloring agents, flavoring agents and preservatives.
  • the diluent may be lactose
  • the disintegrant may be croscarmellose sodium
  • the lubricant may be magnesium stearate
  • the surfactant may be polyethylene glycol.
  • the diluent may be present in an amount of from about 50% to about 85% by weight of the solid dosage form.
  • the disintegrant may be present in an amount of from about 5% to about 30%, while the lubricant may be in an amount of from about 0.1% to about 2% by weight of the solid dosage form, respectively.
  • the invention provides a process for the preparation of a pharmaceutical solid oral dosage form of poorly water-soluble PDE-IV inhibitor comprising:
  • binder is selected from a group consisting of a saccharide, protein, or synthetic polymer, wherein the process comprises the steps of:
  • step (iii) further blending the granules/blend of step (ii) with one or more
  • the invention provides a method of treating chronic obstructive pulmonary disease (COPD), which comprises administering the COPD.
  • COPD chronic obstructive pulmonary disease
  • poorly water-soluble PDE-IV inhibitor includes PDE- IV inhibitors with a solubility in water of less than or equal to 100 mg/L, particularly with a solubility in water of less than or equal to 1 mg/L, at a temperature of 15°C to 25°C, more particularly at 21°C.
  • Examples of poorly water-soluble PDE-IV inhibitors include, but are not limited to, roflumilast, rolipram, ibudilast, piclamilast, cilomilast, and in particular roflumilast.
  • roflumilast includes roflumilast, its enantiomers,
  • the poorly water-soluble PDE-IV inhibitor in particular romflumilast, may be present in an amount of from about 0.1% to about 10% weight by weight (w/w) based on the total weight of the dosage form.
  • the roflumilast used in the present invention has a D 5 o value in the range of from about 2 ⁇ to about 15 ⁇ and D90 value in the range of from about 5 ⁇ to about 40 ⁇ .
  • the pharmaceutical dosage form of the present invention comprises a binder selected from a group consisting of a saccharide, protein or synthetic polymer.
  • the binder may be present in an amount of from about 0.1% to about 10% (w/w) based on the total weight of the dosage form.
  • saccharide includes disaccharides and their derivatives such as sucrose and lactose; polysaccharides and their derivatives such as starches selected from starch, corn starch, preswollen starch, pregelatinized starch; cellulose or modified cellulose such as microcrystalline cellulose; cellulose ethers such as methyl cellulose, hydroxypropyl cellulose (HPC) and hydroxypropylmethyl cellulose (HPMC); agar;
  • tragacanth plasdone
  • alginic acid and its derivatives such as sodium alginate
  • gum arabic and sugar alcohols
  • Particularly preferred saccharides are hydroxypropyl cellulose and hydroxypropylmethyl cellulose.
  • Hydroxypropyl cellulose is a non-ionic water-soluble cellulose ether that is formed by reaction with propylene oxide. It has a longstanding history of safe and effective use in the pharmaceutical industry. Hydroxypropyl cellulose is commercially available from Aqualon and Nippon Soda Co., under the brand names Klucel® and HPC®. It provides a remarkable set of physical properties for tablet binding, modified-release and film-coating.
  • hydroxypropyl cellulose of a desired viscosity range may be selected.
  • the viscosity ranges and corresponding hydroxylpropyl celluloses are classified as low-, medium- and high- viscosity hydroxypropyl celluloses.
  • Examples of low- viscosity hydroxypropyl cellulose include Klucel® EF, Klucel® LF, Klucel® IF and Klucel® OF.
  • the 2% w/w aqueous solutions of these low- viscosity hydroxypropyl celluloses have viscosities of less than about 1000 cPs.
  • Other examples are HPC®-SL, HPC®-L, and HPC®-M.
  • the 2% w/w aqueous solutions of these polymers have viscosities of 3-6, 6-10, and 150-400 cPs, respectively.
  • HPC®-L may be used.
  • Hydroxypropylmethyl cellulose is a methylcellulose modified with a small amount of propylene glycol ether groups attached to the anhydroglucose of the cellulose.
  • HPMCs vary in the chain length of their cellulosic backbone and consequently in their viscosity as measured, for example, at a 2% by weight concentration in water.
  • HPMCs which can be used in the present invention are illustratively available under the brand names Methocel® of Dow Chemical Co. and Metolose® of Shin-Etsu Chemical Co. Examples of particularly suitable HPMCs having low- and medium-viscosities include Methocel® E5 which has a viscosity of 2% w/w in water, of about 5 cPs.
  • the poorly water-soluble PDE-IV inhibitor in particular roflumilast, and low- viscosity hydroxypropyl cellulose and/or hydroxypropylmethyl cellulose are present in a weight ratio of from about 1 : 1 to about 1 :20, in particular about 1 : 10.
  • protein includes gelatin.
  • synthetic polymer includes polyethylene glycol, polyvinyl acetate, polyvinyl alcohol and propylene glycol.
  • pharmaceutical dosage form includes solid dosage forms such as powder, tablet, granule, pellet, spheroid, capsule, caplet, bead,
  • pharmaceutically acceptable excipients may include diluents, disintegrants, lubricants, surfactants, coloring agents, flavoring agents, and preservatives.
  • diluents may include, but are not limited to, calcium phosphate - dibasic, calcium carbonate, lactose, glucose, levulose, sucrose, cellulose - microcrystalline, cellulose - powdered, silicified microcrystalline cellulose, calcium silicate, kaolin, corn starch, potato starch, wheat starch, starch pregelatinized, polyols such as mannitol, sorbitol, xylitol, maltitol and sucrose.
  • the pharmaceutical dosage form may comprise from about 50% to about 85% of the diluent, w/w based on the total weight of the dosage form.
  • disintegrants may include, but are not limited to, croscarmellose sodium, sodium starch glycolate, sodium carboxymethylcellulose, hydroxypropylcellulose, xanthan gum, alginic acid, alginates and carbopols.
  • the pharmaceutical dosage form may comprise from about 5% to about 30% of the disintegrant, w/w based on the total weight of the dosage form.
  • lubricants may include, but are not limited to, sodium lauryl sulfate, talc, magnesium stearate, sodium stearyl fumarate, stearic acid, glycerylbehenate, hydrogenated vegetable oil, or zinc stearate, and suitable glidants may include colloidal silicon dioxide and talc.
  • the pharmaceutical solid dosage form may comprise from about 0.1% to about 2% of lubricant, w/w based on the total weight of the dosage form.
  • surfactants may include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical compositions.
  • These include polyethylene glycols, e.g., Macrogol 4000, Macrogol 3350 and Macrogol 6000; polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4-150 mono dilaurate, polyethylene glycol-20 glyceryl stearate; alcohol-oil transesterification products, for example, polyethylene glycol-6 corn oil; polyglycerized fatty acids, for example, polyglyceryl-6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives,
  • coloring agents may include, but are not limited to, water- soluble FD&C dyes and mixtures thereof with lakes and direct compression sugars such as Di-Pac®.
  • colored dye migration inhibitors such as tragacanth, acacia or attapulgite talc may be added.
  • Specific examples include calcium carbonate, chromium- cobalt-aluminium oxide, ferric ferrocyanide, ferric oxide, iron ammonium citrate, iron (III) oxide hydrated, iron oxides, magnesium carbonate and titanium dioxide.
  • flavoring agents may include, but are not limited to, saccharin, aspartame, cyclamate sodium and maltol.
  • preservatives may include, but are not limited to, potassium sorbate, methylparaben, propylparaben, benzoic acid and its salts, other esters of para- hydroxybenzoic acid such as butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic compounds such as phenol, or quartemary compounds such as benzalkonium chloride.
  • These solid dosage forms may be further coated with one or more functional and/or non- functional coating layers comprising film- forming polymers with or without coating additives.
  • the "coating additives” may comprise one or more of plasticizers, glidants or lubricants, opacifiers and lubricants.
  • film- forming polymers may include cellulose derivatives such as ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, partially hydrolyzed polyvinyl alcohol, cellulose acetate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, cellulose acetate trimellitate; waxes such as polyethylene glycol; or methacrylic acid polymers such as Eudragit® RL and Eudragit® RS.
  • coating compositions comprising film-forming polymers marketed under various trade names, such as Opadry®, may also be used for coating.
  • plasticizers may include, but are not limited to, phosphate esters; phthalate esters; mineral oils; fatty acids and esters; fatty alcohols, vegetable oils and hydrogenated vegetable oils including acetylated hydrogenated cottonseed glyceride and acetylated hydrogenated soybean oil glycerides; acetyl tributyl citrate; acetyl triethyl citrate; castor oil; diacetylated monoglycerides; dipropylene glycol salicylate glycerin; glycerylcocoate; mono- and di-acetylated monoglycerides; phthalylglycolate; diocyl phthalate; sorbitol; sorbitol glyceryltricitrate; sucrose octaacetate; a-tocopheryl polyethylene glycol succinate; phosphate esters; phthalate esters; amides; mineral oils; fatty acids and esters; amides;
  • diisobutyladipate dihexyladipate; triethylene glycol di(beta-ethyl butyrate); polyethylene glycol; diethylene glycol monolaurate; monomeric polyethylene ester; hydrogenated methyl ester of rosin; methoxyethyloleate; butoxyethyl stearate; butyl phthalyl butyl glycolate; glycerol tributyrate; and triethylene glycol.
  • the pharmaceutical acceptable excipients and/or film-forming polymers and coating additives may be selected to provide an immediate-release profile or a modified- release profile.
  • solution/dispersion of the coating composition may include one or more of methylene chloride, isopropyl alcohol, acetone, methanol, ethanol, chloroform, ether and water, or combinations thereof.
  • the granulating fluid is removed using techniques known in the art such as tray drying, fluid bed drying, microwave drying and vacuum drying prior to compression of the bulk material into tablets.
  • Coating may be performed by applying film- forming polymer(s), with or without other pharmaceutically inert excipients, as a solution/suspension using any conventional coating technique known in the art such as spray coating in a conventional coating pan or fluidized bed processor, dip coating, or compression coating.
  • the pharmaceutical solid oral dosage forms of the invention may be prepared by following the process of wet granulation, direct compression or dry granulation.
  • the pharmaceutical oral solid dosage form of a poorly water- soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (b) passing the blend of step (a) through a roller compactor to form a compacted mass
  • step (d) blending the granules of step (c) with extragranular pharmaceutically
  • step (e) compressing the blend of step (d) into tablets using a suitable tooling
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (b) compressing the blend of step (a) in a heavy tabletting press to form slugs
  • step (c) reducing the slugs of step (b) into granules of suitable size
  • step (d) blending the granules of step (c) with extragranular pharmaceutically
  • step (e) compressing the blend of step (d) into tablets using a suitable tooling;
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (b) directly compressing the blend of step (a) into tablets using a suitable tooling
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (c) granulating the blend of step (a) with the granulating fluid of step (b);
  • step (d) blending the granules of step (c) with extragranular pharmaceutically
  • step (e) compressing the blend of step (d) into tablets using a suitable tooling
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (c) dissolving the PDE-IV inhibitor in the granulating fluid of step (b);
  • step (d) granulating the blend of step (a) with the solution of step (c); (e) blending the granules of step (d) with extragranular pharmaceutically acceptable excipients;
  • step (f) compressing the blend of step (e) into tablets using a suitable tooling
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (c) dispersing the PDE-IV inhibitor in the granulating fluid of step (b);
  • step (d) granulating the blend of step (a) with the dispersion of step (c);
  • step (e) blending the granules of step (d) with extragranular pharmaceutically
  • step (f) compressing the blend of step (e) into tablets using a suitable tooling
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of:
  • step (b) passing the blend of step (a) through a hot melt extruder to form extrudes;
  • step (c) sizing the extrudes of step (b);
  • step (d) blending the extrudes of step (c) with one or more pharmaceutically
  • step (e) compressing the blend of step (d) into tablets using a suitable tooling
  • the pharmaceutical oral solid dosage form of a poorly water-soluble PDE-IV inhibitor may be prepared by a process comprising the steps of: (a) dissolving or dispersing the PDE-IV inhibitor in a solvent;
  • step (b) dissolving hydroxypropylmethyl cellulose in a solvent and mixing with solution or dispersion of step (a);
  • step (d) granulating the blend of step (c) with the solution or dispersion of step (b);
  • step (e) blending the granules of step (d) with one or more pharmaceutically inert excipients;
  • step (f) compressing the blend of step (e) into tablets using a suitable tooling
  • granulation may be done by shear granulators, rapid mixer granulators, fluidized bed granulators, spray driers or by spheronizers or pelletizers.
  • HPC®-L was dissolved in purified water to prepare a binder solution.
  • step (1) was granulated with the binder solution of step (2).
  • step (3) The wet granules of step (3) were dried in the fluid bed dryer.
  • step (6) The material of step (6) was added to the dried granules of step (5) and mixed.
  • step (7) was mixed with the lubricant of step (8).
  • step (9) was compressed with appropriate punch and toolings. 1 1.
  • a coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.
  • HPC®-L was dissolved in purified water to prepare a binder solution.
  • step (1) was granulated with the binder solution of step (2).
  • step (3) The wet granules of step (3) were dried in the Fluid Bed dryer.
  • step (4) The dried granules of step (4) were shifted through sieve size # 22 BSS.
  • step (6) The material of step (6) was added to the dried granules of step (5) and
  • step (7) was mixed with the lubricant of step (8).
  • step (9) was compressed into tablets with appropriate punch and toolings. 1 1.
  • a coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.
  • step (1) was lubricated with the material of step (2).
  • step (3) The material of step (3) was compacted and the compacts were crushed in a multi-mill and passed through sieve size # 22 BSS.
  • Magnesium stearate was sifted through sieve size #44 BSS and mixed with the material of step (4).
  • step (5) The blend of step (5) was compressed into tablets with appropriate punch and toolings.
  • step (1) was lubricated with the material of step (2).
  • step (3) was compressed into tablets with appropriate punch and toolings.
  • a coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.
  • HPMC 5 cPs was dissolved in purified water under continuous stirring.
  • Lactose was sifted through mesh # 30 BSS and granulated with the solution of step (2) in RMG.
  • step (3) The granules of step (3) were dried and passed through mesh # 22 BSS.
  • Maize starch was sifted through mesh # 44 BSS and mixed with the granules of step (4) in a blender.
  • Magnesium stearate was sifted through mesh # 44 BSS and mixed with the blend of step (5).
  • step (6) The Lubricated granules of step (6) were compressed into tablets using appropriate punch and toolings.
  • Example 5a Fluid Bed Processor (FBP Granulation Method
  • HPC®-L and Macrogol were dissolved in purified water and then roflumilast was dispersed under continuous stirring.
  • Lactose and maize starch were sifted through mesh # 30 BSS.
  • step (2) was granulated with the dispersion of step (1) in a fluid bed processor.
  • step (3) The granules of step (3) were dried and passed through mesh # 25 BSS.
  • Magnesium stearate was sifted through mesh # 44 BSS and mixed with the blend of step (5).
  • step (6) The lubricated granules of step (6) were compressed into tablets using
  • Example 5b Fluid Bed Processor (FBP Granulation Method
  • HPMC HPMC was dissolved in purified water under continuous stirring.
  • Lactose was sifted through mesh # 30 BSS.
  • step (3) The lactose of step (3) was granulated with the solution of step (2) in a fluid bed processor.
  • step (4) The granules of step (4) were dried and passed through mesh # 22 BSS.
  • Maize starch was sifted through mesh # 44 BSS and mixed with the granules of step (5) in a blender.
  • Magnesium stearate was sifted through mesh # 44 BSS and mixed with the maize starch of step (6).
  • Lactose was mixed with the blend of step (1) and sifted through mesh # 30 BSS.
  • step (2) was extruded using a hot-melt extruder.
  • step (4) The cooled extrudes of step (4) were sized through a multi mill and then passed through mesh # 25 BSS.
  • Lactose and maize starch were sifted through mesh # 44 BSS and mixed in a blender with the sized extrudes of step (5).
  • a coating solution was prepared and core tablets were coated in a suitable coating pan to get an appropriate w/w build up.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une forme pharmaceutique solide orale d'un inhibiteur sélectif de phosphodiestérase4 (inhibiteur PDE-IV) faiblement soluble dans l'eau qu'on utilise en tant qu'ingrédient actif, notamment le roflumilast et des procédés de préparation correspondants.
PCT/IB2012/054476 2011-08-30 2012-08-30 Forme pharmaceutique orale solide contenant un inhibiteur pde-iv faiblement soluble dans l'eau WO2013030789A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2490DE2011 2011-08-30
IN2490/DEL/2011 2011-08-30

Publications (1)

Publication Number Publication Date
WO2013030789A1 true WO2013030789A1 (fr) 2013-03-07

Family

ID=47018330

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2012/054476 WO2013030789A1 (fr) 2011-08-30 2012-08-30 Forme pharmaceutique orale solide contenant un inhibiteur pde-iv faiblement soluble dans l'eau

Country Status (1)

Country Link
WO (1) WO2013030789A1 (fr)

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104473862A (zh) * 2014-11-18 2015-04-01 北京科莱博医药开发有限责任公司 一种罗氟司特固体分散体及其制备方法和罗氟司特制剂
WO2015037017A3 (fr) * 2013-09-13 2015-07-02 Hetero Research Foundation Compositions pharmaceutiques de roflumilast et leur procédé de préparation
WO2015132708A1 (fr) * 2014-03-07 2015-09-11 Torrent Pharmaceuticals Limited Composition pharmaceutique de roflumilast
CN105434328A (zh) * 2014-09-01 2016-03-30 天津药物研究院有限公司 一种含罗氟司特固体分散体的固体制剂及其制备方法
US9884050B1 (en) 2017-06-07 2018-02-06 Arcutis, Inc. Inhibition of crystal growth of roflumilast
WO2019060379A1 (fr) 2017-09-22 2019-03-28 Arcutis, Inc. Compositions pharmaceutiques de roflumilast dans des mélanges aqueux de solvants pharmaceutiquement acceptables miscibles à l'eau
CN111643470A (zh) * 2020-04-30 2020-09-11 山东希尔康泰药业有限公司 罗氟司特薄膜包衣片制备工艺
US11129818B2 (en) 2017-06-07 2021-09-28 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
WO2024058848A1 (fr) 2022-09-15 2024-03-21 Arcutis Biotherapeutics, Inc. Compositions pharmaceutiques de roflumilast et de solvants capables de dissoudre des quantités élevées de médicament
US11992480B2 (en) 2018-11-16 2024-05-28 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
US12011437B1 (en) 2017-06-07 2024-06-18 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12016848B2 (en) 2017-06-07 2024-06-25 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US12042558B2 (en) 2018-06-04 2024-07-23 Arcutis Biotherapeutics, Inc. Method and formulation for improving roflumilast skin penetration lag time
US12042487B2 (en) 2018-11-16 2024-07-23 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5712298A (en) 1993-07-02 1998-01-27 Byk Gulden Lomberg Chemische Fabrik Gmbh Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors
US6403597B1 (en) * 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US6677362B1 (en) 1991-12-18 2004-01-13 Warner-Lambert Company Solid pharmaceutical dispersions
EP1621196A1 (fr) * 2003-03-17 2006-02-01 Kyowa Hakko Kogyo Co., Ltd. Agent therapeutique et/ou preventif pour une maladie de peau chronique
US20060198889A1 (en) * 2005-03-04 2006-09-07 Sandhu Harpreet K Roflumilast and integrin inhibitor combination and treatement method
US7407670B2 (en) 2002-07-04 2008-08-05 Janssen Pharmaceutica, N.V. Solid dispersions comprising two different polymer matrixes
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6677362B1 (en) 1991-12-18 2004-01-13 Warner-Lambert Company Solid pharmaceutical dispersions
US5712298A (en) 1993-07-02 1998-01-27 Byk Gulden Lomberg Chemische Fabrik Gmbh Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors
US6403597B1 (en) * 1997-10-28 2002-06-11 Vivus, Inc. Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation
US7951397B2 (en) 2002-02-20 2011-05-31 Nycomed Gmbh Oral dosage form containing a PDE 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient
US7407670B2 (en) 2002-07-04 2008-08-05 Janssen Pharmaceutica, N.V. Solid dispersions comprising two different polymer matrixes
EP1621196A1 (fr) * 2003-03-17 2006-02-01 Kyowa Hakko Kogyo Co., Ltd. Agent therapeutique et/ou preventif pour une maladie de peau chronique
US20060198889A1 (en) * 2005-03-04 2006-09-07 Sandhu Harpreet K Roflumilast and integrin inhibitor combination and treatement method

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015037017A3 (fr) * 2013-09-13 2015-07-02 Hetero Research Foundation Compositions pharmaceutiques de roflumilast et leur procédé de préparation
US20160213658A1 (en) * 2013-09-13 2016-07-28 Hetero Research Foundation Pharmaceutical compositions of roflumilast and process for preparation thereof
WO2015132708A1 (fr) * 2014-03-07 2015-09-11 Torrent Pharmaceuticals Limited Composition pharmaceutique de roflumilast
CN105434328A (zh) * 2014-09-01 2016-03-30 天津药物研究院有限公司 一种含罗氟司特固体分散体的固体制剂及其制备方法
CN104473862A (zh) * 2014-11-18 2015-04-01 北京科莱博医药开发有限责任公司 一种罗氟司特固体分散体及其制备方法和罗氟司特制剂
CN104473862B (zh) * 2014-11-18 2017-09-29 北京科莱博医药开发有限责任公司 一种罗氟司特固体分散体及其制备方法和罗氟司特制剂
US11129818B2 (en) 2017-06-07 2021-09-28 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
US12005052B2 (en) 2017-06-07 2024-06-11 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half-life
US9907788B1 (en) 2017-06-07 2018-03-06 Arcutis Inc. Inhibition of crystal growth of roflumilast
US10105354B1 (en) 2017-06-07 2018-10-23 Arcutis, Inc. Inhibition of crystal growth of roflumilast
US10172841B2 (en) 2017-06-07 2019-01-08 Arcutis, Inc. Inhibition of crystal growth of roflumilast
US12257242B2 (en) 2017-06-07 2025-03-25 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
US12220409B2 (en) 2017-06-07 2025-02-11 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US10940142B2 (en) 2017-06-07 2021-03-09 Arcutis, Inc. Inhibition of crystal growth of roflumilast
US9884050B1 (en) 2017-06-07 2018-02-06 Arcutis, Inc. Inhibition of crystal growth of roflumilast
US12016848B2 (en) 2017-06-07 2024-06-25 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US11793796B2 (en) 2017-06-07 2023-10-24 Arcutis Biotherapeutics, Inc. Inhibition of crystal growth of roflumilast
US11819496B2 (en) 2017-06-07 2023-11-21 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half-life
US12011437B1 (en) 2017-06-07 2024-06-18 Arcutis Biotherapeutics, Inc. Roflumilast formulations with an improved pharmacokinetic profile
US9895359B1 (en) 2017-06-07 2018-02-20 Arcutis, Inc. Inhibition of crystal growth of roflumilast
US12005051B2 (en) 2017-06-07 2024-06-11 Arcutis Biotherapeutics, Inc. Topical roflumilast formulation having improved delivery and plasma half life
EP4316590A2 (fr) 2017-09-22 2024-02-07 Arcutis Biotherapeutics, Inc. Compositions pharmaceutiques de roflumilast dans des mélanges aqueux de solvants miscibles dans l'eau, pharmaceutiquement acceptables
US11534493B2 (en) 2017-09-22 2022-12-27 Arcutis Biotherapeutics, Inc. Pharmaceutical compositions of roflumilast in aqueous blends of water-miscible, pharmaceutically acceptable solvents
WO2019060379A1 (fr) 2017-09-22 2019-03-28 Arcutis, Inc. Compositions pharmaceutiques de roflumilast dans des mélanges aqueux de solvants pharmaceutiquement acceptables miscibles à l'eau
US12042558B2 (en) 2018-06-04 2024-07-23 Arcutis Biotherapeutics, Inc. Method and formulation for improving roflumilast skin penetration lag time
US11992480B2 (en) 2018-11-16 2024-05-28 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
US12042487B2 (en) 2018-11-16 2024-07-23 Arcutis Biotherapeutics, Inc. Method for reducing side effects from administration of phosphodiesterase-4 inhibitors
CN111643470A (zh) * 2020-04-30 2020-09-11 山东希尔康泰药业有限公司 罗氟司特薄膜包衣片制备工艺
WO2024058848A1 (fr) 2022-09-15 2024-03-21 Arcutis Biotherapeutics, Inc. Compositions pharmaceutiques de roflumilast et de solvants capables de dissoudre des quantités élevées de médicament
US12144802B2 (en) 2022-09-15 2024-11-19 Arcutis Biotherapeutics, Inc. Pharmaceutical compositions of roflumilast and solvents capable of dissolving high amounts of the drug

Similar Documents

Publication Publication Date Title
WO2013030789A1 (fr) Forme pharmaceutique orale solide contenant un inhibiteur pde-iv faiblement soluble dans l'eau
KR101600099B1 (ko) 매트릭스형 의약 고형 제제
US20170000799A1 (en) Oral pharmaceutical composition
EP2400954B2 (fr) Procédé de fabrication de formes posologiques orales de solifénacine succinate
EP2170281A1 (fr) Procédé de production d'un médicament contenant du tadalafil
JP2012184267A (ja) 安定性の向上した固形製剤およびその製造方法
KR20180125574A (ko) 용출성이 우수한 경구 제제
JP2010519200A (ja) シロスタゾールを含む制御放出製剤及びその製造方法
US20230119567A1 (en) Pharmaceutical formulation
WO2015001489A1 (fr) Compositions pharmaceutiques de ticagrélor
CN103505453B (zh) 一种奥利司他口服固体制剂及其制备方法
EP3664778B1 (fr) Préparation pharmaceutique comprenant du 3-fluoro-4-[7-méthoxy-3-méthyl-8-(1-méthyl-1h-pyrazol-4-yl)-2-oxo -2,3-dihydro-imidazo [4,5-c]quinolin-1-yl]-benzonitrile
EP2533766B1 (fr) Mini-comprimés pharmaceutiques à libération prolongée d'acétate de flécaïnide
US20090304755A1 (en) Pharmaceutical formulation of losartan
KR102728350B1 (ko) 고체 분산체
EP1830819A1 (fr) Composition pharmaceutique stable contenant de l'amoxicilline et de l'acide clavulanique
EP3290023B1 (fr) Composition pharmaceutique à libération prolongée contenant de la rivastigmine
CN104487057A (zh) 波生坦控释口服制剂
EP4091604B1 (fr) Granules contenant du posaconazole
JP6847190B2 (ja) 矯味剤含有顆粒を内在する、服用性が改善された口腔内崩壊錠
US20140341990A1 (en) Controlled Release Formulations of Nisoldipine
EA047590B1 (ru) Фармацевтическая композиция, содержащая апиксабан

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12772488

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 12772488

Country of ref document: EP

Kind code of ref document: A1

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载