WO2009016608A2 - Pharmaceutical compositions of fenofibrate - Google Patents
Pharmaceutical compositions of fenofibrate Download PDFInfo
- Publication number
- WO2009016608A2 WO2009016608A2 PCT/IB2008/053091 IB2008053091W WO2009016608A2 WO 2009016608 A2 WO2009016608 A2 WO 2009016608A2 IB 2008053091 W IB2008053091 W IB 2008053091W WO 2009016608 A2 WO2009016608 A2 WO 2009016608A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- capsule
- pharmaceutical composition
- pharmaceutically acceptable
- tablet
- fenofibrate
- Prior art date
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- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 229960002297 fenofibrate Drugs 0.000 title claims abstract description 102
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 35
- 239000000203 mixture Substances 0.000 claims abstract description 70
- 238000000034 method Methods 0.000 claims abstract description 27
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000003826 tablet Substances 0.000 claims description 61
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- -1 disc Substances 0.000 claims description 21
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- 108010039491 Ricin Proteins 0.000 description 1
- HGWPFSBHDACWNL-GFBLOWMDSA-N [(1r,5s)-8-methyl-8-oxido-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate Chemical group C([C@H]1CC[C@@H](C2)[N+]1([O-])C)C2OC(=O)C(CO)C1=CC=CC=C1 HGWPFSBHDACWNL-GFBLOWMDSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000011360 adjunctive therapy Methods 0.000 description 1
- 239000003741 agents affecting lipid metabolism Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 239000007931 coated granule Substances 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940099112 cornstarch Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 229960001760 dimethyl sulfoxide Drugs 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- YHAIUSTWZPMYGG-UHFFFAOYSA-L disodium;2,2-dioctyl-3-sulfobutanedioate Chemical compound [Na+].[Na+].CCCCCCCCC(C([O-])=O)(C(C([O-])=O)S(O)(=O)=O)CCCCCCCC YHAIUSTWZPMYGG-UHFFFAOYSA-L 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 235000010445 lecithin Nutrition 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
- 229940067606 lecithin Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 125000006353 oxyethylene group Chemical group 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920001992 poloxamer 407 Polymers 0.000 description 1
- 229940044476 poloxamer 407 Drugs 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
-
- 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
- A61K9/2027—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
- A61K9/2004—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
- A61K9/2072—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
- 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 invention relates to pharmaceutical compositions comprising non-micronized fenofibrate with one or more pharmaceutically acceptable vehicles.
- the invention also relates to pharmaceutical compositions comprising non-micronized fenofibrate with one or more cyclodextrin derivatives.
- the invention also relates to processes for the preparation of such compositions. Background of the Invention
- Fenofibrate is a lipid-regulating agent and belongs to the family of fibrates or fibric acid derivatives. It is indicated as an adjunctive therapy to diet for the treatment for adult patients with very high elevations of serum triglyceride levels who are at risk of pancreatitis and who do not respond adequately to dietary control. It is particularly useful for the treatment of adult endogenous hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. It is commercially available as oral capsules containing mi- cronized fenofibrate in the strengths of 67 mg, 134 mg and 200 mg
- Fenofibrate is practically insoluble in water and exhibits a low rate of dissolution in aqueous media that results in inadequate bioavailability after oral ingestion. This low rate of dissolution of fenofibrate in aqueous media is also found in gastrointestinal fluids. Chemically, fenofibrate is 2-[4-(4-Chlorobenzoyl) phenoxy]-2-methylpropanoic acid 1-methylethyl ester of Formula I.
- U.S. Patent Nos. 5,145,684; 6,375,986; 6,969,529; and 6,592,903 disclose nanopar- ticulate compositions of fenofibrate.
- U.S. Patent Nos. 6,277,405; 6,652,881; 7,037,529; 7,041,319; 6,589,552; 6,531,158 and U.S. Patent Application Nos. 20040057998; 20040058005 and 2004137055 disclose micronized fenofibrate compositions.
- U.S. Patent Nos. 4,895,726; 5,880,148 and U.S. Application No. 20040071771 describe co-micronizing the fenofibrate with surface- active agents.
- U.S. Patent No. 6,555,135 describes co-micronized mixture of fenofibrate with pharmaceutically acceptable excipient that is not a surfactant.
- U.S. Patent Nos. 6,074,670 and 6,277,405 disclose micronized fenofibrate coated onto hydro soluble carriers with optional surface- active agents.
- U.S. Patent Application No. 20040087656 describes fenofibrate of particle size less than 2000 nm with an improved bioavailability.
- U.S. Patent Application Nos. 20060222706 and 20060222707 describe fenofibrate in intimate association with menthol or surfactant mixture.
- compositions of fenofibrate or salts thereof includes non-micronized fenofibrate and one or more pharmaceutically acceptable vehicles.
- compositions of fenofibrate or salts thereof includes non-micronized fenofibrate, polyethylene glycol or derivatives thereof optionally, with one or more pharmaceutically acceptable excipients.
- a process for preparing a pharmaceutical composition of fenofibrate or salts thereof includes the steps of melting, mixing one or more pharmaceutically acceptable vehicles, non-micronized fenofibrate optionally, with one or more pharmaceutically acceptable excipients.
- compositions of fenofibrate or salts thereof includes non-micronized fenofibrate, cy- clodextrin or a derivative thereof optionally, with one or more pharmaceutically ac- cep table excipients.
- a process for preparing a pharmaceutical composition of fenofibrate or salts thereof includes: a) melting one or more pharmaceutically acceptable vehicles to form a clear solution; b) dissolving non- micronized fenofibrate in the clear solution; c) spraying the fenofibrate solution onto one or more pharmaceutically acceptable excipients; and d) mixing with one or more other pharmaceutically acceptable excipients and converting it into a suitable dosage form.
- Embodiments of the pharmaceutical composition may include one or more of the following features.
- the pharmaceutically acceptable excipients may include one or more of fillers, binders, lubricants, sweeteners, coloring and flavoring agents, glidants, disintegrants, and the like.
- Fenofibrate is practically insoluble in water. This insolubility characteristic causes fenofibrate to exhibit a low rate of dissolution in aqueous media, e. g., gastrointestinal fluids, which results in inadequate bioavailability after oral ingestion.
- aqueous media e. g., gastrointestinal fluids
- the present inventors while working on the fenofibrate formulation have found that when fenofibrate is dissolved in a vehicle at a specific temperature, and further processed with pharmaceutically acceptable excipients, the crystallinity of the fenofibrate is significantly reduced in the product. The reduction in crystallinity significantly enhances the solubility, dissolution and bioavailability of fenofibrate.
- the present inventors also found that when a non-micronized fenofibrate is complexed with cyclodextrin or a derivative thereof, the solubility of the mix so obtained is increased in the aqueous fluids, which in turn leads to a significant increase in percent release of the drug fenofibrate and hence increase in bioavailability.
- fenofibrate refers to fenofibrate having a particle size greater than or equal to about 50 ⁇ m and fenofibrate is not subjected to any comminution techniques, such as milling, spray drying, high pressure homogenization, and the like known to a person skilled in the art.
- Suitable vehicles which can be used in the process of the present invention are known to a person having ordinary skills in the art.
- examples of such vehicles include polyethylene glycol or derivatives thereof, poloxamer, cremophore RH 40, vitamin E TPGS, and the like. Mixtures of vehicles are also suitable.
- Suitable polyethylene glycol (PEG) or derivatives thereof may include all PEGs that are liquid at room temperature or that melt up to about 7O 0 C.
- Suitable polyethylene glycol or derivatives thereof may include one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyg- lycolized glycerides, polyethylene glycol-polyoxyethylene, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylene, and the like.
- the composition of the present invention may be prepared by dissolving non- micronized fenofibrate in a clear solution of one or more melted vehicles.
- the obtained solution may be sprayed onto suitable filler.
- the obtained mixture may be granulated, with one or more pharmaceutically acceptable excipients.
- the obtained granules may be optionally coated and optionally mixed with one or more pharmaceutically acceptable excipients.
- the resulting mixture may be filled into capsules or compressed to make tablets.
- Suitable pharmaceutically acceptable sugars may include one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol, mannitol, and the like.
- Suitable surfactants may include one or more of amphoteric, non-ionic, cationic or anionic surfactants.
- examples of such surfactants include sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of poly- oxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, and the like. Mixtures of surfactants may also be used.
- Suitable cyclodextrin or derivatives thereof may include one or more of hy- droxypropyl- ⁇ -cyclodextrin, ⁇ -cyclodextrin, ⁇ -cyclodextrin, hydroxypropyl- ⁇ - cyclodextrin, and the like.
- composition comprising non-micronized fenofibrate with cyclodextrin or derivatives thereof may be prepared by the processes known in the art.
- the inclusion complex of a portion of total non-micronized fenofibrate with ⁇ -cyclodextrin may be prepared by dissolving fenofibrate and cyclodextrin or a derivative thereof in a suitable solvent followed by mixing and drying.
- the inclusion complex so formed may be mixed with one or more pharmaceutically acceptable excipients.
- the solvents may include one or more of water, methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethylsulf oxide, dimethylformamide, methylene chloride, and the like.
- the melt granulation may be carried out by dissolving the remaining portion in part or full of the non-micronized fenofibrate in one or more pharmaceutically acceptable carriers by melting.
- the obtained melt may be mixed with a solution of a pharmaceutically acceptable sugar and one or more pharmaceutically acceptable excipients to get a molten mixture.
- the obtained mixture may be granulated by adsorbing it on one or more pharmaceutically acceptable excipients.
- portion' refers to from about 1% to about 99% of the total non-micronized fenofibrate used in the formulation that needs to be complexed with cyclodextrin or a derivative thereof.
- the term 'remaining portion' as used herein refers to from about 1% to about 99% of the total non-micronized fenofibrate used in the formulation that needs to be melt granulated with one or more pharmaceutically acceptable carriers.
- the inclusion complex and granules obtained by melt granulation may be mixed together and may be optionally mixed with one or more pharmaceutically acceptable excipients.
- the resulting mixture may be filled into capsules or compressed to make tablets.
- the one or more pharmaceutically acceptable excipients may include one or more of fillers, binders, lubricants, sweeteners, coloring and flavoring agents, glidants, disin- tegrants, and the like.
- Suitable fillers may be one or more of microcrystalline cellulose, silicified micro- crystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like.
- Suitable binders may be one or more of povidone, starch, stearic acid, gums, hydrox- ypropylmethyl cellulose, and the like.
- Suitable lubricants may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate, and the like.
- Suitable glidants may be one or more of colloidal silicon dioxide, talc, cornstarch, and the like.
- Suitable disintegrants may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like.
- the pharmaceutical composition of the invention may be present in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule, granules in capsule and other dosage forms suitable for oral administration.
- the tablets may further be coated with film forming polymers.
- Examples of some film forming polymers that can be used for the coating include but are not limited to cellulose derivatives (hydroxypropyl methylcellulose, hydroxyethyl- cellulose, hydroxypropyl cellulose and their derivatives), acrylic and methacrylic copolymers of different molecular weights, and mixtures thereof.
- the coating layers over the tablet may be applied as a solution/dispersion of the coating ingredients using conventional techniques known in the art selected from spray coating in a conventional coating pan or a fluidized bed processor, dip coating, and the like.
- Example 1 [51] Table- 1 Composition of Fenofibrate Tablets [52] [Table 1] [Table ]
- the granules obtained in the above step were dried and passed through a suitable mesh screen and then were blended with presifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with pre-sifted magnesium stearate for 2-3 minutes. The lubricated blend was compresses into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3% weight gain.
- Example 2 [55] Table-2 Composition of Fenofibrate Tablets [56] [Table 2] [Table ]
- the granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with pre-sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
- Example 3 [59] Table-3 Composition of Fenofibrate Tablets [60] [Table 3] [Table ]
- the granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted, microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min.
- This blend was lubricated with a pre- sifted magnesium stearate for 2-3 minutes.
- the lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
- the granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with a pre-sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
- Example 5 [67] Table-5 Composition of Fenofibrate Tablets [68] [Table 5] [Table ]
- Vitamin E TPGS was melted at 60-70 0 C to form a clear solution.
- Fenofibrate was dissolved in the above solution at 60-70 0 C (below the melting point of fenofibrate).
- Starch 1500/lactose was loaded in a Fluid bed processor and the above solution of fenofibrate was sprayed onto starch 1500/lactose. The temperature of the solution was maintained at 70-75 0 C during spraying.
- the granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with pre- sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
- USP Type 2 Apparatus (rpm 50) was used, wherein 1000 ml of 0.025M SLS in water at 37 0 C + 0.5 0 C was used as a medium.
- USP Type 2 Apparatus rpm 50 was used, wherein 2000 ml of 0.0125M SLS in water at 37 0 C ⁇ 0.5 0 C was used as a medium.
- Example 6 [77] Table-8 Composition of Fenofibrate Tablets [78] [Table 8] [Table ]
- Example 7 [81] Table-9 Composition of Fenofibrate Tablets [82] [Table 9] [Table ]
- the obtained mixture was adsorbed on lactose monohydrate, poloxamer, sodium lauryl sulfate and docusate sodium in a Rapid Granulator Mixer to get uniform granules (Premix B).
- the obtained granules were mixed with Premix (A), Prosolv SMCC 90 and crospovidone.
- the resulting blend was lubricated with magnesium stearate and compressed into tablets using proposed tooling.
- the tablets can be optionally coated with aqueous dispersion of Opadry.
- Example 11 [91] Table- 13 Composition of Fenofibrate Tablets [Table 12] [Table ]
Abstract
The invention relates to pharmaceutical compositions comprising non-micronized fenofibrate with one or more pharmaceutically acceptable vehicles. The invention also relates to pharmaceutical compositions comprising non-micronized fenofibrate with one or more cyclodextrin derivatives. The invention also relates to processes for the preparation of such compositions.
Description
Description
PHARMACEUTICAL COMPOSITIONS OF FENOFIBRATE
Field of the Invention
[1] The invention relates to pharmaceutical compositions comprising non-micronized fenofibrate with one or more pharmaceutically acceptable vehicles. The invention also relates to pharmaceutical compositions comprising non-micronized fenofibrate with one or more cyclodextrin derivatives. The invention also relates to processes for the preparation of such compositions. Background of the Invention
[2] Fenofibrate is a lipid-regulating agent and belongs to the family of fibrates or fibric acid derivatives. It is indicated as an adjunctive therapy to diet for the treatment for adult patients with very high elevations of serum triglyceride levels who are at risk of pancreatitis and who do not respond adequately to dietary control. It is particularly useful for the treatment of adult endogenous hyperlipidemia, hypercholesterolemia and hypertriglyceridemia. It is commercially available as oral capsules containing mi- cronized fenofibrate in the strengths of 67 mg, 134 mg and 200 mg
[3] Fenofibrate is practically insoluble in water and exhibits a low rate of dissolution in aqueous media that results in inadequate bioavailability after oral ingestion. This low rate of dissolution of fenofibrate in aqueous media is also found in gastrointestinal fluids. Chemically, fenofibrate is 2-[4-(4-Chlorobenzoyl) phenoxy]-2-methylpropanoic acid 1-methylethyl ester of Formula I. Several methods of increasing the rate of dissolution of drugs having low solubility in water and other aqueous media have been disclosed in the prior art.
[4]
[5] Formula I
[6] U.S. Patent Nos. 5,145,684; 6,375,986; 6,969,529; and 6,592,903 disclose nanopar- ticulate compositions of fenofibrate. [7] U.S. Patent Nos. 6,277,405; 6,652,881; 7,037,529; 7,041,319; 6,589,552; 6,531,158 and U.S. Patent Application Nos. 20040057998; 20040058005 and 2004137055 disclose micronized fenofibrate compositions. [8] U.S. Patent Nos. 4,895,726; 5,880,148 and U.S. Application No. 20040071771
describe co-micronizing the fenofibrate with surface- active agents.
[9] U.S. Patent No. 6,555,135 describes co-micronized mixture of fenofibrate with pharmaceutically acceptable excipient that is not a surfactant.
[10] U.S. Patent Nos. 6,074,670 and 6,277,405 disclose micronized fenofibrate coated onto hydro soluble carriers with optional surface- active agents.
[11] U.S. Patent No. 6,828,334 describes inclusion complex of fenofibrate with cy- clodextrins.
[12] U.S. Patent No. 6,027,747 describes solid dispersion of fenofibrate.
[13] U.S. Patent Application No. 20040087656 describes fenofibrate of particle size less than 2000 nm with an improved bioavailability.
[14] U.S. Patent Application Nos. 20060222706 and 20060222707 describe fenofibrate in intimate association with menthol or surfactant mixture.
[15] U.S. Patent Application No. 20030138496 micronized fenofibrate with inert hydro soluble carriers.
[16] Several other patents and applications describe specific formulations of micronized fenofibrate with specific polymeric or surface-active agent additives while several others describe emulsion and suspension formulations of fenofibrate.
[17] The solubility of an active pharmaceutical ingredient influences the bioavailability of the drug. Fenofibrate is a poorly soluble drug. Due to its poor hydrosolubility, fenofibrate poses problem of low dissolution. It is also poorly absorbed in the digestive tract and consequently its bioavailability is incomplete and irregular. Clearly, there is a need for improved compositions in which the fenofibrate exhibits better dissolution properties. Summary of the Invention
[18] In one general aspect there is provided a pharmaceutical composition of fenofibrate or salts thereof. The composition includes non-micronized fenofibrate and one or more pharmaceutically acceptable vehicles.
[19] In another general aspect there is provided a pharmaceutical composition of fenofibrate or salts thereof. The composition includes non-micronized fenofibrate, polyethylene glycol or derivatives thereof optionally, with one or more pharmaceutically acceptable excipients.
[20] In another general aspect there is provided a process for preparing a pharmaceutical composition of fenofibrate or salts thereof. The process includes the steps of melting, mixing one or more pharmaceutically acceptable vehicles, non-micronized fenofibrate optionally, with one or more pharmaceutically acceptable excipients.
[21] In another general aspect there is provided a pharmaceutical composition of fenofibrate or salts thereof. The composition includes non-micronized fenofibrate, cy- clodextrin or a derivative thereof optionally, with one or more pharmaceutically ac-
cep table excipients.
[22] In another general aspect there is provided a process for preparing a pharmaceutical composition of fenofibrate or salts thereof. The process includes: a) melting one or more pharmaceutically acceptable vehicles to form a clear solution; b) dissolving non- micronized fenofibrate in the clear solution; c) spraying the fenofibrate solution onto one or more pharmaceutically acceptable excipients; and d) mixing with one or more other pharmaceutically acceptable excipients and converting it into a suitable dosage form.
[23] Embodiments of the pharmaceutical composition may include one or more of the following features. For example, the pharmaceutically acceptable excipients may include one or more of fillers, binders, lubricants, sweeteners, coloring and flavoring agents, glidants, disintegrants, and the like.
[24] The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims. Detailed Description of the Invention
[25] Fenofibrate is practically insoluble in water. This insolubility characteristic causes fenofibrate to exhibit a low rate of dissolution in aqueous media, e. g., gastrointestinal fluids, which results in inadequate bioavailability after oral ingestion. The present inventors while working on the fenofibrate formulation have found that when fenofibrate is dissolved in a vehicle at a specific temperature, and further processed with pharmaceutically acceptable excipients, the crystallinity of the fenofibrate is significantly reduced in the product. The reduction in crystallinity significantly enhances the solubility, dissolution and bioavailability of fenofibrate. The present inventors also found that when a non-micronized fenofibrate is complexed with cyclodextrin or a derivative thereof, the solubility of the mix so obtained is increased in the aqueous fluids, which in turn leads to a significant increase in percent release of the drug fenofibrate and hence increase in bioavailability.
[26] The term 'non-micronized fenofibrate' as used herein refers to fenofibrate having a particle size greater than or equal to about 50μm and fenofibrate is not subjected to any comminution techniques, such as milling, spray drying, high pressure homogenization, and the like known to a person skilled in the art.
[27] Suitable vehicles which can be used in the process of the present invention are known to a person having ordinary skills in the art. Examples of such vehicles include polyethylene glycol or derivatives thereof, poloxamer, cremophore RH 40, vitamin E TPGS, and the like. Mixtures of vehicles are also suitable.
[28] Suitable polyethylene glycol (PEG) or derivatives thereof may include all PEGs that are liquid at room temperature or that melt up to about 7O0C. Suitable polyethylene
glycol or derivatives thereof may include one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyg- lycolized glycerides, polyethylene glycol-polyoxyethylene, polyethylene glycol polypropylenes, polyethylene glycol-polyoxypropylene, and the like.
[29] The composition of the present invention may be prepared by dissolving non- micronized fenofibrate in a clear solution of one or more melted vehicles. The obtained solution may be sprayed onto suitable filler. The obtained mixture may be granulated, with one or more pharmaceutically acceptable excipients. The obtained granules may be optionally coated and optionally mixed with one or more pharmaceutically acceptable excipients. The resulting mixture may be filled into capsules or compressed to make tablets.
[30] Suitable pharmaceutically acceptable sugars may include one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol, mannitol, and the like.
[31] Suitable surfactants may include one or more of amphoteric, non-ionic, cationic or anionic surfactants. Examples of such surfactants include sodium lauryl sulfate, monooleate, monolaurate, monopalmitate, monostearate or another ester of poly- oxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS), lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer, cremophore RH 40, and the like. Mixtures of surfactants may also be used.
[32] Suitable cyclodextrin or derivatives thereof may include one or more of hy- droxypropyl-β-cyclodextrin, β-cyclodextrin, α-cyclodextrin, hydroxypropyl- α - cyclodextrin, and the like.
[33] The composition comprising non-micronized fenofibrate with cyclodextrin or derivatives thereof may be prepared by the processes known in the art. The inclusion complex of a portion of total non-micronized fenofibrate with β-cyclodextrin may be prepared by dissolving fenofibrate and cyclodextrin or a derivative thereof in a suitable solvent followed by mixing and drying. The inclusion complex so formed may be mixed with one or more pharmaceutically acceptable excipients.
[34] The solvents may include one or more of water, methanol, ethanol, isopropanol, acetone, ether, chloroform, dimethylsulf oxide, dimethylformamide, methylene chloride, and the like.
[35] The melt granulation may be carried out by dissolving the remaining portion in part or full of the non-micronized fenofibrate in one or more pharmaceutically acceptable carriers by melting. The obtained melt may be mixed with a solution of a pharmaceutically acceptable sugar and one or more pharmaceutically acceptable excipients to get a molten mixture. The obtained mixture may be granulated by adsorbing it on one
or more pharmaceutically acceptable excipients.
[36] The term 'portion' as used herein refers to from about 1% to about 99% of the total non-micronized fenofibrate used in the formulation that needs to be complexed with cyclodextrin or a derivative thereof.
[37] The term 'remaining portion' as used herein refers to from about 1% to about 99% of the total non-micronized fenofibrate used in the formulation that needs to be melt granulated with one or more pharmaceutically acceptable carriers.
[38] The inclusion complex and granules obtained by melt granulation may be mixed together and may be optionally mixed with one or more pharmaceutically acceptable excipients. The resulting mixture may be filled into capsules or compressed to make tablets.
[39] The one or more pharmaceutically acceptable excipients may include one or more of fillers, binders, lubricants, sweeteners, coloring and flavoring agents, glidants, disin- tegrants, and the like.
[40] Suitable fillers may be one or more of microcrystalline cellulose, silicified micro- crystalline cellulose, mannitol, calcium phosphate, calcium sulfate, kaolin, dry starch, powdered sugar, and the like.
[41] Suitable binders may be one or more of povidone, starch, stearic acid, gums, hydrox- ypropylmethyl cellulose, and the like.
[42] Suitable lubricants may be one or more of magnesium stearate, zinc stearate, calcium stearate, stearic acid, sodium stearyl fumarate, hydrogenated vegetable oil, glyceryl behenate, and the like.
[43] Suitable glidants may be one or more of colloidal silicon dioxide, talc, cornstarch, and the like.
[44] Suitable disintegrants may be one or more of starch, croscarmellose sodium, crospovidone, sodium starch glycolate, and the like.
[45] The pharmaceutical composition of the invention may be present in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule, granules in capsule and other dosage forms suitable for oral administration. The tablets may further be coated with film forming polymers.
[46] Examples of some film forming polymers that can be used for the coating include but are not limited to cellulose derivatives (hydroxypropyl methylcellulose, hydroxyethyl- cellulose, hydroxypropyl cellulose and their derivatives), acrylic and methacrylic copolymers of different molecular weights, and mixtures thereof.
[47] The coating layers over the tablet may be applied as a solution/dispersion of the coating ingredients using conventional techniques known in the art selected from spray coating in a conventional coating pan or a fluidized bed processor, dip coating, and the
like.
[48] The invention is further illustrated by the following examples which are provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention. Examples:
[49] The composition of batches is provided in Table 1 to 13. Following formulations are representatives of the preferred compositions of the invention. The preparation of example is detailed below.
[50] Example 1: [51] Table- 1 Composition of Fenofibrate Tablets [52] [Table 1] [Table ]
[53] Procedure: A mixture of PEG 6000 and Vitamin E TPGS were melted together at 60-700C to form a clear solution. Fenofibrate was dissolved in the above solution at 60-700C (below the melting point of fenofibrate). Starch 1500/Lactose was loaded in a Fluid bed processor and the above solution of fenofibrate was sprayed onto starch 1500/Lactose. The temperature of the solution was maintained at 70-750C during spraying. The granules obtained in the above step were dried and passed through a suitable mesh screen and then were blended with presifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min.
This blend was lubricated with pre-sifted magnesium stearate for 2-3 minutes. The lubricated blend was compresses into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3% weight gain.
[54] Example 2: [55] Table-2 Composition of Fenofibrate Tablets [56] [Table 2] [Table ]
[57] Procedure: A mixture of PEG 6000 and Cremophore RH 40 was melted together at 60-700C to form a clear solution. Fenofibrate was dissolved in the above solution at 60-700C (below the melting point of fenofibrate). A mixture of starch 1500, lactose and calcium silicate was loaded in a Fluid bed processor and the above solution of fenofibrate was sprayed onto s tarch 1500, lactose and calcium silicate mixture . The temperature of the solution was maintained at 70-750C during spraying. The granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with pre-sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
[58] Example 3: [59] Table-3 Composition of Fenofibrate Tablets
[60] [Table 3] [Table ]
[61] Procedure: A mixture of PEG 6000 + Tween 80 were melted together at 60-700C to form a clear solution. Fenofibrate was dissolved in the above solution at 60-700C (below the melting point of fenofibrate). A mixture of starch 1500, lactose and calcium silicate was loaded in a Fluid bed processor and the above solution of fenofibrate was sprayed onto s tarch 1500, lactose and calcium silicate mixture . The temperature of the solution was maintained at 70-750C during spraying. The granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted, microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with a pre- sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
[62] Example 4: [63] Table-4 Composition of Fenofibrate Tablets [64]
[Table 4] [Table ]
[65] Procedure: A mixture of Poloxamer 407 or 188 and Vitamin E TPGS was melted together at 60-700C to form a clear solution. Fenofibrate was dissolved in the above solution at 60-700C (below the melting point of fenofibrate). Starch 1500/lactose was loaded in a Fluid bed processor and the above solution of fenofibrate was sprayed onto starch 1500/lactose. The temperature of the solution was maintained at 70-750C during spraying. The granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with a pre-sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
[66] Example 5: [67] Table-5 Composition of Fenofibrate Tablets [68]
[Table 5] [Table ]
[69] Procedure: Vitamin E TPGS was melted at 60-700C to form a clear solution. Fenofibrate was dissolved in the above solution at 60-700C (below the melting point of fenofibrate). Starch 1500/lactose was loaded in a Fluid bed processor and the above solution of fenofibrate was sprayed onto starch 1500/lactose. The temperature of the solution was maintained at 70-750C during spraying. The granules obtained in the above step were dried & passed through a suitable mesh screen and then were blended with pre-sifted microcrystalline cellulose, Prosolv SMCC 50, Aerosil 200 and Crospovidone (Polyplasdone INF 10) for 10 min. This blend was lubricated with pre- sifted magnesium stearate for 2-3 minutes. The lubricated blend was compressed into tablets using proposed tooling and then coated with aqueous dispersion of Opadry to a 3 % weight gain.
[70] Table 6 -Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg) [71] Table 6 provides the dissolution data for fenofibrate tablets (145mg) prepared as per the formula given in Table 4 and commercially available Tricor® Tablets. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used, wherein 1000 ml of 0.025M SLS in water at 37 0C + 0.50C was used as a medium.
[72]
[Table 6] [Table ]
[73] Table 7 -Dissolution data of Fenofibrate tablets (145mg) and Tricor® Tablets (145mg) [74] Table 7 provides the dissolution data for fenofibrate tablets (145mg) prepared as per the formula given in Table 4 and commercially available Tricor® Tablets. For determination of drug release rate, USP Type 2 Apparatus (rpm 50) was used, wherein 2000 ml of 0.0125M SLS in water at 37 0C ± 0.50C was used as a medium.
[75] [Table 7] [Table ]
[76] Example 6: [77] Table-8 Composition of Fenofibrate Tablets [78]
[Table 8] [Table ]
[79] Procedure: Fenofibrate and PEG were melted in a water bath to get a molten mass. Sucrose and Povidone K-30 were dissolved in a suitable solvent and was added to the molten mass and homogenized. The mixture so obtained was adsorbed on lactose monohydrate, crospovidone, poloxamer, sodium lauryl sulfate, Cremophore RH 40 and docusate sodium in a Rapid Granulator Mixer to get uniform granules. The obtained granules were mixed with Prosolv SMCC 90 and crospovidone. The resulting blend was lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
[80] Example 7: [81] Table-9 Composition of Fenofibrate Tablets [82]
[Table 9] [Table ]
[83] Procedure: Fenofibrate, PEG 6000 and sorbitol were melted in a water bath to get a molten mass and a solution of Povidone K-30 was added to the molten mass and homogenized. The obtained molten mass was adsorbed on lactose monohydrate, crospovidone, poloxamer, sodium lauryl sulfate, Cremophore RH 40 and docusate sodium in a Rapid Granulator Mixer to get uniform granules. The obtained granules were mixed with Prosolv SMCC 90 and crospovidone. The resulting blend was lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
[84] Example 8:
[85] Table- 10 Composition of Fenofibrate Tablets
[Table 10] [Table ]
[86] Procedure: Fenofibrate and beta cyclodextrin were dissolved in a suitable solvent and mixed followed by drying to make an inclusion complex. PEG 6000 and fenofibrate were melted in a water bath to get a molten mass. Sucrose and HPMC were dissolved in a suitable solvent and added to the molten mass. The obtained molten mass was adsorbed on lactose monohydrate, crospovidone, poloxamer, sodium lauryl sulfate and docusate sodium in a Rapid Granulator Mixer to get uniform granules. The obtained granules were mixed with the inclusion complex, Prosolv SMCC 90 and crospovidone. The resulting blend was lubricated with magnesium stearate and compressed into tablets using proposed tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
[87] Example 10:
[88] Table- 12 Composition of Fenofibrate Tablets
[Table 11] [Table ]
[89] Procedure: Fenofibrate and beta cyclodextrin were dissolved in a suitable solvent and mixed followed by drying to make an inclusion complex. Prosolv SMCC 90 and crospovidone were sifted and added to the inclusion complex and the resulting mixture was lubricated with magnesium stearate to form a Premix (A). PEG 6000 and fenofibrate were melted in a water bath to get a molten mass. Sucrose and HPMC were dissolved in a suitable solvent and was added to the molten mass. The obtained mixture was adsorbed on lactose monohydrate, poloxamer, sodium lauryl sulfate and docusate sodium in a Rapid Granulator Mixer to get uniform granules (Premix B). The
obtained granules were mixed with Premix (A), Prosolv SMCC 90 and crospovidone. The resulting blend was lubricated with magnesium stearate and compressed into tablets using proposed tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
[90] Example 11: [91] Table- 13 Composition of Fenofibrate Tablets [Table 12] [Table ]
[92] Procedure: Fenofibrate and PEG were melted in a water bath to get a molten mass. Sucrose and Povidone K-30 were dissolved in a suitable solvent and was added to the molten mass and homogenized. The obtained molten mass was adsorbed on lactose monohydrate in a Rapid Granulator Mixer to get uniform granules. The obtained granules were coated with a solution of crospovidone, poloxamer, sodium lauryl sulfate, Cremophore RH 40 and docusate sodium and dried. The coated granules were
mixed with Prosolv SMCC 90 and crospovidone. The resulting blend was lubricated with magnesium stearate and compressed into tablets using suitable tooling. The tablets can be optionally coated with aqueous dispersion of Opadry.
[93] While the invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.
Claims
[I] A pharmaceutical composition of fenofibrate or salts thereof comprising non- micronized fenofibrate and one or more pharmaceutically acceptable vehicles.
[2] The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable vehicle comprises one or more of polyethylene glycol or derivatives thereof, poloxamer, Cremophore RH 40 and vitamin E
[3] The pharmaceutical composition of claim 1 further comprising one or more pharmaceutically acceptable excipients.
[4] The pharmaceutical composition of claim 3, wherein the pharmaceutically acceptable excipients comprise one or more of binders, lubricants, disintegrants and glidants.
[5] The pharmaceutical composition of claim 1, wherein the composition is in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule and granules in capsule.
[6] A pharmaceutical composition of fenofibrate or salts thereof comprising non- micronized fenofibrate, polyethylene glycol or derivatives thereof optionally, with one or more pharmaceutically acceptable excipients.
[7] The pharmaceutical composition of claim 6, wherein the polyethylene glycol or derivatives comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolized glycerides, polyethylene glycol-polyoxyethylenes, polyethylene glycol polypropylenes and polyethylene gly col-poly oxypropylenes.
[8] The pharmaceutical composition of claim 6 further comprising one or more pharmaceutically acceptable sugars.
[9] The pharmaceutical composition of claim 8, wherein the pharmaceutically acceptable sugar comprises one or more of sucrose, glucose, fructose, galactose, maltose, isomaltose, cellobiose, melibiose, gentiobiose, lactose, sorbitol and mannitol.
[10] The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable sugar is sorbitol.
[I I] The pharmaceutical composition of claim 6 further comprising one or more pharmaceutically acceptable surfactants.
[12] The pharmaceutical composition of claim 11, wherein the surfactant comprises one or more of amphoteric, non-ionic, cationic or anionic surfactants.
[13] The pharmaceutical composition of claim 6, wherein the pharmaceutically acceptable excipients comprise one or more of binders, lubricants, disintegrants and glidants.
[14] The pharmaceutical composition of claim 6, wherein the composition is in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule and granules in capsule.
[15] A process for preparing pharmaceutical composition of fenofibrate or salts thereof, the process comprising: a) melting one or more pharmaceutically acceptable vehicles to form a clear solution; b) dissolving non-micronized fenofibrate in the clear solution; c) spraying the fenofibrate solution onto one or more pharmaceutically acceptable excipients; and d) mixing with one or more other pharmaceutically acceptable excipients and converting it into a suitable dosage form.
[16] The process of claim 15, wherein the pharmaceutically acceptable vehicle comprises one or more polyethylene glycol or derivatives thereof, poloxamer, Cremophore RH 40 and vitamin E TPGS.
[17] The process of claim 16, wherein the polyethylene glycol or derivatives comprise one or more of PEG 200, PEG 300, PEG 400, PEG 600, PEG 1000, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyglycolized glycerides, polyethylene glycol-polyoxy ethylenes, polyethylene glycol polypropylenes and polyethylene glycol-polyoxypropylenes.
[18] The process of claim 15, wherein the pharmaceutically acceptable excipients comprise one or more of binders, lubricants, disintegrants and glidants.
[19] The process of claim 15, wherein the composition is in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule and granules in capsule.
[20] A pharmaceutical composition of fenofibrate or salts thereof comprising non- micronized fenofibrate, cyclodextrin or derivatives thereof optionally, with one or more pharmaceutically acceptable excipients.
[21] The pharmaceutical composition of claim 20, wherein the cyclodextrin or derivatives comprise one or more of hydroxypropyl-β-cyclodextrin, β- cyclodextrin, α-cyclodextrin and hydroxypropyl- α -cyclodextrin.
[22] The pharmaceutical composition of claim 21, wherein the cyclodextrin is β- cyclodextrin.
[23] The pharmaceutical composition of claim 20, wherein the pharmaceutically acceptable excipients comprise one or more of binders, lubricants, disintegrants and glidants.
[24] The pharmaceutical composition of claim 20, wherein the composition is in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule and granules in capsule.
[25] A process for preparing a pharmaceutical composition of fenofibrate or salts
thereof, the process comprising the steps of complexing; melt -granulating non- micronized fenofibrate with cyclodextrin or a derivative thereof; and optionally, mixing with other pharmaceutically acceptable excipients.
[26] The process of claim 25, wherein the cyclodextrin or derivatives thereof comprise one or more of hydroxypropyl-β-cyclodextrin, β-cyclodextrin, α- cyclodextrin and hydroxypropyl- α -cyclodextrin.
[27] The process of claim 26, wherein the cyclodextrin is β-cyclodextrin.
[28] The process of claim 25, wherein the pharmaceutically acceptable excipients comprise one or more of binders, lubricants, disintegrants and glidants.
[29] The pharmaceutical composition of claim 25, wherein the composition is in the form of a tablet, capsule, powder, disc, caplet, granules, pellets, tablet in tablet, tablet in capsule, pellets in capsule, powder in capsule and granules in capsule.
Priority Applications (2)
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|---|---|---|---|
| EP08789518A EP2190415A2 (en) | 2007-08-02 | 2008-08-01 | Pharmaceutical compositions of fenofibrate |
| US12/671,832 US20100285126A1 (en) | 2007-08-02 | 2008-08-01 | Pharmaceutical compositions of fenofibrate |
Applications Claiming Priority (12)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1484MU2007 | 2007-08-02 | ||
| IN1488MU2007 | 2007-08-02 | ||
| IN1485/MUM/2007 | 2007-08-02 | ||
| IN1484/MUM/2007 | 2007-08-02 | ||
| IN1485MU2007 | 2007-08-02 | ||
| IN1487/MUM/2007 | 2007-08-02 | ||
| IN1486/MUM/2007 | 2007-08-02 | ||
| IN1486MU2007 | 2007-08-02 | ||
| IN1488/MUM/2007 | 2007-08-02 | ||
| IN1487MU2007 | 2007-08-02 | ||
| IN600MU2008 | 2008-03-24 | ||
| IN600/MUM/2008 | 2008-03-24 |
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| WO2009016608A2 true WO2009016608A2 (en) | 2009-02-05 |
| WO2009016608A3 WO2009016608A3 (en) | 2009-05-28 |
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|---|---|---|---|
| PCT/IB2008/053091 WO2009016608A2 (en) | 2007-08-02 | 2008-08-01 | Pharmaceutical compositions of fenofibrate |
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| EP (1) | EP2190415A2 (en) |
| WO (1) | WO2009016608A2 (en) |
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| EP2865371A1 (en) * | 2013-10-22 | 2015-04-29 | Disphar International B.V. | Fast dissolving granules |
| CN107126420A (en) * | 2017-05-09 | 2017-09-05 | 上海信谊万象药业股份有限公司 | A kind of high-dissolution fenofibrate and preparation method thereof |
| CN107469091A (en) * | 2017-07-25 | 2017-12-15 | 广东省药品检验所（广东省药品质量研究所、广东省口岸药品检验所） | A kind of magnetic fenofibrate cyclodextrin inclusion compound |
| US11682134B2 (en) | 2016-02-26 | 2023-06-20 | Nikon Corporation | Object detection device, method, information processing device, and storage medium calculating reliability information of detected image data for object shape determination |
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| WO2009016608A3 (en) | 2009-05-28 |
| EP2190415A2 (en) | 2010-06-02 |
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