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

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 ]

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• 2008
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