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
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • 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
  • A61K9/2009—Inorganic compounds

Definitions

• the present invention relates to new rosuvastatin formulations prepared so as to be used in the treatment of hyperlipidemia.
• the characteristic features of the formulations are that said formulations comprise rosuvastatin on effective amounts; a pharmaceutically acceptable phosphate salt is used as the stabilizer, and the ratio of rosuvastatin to the stabilizer in the formulation is in the range of 0.5-20 by weight.
• Rosuvastatin which has the chemical name (3i?,5S,6E)-7-[4-(4-fluorophenyl)-6-(l-methylethyl)-2[methyl(methylsulphonyl)amino]-5- pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid is a HMG Co A enzyme inhibitor and it is displayed in formula (I):
• rosuvastatin which is displayed in formula (I) in the patent numbered US5260440, inhibits the activation of the enzyme named HMG-CoA reductase that is responsible for cholesterol synthesis in the body and prevents cholesterol formation and it is effective in the treatment of hypercholesterolemia, hyperlipoproteinemia and atherosclerosis.
• Statin derivative cholesterol absorption inhibitors can also be used in combination with cardiovascular active agents; for instance fibric acid derivatives, calcium channel blockers and cholesterol absorption inhibitors.
• rosuvastatin easily disintegrates as affected by factors such as moisture and light, and this constitutes a serious impediment to development of stable rosuvastatin formulations and combinations.
• Rosuvastatin calcium is transformed into lactone as a result of "intramolecular esterification" which occurs between carboxylic acid in its structure and hydroxyl groups on ⁇ and ⁇ carbons of this carboxylic acid.
• the reaction takes place in acidic environment and the basic agents cause the reaction to revert back.
• the main disintegration products (3R, 5S) that arise as a result of the disintegration of rosuvastatin are lacton and oxidation products.
• Richter Gedeon NYRT disclosed formulations comprising rosuvastatin calcium as the active agent and calcium acetate, magnesium hydroxide, calcium gluconate, calcium glycerophosphate or aluminum hydroxide as the stabilizing agent in the patent application WO2008035128(Al).
• the first aspect of the invention relates to an enhanced pharmaceutical formulation comprising rosuvastatin in a therapeutically effective amount and a pharmaceutically acceptable phosphate salt as the stabilizer.
• the invention discloses stable rosuvastatin formulations which have longer shelf life than known formulations and in which the ratio of rosuvastatin to the stabilizer is in the range of 0.5- 20 by weight.
• the characteristic feature of the formulations is that said formulations comprise rosuvastatin in an effective amount, a pharmaceutically acceptable phosphate salt and or pharmaceutical derivatives thereof, and the ratio of rosuvastatin to the stabilizer is in the range of 0.5-20 by weight.
• Another characteristic feature of the formulations of the present invention is that the ratio of rosuvastatin to the stabilizer used in said formulations is preferably in the range of 0.5-15, more preferably in the range of 0.5-8 by weight.
• phosphate salt used throughout the text comprises phosphate salts and all pharmaceutically acceptable derivatives thereof. 'Derivatives' refers to all pharmaceutically acceptable hydrates and antihydrates of said phosphate salt.
• Said phosphate salts can be selected from a group comprising monobasic, dibasic or tribasic calcium, magnesium, aluminum, iron phosphate salts and/or hydrates thereof.
• the preferred phosphate salt is in dihydrate form though it is more preferably dibasic calcium phosphate dihydrate and/or pharmaceutically acceptable derivatives thereof.
• Rosuvastatin used in the formulations of the present invention is in the form of pharmaceutically acceptable salt thereof, preferably in calcium salt form.
• Rosuvastatin calcium is used in a particular particle size range in formulations of the present invention.
• D(50) particle size for rosuvastatin calcium is in the range of 5 to 80 micron, preferably in the range of 20 to 80 micron, more preferably in the range of 30 to 80 micron;
• D(90) particle size is in the range of 100 to 400 micron, preferably in the range of 100 to 350 micron, more preferably in the range of 100 to 300 micron.
• D(50) particle size used in the text refers to the particle size of 50% of rosuvastatin particles by volume and "D(90) particle size” refers to the particle size of 90% of rosuvastatin particles by volume, which were measured in the device Malvern Mastersizer 2000 S (Scirocco 2000) by dry method.
• the formulations according to the present invention can comprise at least one sterol absorption inhibitor in an effective amount as a second active agent.
• the sterol absorption inhibitor used in rosuvastatin formulations of the present invention is selected preferably from ezetimibe and/or its pharmaceutically acceptable salts, hydrates, enantiomers, racemates, organic salts, inorganic salts, esters, polymorphs, crystalline and amorphous forms and/or combinations thereof.
• the formulations of the present invention comprise;
• ⁇ at least one pharmaceutically acceptable disintegrant in the range of 5% to 20% by weight, • one or more pharmaceutically acceptable excipients in the range of 1% to 20% by weight.
• the formulations can optionally comprise coating materials.
• substances such as antioxidants, chelating agents, alkalinizing agents and photoprotectives can be used as the stabilizer.
• the stabilizer/stabilizers used in the formulations of the present invention are preferably alkalinizing agents and they can be selected from, but not limited to, a group comprising alkaline metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulfate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines,
• the formulations of the present invention can comprise other pharmaceutically acceptable components such as additives and excipients selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling materials, desiccants, lubricants, diluents, binders, glidants, wetting agents, anti-adhesive agents, solvents, sweeteners.
• additives and excipients selected from a group comprising binders, disintegrants, viscosity enhancing agents, filling materials, desiccants, lubricants, diluents, binders, glidants, wetting agents, anti-adhesive agents, solvents, sweeteners.
• the filling materials used in the present invention comprise one or more components selected from the group comprising lactose, sugar, starch, modified starch, mannitol, sorbitol, inorganic salts, microcrystalline cellulose, cellulose, calcium sulfate, xylitol and lactitol.
• the disintegrant of the present invention enables the dosage form to disperse easily and rapidly in water and it is significant from this aspect.
• the disintegrants can be selected from polymers having high disintegrating characteristics such as cross-linked hydroxypropyl cellulose, polyvinylpyrrolidone, high molecular weight polymers, microcrystalline cellulose, sodium starch glycolate, povidone, crospovidone or colloidal silicone dioxide, alginic acid, sodium alginate, corn starch.
• the disintegrant preferred is crospovidone and its amount in the formulation is in the range of 5% to 20%.
• the anti-adhesive substances of the present invention are used in order to prevent the mixture comprising active agent to adhere on device and machine surfaces during the process and create a rough surface.
• the substances used for this purpose comprise one or more components selected from the group comprising talc, colloidal silicon dioxide (Aerosil, Syloid, Cab-O-Sil), magnesium stearate and corn starch.
• the binders of the present invention comprise one or more components selected from the group comprising potato starch, wheat starch or corn starch; microcrystalline cellulose, for instance Avicel®, Filtrak®, Heweten® or Pharmacel® products; hydroxypropyl cellulose, hydroxyethyl cellulose; hydroxypropylmethyl cellulose, for instance hydroxypropylmethyl cellulose- Tip 2910 USP; hypromellose and polyvinylpyrrolidone, for instance Povidone® K30(BASF); lactose, guar gum, pectin, gelatin, sodium alginate.
• microcrystalline cellulose for instance Avicel®, Filtrak®, Heweten® or Pharmacel® products
• hydroxypropyl cellulose hydroxyethyl cellulose
• hydroxypropylmethyl cellulose for instance hydroxypropylmethyl cellulose- Tip 2910 USP
• hypromellose and polyvinylpyrrolidone for instance Povidone® K30(BASF)
• the lubricants of the present invention comprise one or more components selected from the group comprising metallic stearates (e.g. magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (e.g. sodium stearil fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffines, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulfates (e.g. sodium lauryl sulfate, magnesium lauryl sulfate), sodium chloride, sodium benzoate, sodium acetate and talc and/or hydrates thereof.
• metallic stearates e.g. magnesium stearate, calcium stearate, aluminum stearate
• fatty acid esters e.g. sodium stearil fumarate
• fatty acids e.g. stearic acid
• fatty alcohols g
• the lubricant used in the formulations of the present invention is preferably magnesium stearate.
• the diluents of the present invention comprise one or more components selected from the group comprising alkaline metal carbonates, cellulose derivatives (e.g. microcrystalline cellulose, cellulose acetate etc.), dextrin, fructose, dextrose, glyceryl palmitostearate, lactitol, lactose, direct compression-lactose, maltose, mannitol, simethicone, sorbitol, starch, talc, xylitol and/or hydrates and/or derivatives thereof.
• the diluent used in the formulations of the present invention is preferably direct compression-lactose.
• the solvents of the present invention comprise one or more components selected from the group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptanes, hexane, acetonitrile, alcohol and/or alcohol mixtures.
• the film coating material of the present invention is composed of lactose, hydroxypropyl methyl cellulose, triacetine, titanium dioxide, polyvinyl alcohol, talc, lecithin, polyethylene glycol and/or mixtures thereof. Quality of the coating material plays an important role in maintaining the stability of formulations comprising rosuvastatin during shelf life.
• the coating material according to the present invention comprises sufficient amounts of talc, lecithine and optionally at least one of the components listed above or mixtures of these components in addition.
• the coating material used to coat the tablet dosage form of the present invention is approximately in the range of 0.5% to 10% of the total tablet weight, preferably in the range of 1% to 5%.
• the pharmaceutical formulations to be administered orally can be in tablet, capsule, soluble tablet, effervescent tablet, chewable tablet, coated tablet, soluble granule, soluble powder, emulsion, suspension, solution form.
• the oral dosage form according to the present invention is preferably film coated tablet and the formulations of the present invention can be produced by any production method known in the prior art.
• Rosuvastatin calcium at a particular particle size, at least one pharmaceutically acceptable disintegrant, the diluent and the stabilizer are mixed,
• the obtained mixture is sieved preferably through a 25 mesh sieve and treated with the lubricant,
• the final mixture is sent to the compression machine and tablets are compressed by imposing a compression force in the range of 10 kN to 200 kN, preferably in the range of 30 kN to 200 kN, more preferably in the range of 30 kN to 150 kN,
• the compressed tablets are film coated by the coating material obtained dissolving the sufficient amount of coating material in deionized water.
• rosuvastatin calcium, dibasic calcium phosphate dihydrate, the disintegrant and the diluent are mixed and sieved.
• Magnesium stearate is added into the mixture obtained and the blend is mixed again.
• the final mixture is loaded to tablet compression machine and tablets are compressed imposing 80 kN compression force.
• the compressed tablets are coated with the film coating solution prepared by dissolving the coating material in a sufficient amount of deionized water in advance and the tablet formulations are finalized.
• combination tablet For the combination tablet to be prepared according to the formulation given below, two active agents are formulated separately, and then the two mixtures obtained are mixed. The final mixture is loaded to tablet compression machine and tablets are compressed. The tablets prepared are film coated.

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• 2011
  • 2011-05-03 WO PCT/TR2011/000135 patent/WO2011139256A2/en active Application Filing
  • 2011-05-03 EP EP11725996A patent/EP2566465A2/de not_active Withdrawn

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