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
  • 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
  • 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
  • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
  • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
• • 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
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system

Definitions

• the present invention relates to a solid pharmaceutical formulation which contains licofelone or a pharmaceutically acceptable salt thereof and which rapidly releases the active ingredient.
• Licofelone (ML 3000) is [2,2-dimethyl-6- (4-chlorophenyl) -7-phenyl-2,3-dihydro-1 H-pyrrolizin-5-yl] acetic acid of the formula
• Licofelone is a non-selective, dual inhibitor of cyclooxygenase and 5-lipoxygenase and has analgesic, antipyretic and anti-inflammatory activity.
• the preparation and activity profile of Licofelone are described in European Journal of Pharmacology 271 (1994), 525-531; Pharmaceutical Research / Drug Res. 44 (II), 1994, 1329-1333; Pharm. -Forsch. 1994, 44, 629-636; Arzneim. researchers. 1995, 45, 27-32; Drugs of the Future 1995, 20: 1007-1009; Arch. Pharm. Pharm. Med. Chem. 330, 307-312 (1997); and Inflammopharmacology, 9, 113-124 (2001).
• Licofelone has a very low solubility of only 0.0002 mg / ml at pH 1 and 0.03 mg / ml at pH 7.5.
• the therapeutic activity is an essential quality feature of pharmaceutical formulations. This depends in particular on the dissolution rate of the active ingredient. The rate of dissolution of active ingredients in turn often represents the rate of determining step for absorption. If the active substance has only a low solubility or dissolution rate, it is generally difficult to absorb, so that the therapeutic activity is reduced. This has to be counteracted by galenical measures which improve the solubility or speed of dissolution. This also applies to Licofelone, whose solubility is too low for a satisfactory absorption.
• a standard way to improve the dissolution rate of poorly soluble solid drugs is to increase the specific surface area by reducing the particle size.
• One possibility for this is micronization. Micronization of Licofelone did not, however, have the expected effect. A reduction in the particle size did not lead to the hoped-for improved solution properties, but on the contrary, to a decrease in the solution speed.
• Another common method for improving the dissolution rate is the solubilization of the active ingredient by using surfactants. This facilitates the surface contact of hydrophobic substances with water. If the critical micelle concentration is exceeded, the active ingredient is dissolved in surfactant micelles and thereby distributed in the aqueous phase. In this way, bioavailability can be improved.
• surfactant-containing formulations adversely affect the chemical stability of Licofelone.
• the lecithin known for its good compatibility, leads to a decomposition of almost 40% after the formulation has been stored for 3 months at 40 ° C./70% relative atmospheric humidity.
• Another object is to provide a pharmaceutical formulation containing Licofelone in which the rate of release of Licofelone does not drop significantly even after prolonged storage.
• the present invention therefore relates to a solid pharmaceutical formulation, the licofelone or a pharmaceutically acceptable salt thereof and at least one water-soluble polymer which is selected from hydroxyalkyl celluloses, methyl cellulose, polyvinylpyrrolidones and copolymers thereof, polyvinyl alcohols, saponified or partially saponified copolymers of N-vinyl pyrrolidone and vinyl esters, and / or at least one water-soluble polyol, which is selected from polyethylene glycols with a molecular weight in the range from 8000 to 20,000 and sugar alcohols.
• Physiologically acceptable salts of Licofelone include acid and base addition salts.
• Acid addition salts are, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid or phosphoric acid or salts with organic acids, in particular carboxylic acids such as acetic acid, tartaric acid, lactic acid, citric acid, malic acid, amygdalinic acid, ascorbic acid, maleic acid, fumaric acid or gluconic acid, gluconic acid, acids, such as methanesulfonic acid, methylsulfonic acid and toluenesulfonic acid.
• Base addition salts are, for example, salts with inorganic bases, such as sodium or potassium hydroxide, or with organic bases, such as mono-, di- or triethanolamine.
• Suitable water-soluble polymers are:
• Hydroxyalkyl celluloses the alkyl group of which preferably has 1-4 carbon atoms.
• hydroxyalkyl celluloses are hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxyethyl hydroxypropyl cellulose and hydroxypropyl methyl cellulose.
• Hydroxypropylmethyl cellulose is preferred, in particular with a degree of substitution of 0.12 to 0.25 and a hydroxypropyl content of 5 to 8.5%.
• polyvinylpyrrolidones which in particular have a molecular weight in the range from 7000 to 70,000, preferably 45,000 to 70,000.
• Preferred water-soluble polymers are copolymers of N-vinylpyrrolidone and vinyl esters, in particular a copolymer of N-vinylpyrrolidone and vinyl acetate.
• Such copolymers are commercially available under the designation Kollidon VA 64 (vinyl pyrrolidone / vinyl acetate 60/40), Copolyvidone or Copovidone available.
• Suitable water-soluble polyols are polyethylene glycols with a molecular weight in the range from 8000 to 20,000 and sugar alcohols, for example mannitol and sorbitol.
• the content of water-soluble polymer or water-soluble polyol is so high that a sufficient release rate of Licofelone is achieved.
• less than 1% by weight (here and below% figures always refer to the total weight of the pharmaceutical formulation) are sufficient. In general, however, at least 1% by weight and preferably 1-20% by weight, in particular 3-15% by weight, are used.
• composition according to the invention can be in the form of customary solid pharmaceutical formulations, in particular oral and oral formulations, such as tablets, capsules, pellets, granules, multiparticulate forms etc.
• formulations according to the invention are preferably in the form of tablets.
• the formulations according to the invention can contain customary pharmaceutical auxiliaries, such as binders, fillers, lubricants, disintegrants, flow regulators, mold release agents, colorants, flavorings, etc.
• auxiliaries for the production of tablets are, in particular, starch, in particular corn starch (binder), microcrystalline cellulose (filler), highly disperse silicon dioxide (flow regulator), lactose, lubricants such as talc or magnesium stearate and disintegrant.
• Particularly preferred disintegrants are sodium starch glycolate and in particular a crosslinked polyvinylpyrrolidone (Crospovidone).
• the amount of disintegrant is generally 1-20% by weight, in particular 2-18% by weight and particularly preferably 5-15% by weight.
• the amount of lubricant is generally 0.5-12% by weight, in particular 1-10% by weight and particularly preferably 3-8% by weight.
• the formulations according to the invention are preferably free from surfactants.
• the tablets are tablets which contain a disintegrant.
• Preferred disintegrants are crosslinked polyvinylpyrrolidone, sodium starch glycolate, carboxymethyl cellulose, crosslinked carboxymethyl cellulose and polyacrylic acid. Cross-linked polyvinyl pyrrolidone is particularly preferred.
• a preferred embodiment is tablets which comprise Licofelone, a copolymer of N-vinylpyrrolidone and a vinyl ester, a crosslinked polyvinylpyrrolidone or sodium starch glycolate and a lubricant. Tablets of the following composition are particularly preferred:
• the release rate was determined using the paddle method of US Pharmacopoe 26, Apparatus 2, with the following modifications:
• volume 1000 ml aqueous buffer solution, pH 8.0 with 0.5% sodium dodecyl sulfate.
• a preferred formulation with the stated release rate contains at least one water-soluble polymer and / or water-soluble polyol in an amount suitable for achieving the release rate.
• the formulations according to the invention can be prepared in a customary manner.
• a dry mixture of the components can be produced and the mixture can be processed in the usual manner to the desired dosage form. You can granulate the mixture and compress it into tablets or compress it directly into tablets.
• a premix of the components for example in a fluidized bed granulator.
• the premix may contain only part of the disintegrant and / or part of the filler.
• An aqueous solution of the water-soluble polymer is then sprayed onto the premix. Spraying can take place in a kneader or in particular a fluidized bed granulator.
• the moist granules obtained are then dried to the desired residual moisture and sieved.
• a lubricant and optionally further disintegrant and further filler are then mixed into the sieved mixture.
• the mixture obtained can then be compressed into tablets.
• components (1) and (9) to (11) were premixed in a fluidized bed granulator.
• the components (2) to (4) were in
• Dissolved water (3.75 l water based on 5 kg of Licofelone) and sprayed onto the powdery premix at a spray pressure of 2 bar.
• the granules obtained were dried to a residual moisture of about 2 to 3% at an inlet air temperature of 60 ° C. and sieved.
• the remaining part of components (5) to (8) and components (12) and (13) were then mixed homogeneously with the active ingredient granules.
• the mixture obtained was ready for compression and was compressed on rotary tablet presses to give tablets with an active substance content of 100 mg Licofelone.
• the composition of the tablets is given in Table 1 below.

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Citations (4)

• 2003
  • 2003-10-31 DE DE10351035A patent/DE10351035A1/de not_active Withdrawn
• 2004
  • 2004-10-27 AR ARP040103905A patent/AR046205A1/es unknown
  • 2004-10-29 WO PCT/EP2004/012266 patent/WO2005041920A2/de active Application Filing
  • 2004-10-29 TW TW093133050A patent/TW200524592A/zh unknown

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