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
  • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

• the present invention particularly relates to Nicorandil-containing compositions, process for their preparation, tablets containing these compositions, and their use as a medicament.
• the invention relates to a composition containing Nicorandil, which has the advantage of allowing a significant simplification of the industrial process for manufacturing tablets containing it.
• a process comprising a granulation step is described in EP 0230932 B1.
• Examples 1, 2, 4, 5, and 6 describe processes implementing a granulation step.
• the use of a granulation step makes it possible to obtain tablets having a better stability than when this step is absent (Tables 1 to 7, Examples 3, 7, 8). This is one of the reasons why it was chosen to use a granulation process for the commercial product.
• Example 3 of EP 0230932 B1 describes a process in which, in a first step, the active ingredient is mixed with stearic acid, and then the mixture is micronized. However, the stability of the compositions obtained is not satisfactory (Table 3, page 5: 97.3% after 3 months at 40 ° C., 0% residual moisture). For comparison, Example 2 (99.4%) is the one that has the closest stability to the commercial composition.
• This direct compression composition comprises active ingredient (Nicorandil) and a saturated higher aliphatic acid or a non-micronized saturated higher alcohol.
• a saturated higher aliphatic acid or a saturated higher acceptable alcohol must be solid at ambient temperature, that is to say at a temperature close to 20 to 25 ° C.
• Preferred saturated higher aliphatic acids or alcohols will still be solid at a temperature close to 40 ° C., preferably 50 ° C.
• Particularly preferred saturated aliphatic acids may be chosen from palmitic acid and stearic acid.
• Particularly preferred saturated aliphatic alcohols may be selected from hexadecanoic and octadecanoic alcohols, preferably hexadecan-1-ol and octadecan-1-ol.
• a composition according to the invention advantageously comprises (i) Nicorandil, and (ii) a lubricant chosen from a saturated higher aliphatic acid and its salts and / or saturated higher alcohol, solid at ambient temperature, in which the lubricant is not micronized.
• a preferred lubricant is stearic acid.
• a composition according to the invention may further comprise a disintegrant and a diluent.
• a preferred disintegrant is croscarmellose sodium.
• a preferred diluent is mannitol.
• a composition according to the invention advantageously comprises, by weight, 10% Nicorandil, and a lubricant, solid at room temperature, non-micronized.
• a composition according to the invention preferably comprises 8% non-micronized stearic acid.
• a composition according to the invention advantageously comprises a disintegrant, preferably 5% of croscarmellose sodium.
• a composition according to the invention advantageously comprises a diluent, preferably mannitol, in particular 76% by weight.
• the invention relates to a method for preparing a composition according to its first aspect.
• the preparation method according to the second aspect of the invention comprises a first step in which, by weight, 30 parts of Nicorandil, 15 parts of croscarmellose sodium, 35 parts of mannitol and 3 parts of corn starch are mixed. to form a first premix.
• the first premix is preferably calibrated.
• the method according to the invention may further comprise a second step in which the first calibrated premix is mixed with 193 parts by weight of mannitol to form a second premix.
• the process according to the invention may further comprise a third step in which the second premix is mixed with 24 parts by weight of non-micronized stearic acid.
• the invention relates to a composition for direct compression, obtained by a method according to its second aspect.
• the invention relates to a method for preparing a tablet comprising Nicorandil, comprising a first step (i) in which a composition for direct compression according to its third aspect is disposed in a mold cavity, comprising a second step (ii) in which a counter-cavity of the mold is applied against the impression so that the composition for direct compression is captive in an enclosure of volume V1 of the mold, and further comprising a third step (iii) in wherein the volume V1 of the mold is reduced to a volume VO less than the volume V1 by compression until a tablet is obtained.
• the method according to its fourth aspect advantageously comprises a fourth step (iv), in which the impression and the counterprint are disjoint and the tablet is extracted from the enclosure.
• the invention relates to a tablet obtained according to its fourth aspect.
• the invention relates to a tablet package according to the fifth acceptable aspect, in particular a blister or a bottle.
• CONTAINER Phase 2 Manufacture of Ikorel tablets
• composition comprising Nicorandil according to the invention can be prepared as follows: 1) Composition according to the invention:
• the water content is systematically lower for the batch of product obtained via the process according to the invention.
• Nicorandil are as stable over time for the tablets according to the invention as for the commercial tablets.
• Lot LOP107 CD is a batch obtained by the method according to the invention, described above.
• Figures 1 to 3 are graphical representations of the evolution of the Nicorandil content as a function of time for, respectively, tablets preserved in blisters at 25 ° C, 60% RH; 30 0 C, 65% RH; and 40 0 C, 75% RH; the latter corresponding to the values presented in Table 14.
• FIGS. 4 to 6 are graphical representations of the evolution of the content of impurities as a function of time for, respectively, tablets preserved in blisters at 25 ° C., 60% RH; 30 0 C, 65% RH; and 40 0 C, 75% RH; the latter corresponding to the values presented in Table 14. Discussion
• the active ingredient content of the batch obtained by the process according to the invention is equivalent to that measured in the batches obtained by the current process. It is the same for the concentrations of impurities.
• the active ingredient content of the batch obtained by the process according to the invention is better or equivalent to that measured in the batches obtained by the current process. It is the same for the concentrations of impurities.
• the tablets according to the invention have qualities of stability quite remarkable vis-à-vis the tablets according to the current method. It is necessary to remember that the stability conditions considered here are drastic conditions for this product, for which strict conservation conditions are recommended (temperature ⁇ 25 ° C.).

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• General Health & Medical Sciences (AREA)
• Epidemiology (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Oil, Petroleum & Natural Gas (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Vascular Medicine (AREA)
• Urology & Nephrology (AREA)
• Cardiology (AREA)
• Heart & Thoracic Surgery (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Organic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (1)

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ID=34950297

Family Applications (1)

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Family Cites Families (15)

• 2004
  • 2004-07-08 FR FR0407590A patent/FR2872705B1/fr not_active Expired - Fee Related
• 2005
  • 2005-07-05 CA CA002570863A patent/CA2570863A1/fr not_active Abandoned
  • 2005-07-05 WO PCT/FR2005/001730 patent/WO2006016040A1/fr active Application Filing
  • 2005-07-05 NZ NZ552983A patent/NZ552983A/en not_active IP Right Cessation
  • 2005-07-05 MX MXPA06015151A patent/MXPA06015151A/es active IP Right Grant
  • 2005-07-05 EA EA200700191A patent/EA012967B1/ru not_active IP Right Cessation
  • 2005-07-05 CN CN200580022748A patent/CN100591356C/zh not_active Expired - Fee Related
  • 2005-07-05 JP JP2007519838A patent/JP2008505873A/ja active Pending
  • 2005-07-05 EP EP05786080A patent/EP1776093A1/fr not_active Withdrawn
  • 2005-07-05 ZA ZA200700704A patent/ZA200700704B/xx unknown
  • 2005-07-05 KR KR1020077000276A patent/KR20070030262A/ko not_active Application Discontinuation
  • 2005-07-05 AU AU2005271131A patent/AU2005271131B2/en not_active Ceased
  • 2005-07-05 BR BRPI0513005-0A patent/BRPI0513005A/pt not_active IP Right Cessation
• 2006
  • 2006-12-20 US US11/642,575 patent/US20070190134A1/en not_active Abandoned
  • 2006-12-24 IL IL180285A patent/IL180285A0/en unknown
• 2007
  • 2007-01-11 NO NO20070186A patent/NO20070186L/no not_active Application Discontinuation
  • 2007-02-05 MA MA29654A patent/MA28783B1/fr unknown
  • 2007-11-26 HK HK07112888.3A patent/HK1107256A1/xx unknown

Non-Patent Citations (1)

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