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
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
• • 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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Definitions

• New dosage form of fenofibrate its process of obtaining, its application as medicine.
• the present invention relates to a new galenical form of fenofibrate (DCI) and / or its derivatives, its production process and the medicaments comprising this form.
• DCI fenofibrate
• fenofibrate is isopropyl para- (4-chlorobenzoyl) -phenoxyisobutyrate.
• the expression “fenofibrate and its derivatives” denotes the compounds of formula I
• R 1 represents a phenyl group or a phenyl group substituted by one or more - CH 3 , CF 3 or halogens (in particular fluorine, chlorine or bromine),
• R 2 and R 3 independently represent a hydrogen or halogen atom (preferably fluorine, chlorine or bromine), an alkyl or alkoxy group having 1 to 5 C or a -CF 3 group,
• Y represents a group -OH, a lower alkoxy group, preferably C 1 - C 4 , a group -NR 4 R 5 , a group 4 -ement -NHCH 2 CH 2 NR 4 R 5 or a group -O-alkylene- NR 4 R 5 , the alkylene having in particular 2 to 6 carbon atoms R 4 and R 5 identical or different, each representing a hydrogen atom, a C 1 -C 5 alkyl group, a C 3 cycloalkyy group - C 7 , preferably in C 5 - C 6 an aryl or aryl group substituted on the aromatic residue by one or more halogen groups, methyl or -CF 3 , or else R 4 and R 5 form together with the nitrogen atom to which they are linked, either an n-heterocyclic group having 5 to 7 vertices which may contain a second heteroatom chosen from N, O and S, and which may be substituted, or an amide residue derived from Ivsine
• fenofibrate is used for the treatment of hyperlipidénaies, hypercholesterolimies and endogenous hypertrigiycéridémies of the adult.
• fenofibrate at a rate of 300 to 400 mg per day, a reduction of the cholera steremia of 20 to 25% and a reduction of the triglyceridemia of 40 to 50% . This significant action manifests itself from the first month of treatment and persists after 30 months of treatment.
• hyperiipidemias contribute to the increase in the statistical risk of vascular accident in particular coronary artery.
• the treatment of hyperipidemia with fenofibrate constitutes a long-term symptomatic treatment which is not without risks.
• fenofibrate is presented in the form of capsules dosed with 100 mg of active principle: the average daily dosage is 300 to 400 mg, sometimes 600 mg.
• the subject of the present invention is a new galenical form making it possible to reduce the dosage and the number of administrations thanks to the progressive and delayed release of fenofibrate and / or its derivatives.
• This form is remarkable in that it consists of granules comprising a neutral core consisting of a grit of an inert excipient comprising at least one constituent chosen from sucrose and lactose, optionally in mixture with starch, said neutral core being coated with a first layer containing fenofibrate and / or its derivatives in admixture with an excipient for the first layer comprising at least a first constituent chosen from talc, silica and their mixtures, and a second constituent which is stearic acid, then a second layer, or outer layer constituted by a microporous envelope comprising at least one polymer compatible with oral administration.
• the neutral core consists of sucrose, lactose or their mixtures.
• the neutral core can be a mixture comprising from 20 to 60% by weight of sucrose and / or lactose and from 1 to 40% by weight of starch. These proportions are expressed relative to the total weight of the new dosage form.
• the new dosage form contains from 0.01 to 1% approximately, and in particular from 0.1 to 0.5% by weight, of stearic acid, from 5 to 15% by weight. weight of talc and 2 to 10% by weight of drying silica.
• the neutral core can comprise fenibrate adsorbates and / or its derivatives.
• the new dosage form as defined above contains, relative to its total weight, from 25 to 55% approximately by weight of fenofibrate and / or its derivatives, and from 2 to 10% approximately by weight of polymer constituting the layer external, the rest being constituted by the other inert excipients, present for example in a proportion of 40 to 70% approximately.
• the neutral core generally represents 15 to 60%.
• the grain constituting the neutral core has dimensions of the order of 0.1 to 0.5 mm, and the granules, object of the invention, have dimensions not exceeding approximately 2 mm, these dimensions varying for example from 1 mm to 2 mm in most cases.
• the first layer can itself be composed of several sublayers (generally not more than 4) obtained by successive applications of fenofibrate and / or of its derivatives and of or excipients for said first layer.
• the invention is not limited to granules having determined proportions of polymer or a determined number of said sublayers, because one of the advantages of the new form of the invention is to produce a drug having a delayed effect controlled by the mixture of granules having different release rates of fenofibrate and / or its derivatives.
• the subject of the invention is also a process for obtaining the new galenical form which is remarkable in that the neutral granules are prepared beforehand by granulation, that they are dried and sieved, that these granules are impregnated with a solution of fenofibrate and / or its derivatives, which is then coated with said granules with said excipient for the first layer, which is repeated, if desired, the operations of impregnating fenofibrate and coating, then forming the microporeus ⁇ envelope by coating with said polymer in solution in a solvent.
• a pharmaceutically acceptable organic solvent is used in particular, such as ethane or acetone.
• the present invention relates to medicaments comprising the new form of administration of fenofibrate and / or its derivatives, in the form of active granules optionally mixed with neutral granules not coated with polymer in order to obtain a predetermined concentration in fenofibrate and / or its derivatives, this set of granules being presented in the form of capsules, tablets, suppositories, syrup, granules or powder.
• the corn starch and the sucrose are mixed and granulated, then the grains are sieved and blended for a long time so as to make them perfectly spherical. We sift again and dry perfectly.
• an alcoholic solution of fenofibrate is sprayed onto the neutral cores thus obtained.
• the first layer is then made by incorporating into these granules a part of the mixture of the other excipients (with the exception of shellac) then the spraying of fenofibrate is started again, this coating being repeated several times with sieving and drying if necessary between each undercoat.
• the microporous outer layer is produced, by spraying the shellac granules with gum shellac in solution in absolute ethyl alcohol, in an amount sufficient to impregnate all of the granules. It is then carefully dried, eliminating the ethyl alcohol remaining, it is again sieved and the title of the granules obtained is checked as below before putting into capsules, after having optionally adjusted the titration by addition and homogenized with neutral granules to arrive at the desired titration.
• granules according to the invention were prepared by replacing the shellac with polyvinylpyroli dane or with a polymethacrylate.
• Granules according to the invention have also been prepared in which the neutral core is exclusively made up of sucrose or lactose. Measurement of Fenofibrate Release
• a disintegration device in which a quantity of granules corresponding to approximately 250 mg of active principle is brought into contact with artificial liquids, the device making it possible to maintain constant agitation and a constant temperature of 37 ° ⁇ 0.5 ° C.
• Artificial liquids are solutions buffered at successive pH used according to the scheme below. Period Solutions TTeemmppss ddee pH% of principal active release
• the new dosage form leads to a new, remarkable drug, which is easier to use and whose side effects linked to its use are reduced.

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• Health & Medical Sciences (AREA)
• Engineering & Computer Science (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Emergency Medicine (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
• Medicinal Preparation (AREA)

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• 1980
  • 1980-11-19 FR FR8024568A patent/FR2494112B1/fr not_active Expired
• 1981
  • 1981-11-16 BE BE1/10357A patent/BE891129A/fr not_active IP Right Cessation
  • 1981-11-18 WO PCT/FR1981/000148 patent/WO1982001649A1/fr active Application Filing
  • 1981-11-18 NL NL8120434A patent/NL8120434A/nl unknown
  • 1981-11-18 EP EP81903096A patent/EP0065531A1/fr not_active Withdrawn
  • 1981-11-18 AT AT0906481A patent/AT387517B/de not_active IP Right Cessation
  • 1981-11-18 DE DE19813152519 patent/DE3152519C2/de not_active Expired - Lifetime
  • 1981-11-19 IT IT25185/81A patent/IT1144948B/it active

Non-Patent Citations (1)

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