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
  • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
  • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
  • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
• • 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
  • A61K9/2022—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
  • 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
  • A61K9/2806—Coating materials
  • A61K9/2833—Organic macromolecular compounds
  • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
  • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics

Definitions

• the present invention relates to a novel galenic formulation of fenofibrate for oral administration, to the process for its preparation and to the drugs manufactured from these formulations.
• Fenofibrate which belongs to the fibrate family, has been known for many years as a medicinal active principle because of its efficacy in lowering the blood triglyceride and cholesterol levels.
• fenofibrate is widely prescribed in numerous countries when there is a need to reduce the risk of atherogenesis.
• Fenofibrate was marketed originally in the form of gelatin capsules containing a 100 mg dose of active principle, with a dosage of 3 capsules a day, and then in the form of gelatin capsules containing a 300 mg dose of active principle, prescribed with a dosage of one capsule a day.
• the maximum circulating level of fenofibric acid is about 6 to 9 mg/l and the area under the curve is 145 to 170 mg/l.h.
• Another formulation results from a process that consists in comicronizing the fenofibrate with a solid surface-active compound to give an intimate and finely divided mixture of the two products.
• This type of formulation enables the dosage to be reduced to 200 mg/day in a single dose to give plasma fenofibric acid concentrations that are very close to those obtained with a 300 mg dose of non-comicronized fenofibrate (Journal International de Médecine (1991) no. 206, pp 48-50).
• This formulation offers approximately a 30% improvement in bioavailability compared with the original formulation.
• Patent document FR 2 494 112 proposes another type of formulation, namely microgranules in which a neutral core, consisting of sucrose and starch, is coated with micronized fenofibrate and then covered with a microporous protective layer.
• the recommended dosage in this case is 250 mg/day, which corresponds to an intermediate bioavailability compared with the previous formulations.
• patent document EP 757 911 discloses a process for the preparation of a fenofibrate formulation which consists in making up a solution of the active principle in diethylene glycol monoethyl ether and packaging this solution in soft capsules.
• the administration of 100 mg/day of fenofibrate affords the plasma fenofibric acid concentrations required to ensure the efficacy of the drug.
• this formulation has twice the bioavailability of the formulation described in patent document EP 330 532.
• such a formulation throws up the problem that results from the oral administration of a relatively large amount of solvent.
• the administration of 100 mg of fenofibrate corresponds to the simultaneous administration of 1500 mg of a diethylene glycol ether.
• fenofibrate is a hypolipidemic intended for prescription over prolonged periods
• the use of such a formulation would amount to the regular daily absorption by the patient of 1.5 g of a diethylene glycol ether, the biological effects of which are not totally neutral (cf. Food Cosmet. Toxicol. (1968) 6 (6) pp 689-705; Arzneim. Forsch. (1978) 28(9) pp 1571-1579; Occup. Hyg. (1996) 2 (1-6, Proceedings of the Int. Symposium on Health Hazards of Glycol Ethers, 1994) 131-151).
• Patent document WO 00/57918 also proposes a fenofibrate formulation in solution in the form of a preconcentrate that is intended to form an emulsion in the presence of an aqueous phase, i.e. in the patient's stomach after administration.
• this type of formulation requires the use of leaktight capsules resistant to the oily substance.
• Patent document WO 00/30615 also proposes a liquid fenofibrate formulation consisting of micronized particles of fenofibrate held in suspension in a liquid in the presence of surfactants.
• the fenofibrate is formulated in the form of a coprecipitate with a water-soluble excipient such as, in particular, hydroxypropyl methyl cellulose.
• a water-soluble excipient such as, in particular, hydroxypropyl methyl cellulose.
• the process for the manufacture of such a coprecipitate requires the use of organic solvents, which have to be completely removed from the finished product and which also present safety problems during drying by atomization.
• a formulation similar to this is described in patent document EP 761 208.
• patent document CA 2 270 306 discloses gelatin capsules or tablets containing fenofibrate comicronized with lactose, for which the bioavailability of the active principle is improved by comparison with a formulation in which the fenofibrate is micronized on its own and then mixed with lactose.
• patent document FR 2 758 459 discloses a composition in the form of granules or tablets in which the fenofibrate, in micronized form, is associated with a hydrophilic polymer (especially polyvinylpyrrolidone) and optionally with a surfactant.
• a hydrophilic polymer especially polyvinylpyrrolidone
• surfactant especially polyvinylpyrrolidone
• This last formulation can be presented in the form of tablets, but in this case the tablets that result have a unit weight of about 750 mg for a 160 mg dose of fenofibrate. Because of their relatively large size, such tablets are difficult to administer and are thus of limited value.
• the tablet form is more advantageous than the gelatin capsule form insofar as:
• weight for weight a tablet is smaller than a gelatin capsule
• the industrial production rates are higher for tablets than for gelatin capsule forms or soft capsule forms.
• the tablet form avoids the use of raw materials of animal origin, such as gelatin, which is the essential constituent of gelatin capsules.
• the object of the present invention is to solve the technical problem that consists in the provision of a novel fenofibrate formulation which has a good bioavailability and which makes it possible to produce tablets of reduced size which are easier to administer than those described in the state of the art, especially in patent document FR 2 758 459.
• the invention relates to a pharmaceutical composition in the form of a tablet for oral administration which can be obtained by compressing a mixture comprising:
• said granules being obtained by granulating the mixture with the aid of an aqueous solution of polyvinylpyrrolidone;
• Such a formulation makes it possible to solve the aforementioned technical problem in a particularly advantageous manner since it affords tablets which can be produced industrially, which have excellent crushing strength and friability characteristics and which are sufficiently small to be acceptable to patients, which is particularly important in the context of a long-term hypocholesterolemic treatment. Furthermore, the tablets obtained unexpectedly show an equivalent bioavailability to that of gelatin capsules containing the active principle in the form of a comicronizate with the surfactant.
• the aforementioned surfactant is solid and takes the form of a comicronizate with the fenofibrate.
• the aforementioned surfactant is introduced into the granules in the granulating solution with the polyvinylpyrrolidone.
• the tablet contains between 50 and 250 mg of fenofibrate.
• the aforementioned solid surfactant is sodium laurylsulfate.
• one of the aforementioned solid excipients is pregelatinized starch, which is present in an amount of 15 to 40% of the weight of the fenofibrate.
• one of the excipients is microcrystalline cellulose, which is present in an amount of 5 to 30% of the weight of the fenofibrate.
• the aforementioned tablet has a coating consisting of a film of varnish for protection against moisture, preferably based on a water-dispersible polymer.
• the invention relates to a process for the preparation of a pharmaceutical fenofibrate composition in the form of a tablet for oral administration, as described above.
• this process is essentially characterized in that it comprises:
• this process is essentially characterized in that it comprises:
• the invention therefore proposes a novel galenic form of fenofibrate for oral administration in the form of a tablet, as defined above, said tablet form being obtained by the compression of a novel formulation.
• This formulation consisting of the aforementioned granules mixed with crosslinked polyvinylpyrrolidone, has a good compressibility and makes it possible in a particularly novel manner to obtain tablets of reduced size containing more than 50% by weight of active principle.
• the fenofibrate is first micronized on its own or comicronized with a solid surfactant to give a powder whose mean particle size is preferably less than 30 ⁇ m and particularly preferably less than 10 ⁇ m. More precisely, in the case of comicronization, the crystalline fenofibrate and the powdered solid surfactant are mixed and the mixture is then ground in a micronizer, for example according to the technology described in patent document EP 330 532, thereby making it possible to obtain an intimate mixture of the two constituents and substantially to improve the bioavailability of the fenofibrate.
• a micronizer for example according to the technology described in patent document EP 330 532
• the fenofibrate or the fenofibrate/surfactant mixture is advantageously micronized in an air jet micronizer, which makes it possible to obtain a powder with a mean particle size in the order of 5 to 10 ⁇ m without heating the products.
• the amount of solid surfactant is in the order of 1 to 5% of the amount of fenofibrate, preferably in the order of 3 to 4%.
• an ionic or non-ionic solid surfactant is chosen.
• sodium laurylsulfate is preferred.
• the comicronized fenofibrate and surfactant are then mixed with at least one pulverulent excipient and the mixture is granulated, preferably with the aid of an aqueous solution of polyvinylpyrrolidone.
• fenofibrate micronized on its own the latter is mixed with at least one pulverulent excipient, and the surfactant (also used in an amount in the order of 1 to 5% by weight, expressed relative to the weight of fenofibrate) is preferably introduced with the polyvinylpyrrolidone in aqueous solution, i.e. with the granulating liquid.
• the surfactant also used in an amount in the order of 1 to 5% by weight, expressed relative to the weight of fenofibrate
• This mode of preparation is applied especially in the case of a liquid or viscous surfactant, for example polysorbates or medium-chain fatty acid esters.
• pulverulent excipients which can be used within the framework of the invention, preference is given to starch and/or cellulose or derivatives thereof, for example carboxymethyl cellulose, with the exception of C 12 disaccharides.
• starch which is a good disintegrating agent, and microcrystalline cellulose, which makes it possible to obtain a good cohesion and reduce the risks of the tablet splitting, are particularly preferred.
• the tablet according to the invention does not contain C 12 disaccharides, particularly lactose, which is often present in the known tablet formulations. It has unexpectedly been discovered that, in the case of a tablet based on fenofibrate, replacing the lactose with appropriately chosen pulverulent excipients makes it possible to improve the bioavailability of the active principle while at the same time substantially reducing the amount of excipients required, and thereby to obtain a smaller tablet, which is very advantageous.
• these excipients are added in a total amount corresponding to about 30 to 70% and preferably 45 to 55% of the weight of fenofibrate, each of the excipients, considered independently, being present in an amount of between 5 and 40% and preferably of between 10 and 35% by weight, relative to the weight of fenofibrate.
• the pulverulent mixture consisting of the fenofibrate and the aforementioned excipients is granulated, for example in a paddle mixer or any other apparatus suitable for producing granules, by means of a binding solution advantageously comprising polyvinylpyrrolidone in water.
• This granulation is preferably carried out using a polyvinylpyrrolidone with an average molecular weight of between 25,000 and 100,000.
• the granules obtained are then sized by passage through a grid with a mesh size advantageously of 1 to 2.5 mm, after which they are dried, preferably in a fluidized bed granulating dryer.
• the dry granules obtained can then be mixed with a solid external phase consisting of formulating agents such as lubricants, flow aids, binders or disintegrating agents.
• formulating agents such as lubricants, flow aids, binders or disintegrating agents.
• the excipients constituting the external phase of the granules are generally present in an amount corresponding to about 5 to 25% and preferably of 8 to 15% of the weight of fenofibrate.
• the external phase comprises crosslinked polyvinylpyrrolidone as the disintegrating agent, advantageously in an amount of 6 to 18% and preferably of 10 to 14% by weight, based on the weight of fenofibrate.
• the crosslinked polyvinylpyrrolidone also known as crospovidone
• the mixture of granules and these excipients is advantageously homogenized, for example in a horizontal or vertical paddle mixer.
• the resulting mixture is then converted to tablets sized so that each tablet contains 50 to 250 mg of fenofibrate and thus weighs between about 100 and 500 mg.
• the compression operation is carried out on an alternating or, preferably, rotary machine equipped with dies having a diameter in the order of 5 to 12 mm and preferably of 8 to 10 mm so as to produce small tablets.
• the resulting tablets can be used directly in therapeutics but, in view of the hydrophilic character of certain excipients, the tablets are preferably coated with a protective varnish, preferably based on water-dispersible polymers, in order to preserve the drug better. Nevertheless, this film-coating is not essential and the tablet can be preserved well by other means, for example by a packaging that limits the exchanges of water vapor with the outside.
• the film-coating can be carried out in conventional manner by processes known to those skilled in the art, for example by spraying a solution of film-forming polymer onto the tablets placed in a turbine. This film-coating also makes it possible, if appropriate, to color the tablets by adding a colored pigment to the solution of film-coating polymer.
• the resulting granules are sized by passage over an oscillating granulator (ERWEKA) equipped with a grid having a mesh size of 2.5 mm.
• ERWEKA oscillating granulator
• the sieved granules are then transferred to a fluidized bed dryer and dried by the passage of air at 50-60° C.
• the mixture obtained above is compressed in a rotary machine equipped with six 10R10 die stations.
• the machine is adjusted to produce tablets with a unit weight of 350 mg, which corresponds to a 200 mg dose of fenofibrate per tablet.
• the tablets obtained have a hardness of about 89 N.
• the tablets obtained according to the above operation are placed in a stainless steel turbine (ERWEKA) equipped with a spray gun, a hot-air blower and a suction system.
• the rotation of the turbine is set to 16 rpm and a solution of 75 g of film-forming polymer (reference OPADRY OYS®, marketed by COLORCON) in 1.425 kg of 80% ethanol is sprayed in.
• the spraying lasts about 2 hours.
• the film-coated tablets obtained are then cooled and packaged.
• Each tablet has a diameter of 10 mm and a weight of about 360 mg for a 200 mg dose of fenofibrate.
• This mixture is then granulated in the mixer by spraying with a solution of 178.5 g of polyvinylpyrrolidone (KOLLIDON K 30) and 119 g of polysorbate 80 (TWEEN® 80 obtained from Uniqema) in 1.813 1 of purified water.
• the spraying lasts about 30 min.
• the granules obtained are sized by passage over an oscillating granulator (ERWEKA) equipped with a grid having a mesh size of 2.5 mm.
• the sieved granules are then dried in a fluidized bed dryer (GLATT) with an air inlet temperature of 50-60° C.
• the mixture obtained above is compressed in an alternating machine equipped with a 10R10 die.
• the machine is adjusted to produce tablets with a unit weight of 350 mg, which corresponds to a 200 mg dose of fenofibrate per tablet.
• the tablets obtained have a hardness of about 89 N.
• the tablets obtained according to the above operation are placed in a stainless steel turbine equipped with a spray gun, a hot-air blower and a suction system.
• the rotation of the turbine is set to 16 rpm and a solution of 12.8 g of film-forming polymer (reference OPADRY OYS®) in 243 g of 80% ethanol is sprayed in.
• the spraying lasts about 1 hour.
• the film-coated tablets obtained are then cooled and packaged.
• Each tablet has a diameter of 10 mm and a weight of about 360 mg for a 200 mg dose of fenofibrate.
• a batch of fenofibrate tablets was also prepared by following a protocol conventionally used by those skilled in the art, in which the excipients constituting the internal phase of Preparation 1b of Example 1 above were replaced with 2.550 kg of lactose, 952 g of sodium carboxymethyl starch and 595 g of microcrystalline cellulose, and using 238 g of PVP XL10 and 170 g of magnesium stearate as the excipients of the external phase of Preparation 1c, the compression and film-coating being carried out analogously to the manufacturing process of Example 1 with a 200 mg dose of fenofibrate for a 360 mg film-coated tablet.
• the tablets obtained have a hardness of about 72 to 75 N.
• Example 1 of the invention The tablets according to Example 1 of the invention and the tablets obtained according to the Comparative Example were evaluated from a pharmacokinetic point of view during clinical studies on healthy humans.
• the first study was conducted on 6 subjects in order to compare LIPANTHYL® 200M gelatin capsules (formulation marketed in France) with the tablets obtained according to the Comparative Example.
• the treatment was administered orally 30 min after breakfast and the efficacy of the treatment was evaluated by assay of the serum fenofibric acid level as a function of time. From these measurements it was possible to calculate the area under the curve (AUC 0- ⁇ ), the maximum concentration attained (C max ), the time corresponding to this maximum concentration (T max ) and the half-life of the product (T 1/2 ).
• Example 1 Example 2 0 0 0 10 37.1 44.8 20 63.1 69.1 30 74.1 77.5 40 79.6 82.6 50 83.9 85.6 60 86.2 88.1
• the tablets according to the invention therefore make it possible to obtain a treatment efficacy equivalent to that of LIPANTHYL® 200M gelatin capsules, with the advantages of dispensing with the presence of gelatin in the gelatin capsule, providing a more compact dosage unit that is easier to swallow, and finally allowing a greater production rate than that of gelatin capsules.

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• 2001
  • 2001-01-22 FR FR0100833A patent/FR2819720B1/fr not_active Expired - Fee Related
• 2002
  • 2002-01-22 EP EP02700354A patent/EP1353663B1/fr not_active Expired - Lifetime
  • 2002-01-22 WO PCT/FR2002/000245 patent/WO2002056881A1/fr active Application Filing
  • 2002-01-22 ES ES02700354T patent/ES2332880T3/es not_active Expired - Lifetime
  • 2002-01-22 CA CA2435714A patent/CA2435714C/fr not_active Expired - Fee Related
  • 2002-01-22 JP JP2002557389A patent/JP4856843B2/ja not_active Expired - Fee Related
  • 2002-01-22 US US10/466,962 patent/US20040115264A1/en not_active Abandoned
  • 2002-01-22 DE DE60233552T patent/DE60233552D1/de not_active Expired - Lifetime
  • 2002-01-22 AT AT02700354T patent/ATE441410T1/de not_active IP Right Cessation
• 2009
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