FR2502952A1 - NEW BENFLUOREX HYDROCHLORIDE DRUG FOR THE TREATMENT OF DIABETES - Google Patents

Abstract

THE OBJECT OF THE INVENTION IS NEW PHARMACEUTICAL COMPOSITIONS CHARACTERIZED IN THAT THEY CONTAIN 200 TO 500 MG OF BENFLUOREX HYDROCHLORIDE PER UNIT TAKEN. THESE PHARMACEUTICAL COMPOSITIONS ARE MADE BY INCORPORATING THE ACTIVE PRINCIPLE IN A DIGESTIBLE HYDROPHOBIC MATRIX WHICH IS DIVIDED AND THEN COMPRESSED WITH HYDROPHILIC EXCIPIENTS. THE COMPOSITIONS ACCORDING TO THE INVENTION ARE USED FOR THE TREATMENT OF METABOLIC DISORDERS RELATED TO DIABETES.

Description

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  The subject of the present invention is new pharmaceutical compositions

  for the treatment of pathological manifestations related to

  diabetes and a special procedure for preparing them.

  The present invention more particularly relates to composi-

  prolonged-acting pharmaceutical formulations containing as an active ingredient benfluorex hydrochloride in admixture with suitable

  achieve a gradual and prolonged release inside the digestive tract

tif.

  The subject of the invention is specifically pharmaceutical compositions

  prolonged effect, characterized by the inclusion of chlorhy-

  benfluorex drate included in a hydrophobic digestible and dispersed matrix

  in compressional excipients forming a hydrophilic network.

  The amount of active ingredient included in these dosage forms

  ranges from 200 to 500 mg per unit dose. This dosage is sen-

  significantly higher than that previously mentioned in French Patent No. 6564 M. The new pharmaceutical compositions object of

  patent, not only provide significantly higher bioavailability

  to that of equivalent doses administered in ordinary oral forms, but above all provide therapeutic properties which could not have been

hitherto highlighted.

  The pharmaceutical compositions according to the invention are presented in one of the forms suitable for oral administration such as tablets, coated tablets, dragees or capsules. The active ingredient content ranges between 200 and 500 mg and preferably is

300 mg.

  The usual dosage is two tablets a day, but it may

  be reduced to one tablet per day based on biological results.

  Pharmacokinetic studies have shown that the administration of a tablet according to the invention to 300 mg makes it possible to obtain a maximum peak blood in five hours instead of one hour with the previously known pharmaceutical forms and a plasma half-life of more twenty hours against five hours for normal forms. This results in a similar bioavailability

100%.

  Another advantage of the pharmaceutical compositions according to the invention lies in the fact that the maximum peak plasma obtained is substantially less than that obtained with an equivalent amount of active ingredient administered in the form of conventional pharmaceutical compositions. In other words, the effect produced is less brutal, as fast in its appearance -2502952 and much longer. The pharmacokinetic curve still shows the presence of active principle after fifty hours with the compositions according to the invention whereas the administration of the same dose in a usual oral form no longer makes it possible to detect that

  bloods hardly appreciable after twenty hours.

  The compositions according to the invention have hypo-

  glycemic, hypolipidemic and hypo-uricemic.

  They therefore make it possible to treat effectively with a posology

  simple manifestations of diabetes. They are active on hyperglyca

  mies. They lead to a significant decrease and a normalization of

  plasma levels throughout the nycthemeron without significant variation.

  In addition, they lead to a significant decrease in plasma

  of triglycerides and cholesterol with a favorable

  ficative on the high density lipoprotein (HDL) level.

  They still have the advantage of being a safe and acceptable medicine.

  tability, which can not lead to hypoglycaemia, lactic acidosis or drug interferences. They do not cause more trouble

  gastrointestinal effects or effects on the central nervous system.

  They are therefore suitable for the treatment of diabetes at maturity

  with or without overweight, isolated or associated with lipid abnormalities

  c. They are also useful in the treatment of hyperlipidemias (hypertriglyceridemia and / or hypercholesterolemia) and in the treatment

metabolic overloads.

  The invention also relates to a process for obtaining new

  pharmaceutical compositions characterized in that the principle of

  active pe in the crystalline structure of a digestible hydrophobic matrix, then divide this mass by extrusion and mix the resulting vermicelli to

  compressive excipients forming a hydrophilic network, compresses the

  lange obtained on a press equipped with punches, enrobes the formed tablets

  with a coating suspension and then with a polishing solution.

  In a presently preferred embodiment, the hydrophobic matrix

  digestible is a semi-synthetic glyceride of fatty acids such as trimethyl-

  glyceride ristate sold under the trademark Dynasan 114 by Dynamit Nobel. Glyceryl palmito stearate can also be used

  sold under the Softisan brand sold by the firm Dynamit Nobel, which is

  by a 50% mixture of glyceryl palmitate and glycerol stearate.

  ceryl. The nature of this matrix is chosen to have a point

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  melting point greater than 50 allowing extrusion without liquefying and ability to be hydrolyzed under the influence of lipase enzymes of the digestive tract. Compression excipients include disintegrating agents, binding agents and diluents. As a diluting agent, colloidal silica or cellulose is used. As a disintegrant, carboxymethyl starch, polyvinyl pyrrolidone and Primojel are used. As a binding agent, a modified cellulose is used, for example that

sold under the brandAvicel PH 102.

  The coating agents are an associated hydroxypropyl cellulose or

  to a surfactant, a plasticizer and / or a lubricating agent.

  brification. The polishing agents are polymers of high ethylene glycol

molecular weight.

  The delay effect is obtained essentially by the dispersion of the digestible hydrophobic fatty matrix after extrusion into the compression excipient. The same non-extruded hydrophobic mass does not manifest the same

  delay in the release of the active ingredient.

  The tablets thus obtained may also contain an opacifying agent

proud or dye.

  The outer layer can be further coated with a film, a plastic film, by dispersion of a cellulose ester or a protein

digestible like Keratin.

  The dissolution rates from one manufacture to another are very constant. The release of the active ingredient measured by the Poste method (Biopharmaceutics and relevant pharmacokinetics 1st edition, p.

greater than eight hours.

  The following examples illustrate the invention without limiting it.

EXAMPLE 1

  Preparation of 300 mg tablets of active principle Benfluorex hydrochloride 3.450 g Sodium salt of Carboxymethyl starch 230 g Microcrystalline cellulose 2.300 g Glycerol trimer 0.450 g

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  Glycerol 9.7 g Hydroxypropyl cellulose 250 g Sodium lauryl sulfate 1.2 g Mineral dyes 9.6 g Mineral opacifier 48 g Polyethylene glycol 6000 8.2 g Polyvinylpyrrolidone 371.45 g Colloidal silica 8.05 g Magnesium stearate 15 g Talc 195,5 g Water (for the coating suspension) 17,702 g Water (for the polishing solution) 100 g

Mass for 10,000 tablets.

  Glyceryl trimyristate is weighed and introduced into a mixture of

  planetary ger I hot tub. We heat up to 60 'to make

  completely melt this mass. We then introduce benfluorine hydrochloride

  rex in glyceride melted in small portions and mixed while hand

  holding the temperature at around 45.

  The suspension obtained is extruded on an extruder provided with a grid whose orifices are 1.1 mm in diameter. The extrusion assembly is maintained at a temperature of the order of 40 to 45 '. The extruder operates in radial or frontal extrusion. The granule obtained cooled to about 20 ', is calibrated on an oscillating granulator, equipped with a grid whose meshes have 2.5.m of opening. The grain obtained is then mixed with the colloidal silica and then with

  compressive excipients (cellulose, carboxymethylbenzamide, polyvinyl

  pyrrolidone and talc). The mixture thus obtained is compressed on a press

  equipped with bitonnette punches (19 x 8 mm) to form

  finished with the average unit weight of 0.87 g. The tablets are then coated with 3 kg of the coating suspension to obtain a unit average weight.

  0.89 g. Finally, the coated tablets are waxed with 0.150 liter of the solution.

  waxing. Dandruff tablets thus formed after drying weigh

on average 0.895g.

  The disintegration time is about two minutes.

  The dissolution time of the active ingredient is: minutes 28 - 30% minutes 34 - 37%

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  minutes 42.6 - 46.5 Z 240 minutes 52.8 - 58 X 480 minutes 66 - 71 Z

EXAMPLE II

  The compositions according to the invention have been the subject of an experimental

  a double-blind, multicenter clinical trial with placebo in obese diabetics. It was found that for the same diet, the weight loss was about the same for the subjects treated as for the subjects receiving the placebo, but that the normalization of blood glucose

  only intervened in subjects receiving the composition according to the invention.

  In subjects receiving placebo, no significant change in

blood sugar was observed.

EXAMPLE III

  Comparative kinetic blood study by administration of a tablet

  300 mg of Benfluorex hydrochloride, obtained according to the process of the invention.

  and by administration of 300 mg of a solution of Benfluorex hydrochloride.

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Claims (4)

R E V E N D I C A T I 0 N S   1) Novel pharmaceutical compositions intended to treat diabetic pathological manifestations characterized in that they contain as an active ingredient Benfluorex hydrochloride included in a digestible hydrophobic matrix, then dispersed in compression excipients forming a hydrophilic network and covered with a protective film. 2) novel compositions according to claim 1 wherein   the amount of active ingredient ranges between 200 and 500 mg.   3) novel compositions according to claim 1 wherein the digestible hydrophobic matrix is formed of a semi-synthetic glyceride of fatty acids.   4) New compositions according to claim 1 wherein   the digestible hydrophobic matrix is formed of glyceryl trimyristate.   ) A process for obtaining pharmaceutical compositions according to one of   Claims 1 to 4, characterized in that the chlorophyll is incorporated in   Benfluorex drate in a matrix of glyceryl trimyristate, then   divide this mass by hot extrusion, mix the vermicelli as a result of   both to compressive excipients forming a hydrophilic network, compresses the mixture obtained on a press equipped with punches, encapsulates the tablets   formed with a coating suspension, then with a polishing solution.