AU706027B2

AU706027B2 - Pharmaceutical composition for oral administration of flavonoids

Info

Publication number: AU706027B2
Application number: AU36695/95A
Authority: AU
Inventors: Alain Cuine; Bruno Huet De Barochez; Noel Piot
Original assignee: ADIR SARL
Current assignee: Les Laboratoires Servier SAS
Priority date: 1994-11-08
Filing date: 1995-11-06
Publication date: 1999-06-10
Anticipated expiration: 2015-11-06
Also published as: EP0711560B1; EP0711560A1; CA2162299A1; CN1131538A; NO311402B1; FI955310A0; AU3669595A; FI117123B; PT711560E; CA2162299C; JPH08208469A; DE69521477D1; FI955310L; CY2265B1; GR3036244T3; FR2726469A1; ZA959473B; DE69521477T2; NZ280418A; KR960016901A

Abstract

Oral compsns. contain a rutaceous flavonoid, partic. micronised diosmin (I), as an effervescent granulate in the form of tablets or sachets. The compsn. pref. comprises 0.1-5 g (I) which is pref. micronised to a particle size of 0.1-10 mu m. The effervescent formulation is achieved by use of a carboxylic acid and one or more carbonates. Other ingredients include sweeteners, flavourings and carriers. The small amt. of water present in (I) is used to start a single phase granulation process.

Description

The subject of the present invention is a new pharmaceutical composition intended for oral administration of flavonoids extracted from Rutaceae and more particularly of diosmin.

Diosmin is a molecule used in the treatment of venous diseases, as venotonic and vasculoprotector. In this capacity, it is administered at doses ranging from 150 to 1000 mg per dose and in 2 to 4 daily administrations so as to treat the manifestations of chronic venous insufficiency of the lower limbs, which is functional and organic, as well as for the treatment of the functional signs which are linked to the hemorrhoidal crisis. Diosmin is usually administered in the form of tablets containing doses of between 150 and 450 mg. A sachet form containing a dose of 300 mg also exists on the market. Diosmin is a flavonoid extracted S from Rutaceae which is difficult to separate from other flavonoids. The purified flavonoic S fractions used in the invention contain 90% of pure diosmin and 10% of other flavonoids.

Recent studies have shown the value of administering high doses of diosmin. This number of S doses and of daily administrations is relatively high because the active ingredient is highly metabolized in the gastrointestinal tract. This results in one of the principal difficulties in the use of diosmin, namely a high dose of active ingredient to be administered.

It is therefore necessary to administer high quantities of diosmin orally and in a form easy to ingest, the treatments with diosmin often being long-term treatments. Now, the size of the tablets or of the gelatin capsules to be swallowed cannot be increased above a certain limit.

Accordingly, the effervescent diosmin granules which are the subject of this invention, provided in the form of effervescent tablets or of sachets of effervescent granule, are an alternative which is quite advantageous. It is easy, by this means, to administer relatively high quantities of powder; these powders can be easily dispersed in a glass of water.

The prior state of the art is especially illustrated by Patent Application EP 541874 which describes a powdered diosmin preparation to be suspended in water at the time of use. This preparation contains more particularly diosmin having a particle size of between 100 and 400 micrometers and a nonionic surfactant wetting agent.

It is indeed important that diosmin is easily wetted in order to become properly dispersed in water. The finer the dispersion, the easier the administration, and the easier the absorption of the active ingredient. Indeed, diosmin is a compound which is very sparingly soluble in water, and one of the means of increasing its solubility is to increase the area of contact between water and diosmin. Among the means of increasing this area, grinding and micronization may be mentioned. Micronization is usually intended to mean an operation for reducing the size of particles, for example by means of an air jet micronizer, until the mean particle size of the powders is between 0.1 and 10 micrometers.

The principle adopted in the present invention is a micronization of diosmin and the presentation of this diosmin in an effervescent granule.

Finely micronized diosmin is associated with a formula of effervescent granule. It was indeed observed, surprisingly, that by virtue of the dispersion suddenly created by the effervescence, Sthe suspension of diosmin was very easy even when the particle size of this same diosmin was very small, which is generally an obstacle to dispersing in water products which are sparingly 15 soluble or insoluble in this solvent.

This novel process also avoids the use of a surfactant, a product which is not always well tolerated by the body and which generally gives an unpleasant taste to the preparations.

The formula of the invention described combines diosmin with a carboxylic acid and one or more carbonates for creating the effervescence, a sweetening agent and a flavoring Also included in the formula are pharmaceutically acceptable excipients such as a coloring. so as to give a pleasant appearance to the reconstituted suspension (diosmin has a natural color k hich is not very pleasant to the eye), such as for example orange yellow S, an artificial sw'Atener, so as to decrease the quantity of sugar used, such as for example sodium saucharinate.

aspartame or neohesperidin dihydrochalcone, a compound intended to limit the foam formed by the effervescent pair, such as for example polyvidone or a maltodextrin, lubricants. such as for example magnesium stearate or sodium benzoate, flow-enhancing agents, such as for example anhydrous colloidal silica.

Moreover, the process for preparing these effervescent granules, which is also a subject of the invention, has a completely surprising characteristic. Indeed, diosmin is a hygroscopic product which generally contains between 4 and 6% water. This water constitutes an interference as regards the stability of the effervescent granule in that it can cause spontaneous effervescence of the granule. The simultaneous use of sodium bicarbonate and carbonate makes it possible to trap part of the internal moisture of the granule, but is not sufficient to lead to a good stability.

One of the possibilities normally used in order to avoid this disadvantage is to employ a double granulation, namely a separation of the carboxylic acid and the sodium bicarbonate into two different granules, combined in the end in the sachet. This is a great constraint for the industrial production of such sachets.

The manufacturing process according to the invention is a novel single-phase process. It consists in using the internal water of the diosmin to start the granulation, this internal water causing a beginning of effervescence which is controlled during the granulation phase. The addition of a minimum quantity of ethyl alcohol makes it possible to complete the granulation. After drying, the final moisture of the granule is less than Under these conditions, the effervescent granule is stable.

This granule may then be distributed into sachets or may be compressed into tablets.

Thus, the pharmaceutical composition according to the invention is an effervescent granule presented in the form of tablets or of sachets which allow a fine suspension of micronized diosmin to be prepared whose mean diameter is between 0.1 and 10 micrometers.

S This pharmaceutical composition contains no surfactant or thickening agent.

i The pharmaceutical composition according to the invention contains a sweetening agent which may be sucrose or another sugar such as mannitol or lactose.

The process for the manufacture of the pharmaceutical composition according to the invention is a single-phase granulation process using the internal water of the diosmin to start the granulation.

Finally, the pharmaceutical compositions thus produced contain between 0.1 and 5 g of micronized diosmin per unit dose.

The following examples illustrate the invention without however limiting it.

EXAMPLE 1: Formula for sucrose-containing effervescent granule Constituents Quantities (mg) Micronized purified flavonoic 1000 fraction comprising: diosmin flavonoids expressed as hesperidin Anhydrous citric acid 570 Orange flavor 150 Anhydrous sodium carbonate Sodium bicarbonate 450 Orange yellow S 3 Sodium saccharinate 2 Sucrose 2715 Hydrophobic colloidal silica For a finished sachet containing 5000 mg EXAMPLE 2: Formula for mannitol-containing effervescent granule Constituents Quantities (mg) Micronized purified flavonoic 1000 fraction comprising: diosmin flavonoids expressed as hesperidin Anhydrous citric acid 570 Orange flavor 150 Sodium bicarbonate 450 Anhydrous sodium bicarbonate Orange yellow S 3 Mannitol 2461 Polyvidone 250 Sodium saccharinate 6 Hydrophobic colloidal silica For a finished sachet containin2 5000 mp For fiishd sche cotaiing5000 mg EXAMPLE 3: Formula for lactose-containing effervescent granule Constituents Quantities (mg) Micronized purified flavonoic 1000 fraction comprising: diosmin flavonoids expressed as hesperidin Anhydrous citric acid 570 Orange flavor 150 Sodium bicarbonate 450 Anhydrous sodium bicarbonate Orange yellow S 3 Lactose 2332 Polyvidone 375 Sodium saccharinate Hydrophobic colloidal silica For a finished sachet containing 5000 mg too.

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EXAMPLE 4: Formula for an effervescent tablet Constituents Quantities (mg) Micronized purified flavonoic 1000 fraction comprising: diosmin flavonoids expressed as hesperidin Anhydrous citric acid 600 Orange flavor Sodium benzoate Sodium bicarbonate 450 Anhydrous sodium bicarbonate Orange yellow S 1 Polyvidone 100 Sodium saccharinate 1 Sorbitol 723 For a finished sachet containing 3000 mg I 4 -6- XXxeLAIMS THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1.A pharmaceutical composition for oral administration of flavonoids extracted from Rutaceae and more particularly of diosmin, wherein this composition is an effervescent granule provided in the form of a tablet or a sachet containing micronized diosmin.

2.The pharmaceutical composition as claimed in claim 1, wherein the diosmin in micronized form has a particle size of between 0.1 and 10 micrometers.

3.The pharmaceutical composition as claimed in claim 1, wherein the granule is made effervescent by the use of a carboxylic acid and of one or more carbonates.

4.The pharmaceutical composition as claimed in claim 1, wherein the effervescent granule 10 contains a sweetening agent, a flavoring and pharmaceutically acceptable excipients.

5.The pharmaceutical composition as claimed in claim 1, which contains 0.1 to 5 g of micronized diosmin.

6.A process for preparing the pharmaceutical composition as claimed in claim 1, which is a single-phase granulation process which uses the internal water of the diosmin to start the granulation.

DATED this 6th day of November 1995.

ADIR ET COMPAGNIE WATERMARK PATENT TRADEMARK

ATTORNEYS

290 BURWOOD ROAD HAWTHORN. VIC. 3122.

Claims

9.* *o S." ABSTRACT PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION OF FLAVONOIDS ADIR ET COMPAGNIE 1 rue Carle Hebert 92415 COURBEVOIE Cedex The subject of the present invention is a new pharmaceutical composition intended for oral administration of flavonoids extracted from Rutaceae and more particularly of diosmin.