GB1569036A - Pharmaceutical compositions containing vincamine - Google Patents

Description

(54) PHARMACEUTICAL COMPOSITIONS CONTAINING VINCAMINE (71) I, ENRICO CORVI MORA, a citizen of the Italian Republic. of Via Scalabrini 49, Piacenza, Italy, do hereby declare the invention, for which I pray that a patent may be granted to me, and the method by which it is to be performed to be particularly described in and by the following statement: The present invention relates to a therapeutical composition for the treatment of cerebral pathologic conditions deriving from several factors of circulatory nature and, more particularly, from phenomena of circulatory insufficiency of thrombotic or arterio-sclerotic type.

The use of the vincamine for the treatment of these pathologic conditions is already known, such an use being based on the vasodilating effect at the level of the cerebal network thereof, which is related to a specific vasodilating action which permits the blood requirements to be better adapted to the metabolic needs of the brain. The action of the vincamine is also carried out through a metabolic activity involving an enhanced respiratory activity of the nervous cells, especially when subjected to pathologic conditions.

The treatment by vincamine is effected either oraliv or by parenteral route; for reasons of local and general tolerability and due to pharmacokinetic causes the daily dosage must be fractionated into well defined time intervals (every 8 or 12 hours).

The daily dosage is consequently comprised between 60 and 80 mg. per os or between 15 and 45 mg. per intra-muscular or intravenous route.

It is furthermore important to point out that, although bv parenteral administration some alterations due to circulatory disease (vasospasms) can be treated in the acute phase, the oral administration, in order to achieve an efficacious action in the cerebral pathologic conditions of chronic type (arteriosclerosis, post-thrombotic conditions. etc.). requires a prolonged treatment of about 20 to 30 days.

However, in the case of continued treatments. a discontinuity of therapeutical effect occurs, whereby therapeutical action is reduced. especially during the first days of administration of the drug, to time periods well defined and limited after the administration.

With respect to oral administration pharmacokinetic research work has been therefore carried out, both on experimental animals and on human beings. in order to assess the relationships between oral administration of vincamine. the absorption at the gastro-enteric level, the hematic concentrations, the concentrations in the cerebral tissues and the elimination rate of the drug. These researches have been carried out by a multicompartmental system and by using the method of minimum square differences.

More specifically the research work aimed to establish: a) the relationship between hematic levels and concentrations in the cerebral tissue; b) the cerebral "threshold" concentration capable of causing a pharamacological or metabolic effect; c) the hematic levels within which the pharmacotherapeutical activity of the vincamine occurs.

From the results of such a research work it was found that in the rat and in man the pharmacological activity of vincamine is obtained at two levels of hematic concentrations.

More particularly, as regards the metabolic activity of vincamine, it has been found that such an activity is ensured with continuity by maintaining in the man a hematic level of between 0.1 and 0.3 llg/ml. corresponding to a cerebral concentration. as obtained by extrapolation carried out by mathematic-statistic methods. of between 0.2-0.6 Ftg/g.

Such a finding was already preceded by analogous tests carried out on the rat. hematic levels of between 6 and 12 Itg/ml, corresponding to concentrations of 4 to 11 Fglg. of cerebral tissue, having been then determined.

More particularly, in the case of the rat reference was made to the favourable influence of vincamine on the tests of conditioning and of behaviour. whereas in the case of the man reference was made to improvement of the memory. of attention and of learning capacity, as evaluated through psicometric and intelligence tests.

With respect to the pharmacological and therapeutical activity connected to the vasodilating activity at the cerebral level, it has been found, that it is necessary to maintain in the man a hematic concentration of 0.2-0.5 Ftg/ml, corresponding, on the basis of the same determining method, to a vincamine concentration in the cerebral tissue of between 0.8 and 1.6 ltg/g. of cerebral tissue.

In this case also the preliminary tests in the laboratory animals resulted in hematic concentrations of 12 to 25 Ftg/ml.

The activities of this second type have been experimented in the rat through microcirculation tests and in man bv means of angioscintigraphic techniques.

Thus, for the treatment of cerebral pathologic conditions through the administration of vincamine characterized in that the drug is administered in dosages such as to maintain: a) with reference to the achievement of a metabolic effect. a hematic concentration of 0.1 to 0.3 Ftg/ml, and b) with reference to the achievement of a central vasodilating action, a hematic concentration of 0.2 to 0.5 ,ug/ml.

For general therapeutical use the administration of vincamine per oral route is preferably in a dosage such as to maintain a hematic level of at least 0.2 Ftg/ml.

For the preceding considerations it is evident that one of the essential conditions for success resides in maintaining some hematic levels constant. Of course, this can be ensured by properly dividing the daily administrations or. better. their frequency. or. preferably. by having recourse to one of the well known pharmaceutical formulations with sustained release.

An object of the present invention is characterized in that it provides a therapeutical composition containing vincamine, wherein the active substance is formulated so as to ensure a released delayed with time, said release being such as to maintain the aforesaid hematic levels.

This invention provides a pharmaceutical composition for oral administration. suitable for use in the treatment of cerebral circulatory diseases. consisting essentially of vincamine, as the free base of the hydrochloride salt. incorporated in a sustained release matrix which matrix continuously releases vincamine for up to 24 hours after oral administration.

The experimental work has furthermore permitted to ascertain that the practical application of the method and thus of the therapeutical compositions according to the present invention permits, the therapeutical action being the same. the use of dosages definitely lower than those conventionally admitted. with the self-evident advantages.

On the basis of the previously stated considerations. namely of the constant hematic levels which must be maintained in the patient undergoing the therapy. it will be easy to determine the dosages of the pharmaceutical preparations. these dosages being moreover necessarily dependent on a selected posology as well as on the respect of the toxicitv limits.

The latter, the vincamine being a compound well known in the pharmaceutical art and since long time studied and investigated. are already well known in this field of the art.

This invention provides a composition in a preferred form in unit dosage form and containing at least 25 mg of vincamine per dosage unit.

As regards the preferred embodiment of the therapeutical composition according to the present invention. it consists. as already stated. in the sustained release composition.

A predetermined unit amount of vincamine andlor vincamine hydrochloride is incorporated in a matrix so as to cause a programmed release up to 24 hours from the administration.

A sustained release composition is achieved bv granulated preparations in which the active substance is embedded in a matrix formed of Carbowax (Registered Trade Mark) and ethyl cellulose or hydroxy-propylcellulose, metasilicic acid polymers. polyvinyl chloride or acetate. styrene-maleic acid copolymers or natural rubber. either alone or in admixture.

together with inert fillers.

The granulated formulations are prepared bv means of the known conventional techniques (granulation. melting, mixing etc.), and are utilized for the preparation of tablets, capsules and dragees. as well as liquid suspensions.

Therapeutical compositions with sustained release have been prepared according to the following examples.

Example 1 100 mg. of vincamine or its hydrochloride are intimately admixed with 10 mg of Eudragit (Registered Trade Mark) RL-PM and 20 mg. of Eudragit RS-PM (Eudragit RL-PM and RS-PM being the Registered Trade Marks of acrylic resins sold by Rohm & Haas Co.).

After sieving through a 200 mesh/sq.cm sieve, the mixture is kneaded with 5 parts by weight of methylene chloride, until a mass having elastic consistency is obtained. The mass is granulated and passed through a 4 mesh/sq.cm sieve and dried in a ventilated drier..

The dried granulate is again granulated on a 36 mesh/sq.cm sieve and then formed into tablets, which are obtained by mixing with granulated calcium phosphate. talc. magnesium stearate, ethocel and then compressed to a weight of 100 or 200 mg by a conventional technique, each tablet having the following composition: Composition A B Vincamine (mg) 75 25 Eudragit mixture, mg. 22.5 7.5 Calcium phosphate, mg. 88.5 30.5 Talc, mg. 9 4.5 Magnesium stearate, mg. 5 2.5 Ethocel, mg. -- 30 200 100 Ethocel is a Registered Trade Mark.

The release in vitro was measured by the test apparatus Sartorius (Registered Trade Mark) SM 16750 with the following results: Composition A B Release after 1 hour 18.2%' 12.5% Release after 2 hours 31.5% 23% Release after 3 hours 42.c"^ 31.5C/c Release after 4 hours 53.2CHc 38a/c Release after 6 hours 67% 50% Example 2 15 parts of ETHOCEL 20-SE (ethyl cellulose) are dissolved in 40 parts of methylene chloride, and to the solution is added under stirring. 100 parts by weight of vincamine base or hydrochloride until a homogeneous granulate is obtained. The granulate is sieved through a 4 mesh/sq.cm sieve and dried in a drying cabinet until the solvent is completely evaporated. The granulate is granulated again in a 36 mesh/sq.cm sieve and used for the preparation of tablets, which are obtained by compressing the granulate with granulated calcium phosphate, talc, and magnesium stearate to a weight of 100 or 200 mg, each having the following composition: Composition C D E Vincamine, mg. 75 25 25 ETHOCEL, mg. 11.25 30 40 Calcium phosphate, mg. 99.75 30.5 20 Talc, mg. 9 4.5 10 Magnesium stearate, mg. 5 2.5 5 2()0 100 100 The above compositions have been tested for sustained release, either iil vitro or in vivo with the following results: I - Release in vitro as measured with the apparatus Sartorius SM 16750 Composition C D E Release after 1 hour 25.7cue l2.56/c 15.7% Release after 2 hours 38.5% 23% Release after 3 hours 50.9% 32C/c 47.5% Release after 4 hours 60.OC/e 40% 6l.56 Release after 6 hours 75.OC/e 556/c 77% II - Release in vivo by measurement in the dog.

In the following table the blood levels determined in vivo after administration of composition C in comparison with these provided by a normal release composition K are reported.

TABLE TIME COMPOSITION O' 1h 2 h 4 h 8 h 12 h 24 h 30 h Dog No.20 K( ) 0.227 0.362 0.315 0.164 0.120 0.120 0.075 C O 0.200 0.285 0.402 0.417 0.350 0.208 0.188 Dog No.26 K 0 0.224 0.349 0.375 0.205 0.120 0.120 - C 0 0.255 0.339 0.399 0.418 0.300 0.203 0.150 Dog No.27 K - 0.457 0.633 0.676 0.240 0.150 0.120 - C - 0.244 0.310 0.398 0.440 0.380 0.203 0.165 Dog No.19 K 0 0.278 0.750 0.745 0.216 0.121 0.121 0.104 C 0 0.240 0.351 0.423 0.485 0.364 0.281 0.162 ( ) K = normal release composition The preceding tests confirmed that the tablets having the aforesaid compositions containing resins. fatty substances and macromolecular compounds. and prepared according to the described preparing techniques give a programmed and homogeneous release within the limits of the most appropriate dosage (25 to 75 mg per unit). The release tests, parallely carried out in vitro and in vivo. demonstrated that a regular and continuous release of the active substance. such as to keep the hematic levels within. the minimum and maximum limits of the defined therpeutical threshold for a time up to 24 hours. takes place when the in vitro dissolution shows a constant release starting from 15 to 20roc of the total amount in the first hour to achieve about 55 to 7c after 6 hours.

WHAT I CLAIM IS: 1. A pharmaceutical composition for oral administration. suitable for use in the treatment of cerebral circulatory diseases consisting essentially of vincamine. as the free base or the hydrochloride salt incorporated in a sustained release matrix which matrix continuously releases vincamine for up to 24 hours after oral administration.

2. A composition as claimed in claim 1 wherein the matrix is made up of one or more of polyethylene glycol and ethyl or hydroxpropyl cellulose; metasilicic acid polymers; polyvinyl chloride; polyvinyl acetate: styrene-maleic acid copolymers; and natural rubber.

3. A composition as claimed in either claim 1 or claim 2 in granular form.

4. A composition as claimed in either claim I or claim 2 in tablet form.

5. A composition as claimed in any one of claims 1 to 4 in unit dosage form and containing at least 25 mg of vincamine per dosage unit.

6. A composition as claimed in claim 1 and substantially as hereinbefore described with reference to the Examples.

**WARNING** end of DESC field may overlap start of CLMS **.

Claims (6)

**WARNING** start of CLMS field may overlap end of DESC **. II - Release in vivo by measurement in the dog. In the following table the blood levels determined in vivo after administration of composition C in comparison with these provided by a normal release composition K are reported. TABLE TIME COMPOSITION O' 1h 2 h 4 h 8 h 12 h 24 h 30 h Dog No.20 K( ) û 0.227 0.362 0.315 0.164 0.120 0.120 0.075 C O 0.200 0.285 0.402 0.417 0.350 0.208 0.188 Dog No.26 K 0 0.224 0.349 0.375 0.205 0.120 0.120 - C 0 0.255 0.339 0.399 0.418 0.300 0.203 0.150 Dog No.27 K - 0.457 0.633 0.676 0.240 0.150 0.120 - C - 0.244 0.310 0.398 0.440 0.380 0.203 0.165 Dog No.19 K 0 0.278 0.750 0.745 0.216 0.121 0.121 0.104 C 0 0.240 0.351 0.423 0.485 0.364 0.281 0.162 ( ) K = normal release composition The preceding tests confirmed that the tablets having the aforesaid compositions containing resins. fatty substances and macromolecular compounds. and prepared according to the described preparing techniques give a programmed and homogeneous release within the limits of the most appropriate dosage (25 to 75 mg per unit). The release tests, parallely carried out in vitro and in vivo. demonstrated that a regular and continuous release of the active substance. such as to keep the hematic levels within. the minimum and maximum limits of the defined therpeutical threshold for a time up to 24 hours. takes place when the in vitro dissolution shows a constant release starting from 15 to 20roc of the total amount in the first hour to achieve about 55 to 7üc after 6 hours. WHAT I CLAIM IS:

1. A pharmaceutical composition for oral administration. suitable for use in the treatment of cerebral circulatory diseases consisting essentially of vincamine. as the free base or the hydrochloride salt incorporated in a sustained release matrix which matrix continuously releases vincamine for up to 24 hours after oral administration.

2. A composition as claimed in claim 1 wherein the matrix is made up of one or more of polyethylene glycol and ethyl or hydroxpropyl cellulose; metasilicic acid polymers; polyvinyl chloride; polyvinyl acetate: styrene-maleic acid copolymers; and natural rubber.

3. A composition as claimed in either claim 1 or claim 2 in granular form.

4. A composition as claimed in either claim I or claim 2 in tablet form.

5. A composition as claimed in any one of claims 1 to 4 in unit dosage form and containing at least 25 mg of vincamine per dosage unit.

6. A composition as claimed in claim 1 and substantially as hereinbefore described with reference to the Examples.