CH672887A5 - - Google Patents

Description

DESCRIPTION

The subject of the present invention is a pharmaceutical composition, more particularly a composition allowing the sustained and controlled release of an effective dose of a determined medicinal substance.

There are numerous examples of therapeutic treatments in which it is desirable to obtain, with the aid of a single administration, a prolonged release over time of the drug substance and controlled as to the dose passing into the body. Various solutions have already been proposed in this field, such as subcutaneous implants or injectable suspensions of microparticles or microcapsules. Such compositions are based on biocompatible and biodegradable polymers, for example based on polymers or copolymers of D, L-lactic and / or glycolic acid (see for example EP-A-0052510 and EP-A-0058481).

In practice, interesting results have been obtained during therapeutic treatments using polypeptides such as LHRH or its analogs, used in the form of microparticles or injectable microcapsules, based on a copolymer of acid D, L- lactic and glycolic (around 50:50), with an average molecular weight of around 50,000. This type of copolymer hydrolyzing relatively easily in vivo, we are therefore forced to use forms with high molecular weight: in such cases, for synthesis, we must resort to the use of polymerization catalysts organometallic and, at the end of the reaction, it is imperative to remove all traces of it, for toxicological reasons. Such operations are often very long and very expensive. More generally, non-catalytic polymerization techniques do not lend themselves well to the preparation of biodegradable polymers with an average molecular weight of the order of 30,000 and more.

In addition, in order to prevent degradation by too rapid hydrolysis, in vivo, of this type of polymer (lactide / coglycolide), it is necessary to prepare microparticles or injectable microcapsules of relatively high average size: during the injection, very often observes an inflammatory response of the tissues,

sometimes very painful for the subject treated.

It has also been found, in certain cases, that the regularity of the release of a drug substance of peptide type in the form of microparticles (see for example EP-A-0058481) was a source of difficulties, in particular when it was to avoid the phenomenon of biphasic release.

The pharmaceutical industry is therefore always looking for biodegradable polymers suitable for use as carriers of medicinal substances, in particular for a prolonged and controlled release of the active substance, and which would not have the disadvantages listed above, inherent in the biodegradable polymers recommended to date. The present invention offers an advantageous solution to this problem; it is defined in claim 1.

Certain polyesters or copolyesters derived from Krebs cycle carboxylic acids such as succinic, malic, fumaric or oxaloacetic acids are known, for example, and from polyols such as triols such as glycerol, mannitol or sorbitol: according to US-A -3.978.203, they can, inter alia, be used as carriers of medicinal substances, mainly steroids, in the form of matrices. The polyesters described, however, have a relatively high average molecular weight, between approximately 20,000 and 200,000. In US-A-4,481,353, the use of polyesters of acids of the Krebs cycle such as those mentioned above and of aliphatic diols in C2 to C8 is recommended in the preparation of surgical articles such as microtubules, ligatures or sutures for example. In this patent, however, no mention or suggestion is made of the use of this type of polyesters as a carrier for medicinal substances.

The present invention relates to a well-defined class of polyesters or copolyesters which can advantageously be used for the intended purpose. They are more particularly polymers, copolymers

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672,887

or mixtures of biodegradable polymers and / or copolymers of a dicarboxylic acid chosen from fumaric and succinic acids, and of an aliphatic diol containing 4 carbon atoms or 1,4-cyclohexanedimethanol. Preferably, as the C 4 aliphatic diol, 1,4-butanediol or 2,3-butanediol, in addition to 1,4-cyclohexanedimethanol.

According to the invention, it is advantageously possible to use a polymer such as poly-1,4-butylenesuccinate, poly-1,4-butylene fumarate, poly-1,4-cyclohexanedimethylenesuccinate or -fumarate, or also poly-2,3 -butylenesuccinate or -fumarate. The aforementioned polyesters can be used in the pure state or in the form of mixtures of at least two aforementioned polyesters. According to the invention, it is also possible to use a copolymer of fumaric and succinic acids and 1,4- or 2,3-butanediol for example. One can also use a copolymer of fumaric acid and 1,4- and 2,3-butanediol. Interesting results have been obtained using poly-1,4-butylenesuccinate, poly-1,4-cyclohexanedimethylenesuccinate and poly-2,3-buty-lene fumarate, although this list is not exhaustive.

In a particular implementation of the invention, one can also use one of the abovementioned polymers or copolymers in admixture with a polymer or copolymer of an alpha-hydroxycarboxylic acid such as D- or L-lactic acid and l glycolic acid. Interesting results have been obtained using a mixture of poly-1,4-butylenesuccinate and poly-D, L-lactide / coglycolide.

The polymers, more precisely the polyesters, used according to the present invention are characterized by a relatively low average molecular weight, most generally between 2000 and 50,000 approximately, preferably less than 10,000. This has a decisive advantage as regards their synthesis , which can be carried out without any use of organometallic polymerization catalysts. They can be easily obtained using standard techniques such as melt phase polymerization in the presence of an organic esterification catalyst (p-toluenesulfonic acid for example), or pearl phase polymerization (pearl phase polymerization).

The polyesters thus obtained are characterized by a more marked lipophilic behavior than that of the polymers or copolymers of lactic or glycolic acids known to date; they are also less sensitive to degradation by hydrolysis than the latter.

This feature makes it easy to achieve one of the aims, namely the preparation of microparticles or injectable microcapsules of very small dimensions, of the order of a few microns or only a few tens of microns.

The aforementioned polyesters or their blends are suitable for the production of any form of support for medicinal substances: for this purpose, it is possible to envisage a matrix within which the active substance is dispersed or dissolved, such as beads, implants, microspheres or microparticles for example. These polyesters or their blends are particularly well suited to the implementation of microencapsulation techniques for active substances, such as microencapsulation by phase separation or microencapsulation by evaporation (solvent evaporation microencapsulation). To obtain the supports in the suitable form, it is also possible to implement processes such as hot drying (spray drying), cryodessiccation (spray con-gealing), which both lead to obtaining microparticles containing the substance active, or extrusion, which allows the preparation of implants of predetermined shapes. These are known techniques: some of them will be described in more detail in the examples below.

For the preparation of microcapsules, polyesters of average molecular weight of the order of approximately 2000 to 5000 are preferably used, for example of the order of approximately 2500. In a particular implementation of the invention, such a polyester is used in admixture with a copolymer of D, L-lactic and glycolic acid (approximately 50:50) of average molecular weight of between approximately 35,000 and 60,000, preferably around 45,000. This list is not exhaustive, however.

Depending on the case, it is also possible to incorporate into the polymer mass a biocompatible hydrolysis modifying agent, such as a carboxylic acid such as citric acid, or a salt such as sodium chloride (neutral) or carbonate of sodium (alkaline).

Despite their lipophilic nature mentioned above, the polyesters which are the subject of the present invention have sufficient affinity for hydrophilic medicinal substances such as polypeptides. As medicinal substances, use will be made, for example, of polypeptides comprising from 3 to 60 units of amino acids, natural or synthetic, or alternatively a polypeptide derivative such as a non-toxic salt of a polypeptide. For example, it is advantageously possible to use a decapeptide such as the luteinizing hormone releasing hormone and the follicle stimulating hormone (LHRH) or one of its natural or synthetic analogs, or even the hormone releasing tyrosine (THRH), insulin, somatostatin or one of its synthetic analogs, human or animal calcitonin, human or animal growth hormone, growth hormone releasing hormone (GHRH), a cardiopeptide such as ANP (human 1-28), or a natural or recombinant interferon. Such active substances lend themselves well to various microencapsulation techniques.

More generally, the drug substances which can advantageously be used in the preparation of compositions according to the invention can be chosen from substances with anti-inflammatory, antitumor, immunosuppressive, antithrombotic, neuroleptic, antidepressant, antihypertensive effect. or a non-toxic salt of such substances. This list is not exhaustive.

As a general rule, the pharmaceutical compositions according to the invention contain the medicinal substance chosen in an amount of approximately 0.5 to 20% by weight, although such limits may be exceeded depending on the case. One of the preferred forms of such compositions consists of injectable microparticles or microcapsules having an average size of between 1 and 500 microns approximately, dispersed in a vehicle intended for parenteral injection.

Administered in vivo, or placed in an aqueous environment of physiological type, the pharmaceutical composition according to the invention releases the drug substance into the ambient medium constantly during a period of at least one week.

The examples below are intended to illustrate the present invention, without however limiting it.

Example 1 Preparation of a polyester of succinic acid

29.25 g (0.25 mole) of succinic acid were mixed with 22.53 g (0.25 mole) of 1,4-butanediol, 0.43 g of p-toluenesulfonic acid 45 (1% in weight based on theoretical polyester yield) and 90 ml of toluene, all placed in a reactor equipped with a magnetic stirrer, a thermometer, an introduction of inert gas (N2) and a separator d 'water. The reaction mixture was brought to 110 ° C. and, after 10 h of heating, a first sample of polymer was taken in order to determine its intrinsic viscosity (I.V. - intrinsic viscosity). Samples were taken at regular intervals until an IV index of 0.34 was obtained (measured at 25 ° C in chloroform): from this point on, the heating was stopped and the reaction mixture allowed to cool 55 to room temperature, with stirring.

Example 2 Preparation of a polyester of succinic acid

47.24 g (0.40 mole) of succinic acid were mixed with 60.57 g (0.42 mole) of 1,4-cyclohexanedimethanol, the whole being placed in a reactor fitted with a magnetic stirrer, a thermometer and a distillation bridge suitable for the introduction of inert gas (N2)

as well as a vacuum pump. Once the reaction mixture was placed under an inert atmosphere, the temperature was gradually raised from 130 to 170 ° C over a period of 22 h to then be maintained at 65 180 ° C under a pressure of 1 mmHg. After 72 h of heating to this temperature and cooling to approximately 25 ° C., the desired polymer was collected having an I.V. index of 0.27 (measured at 25 ° C. in chloroform).

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Example 3 Preparation of a polyester of fumaric acid

34.83 g (0.3 mole) of fumaric acid were mixed with 28.4 g (0.315 mole) of 2,3-butanediol and placed in a reactor identical to that described in Example 2. Once placed under an inert atmosphere, the reaction mixture was gradually brought to a temperature of 130 to 180 ° C for 6 h, then maintained at 170-180 ° C for 20 h under a pressure of 5 mmHg. The desired polymer was thus collected having an average molecular weight of approximately 2000 (measurement of the vapor pressure by osmometry).

Example 4 Preparation of a polyester-based pharamceutical composition by microencapsulation

0.10 g of a decapeptide of formula

(pyro) Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH2

(hereinafter referred to as LHRH-D-Trpö) was suspended in a solution of 2.0 g of poly-1,4-butylenesuccinate (index IV 0.35; see example 2) in 100 ml of methylene chloride . The suspension obtained was then emulsified with a solution of 1.35 g of methylcellulose in 500 ml of distilled water (speed of rotation 1900 rpm), then the organic solvent eliminated by rotary evaporation (speed of rotation 470 rpm ) for 2 h at 40 ° C under a pressure of 380 mmHg. The resulting microcapsules were filtered, washed with cold H2O and finally dried in vacuo.

Example 5 Preparation of a Pharmaceutical Composition Based on Polyester by Microencapsulation

0.037 g of LHRH-D-Trp6 was suspended in a solution of 1.0 g of poly-1,4-butylenesuccinate (average molecular weight 2600) in 36 ml of methylene chloride, then 30 ml of oil silicone were gradually added to the suspension, at a rate of approximately 5 ml / min, at room temperature. The resulting suspension, containing the embryonic microcapsules, was then poured, with good stirring, into 3000 ml of 1,1,2-trichlorotri-fluoroethane (Freon 113) maintained at room temperature. After 5 min of stirring, the resulting microcapsules were filtered, then dried under vacuum.

Analysis of the microcapsules thus obtained has demonstrated that they were completely free of any trace of residual solvent, in particular Freon 113. By way of comparison, a solvent residue of at least 5% by weight is observed during the preparation. , under identical conditions, of microcapsules from a copolymer of D, L-lactide / glycolide.

Example 6 Preparation of a Pharmaceutical Composition Based on a Mixture of Polymer and Copolymer by Microencapsulation

0.037 g of LHRH-D-Trp5 was suspended in 36 ml of methylene chloride containing the following mixture in solution: - 0.40 g of poly-1,4-butylenesuccinate (average molecular weight approximately 2600);

- 0.60 g of D, L-lactide / glycolide copolymer 50:50 (average molecular weight about 45,000).

After having undergone the treatments described in Example 5, the suspension obtained has led to the production of microcapsules having the following characteristics: by means of a solubilization treatment with dimethylformamide, it has been demonstrated that the copolymer of D, L-lactide / glycolide constituted the core of the microcapsules and that the poly-1,4-butylenesuccinate constituted the external wall of these microcapsules.

It has also been observed that the dried microcapsules have a better flowability than comparable microcapsules, prepared either from copolymer of D, L-lactide / glycolide only, or from poly-1,4- butylenesuccinate only.

Comparable results have been obtained from mixtures containing 0.20, respectively 0.30 g of poly-1,4-butylenesuccinate (average molecular weight approximately 2,600) for 0.80, respectively 0.70 g of copolymer of D, L-lactide / glycolide 50:50 (average molecular weight about 45,000).

Example 7: Determination of the activity of a pharmaceutical composition in the form of microcapsules

LHRH-D-Trp6 microcapsules prepared according to the method of Example 5, suitably dried and sterilized, were used for these tests.

The microcapsules were injected into rats (laboratory subjects) at a rate of 300 μg / kg, in the form of a sterile aqueous suspension (1% Tween / 2% NaCMC). The blood tests for released LHRH-D-Trp6 and testosterone were carried out by radio-immune measurement, according to standard techniques. The results obtained are collated in the table below (measurements carried out on 4 subjects).

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Testosterone

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(ng / ml)

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After an initial burst effect, the LHRH-D-Trp6 is released continuously and at a constant rate until the eleventh day and even beyond. The testosterone level decreases to reach from the fourth day a level of castration; this level of castration is maintained until the twenty-first day.

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Claims (13)

672,887 CLAIMS 1. Pharmaceutical composition intended for the prolonged and controlled release of an effective dose of drug substance, characterized in that it comprises, as carrier for drug substance, a polymer, a copolymer or a mixture of polymers and / or copolymers biodegradable with a dicarboxylic acid chosen from fumaric and succinic acids and with an aliphatic diol containing 4 carbon atoms or 1,4-cyclohexanedi-methanol. 2. Composition according to claim 1, characterized in that the C 4 aliphatic diol is chosen from among 1,4-butanediol and 2,3-butanediol. 3. Composition according to one of claims 1 and 2, characterized in that the polymer or copolymer of dicarboxylic acid and diol has an average molecular weight between 2000 and 50,000, preferably between 2000 and 10,000. 4. Composition according to one of claims 1 to 3, characterized in that the mixture of polymers and / or copolymers comprises at least one polymer or copolymer of a dicarboxylic acid chosen from fumaric acid and succinic acid and d a diol chosen from 1,4-butanediol, 2,3-butanediol and 1,4-cyclohexane-dimethanol and at least one polymer or copolymer of lactic and / or glycolic acid. 5. Composition according to claim 4, characterized in that the polymer or copolymer of lactic and / or glycolic acid has an average molecular weight of between 35,000 and 60,000 and preferably represents from 60 to 80% by weight of the mixture of polymers and / or copolymers. 6. Composition according to one of claims 1 to 5, characterized in that it further comprises an agent modifying the hydrolysis of the polymer. 7. Composition according to one of claims 1 to 6, characterized in that the drug substance is a substance having an anti-inflammatory, antitumor, immunosuppressive, antithrombotic, neuroleptic, antidepressant, antihypertensive or a non-toxic salt 'such a substance. 8. Composition according to one of claims 1 to 7, characterized in that the drug substance is a polypeptide or a polypeptide derivative such as a non-toxic salt of a polypeptide. 9. Composition according to claim 8, characterized in that the polypeptide is a decapeptide such as the hormone releasing the luteinizing hormone and the follicle stimulating hormone (LHRH) or one of its natural analogues or synthetic, or tyrosine releasing hormone (THRH), insulin, somatostatin or one of its synthetic analogs, human or animal calcitonin, human or animal growth hormone, hormone release of growth hormone (GHRH), a cardiopeptide such as ANP (human 1-28), or an interferon, natural or recombinant. 10. Composition according to one of claims 1 to 9, characterized in that it contains the medicinal substance in an amount of 0.5 to 20% by weight. 11. Composition according to one of claims 1 to 10, characterized in that it is in the form of a matrix within which the drug substance is dispersed or dissolved, such as beads or implants, microparticles or microspheres, or in the form of microcapsules. 12. Composition according to claim 11, characterized in that it is in the form of microparticles or injectable microcapsules having an average size of between 1 and 500 microns, dispersed in a vehicle intended for parenteral injection. 13. Composition according to one of claims 1 to 12, characterized in that, when administered in vivo, or placed in an aqueous medium of physiological type, it releases the drug substance in the ambient medium constantly during a period of at least one week.