NL8802490A - POLYESTER PREPARATION FOR THE REGULATED DELIVERY OF MEDICINAL PRODUCTS. - Google Patents

Description

- Polyester-based formulation for controlled-release medicines -

The invention relates to a pharmaceutical composition, in particular a composition which allows the slow and controlled release of an effective dose of a particular drug.

There are numerous examples of therapeutic treatments where it is desirable to obtain a slow and controlled release of the drug with a single administration. Various solutions have been proposed in this field, such as subcutaneous implants or injectable suspensions of microscopic particles or microcapsules.

Such formulations are based on biocompatible and biodegradable polymers, for example, polymers or copolymers of D, L-lactic acid and / or glycolic acid (see, e.g., EP-A-0052510 and EP-A-0058481).

In practice, interesting results have been obtained in therapeutic treatments with polypeptides such as LHRH or analogs thereof, which have been used in the form of injectable microscopic particles or microcapsules, based on a copolymer of D, L-lactic acid and glycolic acid (about 50: 50), with an average molecular weight of about 50,000. Since this type of copolymer hydrolyses relatively easily in vivo, it is forced to use high molecular weight forms: in such cases, synthesis involves resorting to the use of organometallic polymerization catalysts and, for toxicological reasons, after reaction remove any trace. Such operations are often very lengthy and very expensive.

In general, it has been found that polymerization methods without organometallic catalysts are not well suited for the preparation of biodegradable polymers having an average molecular weight of about 30,000 or more.

In addition, in order to prevent too rapid degradation by hydrolysis in vivo of this type of polymer (lactic acid-glycolic acid) 8802490-2, it has been forced to prepare injectable microscopic particles or microcapsules of relatively large average dimensions: the injection involves very often an inflammatory response of the tissues is true, which is sometimes very painful for the treated patient.

In addition, it has been found in certain cases that the regular release of a peptide drug in the form of microscopic particles (see, for example, EP-A-0058481) presented difficulties, especially when it came to preventing two-phase delivery.

The pharmaceutical industry is therefore looking for biodegradable polymers which are suitable for use as carriers for medicines, especially in view of slow and controlled release of the active substance, and which do not have the above drawbacks, which adhere to the biodegradable polymers currently recommended. The invention provides an advantageous solution to this problem.

The invention provides a pharmaceutical composition suitable for the slow and controlled release of an effective dose of drug, characterized in that it comprises as a carrier for the drug a biodegradable polymer, copolymer or mixture of polymers and / or copolymers of a dicarboxylic acid from the Krebs cycle and an aliphatic diol with 4 carbon atoms or 1,4-cyclohexane dimethanol.

Certain polyesters or copolyesters which are derived from Krebs cycle carboxylic acids, such as, for example, succinic acid, malic acid, fumaric acid or oxalacetic acid, and polyols such as the triols, for example glycerol, mannitol or sorbitol: according to the American they can be used, inter alia, as carriers for drugs, mainly steroids, in the form of matrices. However, the described polyesters have a relatively high average molecular weight; between about 20,000 and 200,000. U.S. Pat. No. 4,481,353 recommends the use of Krebs cycle acid polyesters such as those mentioned above and of aliphatic * 8802490-3 diols having 2 to 8 carbon atoms in the preparation of surgical objects such as, for example, for microscopic tubes, tapes, or sutures. However, this patent does not mention or suggest the use of this type of polyesters as a drug carrier.

The present invention relates to a well-defined group of polyesters or copolyesters which can be used advantageously for the intended purpose. In particular, it concerns biodegradable polymers, copolymers or mixtures of polymers and / or copolymers of a dicarboxylic acid from the Krebs cycle and an aliphatic diol with 4 carbon atoms or 1,4-cyclohexane dimethanol. The dicarboxylic acid from the Krebs cycle is preferably used with fumaric or succinic acid, and as aliphatic diol with 4 carbon atoms 1,4-butanediol or 2,3-butanediol, in addition to 1,4-cyclohexane-dimethanol.

According to the invention, a polymer such as poly-1,4-butylene succinate, poly-1,4-butylene fumarate, poly-1,4-cyclohexane-dimethylene succinate or fumarate or poly-2,3-butylene succinate or - use fumarate. The above-mentioned polyesters can be used in the pure state or in the form of mixtures of at least two of the above-mentioned polyesters. According to the invention, it is also possible, for example, to use a copolymer of fumaric acid and succinic acid and 1,4- or 2,3-butanediol. A copolymer of fumaric acid and 1,4- and 2,3-butanediol can also be used.

Interesting results have been obtained with poly-1,4-butylene succinate, poly-1,4-cyclohexane dimethylene succinate and poly-2,3-butylene fumarate, although this list is not limitative.

In a particular embodiment of the invention, one of the above-mentioned polymers or copolymers can be mixed with a polymer or copolymer of an o -hydroxycarboxylic acid such as D- or L-lactic acid and glycolic acid. Interesting results have been obtained with mixtures of poly-1, 4-butylene succinate and a copolymer of D, L-lactic acid and glycolic acid.

The polyesters used according to the invention are characterized by a relatively low average molecular weight, generally between about 2000 and 50,000, preferably less than 10,000. This represents a significant advantage in their -8802490-4 synthesis which can be accomplished without organometallic polymerization catalysts. They can be easily obtained by conventional methods such as melt phase polymerization in the presence of an organic esterification catalyst. e.g. p-toluenesulfonic acid) or pearl phase polymerization.

The polyesters thus obtained are characterized by a lipophilic behavior which is stronger than that of the currently known polymers or copolymers of lactic acid or glycolic acid; moreover, they are less sensitive to hydrolysis degradation than the latter 1.0. This particular feature makes it easy to achieve one of the intended purposes, which is to prepare injectable microscopic particles or microcapsules of very small dimensions, on the order of only a few µm or a few tens of µm.

The above polyesters or their blends are suitable for the manufacture of any drug carrier form: this may be, for example, a matrix in which the active substance is dispersed or solubilized, such as, for example, spheres, implants, microspheres or microscopic particles.

These polyesters or their blends are particularly well suited for the use of microencapsulation methods for active substances, such as microencapsulation by phase separation or microencapsulation by solvent evaporation. To obtain the carriers in the appropriate form, one can also use methods such as spray drying and freeze drying, both of which lead to the obtainment of microscopic particles containing the active substance, or extrusion, with which implants of a fixed shape can be prepared. These are known methods, some of which will be described in more detail in the examples below.

Polyesters with an average molecular weight of about 2000 to 5000, for example about 2500, are preferably used for the production of microcapsules.

In a preferred embodiment of the invention, such a polyester is used in admixture with a copolymer of D, L-lactic acid and glycolic acid (about 50:50) with an average molecular weight between about 35,000 and 60,000, preferably about 45,000. This .8802490 - 5 - list is however not exhaustive.

Optionally, a biocompatible hydrolysis modifier, such as a carboxylic acid, for example citric acid, or a salt such as sodium chloride (neutral) or sodium carbonate (basic) can be included in the polymer mass.

Despite their aforementioned lipophilic properties, the polyesters of the invention have a strong affinity for hydrophilic drugs such as polypeptides.

As drugs, for example, one will use natural or synthetic polypeptides having 3 to 60 amino acid units, or a polypeptide derivative such as a non-toxic salt of a polypeptide. For example, one may advantageously use a decapeptide such as the hormone that triggers release of luteinizing hormone and the hormone that stimulates follicle cells (LHRH) or one of its natural or synthetic analogues, or the hormone that triggers to release tyrosine (THRH), insulin, somatostatin or one of its synthetic analogs, human or animal calcitonin, human or animal growth hormone, the hormone that triggers growth hormone (GHRH), a cardiopeptide such as ANP (human 1 -28) or a natural or recombined interferon. Such active substances are ideal for the various microencapsulation methods.

In general, the drugs which can be used advantageously in the manufacture of compositions according to the invention can be selected from substances having an anti-inflammatory, anti-tumor, immunodepressive, antithrombotic, neuroleptic, antidepressant or antihypertensive activity, or a non-toxic salt of the like fabrics. This list is not exhaustive.

Generally, the pharmaceutical compositions of the invention contain the selected drug in an amount of about 0.5-20% by weight, although such limits may be exceeded, if desired. One of the preferred forms of such compositions consists of injectable microscopic 55 small particles or microcapsules having an average size of about 1 to 500 µm dispersed in a carrier for a parent injection.

When the pharmaceutical composition according to the invention has been administered in vivo or has been placed in an aqueous physiological medium, it constantly releases the drug 5 to the surrounding medium for at least one week.

Example I

Preparation of a polyester of succinic acid 29.25 g (0.25 mol) succinic acid was mixed with 22.53 g (0.25 mol) 1,4-butanediol, 0.43 g p-toluenesulfone -acid (1% by weight, based on the theoretical yield of polyester) and 90 ml of toluene, in a reactor equipped with a magnetic stirrer, a thermometer, an inert gas supply (1) and a water separator. The reaction mixture was brought to 110 ° C, and, after heating for 10 hours, a first polymer sample was taken to determine its intrinsic viscosity (I.V.). Samples were taken at regular intervals until an IV index of 0.34 (measured at 25 ° C in chloroform) was obtained: from then on.

heating was stopped and the reaction mixture was allowed to cool to ambient temperature with stirring.

Example II

Preparation of a polyester of succinic acid 47 # 24 g (0.40 mol) of succinic acid was mixed with 60.57 g (0.42 mol) of 1,4-cyclohexane dimethanol, in a reactor equipped with a magnetic stirrer, a thermometer and 3Q a distillation set-up equipped with an inert gas supply (^) and a vacuum pump. When the reaction mixture was brought into an inert atmosphere, the temperature was gradually brought to 130-170 ° C over 22 hours and then kept at 180 ° C under a pressure of 1 mm Hg. After heating at this temperature for 72 hours and cooling to about 25 ° C, the desired polymer was obtained with an I.V. index of 0.27 (measured at 25 ° C in chloroform).

o 8802490 - 7 -

Example HI

Preparation of a Polyester of Fumaric Acid 34.83 g (0.3 mol) of fumaric acid was mixed with 28.4 g (0.315 mol) of 2,3-butanediol and placed in a reactor similar to that of Example 2. When the reaction mixture under inert atmosphere; it was gradually brought to a temperature of 130 to 180 ° C for 6 hours, and then held at 170-180 ° C under a pressure of 5 mm Hg for 20 hours. Thus, the desired polymer was obtained with an average molecular weight of about 2000 (measurement of the vapor pressure by osmometry).

Example IV

Manufacture of a polyester-based pharmaceutical preparation -15 by microencapsulation 0.10 g of a decapeptide of formula (pyro) Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Prd-Gyl-NH2 (hereinafter LHRH- Named D-Trpg) was suspended in a solution of 2.0 g of poly-1,4-butylene succinate (IV index 0.35; see Example II) in 100 ml of methylene chloride. The resulting suspension was then emulsified with a solution of 1.35 g of methyl cellulose in 500 ml of distilled water (rotational speed 1900 rpm) and the organic solvent was removed by rotary evaporation (rotational speed 470 rpm) for 2 hours at 40 ° C under a pressure of 380 mm Hg. The microcapsules obtained were then filtered, washed with chod water and finally dried under vacuum.

Example V

Manufacture of a polyester-based pharmaceutical preparation 30 by microencapsulation 0.037 g LHRH-D-Trpg was suspended in a solution of 1.0 g poly-1,4-butylene succinate (average molecular weight 2600) in 36 ml methylene chloride, followed by 30 ml silicone oil at ambient temperature The suspension was gradually added at a rate of about 35 ml / min. The resulting suspension containing the microcapsules was then poured into 3000 ml of 1,1,2-trichlorotrifluoroethane with good stirring. 8802490-8 (Freon 113) which was kept at ambient temperature. After stirring for 5 min, the obtained microcapsules were filtered and then dried under vacuum.

Analysis of the microcapsules 5 thus obtained showed that they were completely free of any trace of solvent, in particular Freon 113. On the other hand, the manufacture of microcapsules from copolymer of D, L-lactic acid and glycolic acid took a solvent residue of at least 5 wt% true.

10. Example VI

Manufacture of a pharmaceutical composition based on a mixture of polymer and copolymer by micro-encapsulation.

0.037 g of LHRH-D-Trpg was suspended in 36 ml of methylene chloride in which the following mixture was dissolved: - 0.40 g of poly-1,4-butylene succinate (average molecular weight about 2600) - 0.60 g of copolymer of D, L -lactic acid and glycolic acid (50:50; average molecular weight about 45,000), 20 The suspension was subjected to the treatments described in Example V to obtain microcapsules having the following properties: Solubilization treatment with dimethylformamide demonstrated that the copolymer of D, L-lactic acid and glycolic acid formed the core of the microcapsules and the poly-1,4-butylene succinate formed the outer wall of these microcapsules.

In addition, the dried microcapsules were observed to exhibit better fluidity than comparable microcapsules prepared from either the D, L-lactic acid and glycolic acid copolymer alone or poly-1,4-butylene succinate alone.

Similar results were obtained starting from mixtures with 0.20 and 0.30 g of poly-1,4-butylene succinate (average molecular weight about 2600) per 0.80 and 0.70 g of 50:50 copolymer of D, L, respectively -lactic acid and glycolic acid (average molecular weight about 45,000).

35

Example VII

Determination of the activity of a pharmaceutical preparation in the form of microcapsules «8002490 - 9 -

For these tests, microcapsules with LHRH-D-Trpg prepared according to the procedure of Example V were used, dried and sterilized appropriately.

The microcapsules were injected into laboratory rats at 300 µg / kg in the form of an aqueous sterile suspension (1% Tween / 2% NaCMC). The blood levels of LHRH-D-Trpg and testosterone released were determined by radioimmunoassay according to standard methods. The results obtained are shown in the table below: (assays performed on four test animals).

Period LHRH-D-Trpg Testosterone (days) (ng / ml) (ng / ml) 0 0.05 3.58 15 0.25 7.09 not determined 2 1.53 7.15 4 0.32 1.25 7 0.28 1.13 11 0.23 1.07 20 14 0.07 1.40 18 0.06 1.72 21 0.07 1.55 2S: 0.07 2.40 25. —-

After an initial "burst" effect, LHRH-D-Trp1 was released continuously and in a constant amount up to the eleventh day and even beyond. Testosterone level 30 decreased to reach castration level from the fourth day; this castration level was maintained until the 21st day.

-8802490

Claims (14)

Pharmaceutical composition suitable for the slow and controlled release of an effective dose of drug, characterized in that it comprises as a carrier for the drug a biodegradable polymer, copolymer or mixture of polymers and / or copolymers of a dicarboxylic acid the Krebs cycle and an aliphatic diol with 4 carbon atoms or 1,4-cyelohexanedimethanol. Preparation according to claim I, characterized in that the dicarboxylic acid from the Krebs cycle is fumaric or succinic acid. Preparation according to claim 1 or 2, characterized in that the aliphatic diol with 4 carbon atoms is 1,4-butanediol or 2,3-butanediol. 4. A composition according to any one of claims 1-3, characterized in that the polymer or copolymer of a dicarboxylic acid from the Krebs cycle and a diol has an average molecular weight of 2000-50000, preferably 2000-10000. Preparation according to any one of claims 1 to 4, characterized in that the mixture of polymers and / or copolymers comprises at least one polymer or copolymer of fumaric or succinic acid 20 and 1,4-butanediol, 2,3-butanediol or 1, 4-cyclohexanedimethanol and at least one polymer or copolymer of lactic acid and / or glycolic acid. Preparation according to claim. 5, characterized in that the polymer or copolymer of lactic acid and / or glycolic acid has an average molecular weight of 350.00-60000 and preferably 60-80 wt. % of the mixture of polymers and / or copolymers. Preparation according to any one of claims 1 to 6, characterized in that it additionally comprises a hydrolysis modifier of the polymer. Preparation according to any one of claims 1 to 7, characterized in that the medicament is a substance having an anti-inflammatory, anti-tumor, immunodepressive, anti-brombotic, neuroleptic, antidepressant or antihypertensive activity or a non-toxic salt of such dust. r- 8 8 0 Z 4 9 6 -ia - Preparation according to any one of claims 1 to 8, characterized in that the medicament is a polypeptide or a polypeptide derivative such as a non-toxic salt of a polypeptide. 10. A composition according to claim 9, characterized in that the polypeptide is a decapeptid such as the hormone which triggers release of luteinizing hormone and of the hormone stimulating follicle cells (LHRH) or one of its natural or synthetic analogues , or the hormone that triggers the release of tyrosine (THRH), insulin, somatostatin, or its synthetic analogs, human or animal calcitonin, human or animal growth hormone, the hormone that stimulates growth hormone (GHRH), a cardiopeptide such as ANP (human 1-28) or a natural or recombined interferon. 11. A composition according to any one of claims 1-10, characterized in that it contains the medicament in an amount of about 0.5-20% by weight. 12. A composition according to any one of claims 1-11, characterized in that it exists as a matrix in which the medicament is dispersed or solubilized, such as balls or implants, microscopic particles or microspheres, or in the form of microcapsules . 13. A composition according to claim 12, characterized in that it exists as injectable microscopic particles or microcapsules having an average size of 1-500 µm dispersed in a carrier for a parenteral injection. Preparation according to any one of claims 1 to 13, characterized in that, when administered in vivo or placed in an aqueous physiological medium, it continuously releases the medicament into the surrounding medium for at least one week. —O — o — o — o-o— <83 0 243 0