is defined in Claim 1.
In fact, certain polyesters or copolyesters are known which are derived from carboxylic acids of the Krebs cycle, such as, for example, succinic, malic, fumaric or oxaloacetic acids, and from polyols such as triols like glycerol, mannitol or sorbitol: according to US patent application A-3,978,203, they can be used inter alia as carriers for medicinal substances, mainly steroids, in the form of matrices. However, the poly esters described have a relatively high average molecular weight of between about 20 000 and 200 000.
A 3 U.S. patent application A-4,481,353 recommends the use of polyesters derived from acids of the Krebs cycle, such as those mentioned above, and from C2 to C 8 aliphatic diols in the preparation of surgical requisites such as, for example, microtubes, ligatures or sutures. In the said patent, however, there is no mention or suggestion of the use of this type of polyester as a carrier for medicinal substances.
The present invention relaltes to a well-defined class of polyesters or copolyesters which can advantageously be used for the stated purpose. More particularly, they are biodegradable polmers or copolymers or mixtures of biodegradable polymers and/or copolymers derived from a dicarboxylic acid selected from the acids of the Krebs cycle,and from an aliphatic diol containing 4 carbon atoms or from cyclohexane-1, 4-dimethanol. Fumaric or succinic acid is preferably used as the dicarboxylic acid of the Krebs cycle and butane-1,4-diol or butane-2,3-diol is preferably used 20. as the C4 aliphatic diol, apart from cyclohexane-1,4---dimethanol.
According to the invention, it is advantageously possible to use a polymer such as poly-1,4-butylene succinate, poly-1,4-butylene fumarate, poly-1,4-cyclo- hexanedimethylene succinate or fumarate or else poly2,3-butylene succinate or fumarate. The above-mentioned polyesters can be used in the pure state or in the form of mixtures of at least two of the said polyesters. According to the invention, it is also possible to use a copolymer derived from fumaric and succinic acids and from butane-1,4- diol or butane-2,3-diol, for example._ A copolymer derived from fumaric acid and from butane1,4-diol and butane-2,3-diol can also be used. Interesting results have been obtained using poly-1,4- butylene succinate, poly-1,4-cyclohexanedimethylene 4 succinate and poly-2,3-butylene fumarates although this list does not imply a limitation.
In a particular embodiment of the invention, a further possibility is to use one of the above- mentioned polymers or copolymers mixed with a polymer or copolymer derived from an alpha-hydroxycarboxylic acid such as D- or L-lactic acid and from glycolic acid. Interesting results have been obtained using mixtures of poly-1,4-butylene succinate and D,1-1actide/glycolide copolymer.
The polymers, more precisely the polyesters, used according to the present inventijn are characterized by a relatively low average molecular weight which is more generally between about 2000 and 50 000 and preferably less than 10 000. This has a decisive advantage when it comes to their synthesis, which can be carried out without any need to use organometallic polymerization catalysts. They can easily be obtained by means of the customary techniques such as melt phase polymerization in the presence of an organic esterification catalyst (e.g. p-toluenesulphonic acid), or pearl phase polymerization.
The polyesters obtained by these methods are characterized by a lipophilic behaviour which is more pronounced than that of the lactic or glycolic acid polymers or copolymers known hitherto; they are also less sensitive than the latter to degradation by hydrolysis. This feature makes it possible easily to achieve one of the stated aims, namely to prepare injectable microcapsules or microparticles with very small dimensions of the order of only a few microns or tens of microns.
The polyesters mentioned above, or mixtures thereof, are suitable for the preparation of any form of carrier for medicinal substances: a matrix in which the active substance is dispersed or solubilized can be considered for this purpose, examples being beads, implants, microspheres or microparticles. These polyesters or mixtures thereof are particularly suitable for carrying out the techniques of microencapsulation of active substances, such as microencapsulation by phase separation or microencapsulation by evaporation (solvent evaporation microencapsulation). To obtain the carriers in the appropriate form, it is also possible to use processes such as spray drying or spray congealing, which both produce microparticles containing the active substance, or alternatively extrusion, which makes it possible to prepare implants of predetermined shape. These are known techniques: some of them will be described in greater detail in the Examples below.
Microcapsules are preferably prepared using polyesters with an average molecular weight of the order of about 2000 to 5000, for example of the order of about 2500. In a particular embodiment of the invention, a polyester of this type is used in a mixture with a acid copolymer (approx. 50:50) with an average molecular weight of between about 35 000 and 60 000, preferably of the order of about 45 000.
However, this is not an exhaustive list.
Depending on the particular case, it is also possible to incorporate into the polymer composition a biocompatible hydrolysis modifier such as a carboxylic acid, like citric acid, or else a salt such as sodium chloride (neutral) or sodium carbonate (alkaline).
Despite their lipophilic character mentioned earlier, the polyesters forming the subject of the present invention have a sufficient affinity for hydrophilic medicinal substances such as polypeptides. Examples of medicinal substances which may be used are natural or synthetic polypeptides containing from 3 to 60 amino acid units, or else a polypeptide derivative 6 such as a non-toxic salt of a polypeptide. For example, it may be advantageous to use a decapeptide such as luteinizing hormone/follicle- stimulating hormone releasing hormone (LH/FSH-RH) 'Or one of its natural or synthetic analogues, or else thyrotropin releasing hormone (TRH), insulin, somatostatin or one of its synthetic analogues, human or animal calcitonin, human or animal growth hormone, growth hormone releasing hormone (GHRH), a cardiopeptide such as ANP (humafi 1-28) or a natural or recombinant interferon. Such active substances are suitable for the various microencapsulation techniques.
More generally, the medicinal'substances which can advantageously be used in the preparation of compositions according to the invention can be selected is from substances having an antiinflammatory, antitumoral, immunosuppressive, antithrombotic, neuroleptic, antidepressant or antihypertensive effect or a non-toxic salt of such substances. This is not an exhaustive list.
20. As a general rule, the pharmaceutical composi tions according to the invention contain the chosen medicinal substance in a proportion of about 0.5 to 20% by weight, although these limits can be exceeded in particular cases. One of the preferred forms of such compositions consists of injectable microcapsules or microparticles with a mean size of between about 1 and 500 microns, dispersed in a vehicle intended for parenteral injection.
When administered in vivo or placed in an aqueous environment of physiological type, the pharma- ceutical composition according to the invention releases the medicinal substance into the surrounding medium at a constant rate over a period of at least 1 week.
The Examples below serve to illustrate the 7 present invention without thereby.implying a limitation.
Example 1 Preparation of a succinic acid polyester 29.25 g (0.25 mol) of succinic acid were mixed with 22.53 g (0.25 mol) of butane-1,4-diol, 0.43 g of p-toluenesulphonic acid (1% by weight, based on the theoretical yield of polyester) and 90 ml of toluene, the mixture being placed in a reac.tor equipped with a magnetic stirrer, a thermometer,,a means for introducing inert gas (N 2) and a water separator. The reaction mixture was heated to MCC and, after 10 hours of heating, a first sample of polymer was taken in order to determine its intrinsic viscosity (I.V.). Samples were taken at regular intervals until the I.V. index had reached 0.34 (measured at 25'C in chloroform):
heating was stopped at that point and the reaction mixture was left to cool to room temperature, with stirring.
-Example 2 Preparation of a succinic acid polyester 47.24 g (0.40 mol) of succinic acid were mixed with 60.57 g (0.42 mol) of cyclohexane-1,4-dimethanol, the mixture being placed in a reactor equipped with a manetic stirrer, a thermometer and a distillation bridge fitted to a means for introducing inert gas (N 2) and to a vacuum pump. With the reaction mixture placed under an inert atmosphere, the temperature was gradually raised to 130 to 170C over a period of 22 h and then kept at 18CC under a pressure of 1 mm Hg. After 72 h of heating at this temperature and cooling to about 25'C, the desired polymer was collected; it had an I.V.
index of 0.27 (measured at 25C in chloroform).
8 Example 3 Preparation of a fumaric acid polyester 34.83 g (0.3 mol) of fumaric acid were mixed with 28.4 g (0.315 mol) of butane-2,3-diol and the -5 mixture was placed in a reactor identical to that described in Example 2. With the reaction mixture placed under an inert atmosphere, the temperature was gradually raised to 130 to 18CC over 6 h and then kept at 170-18CC for 20 h under a pressure of 5 mm Hg.
The desired polymer was thus colZected and had an average molecular weight of about 2000 (measurement of the vapour pressure by osmometry).
Example 4 Preparation of a polyester-based pharmaceutical composition by microencapsulation 0.10 g of a decapeptide of the formula (pyro)Glu-His-Trp-Ser-Tyr-D-Trp-Leu-Arg-Pro-Gly-NH 2 (hereafter called LHRH-D-Tr P6) was suspended in a solution of 2.0 g of poly-1,4-butylene succinate (I.V.
-Index 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 methyl cellulose in 500 ml of distilled water (rotation speed 1900 rpm) and the organic solvent was then removed by rotary evaporation (rotation speed 470 rpm) for 2 h at WC under a pressure of 380 mm Hg. The resulting microcapsules were then filtered off, washed with cold H2 0 and finally dried under vacuum. Example 5 30 Preparation of a polyester-based pharmaceutical composition by microencapsulation 0.037 g of MRH-D-Tr P6 was suspended in a solution of 1.0 g of poly-1,4-butylene succinate (average 9 - molecular weight 2600) in 36 ml of methylene chloride, and 30 ml of silicone oil were then added gradually to the suspension, at a rate of about 5 ml/min, at room temperature. The resulting suspension, containing the embryonic microcapsules, was then poured, with thorough stirring, into 3000 ml of 1,1,2-trichlorotrifluoroethane (FREON 113) kept at room temperature. After 5 min of stirring, the resulting microcapsules were filtered off and then dried undeT.vacuum.
Analysis of the microcapules obtained by this method showed that they were totally devoid of all traces of residual solvent, especially FREON 113. By way of comparison, a solvent residue of at least 5% by weight is observed in the preparation of micro- capsules from D,L-lactide/glycolide copolymer under identical conditions.
Example 6 Preparation, by microencapsulation, of a pharma ceutical composition based on a mixture of polymer and copolymer 0.037 g of LHRH-D-Tr P6 was suspended in 36 ml of methylene chloride containing the following mixture in solution:
- 0.40 g of poly-1,4-butylene succinate (average molecular weight approx. 2600) and - 0.60 g of 50:50 D,L-lactide/glycolide copolymer (average molecular weight approx. 45 000).
After undergoing the treatments described in Example 5, the suspension obtained produced microcapsules having the following characteristics: by means of a solubilization treatment with dimethylformamide, it was demonstrated that the D,L- lactide/glycolide copolymer formed the core of the microcapsules and that the poly-1,4-butylene - succinate formed the outer wall of these microcapsules.
Furthermore, it was observed that the dried microcapsules had a better flow property than comparable microcapsules prepared either from D,Llactide/ glycolide copolymer on its own or from poly-1,4butylene succinate on its ovn.
Comparable results vere obtained using mixtures containing 0.20 or 0.30 g of poly-1,4-butylene succinate (average molecular weight approx. 2600) and 0.80 or, respectively, 0.70 g of 50:50 D,L-lactide/glycolide copolymer (average molecular weight approx. 45 000).
Example 7 Determination of the activity of a pharmaceutical composition in the form of microcapsules These experiments were carried out using microcapsules of URH-D-Tr P6 prepared by the process of Example 5 and appropriately dried and sterilized.
The microcapsules were injected into rats (laboratory subjects) at a rate of 300 micrograms/kg, in the form of a sterile aqueous suspension (1% TWEEN/ 2% NaCMC). The LHRH-D-Tr P6 released and the testosterone were determined in the blood by radioimmunoassay according to the standard techniques. The results obtained are collated in the Table below (measurements made on 4 subjects).
-1 1^ k_ 1 C' - 11 - Period URH-D-TrP6 Testosterone (days) (ng/M1) (ng/ml) 0 0.05 3.58 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 14 0.07 1.40 is 0.06 1.72 21 0.07 1.55 0.07 2.40 After an initial stimulation phase (initial burst effect), the LHRH-D-Tr P6 is released continuously and at a constant rate up to day 11 and even beyond. The testosterone decreases and reaches a castration level as from day 4; this castration level is maintained up to day 21.
12 CLAIMS 1. A pharmaceutical composition, in particular a pharmaceutical composition intended for the sustained and controlled release of an effective dose of a medicinal substance, characterized in that it comprises, as a carrier for the medicinal substance, a biodegradable polymer or copolymer or a mixture of biodegradable polymers and/or copolymers derived.from a dicarboxylic acid selected from the acids of the Krebs cycle, and from an aliphatic diol containing 4 carbon atoms or from cyclohexane-1,4-dimethanol. 2. A composition according to Claim 1, characterized in that the dicarboxylic acid of the Krebs cycle is selected from fumaric acid and succinic acid. 3. A composition according to Claim 1 or Claim 2, characterized in that the C4 aliphatic diol is selected from butane-1,4-diol and butane-2,3-diol. 4. A composition according to any one of Claims 1 to 3, characterized in that the polymer or copolymer derived "--from a dicarboxylic acid of the Krebs cycle and from a diol has an average molecular weight of between 2000 and 50 000, preferably of between 2000 and 10 000. 5. A composition 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 derived from a dicarboxylic acid selected from fumaric acid and succinic acid,and from a diol selected from butane-1,4-diol, butane-2,3-diol and cyclohexane-1,4dimethanol, and at least one lactic and/or glycolic acid polymer or copolymer. 6. A composition according to Claim 5, characterized in that the lactic and/or glycolic acid polymer or copolymer 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.
13 - 7. A composition according to any'one of Claims 1 to 6, characterized in that it also comprises an agent for modifying the hydrolysis of the polymer. 8. A composition according to any one of Claims 1 to 7, characterized in that the medicinal substance is a substance having an antiinflammatory, antitumoral, immunosuppressive, antithrombotic, neuroleptic, antidepressant or antihypertensive effect or a non-toxic salt of such a substance. 9. A composition according to any one of Claims 1 to 8, characterized in that the medicinal substance is a polypeptide or a polypeptide derivative such as a nontoxic salt of a polypeptide. 10. A composition according to Claim 9, characterized in that the polypeptide is a decapeptide such as luteinizing hormone/follicle-stimulating hormone releasing hormone (LH/FSH-RH) or one of its natural or synthetic analogues, or else thyrotropin releasing hormone (TRH), insulin, somatostatin or one of its synthetic analogues, 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. 11. A composition according to any one of Claims 1 to 10, characterized in that it contains the medicinal substance in a proportion of about 0.5 to 20% by weight. 12. A composition according to any one of Claims 1 to 11, characterized in that it is in the form of a matrix in-which the medicinal substance is dispersed or solubilized, such as beads or implants, microparticles or microspheres, or in the form of microcapsules. 13. A composition according to Claim 12, characterized in that it is in the form of injectable microcapsules or microparticles with a mean size of between 1 and 500 microns, dispersed in a vehicle intended for - 14 parenteral injection. 14. A composition according to any preceding claim, characterised by, when administered in vivo or placed in an aqueous medium of physiological type, its release of the medicinal substance into the surrounding medium at a constant rate over a period of at least 1 week. 15. A composition according to claim 1, substantially as exemplified herein.
is fed 1989 atThe Patent Office, House HolboMLondor. WC1R4TP. Further copies maybe obtalnedfrom The Patent 0Ince.
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