NO900943L - COPOLYMERS, THE PROCEDURE FOR THEIR PREPARATION AND USE. - Google Patents

Description

The present invention relates to a copolymer with polyester-silicone blocks, a method for its production and use as a matrix or as a capsule coating containing an active substance for controlled release of the active substance by simple breakdown by hydrolysis of this matrix or capsule and/or by diffusion of the active substance over the matrix or capsule before or during its breakdown.

In this type of controlled release system, the release of the active substance, which is a mineral compound, organic or vegetable substance, will be a function of the nature of the active substance, of the matrix and of the degradable nature of the matrix and will determine the release profile of the active substance.

The polymers which can be split by hydrolysis, especially the biodegradable ones which have so far been described in the literature, are mainly polyethylene cyanoesters, polyamides, polyurethanes, polyacetates, polyacetones, polyanhydrides, polyorthoesters and polyesters.

The silicone polymers have long been used, in cross-linked form as a matrix, where the active substance is dispersed in the matrix or as basic material in the capsule, i.e. the encapsulating coating for the active substance.

There are a number of patents that describe the matrix systems (e.g. US-A-4,053,580 and FR-A-2,560,768) and the encapsulation systems (e.g. EP-A-171,907, US-A-4,011. 312 and US-A-4,273,920).

In this type of application, the silicone polymers are not cleavable by hydrolysis and are therefore not degradable.

Furthermore, the crosslinking of these silicone polymers is carried out in the presence of the active substance. This cross-linking is generally carried out by means of an organometallic curing catalyst, by means of heating or irradiation (ultraviolet, infrared, electron current, gamma), or by a combination of the above. This cross-linking involves chemical or photochemical reactions in the presence of the active substance, and can therefore have a bad effect on the active substance.

Incidentally, the specific physiochemical properties of the active substance can disrupt and completely inhibit the cross-linking processes.

In pharmaceutical and biological applications, the biocompatible character of the polymer is also very important.

It is very difficult, and sometimes impossible, to remove the unwanted products from the crosslinked silicone polymer, such as catalysts and the remaining silicone polymers that are not integrated into the crosslink. Finally, the use of cross-linked silicone polymer which cannot be degraded will prevent the release of a macromolecular active substance.

The use of degradable polyesters of the type polylactic acid, polyglycolic acid and their copolymers is primarily described for the production of biodegradable surgical suture (US-A-2,703,316, US-A-2,758,987 and FR-A-1,425,333).

These polyesters are also referred to as matrices for controlled release of active substance (EP-A-171,907, US-A-4,011,312 and US-A-4,273,920).

For use in connection with controlled release, the cleavable polyesters have the following important advantages: - they are not toxic as their cleavage products occur during hydrolysis, - to a certain extent, the duration, release profile of the active substance, hydrolysis kinetics, in particular when choosing starting monomers, chain length, crystallinity, etc.

They nevertheless have a glass transition temperature that has been high to allow diffusion of a large number of active substances.

They often necessitate increased application temperatures which may be incompatible with the thermal stability of a number of active substances.

The object of the present invention is a copolymer which can be split by hydrolysis, which is degradable, thermoplastic and which has good mechanical properties and which is easy to shape.

Another object of the present invention is a copolymer which at the same time has the advantageous properties of cleavable silicones and polyesters without their disadvantages, or at least to a very small extent.

This purpose is achieved by the present invention, which thus relates to a block copolymer of diorganopolysiloxane polyester with from 1 to 99% by weight, preferably from 10 to 90% by weight of diorganopolysiloxane unit with average formula: and with from 99 to 1% by weight of the polyester unit with average formula :

units 1 and 2 being linked to each other by means of an organic or organosilicon bridge with a urethane bond at each end.

In formula 1, the radicals R, which are the same or different, are monovalent organic radicals. They are preferably chosen from among the radicals Ci~Cq, phenyl, vinyl and trifluoro-3,3,3-propyl.

The diorganosiloxy moieties which are preferred due to their commercial availability are the dimethylsiloxy, methylphenylsiloxy and diphenylsiloxy moieties.

m is a number between 1 and 500, preferably between 5 and 200.

y is a divalent organic radical which is bound to the silicon atom by a SiC bond.

In formula 2, p<1>, p<2>, r<1> and r<2> are numbers between 0 and at most 10,000, in which r-L+r2+pl+p<2> is greater than 1 and less than 10,000, preferably between 10 and a maximum of 200.

Z is a divalent hydrocarbon radical with formula:

wherein W is a saturated or unsaturated, straight-chain, branched or cyclic divalent hydrocarbon radical having from 1 to 8 carbon atoms, or symbolizes a covalent bond.

In the polyester unit of formula 2, the lactic and glycolic acid sequences can be distributed statistically, alternately or in blocks.

The weight amount of units 1 and 2 is calculated in relation to the total amount of units 1 and 2.

The bridge connecting units 1 and 2 has the formula:

in which B is a divalent organic or organosilicon radical which optionally comprises a diorganopolysiloxane unit of average formula:

in which R<1> has the same meaning as given for R and n has the same meaning as given for m in formula 1. In the case in which the copolymer according to the invention simultaneously comprises the units of formula 1 and 1', the meanings of R and R are <1>, m and n the same or different.

The copolymers according to the invention are prepared by starting from the following starting compounds a), b) and c):

a) - a diorganopolysiloxane oligomer with the average general formula:

wherein the symbols Y, which are the same or different, represent a divalent organic radical bound to a silicon atom by a SiC bond, and R and m have the same meaning as above.'

The bond Y preferably represents a straight-chain or branched alkylene bond with from 1 to 18 carbon atoms, optionally extended with a polyether bond selected from ethylene polyoxide, propylene polyoxide and their mixtures comprising from 1 to 50, preferably from 5 to 30 ethylene oxide units or propylene oxide units.

Examples of Y bonds include:

b) - a polyester oligomer with the general average formula:

in which Z, p1, p<2>, r-<*-> and r<2> are as indicated in the above formula 2. ;W is therefore a single covalent bond, or an alkylene or cycloalkylene bond such as, for example: ; The methods for obtaining the polyester of formula 5 are two different: by polycondensation or by polymerization by ring opening. Methods of this type are described in the following patents: US-A-2,676,945, US-A-4,273,920, FR-A-1,425,333, FR-A-2,086,047, EP-A-171,907 and EP -A-172,636. According to the polycondensation procedure, lactic acid, glycolic acid or a mixture of these two monomers is placed in a closed reactor in the presence of a diol with the formula HO - CH2- W - CH2- OH. The polycondensation is preferably carried out without a catalyst and with an increase in temperature and a simultaneous reduction in pressure. The reaction time can e.g. be from 5 to 120 hours, with a temperature increase from 20 to 220°C and a simultaneous reduction in pressure to atmospheric pressure of 0.02 KPa or less. According to a method for polymerization which is within the scope of the present invention, the cyclic dimers of the lactic acids or glycolic acids called lactides or glycolides and their mixtures are used in the presence of diol. The lactide used can be the optically pure lactide L(-) or the racemic lactide DL. ;This depends on the stereoregularity of the obtained polylactic acid. In the case of lactide L(-), a semi-crystalline polymer is thus obtained, while with lactide DL an amorphous polymer is obtained. The polymerization is carried out in bulk in the presence of a catalyst. ;The conditions for reaction time, temperature and pressure are as follows: ;- reaction time between 3 and 120 hours, ;- temperature between 110 and 180°C, and ;- pressure less than 0.02 KPa. ;Molecular weight, polydispersity and crystallinity of the polymer obtained according to one or the other procedure are controlled by the experimental conditions and the composition of starting monomers. ;c) - a diisocyanate compound with formula: ; ; wherein B is a divalent organic or organosilicon radical which may comprise a unit of formula 1' as stated above. In the case where B is a divalent organic radical, the radical comprises from 3 to 30 carbon atoms, preferably from 4 to 20 carbon atoms. ;As organic diisocyanate compounds, one can particularly use: ;- diisocyanate-1,2 propane, ;- diisocyanate-1,2 butane, ;- diisocyanate-1,3 butane, ;- diisocyanate-1,6 hexane, ;- diisocyanate-1 ,3 benzene, ;- diisocyanate-1,4 benzene, ;- diisocyanate-2,4 toluene, ;- diisocyanate-2,6 toluene, ;- diisocyanate-2,4 xylene, ;- diisocyanate-2,6 xylene, ; - diisocyanate-3,3' biphenyl, - diisocyanate-4,4' biphenyl, - diisocyanate-3,3' diphenylmethane, - diisocyanate-4,4' diphenylmethane, - diisocyanate-4,4' dimethyl-3,3' diphenyl , - diisocyanate-4,4' dimethyl-3,3' diphenylmethane, - diisocyanate-4,4' diphenylethane, - diisocyanate-3,3' diphenylether, - diisocyanate-4,4'-diphenylether, - diisocyanate-3,3 ' diphenylsulfone, - diisocyanate-4,4' diphenylsulfone, - diisocyanate-3,3' benzophenone, - diisocyanate-4,4' benzophenone, - diisocyanate-3,3' dicyclohexylmethane, - diisocyanate-4,4' dicyclohexylmethane, - diisocyanate -1,5 naphthalene, - diisocyanate-4,4' dichloro-3,3 biphenyl, - diisocyanate-4,4' dimethoxy-3,3' biphenyl. The diisocyanates which are preferably used are the following: - diisocyanate-1,6 hexane, - diisocyanate-2,4 toluene, - diisocyanate-2,6 toluene, - diisocyanate-2,4 xylene, - diisocyanate-4,4' biphenyl, - diisocyanate-4,41 diphenylmethane, - diisocyanate-4,4' diphenyl ether, - diisocyanate-4,4' diphenylsulfone, - diisocyanate-4,4' benzophenone, - diisocyanate-4,4' dicyclohexylethane, ;- diisocyanate-1, 5 naphthalene. The copolymer according to the invention is obtained by polyaddition, preferably in an organic solvent, of the starting compounds a), b) and c) in amounts such that the molar ratio between the isocyanate groups and the OH groups is between 0.95 and 1.05. The preferred solvents are aliphatic or aromatic halogenated hydrocarbons. Among these, o-dichlorobenzene or tetrachloroethane are preferably used. The polyaddition reaction can optionally be carried out in the presence of a catalyst. Dialkyltin dicarboxylates such as dibutyltin dilaurate can be mentioned as preferred catalysts. The polyaddition reaction is carried out by simply heating the reaction components at a temperature which is generally between 100 and 180°C. According to a preferred embodiment, the polyester b) is introduced into a part of the solvent which is kept at a temperature of between 100 and 180°C, after which the catalyst and starting products a) and c) are added together with the rest of the solvent. Completion of the reaction is checked by chemical determination of remaining isocyanate functions. The copolymer is recovered after removal of the solvent. In the case where B is an organosilicon radical in compound 6, B may comprise a diorganosiloxane unit of formula 1'. In this case, the copolymer according to the invention cannot comprise the diorganopolysiloxane unit of formula 1. The compounds 6 comprising a unit of formula 1' can be obtained by a hydrosilylation reaction between an a,w-(dihydrogen)poly-diorganosiloxane with an olefin compound bearing an isocyanate group . The same compounds 6 are particularly described in EP-A-77,744 incorporated by reference. When compound 6 contains a diorganopolysiloxane unit, it is therefore not mandatory to use starting product a). In this case, the use of the following method for producing copolymers with alternating blocks according to the invention is recommended: In a first step, the polyester oligomer b) of formula 5 is reacted with a molar excess of an olefin compound with an isocyanate group which is particularly described in EP-A -77,744, preferred with the general formula: ; wherein R<2> is selected from a hydrogen atom and an alkyl radical of 1 to 6 carbon atoms, E is a hydrocarbon radical without olefinic unsaturation of from 1 to 20 carbon atoms, and comprising at least one heteroatom selected from 0 and Si, preferably in an organic solvent in the presence of a tin catalyst such as dibutyl tin dilaurate. ;The most preferred compounds of formula 7 are as follows: ; ; In a second step, the polyester (bis-α, u vinyl) oligomer obtained in the first step is reacted with a diorganopolysiloxane of formula: ; wherein R<1> has the meanings given for the formula 1' above, in the presence of a catalytically effective amount of a hydrosilylation catalyst, preferably a platinum catalyst, the molar ratio between SiH and ; is between 0.9 and 1.5. The platinum catalysts which are used to carry out the hydrosilylation reaction of the polymers of formula 8 with the derivative of formula 7 are fully described in the literature, in particular the complexes of platinum and an organic product which are described in US-A-3,159,601, US -A-3,159,602, US-A-3,220,972, and EP-A-57,459, EP-A-188,978 and EP-A-190,530, and the complexes of platinum and vinyl organopolysiloxane described in US-A-3,419. 593, US-A-3,715,334, US-A-3,377,432 and US-A-3,814,730. To react the polymer with SiH of formula 8 with the derivative of formula 7, an amount of platinum catalyst, calculated in weight amounts of platinum metal, is generally used between 5 and 600 ppm, preferably between 10 and 200 ppm based on the weight amount of polymer with SiH and with formula 8. The hydrosilylation reaction can be carried out in bulk or in a volatile organic solvent such as toluene, heptane, xylene, tetrahydrofuran and tetrachloroethylene. ;It is generally desirable to heat the reaction mixture to a temperature of from 60 to 120°C for the time period necessary to carry out the reaction. It is also desirable to add the polymer with SiH dropwise to the derivative with formula 7 in solution in an organic solvent. The extent to which the reaction has developed is confirmed by determining the SiH residues with KOH in alcohol, after which the solvent is removed, e.g. by distillation under reduced pressure. The impure oil obtained can e.g. is purified by passing it through an absorbent silica column. ;The copolymers according to the invention are thermoplastic and degradable by hydrolysis and can be made up, in whole or in part, of substances that can be broken down by hydrolysis. ;They have sufficient mechanical properties that at ambient temperature they constitute objects in any form, which can be broken down by hydrolysis and which contain an active substance in an amount which is generally between 0.1 and 40% by weight and which in particular can be a active drug compound, a plant protection agent (such as a fertilizer, an insecticide, a pesticide, a fungicide, a herbicide), a plant sprout, a plant seed, a catalyst, a cosmetic product, etc. In the case in which the active substance is encapsulated, the above content can be from 0.1 to 99% by weight depending on the encapsulation procedure used. ;Among the active drug compounds, one can mention: ;- anti-inflammatory agents such as: ;ketoprofen, ;ibuprofen, ;indomethacin, ;- hormones, such as: ;steroids, ;peptide hormones, ;- antitumor agents, ;- antibacterial agents such as: ;penicillins, ; cephalosporins, streptomycins. The copolymers in accordance with the invention therefore have sufficient mechanical properties that they can be used for controlled release. They can also be easily shaped at a low temperature. They can be used for the controlled release of macromolecular active substances, which is not possible using simple silicone polymers. Another advantage of the copolymer according to the invention is that it allows the encapsulation, in the form of successive layers, of an active substance using a method which comprises at least one step of spraying a layer-forming mixture containing the copolymer in solution in an organic solution -agent or in the form of an aqueous emulsion or dispersion followed by at least one drying, i.e. evaporation of the organic solvent and/or water. In this case, the content of active substance in the capsule is from 40 to 99% by weight in relation to the total weight of the object. An example of such a procedure is the one known under the term "spray coating" where the particles to be encapsulated are mixed (fluidized) with the help of a gaseous stream which also ensures drying, i.e. evaporation of the organic solvent and/or of the water. ;The coating mixture is atomized in one or more nozzles which are placed in the different reactor zones, in the middle or at the bottom of the particle stream, depending on the type of procedure used, e.g. the above. In the procedure according to Wurster, this atomization is thus at the bottom of the fluidized particle layer. The Wurster pulverization technique is described in detail in US-A-2,799,241, US-A-3,089,824, US-A-3,117,027, US-A-3,196,827, US-A-3,207,824, US-A -3,241,520, US-A-3,523,994 and EP-A-188,953. According to other procedures that can be used within the scope of the present invention, the mixing of the particles of active substance is carried out mechanically, e.g. by means of a drum or a rotating container, and the gaseous stream is used only for drying. In order to achieve an effective encapsulation, it is recommended that the coating has an average thickness between 1 and 200 µm, preferably between 5 and 100 µm. Of course, the person skilled in the art can easily adapt the coating thickness to the nature of the active substance, to its surface, to the nature of the copolymer used, to the desired release kinetics for the active substance, etc., by means of routine tests. It is also possible to encapsulate the particles by e.g. application of a first capsule of a copolymer according to the invention with subsequent application of another layer of a different type, e.g. a natural or synthetic wax using a different procedure. The active drug substances which are encapsulated by means of the above-mentioned copolymers also form part of the invention. They have very interesting release kinetics when administered to humans. Most of these drugs have an activity profile "in vivo" and to achieve this profile a specific pharmaceutical preparation is required, especially when a carefully controlled plasma concentration is desired. The availability of the medication over long periods of time and a simplified ongoing treatment also lead to requirements regarding the nature of the excipients used. Any sick person prefers to take his medication once a day. day than several times per day in the same period. In addition, the release of the active substance should be as regular as possible, especially for painkillers, to avoid the patient having painful periods during the time when the active substance is not active. The encapsulated active substances according to the invention meet these needs. ;The following examples illustrate the invention: ;GPC means gas permeation chromatography, ;DSC means differential calorimetry, ;Mn means number average molecular weight, ;Mw means weight average molecular weight, ;lp means polydispersity index. ;The breaking strength R/R is measured in MPa according to the standard ;AFNOR-T 46 002. ;The elongation at break A/R is measured in percent according to the standard AFNOR-T 46 002. ;Tg is the glass temperature, ;Tm is the melting point, ; cp represents the phenyl radical, ;PLA DL: racemic polylactic acid. Reference is also made to the attached drawings where fig. 1, in the ordinate, gives percent liberated ketoprofen as a function of time (on the abscissa and in days), for examples 13 and 14, fig. 2 gives percent liberated nicergoline, for examples 16, 17 and 18, and fig. 3 gives the percentage of released bovine albumin, for examples 19, 20 and 21. ;EXAMPLE 1 ;la. - Production of a polyester with formula: ; ; 291 g of lactide L(-) which has recently been recrystallized in ethyl acetate, 8.2 ml of ethylene glycol distilled under vacuum and 0.510 g of tin octanoate are introduced into a 1 liter reactor. A vacuum of less than 0.02 KPa is established in the reactor, after which it is heated to 120°C for 48 hours. After cooling, the reaction product is dissolved in 500 ml of CH2CI2, after which it is purified by pouring the solution into water at 65°C with vigorous stirring. After evaporation of the solvent, 268 g of the polymer is obtained which is dried under vacuum and which has the following properties: ;Tg: 30°C ;Tm: 78°C ;Mn: 2,010 ;Content of OH function: 0.97 equivalent per . kg. ; lb. - Preparation of diisocyanate bridge with formula: ABA ; with A: ; and B: ; In a 500 ml glass reactor equipped with a stirrer and a cooling attachment, introduce: ;- 40 ml toluene, ;- 38.7 g (0.166 mol) silane isocyanate with formula: ; whose preparation is described in example 8 in US-A-4,088,670, ;- 10 mg (calculated on platinum metal) per kg reagent, of chloroplatinic acid in solution in ethyl-2-hexanol. ;BThe mixture is stirred and heated to 70°C and, within 35 minutes, 75 g of an a, co-(dihydrogen) polymethylphenyl siloxane with the formula: ; in solution in toluene. The mixture was then stirred and heated to 90°C for four hours. The reaction mixture is then evaporated at 120°C under reduced pressure (0.07 KPa). The fluid obtained is clear and colorless. Chemical measurement of the isocyanate functions allows the calculation of a molecular weight Mn of 1.515 g/mol, i.e. 1.32 equivalent isocyanate function/kg. ;lc. - Preparation of copolymer: In a 100 ml glass reactor equipped with a stirrer and a cooling attachment, introduce: 15.2 g of the oligomer obtained in example 1b, 20.6 g of polyester obtained in example 1a and 45 ml of o-dichlorobenzene. ;The polyester is first introduced with part of the solvent. The mixture is stirred and heated until a homogeneous solution is obtained. The silicone oil which has been diluted beforehand with the rest of the solvent is then added with stirring. Then 18 mg of di-n-butyltin dilaurate are introduced to catalyze the reaction. Stirring is maintained at 125°C for five hours and ten minutes. Chemical analysis confirms that the reaction mixture no longer contains detectable isocyanate functions. The solvent is removed in a rotary evaporator at 130°C and under a pressure of 0.133 KPa. ;34.35 g of the copolymer are obtained which are redissolved in 40 ml of dichloromethane and which are precipitated in 500 ml of hexane which has been cooled to 3.5°C. ;The copolymer is separated and then dried in a drying cabinet at 100°C under a reduced pressure. The dry product is ground to give a fine powder which gives a stiff and transparent solid when shaped by compression. The amount of powder obtained represents a mass of 30.8 g. ;Characterization of purified copolymer: ;intrinsic viscosity (in chloroform at 25°C, C = 3 g/dl): ;0.17 dl/g, ;molecular weights (by GPC , polystyrene standard): ;Mn: 4,620 g/mol, Mw: 16,400 g/mol, ;glass transition temperature (by DSC at 10°C/min after an initial heating to 180°C): Tg = 30°C. ;EXAMPLE 2 ;Into a 100 ml glass reactor equipped with a stirrer and a cooling attachment, introduce: ;- 10.3 g polyester from example la, ;5.4 g functionalized polymethylphenylsiloxane oil with formula: ; ; with a content of OH function equal to 1.84 equivalent/kg, ;1.7 g diisocyanate-1,6 hexane with formula: ;OCN-(CH2)6~NCO, ;- 25 ml o-dichlorobenzene. The polylactic acid diol is first introduced with part of the solvent part. The mixture thus formed is stirred and heated using an oil bath until the polyester completely dissolves and a homogeneous solution is obtained. The functionalized silicone oil and diisocyanate-1,6 hexane, which have first been mixed and diluted with the rest of the solvent, are then added to the reactor. Finally, the mixture is catalysed by adding 12 mg of dibutyltin dilaurate. After six hours and fifteen minutes of stirring at 120°C, it is confirmed by chemical analysis that the reaction mixture no longer contains detectable isocyanate functions. ;After removing the solvent in a rotary evaporator (at 130°C under a pressure of 0.133 KPa), 17.3 g of an almost colorless, elastic and transparent material is obtained. ;Properties: ;intrinsic viscosity (in chloroform at 25°C, C = 3 g/dl): ;0.30 dl/g, ;molecular weights (with GPC, polystyrene standard): ;Mn = 4,870 g/mol, Mw = 38,210 g /mol, ;glass transition temperature (with DSC): 10 - 30°C, ;softening temperature: 60-70°C (Kofler bench), ;mechanical properties at 20°C: the copolymer is placed in a mold and compressed at 100 KPa and 80 °C. A cast plate with a thickness of 1 mm is obtained from which test pieces of type H3 are cut out. ;Measurements of the mechanical properties are carried out with an apparatus of the type INSTRON 1,026 on nine test pieces H3: ;- breaking strength: 1.17 ± 0.25 MPa, ;- breaking elongation: 360 ± 76%. ;EXAMPLE 3 ;Into a 100 ml glass reactor equipped with a stirrer and a cooling attachment, introduce: ;- 10.3 g of polyester obtained in example la, ;- 13.0 g of functionalized polydimethylsiloxane oligomer with the following formula: ; and characterized by content of OH function which is equal to: 0.77 equivalent per kg. ;- 1.7 g diisocyanate-1,6 hexane, ;- 27 ml o-dichlorobenzene. The polylactic acid diol is first introduced with part of the solvent part. The mixture is stirred and heated using an oil bath to dissolve the polyester and obtain a homogeneous solution. The polysiloxane oligomer and the diisocyanate, which have been previously mixed and diluted with the rest of the solvent, are then introduced into the reactor. Finally, 12 mg of dibutyltin dilaurate (catalyst) is added. The heating at 20°C is continued with stirring for six hours and fifteen minutes. After it has been confirmed that the reaction mixture no longer contains detectable isocyanate functions, the solvent is evaporated in a rotary evaporator (130°C, 0.133 KPa). Thus, 22.4 g of a material which is weakly coloured, opaque and very soft (elastomer) is obtained. ;Properties: ;intrinsic viscosity (in chloroform at 25°C, C = 3 g/dl): ;0.33 dl/g, ;molecular weights (with GPC, polystyrene standard): ;Mn = 4,330 g/mol, Mw = 44,770 g /mol, ;softening temperature: about 60°C (in Koefler bench). ;EXAMPLE 4 ;Into a 100 ml glass reactor equipped with a stirrer and a cooling attachment are introduced: ;- 15.79 g polyester produced in example la, ;8.25 g functionalized polymethylphenylsiloxane with formula: ; ; and characterized by a content of hydroxyl functions of: 1.82 equivalent per kg, 2.55 g diisocyanate-1,6 hexane, 30 g orthodichlorobenzene. ;The polyester is first introduced into the reactor together with part of the solvent. The thus formed mixture is stirred and heated using a thermostatically controlled oil bath. A homogeneous solution is obtained. ;The functionalized polysiloxane and diisocyanate-1,6 hexane are then added, both of which have previously been mixed and diluted with the rest of the solvent. ;Finally, when the temperature of the reaction mixture is approximately 110°C, 0.0132 g of dibutyltin dilaurate (catalyst) is added. ;The course of the reaction is followed when determining the isocyanate functions. After two hours of heating at 120°C, the reaction mixture is placed in a rotary evaporator at 130 to 140°C under a pressure of approximately 0.13 3 KPa to remove the solvent. The product obtained is dissolved in dichloromethane, precipitated in hexane and dried in a drying cabinet for fifteen hours. 21.0 g of a material which is weakly colored, transparent and thermoplastic (quite rigid) is obtained. Properties: intrinsic viscosity (in chloroform at 25°C, C = 1.5 g/dl): 0.49 dl/g. ;molecular weights (with GPC, polystyrene standard): ;Mn = 7,550 g/mol, Mw = 61.7 20 g/mol, ;softening temperature: 60-70°C (in Kofler bench), ;mechanical properties at 20°C: the product is placed in a mold which is heated to 170°C and compacted at 80 MPa. A cast plate with a thickness of 0.5 mm is thus obtained from which test pieces of type H3 are cut out. ;The mechanical properties are determined using an apparatus of the type INSTRON 1 0 26: ;- breaking strength: 9.7 MPa, ;- elongation at break: 87%. ;EXAMPLE 5 ;Into a 100 ml glass reactor equipped with a stirrer and a cooling attachment are introduced: ;6.27 g of polyester prepared as in example la, ;- 13.21 g of functionalized polymethylphenylsiloxane oligomer with formula: ; and which is characterized by a content of hydroxyl functions of: 1.82 equivalent per kg, 2.55 g diisocyanate-1,6 hexane, 25 g orthodichlorobenzene. ;The polyester is first added to the reactor with part of the solvent. The thus formed mixture is stirred and heated using a thermostatically controlled oil bath. A homogeneous solution is obtained. Next, the functionalized polysiloxane and diisocyanate-1,6-hexane, which have been previously mixed and diluted with the rest of the solvent, are introduced into the reactor. Then, while the temperature of the mixture is approximately 110°C, 0.010 g of dibutyltin dilaurate (catalyst) is added. The course of the reaction is followed by measuring the NCO functions. The reaction mixture is stirred at 120°C for one and a half hours. The solvent is then removed in a rotary evaporator at 130 to 140°C and under a pressure of 0.133 KPa. The polymer is then redissolved in 25 ml of dichloromethane and precipitated, with vigorous stirring, in 250 ml of hexane. The obtained copolymer is then dried in a drying cabinet under reduced pressure (13.3 KPa), at 50°C. Thus 19.9 g of the dry product is obtained. This material is weakly coloured, transparent, very soft and thermoplastic. ;Properties: ;intrinsic viscosity (in chloroform at 25°C, C = 1.5 g/dl): ;0.27 dl/g, ;molecular weights (with GPC, polystyrene standard) : ;Mn = 7,570 g/mol, Mw = 3 3,890 g/mol, ;mechanical properties at 20°C: ;the product is placed in a mold that is heated to 150°C and it is compressed at 80 MPa. A cast plate with a thickness of 0.8 mm is thus obtained from which test pieces of type H3 are cut out. The mechanical properties are determined using an apparatus of the type INSTRON 1 026: ;- breaking strength: 0.4 MPa, ;- elongation at break: 1,375%. ;EXAMPLE 6 ;The same operation as in example 5 is repeated, except that the reactor is fed: ;- polylactic acid diol: 10.75 g, ;- polymethylphenylsiloxane functionalized with NCO: 10.88 g, ;- diisocyanate-1,6 hexane : 2.55 g, ;- orthodichlorobenzene: 30 g, ;- dibutyltin dilaurate (catalyst): 0.012 g. ;Thus, 22.2 g of the dry product which is reprecipitated in hexane is obtained. Properties of the copolymer: same test conditions as in example 5: intrinsic viscosity (in chloroform at 25°C, C = 1.5 g/dl) 0.30 dl/g, molecular weights (with GPC, polystyrene standard): Mn = 7,610 g/mol, Mw = 36,660 g/mol, ;mechanical properties at 20°C: ;the product is placed in a mold heated to 170°C and compressed at 80 MPa. A cast plate with a thickness of 0.5 mm is thus obtained from which test pieces of type H3 are cut out. The mechanical properties are determined using an apparatus of the type INSTRON 1 026: ;- breaking strength: 7.5 MPa, ;- elongation at break: 212%. EXAMPLE 7 7a. - Production of a bis (a, covinvl) polyester: 165 g of the polyester produced in example 1a, 450 g of toluene and 56 g of allyl isocyanate are introduced into a reactor of 1 litre. The reaction mixture is kept at 70°C for twelve hours and thirty minutes and the solvent and excess allyl isocyanate are removed by heating under reflux. The polymer obtained (180 g) is dissolved in dichloromethane, precipitated in n-hexane and dried under vacuum. ; 7b. - Preparation of a copolymer with alternating blocks: In a closed feed funnel, introduce 35.3 g of a,co-dihydrogen-polysiloxane with the formula: ; in 200 g of toluene. Into a reactor of 1 liter, 25 g of bis (a, to-vinyl) polyester prepared in example 7a, 200 g of toluene and 49 mg of the platinum catalyst (H 2 PtClg) calculated for platinum metal are introduced. ;The solution is kept in the reactor at the reflux temperature for toluene while the contents of the feed funnel are added drop by drop over a time t. ;The course of the reaction is followed by the disappearance of SiH functions with the help of I.R. spectrum (characteristic absorption band at 2,100 cm<1>). ;The reaction is stopped when the concentration of the SiH function is approximately constant. The toluene is removed in a rotary evaporator at 80°C under a pressure of 0.133 KPa. 60 g of the block copolymer is obtained, which is redissolved in 600 ml of tetrahydrofuran and which is precipitated in 5,000 ml of distilled water. The copolymer is removed and then dried in a drying cabinet at 100°C under reduced pressure. The product, which is dried and ground to give a fine powder, has the following properties: ;- Mn = 25,100 g/mol, ;- Ip = 2.2. ;EXAMPLES 8 TO 11 ;The method of Example 7 is repeated exactly except that the amount Q (in mg) of the platinum catalyst and/or the duration t (in hours and minutes) of the reaction is modified. ;The results obtained are given in the following table 1. ; ; EXAMPLE 12 ;Synthesis of a silicone/milk curd copolymer: A ;In a glass reactor equipped with a stirrer and a cooler, introduce: ;- 16.84 g of functionalized polylactic acid with the following formula and properties: ; Tg = 15°C, ;Mn = 2,200. ;Content of OH functions: 0.95 equivalent per kg, ;- 10 g of functionalized polydimethylsiloxane with the following formula and properties: ; Content of OH functions: 1.6 equivalent per kg, ;- 2.7 g diisocyanate-1,6 hexane, ;- 30 ml o-dichlorobenzene. The polylactic acid diol is first introduced with part of the solvent part. The mixture is stirred and heated using an oil bath until the polyester has dissolved and until a homogeneous solution has been obtained. Next, the polysiloxane oligomer and the diisocyanate, which have been previously mixed and diluted with the rest of the solvent, are introduced into the reactor. Finally, 12 mg of dibutyltin dilaurate (catalyst) is added. The mixture is heated at 120°C and with stirring for four hours and thirty minutes. After it has been confirmed that the reaction mixture no longer contains detectable isocyanate functions, the solvent is evaporated in a rotary evaporator (130°C, 0.133 KPa). Thus, 28.2 g of a light yellow material which is transparent and very soft (elastomer) is obtained. The product thus obtained is dissolved in 30 ml of methyl chloride and the polymer is precipitated in 300 ml of hexane at 10°C. After extraction and drying in the rotary evaporator (35°C, ;0.133 KPa), 24.6 g of copolymer are obtained. ;Properties: ;intrinsic viscosity (in chloroform at 25°C, C = 3 g/dl): ;0.21 dl/g, ;molecular weights (with GPC, polystyrene standard): ;Mn = 6,000 g/mol, Mw = 22,000 g /mol, ;Tgl= -120°C, Tg2= +15°C. ;(Tg-)_ is related to the silicone part and Tg2 to the lactic acid part) . ;EXAMPLE 13 ;Release of ketoroprofen: ;A solution is prepared which contains: ;- 25 ml chloroform, ;- 1.7 g ketoprofen, ;- 4.1 g of the copolymer A obtained in example 12. ;The solvent is evaporated and dried under vacuum. The product is then extracted and compressed at 70°C to obtain a film with a thickness of 1.5 mm. This is placed in a thermostatically controlled chamber at 37°C containing 1 liter of a buffer solution with the following composition: ; and with vigorous stirring. Follow-up of the elution kinetics for ketoprofen is carried out by UV measurement at 261 mm. The results obtained are shown in fig. 1 which shows a diffusion-type release over 15 days followed by a release of the rest of the ketoprofen by degradation of the copolymer. In fig. 1 relates to curve 1 example 13. ;EXAMPLE 14 ;Release of ketoprofen: ;One operates as in example 13 except that copolymer A is replaced by an amorphous polylactic acid PLA-DL with the following properties: - Mn = 18,300, - Mw = 39 . 800, ;- Tg = 45°C. The release of ketoprofen is carried out under the same conditions as in example 13, where in fig. 1 shows an initially slow release of ketoprofen (latency time) which increases after 15 days of elution under the influence of polylactic acid degradation. In fig. 1 relates to the plotted curve 2 example 14. Unlike in example 13, no release of the diffusion type is observed here. ;EXAMPLE 15 ;Release of ketoprofen: ;One operates as in example 13 but the copolymer A is replaced with an elastomeric silicone mixture which can be cross-linked by a polyaddition reaction with platinum and which is commercialized by La Société Rhone-Poulenc under the trade name ;RHODORSIL ± RTV 141. ;The presence of ketoprofen inhibits the cross-linking of silicone and does not result in obtaining a final product in solid form after heating at 100°C for several hours. ;Comparison of Examples 13, 14 and 15 shows that the copolymer A achieves the advantages of silicone (release of ketoprofen by diffusion) and of polylactic acid (release by degradation of material), while avoiding the disadvantages inherent in the problems of crosslinking of silicone and latency for PLA-DL. EXAMPLE 16 Release of nicergoline: Proceed as in example 13, replacing ketoprofen with nicergoline to obtain a film with a thickness of 1.5 mm. ;One takes out 200 mg of this film which is placed in a thermostatically controlled chamber at 37°C, which is protected from light and which contains 1 liter of a buffer solution with the following composition: ; and with vigorous stirring. The release kinetics for nicergoline is followed by UV measurement at 288 nm. The obtained results (curve 3) are shown in fig. 2 and shows that the release of nicergoline is complete after 70 days and at an almost constant rate. ;EXAMPLE 17 ;Release of nicergoline: ;Proceed as in example 16, but the copolymer A is replaced with an amorphous polylactic acid PLA-DL with the following properties: - Mn = 29,800, - Mw = 84,700, ;- Tg = 45°C. The elution of nicergoline carried out under the same conditions as shown in example 16, in fig. 2 (curve 4), a very small release during a latency period of 21 days. This is characteristic of the ongoing degradation of PLA-DL. Nicergoline is then released very quickly. ;EXAMPLE 18 ;Release of nicergoline: ;One proceeds as in example 16, but the copolymer A is replaced with an elastomeric silicone mixture which can be crosslinked by polyaddition with platinum and which is marketed by La Société Rhone-Poulenc under the trade name RHODORSIL RTV 141. ;The crosslinking of RTV 141 is carried out at 120°C within one hour and no compression is necessary to obtain a film with a thickness of 1.5 mm. Elution of nicergoline which has been carried out with the conditions indicated in example 16, shows in fig. 2 (curve 5), an almost constant release of nocergoline during at least 70 days, but at a slow rate. Comparison of Examples 16, 17 and 18 shows that, under the same conditions, the copolymer A gives total release of the active substance and at a rate much greater than that of the pure silicone elastomer. Furthermore, the latency period associated with the use of PLA-DL is avoided. EXAMPLE 19 Release of bovalbumin (BSA): Proceed as in example 13, replacing ketoprofen with finely ground BSA with an average grain size equal to 35 µm. The film obtained after compression at 70°C is placed in a thermostatically controlled chamber at 37°C containing 500 ml of a buffer solution with the following composition: ; and with vigorous stirring. ;The release kinetics for BSA is followed by UV measurement at 278 nm. The results obtained are shown in fig. 3 (curve 6) which shows that 80% of BSA is released within a few days. ;EXAMPLE 20 ;Release of BSA: ;One proceeds as in example 19, but the copolymer A is replaced with an amorphous polylactic acid PLA-DL with the following properties: - Mn = 29,800, - Mw = 84.7 00, ;- Tg = 45°C . The elution of BSA which is carried out under the same conditions as in example 19 shows, in fig. 3 (curve 7), a rapid release of BSA over six days. The obtained release profile is similar to that obtained with the copolymer A. ;EXAMPLE 21 ;Release of BSA: ;One proceeds as in example 19, but the copolymer A is replaced with the elastomeric silicone mixture used in example 18. The crosslinking is carried out at 120°C in within an hour and the resulting film is not compressed. The elution of BSA which is carried out under the same conditions as in example 19 shows, in fig. 3 (curve 8), that BSA is not released. In fact, BSA, which is a macromolecule (molecular weight = 63,000) cannot diffuse through the cross-linked silicone elastomer. Comparison of Examples 19, 20 and 21 shows that, in contrast to the cross-linked silicone elastomer, the copolymer A provides the release of macromolecules of the BSA type and with release profiles close to those obtained with a commercial lactic acid solution. ;EXAMPLE 22 ;Use of a membrane of a thermoplastic copolymer with several units of polysiloxane/poly-L-lactic acid for controlled release of the ketopropfen: Preparation of copolymer: an α,u>-hydroxylated poly-L is used -lactic acid oligomers which are produced under the following conditions: In a 1 liter reactor which is equipped with a stirrer, a cooling unit and which is flushed with a stream of nitrogen, introduce: ;- 288 g crystallized dimer-L-lactic acid, ;9 g distilled ethylene glycol, ;- 500 ml distilled toluene, ;- 0.5 g tin octoate. The mixture is heated under gentle reflux, with stirring, for five hours. It is then concentrated under reduced pressure, up to 80-90°C, in a rotary evaporator. After dilution with 150 ml of dichloromethane, the solution is precipitated in 2 liters of demineralized water at 65°C. After filtering and drying overnight under reduced pressure at 45°C, 297 g of a white solid are obtained. ;Characterization of the product: ;- determination of OH functions (total): ;124.8 milliequivalents/100 g, ;- determination of CO^H functions: ;7.6 milliequivalents/100 g. ;The copolymer is then prepared on the following method: ;Into a 500 ml three-neck glass flask equipped with a stirrer, a cooling device and a feed funnel, introduce: ;- 130 g of the above-mentioned poly-L-lactic acid oligomers, ;- 94.7 g of an a,co- hydroxypropylated poly (dimethylsiloxane) oligomer with 161 milliequivalents of OH/100 g, ;- 25.62 g diisocyanate-1,6 hexane, ;- 230 ml ortho-dichlorobenzene. ;The mixture is stirred and heated. Up to 110°C, add 0.125 ml of STAVINOR 1200 SN (catalyst). The heating is then continued with stirring and at 120°C for six hours. A portion of the solvent is then removed in a rotary evaporator at 120-130°C under a pressure of 2 mm Hg. It is diluted with 250 ml of dichloro-1,2-ethane, after which it is precipitated in 3 liters of hexane. After drying in a drying cabinet under reduced pressure, a white solid (233.6 g) is obtained. ;The product is characterized by gel permeation chromatography (GPC): ;- Mn = 12.250 g/mol, ;- Mw = 37.99 0 g/mol, ;(polystyrene standard). ;a) - Conditions for coating formation: An apparatus for coating formation with a fluidized layer of the UNI-GLATT type is used, which is equipped with a WURSTER system. ;350 g of ketoprofen are produced, which is obtained in the following way: ;Raw materials: ;- Avicel PH 101, FMC (E.U.), ;- Courlose, Courtaulds Acetate Ltd. (G.B.), ;- Ketoprofen B.P., Rhone-Poulenc Ltd. (G.B.). The granules are prepared according to an extrusion ball forming procedure. 3 kg of ketoprofen are mixed with 9 65.6 g of Avicel PH 101 in a planetary mixer of the HOBART type at a speed of 1. The powder mixture is granulated with 2,363 g of a 1.5% (w/w) Courlose solution for two minutes. The moist mass is extruded in an apparatus of the RUSSEL FINEX type. The device is equipped with a perforated plate with a diameter of 1 mm and a thickness of 1 mm. The extruded cylindrical material is fed into a machine to tumble the spherical granules (Spheronizer JB Caleva) for three minutes at a speed of 500 rpm. They are then sieved in an apparatus of the type FRITSCH SIEVE ANALYZER to obtain a size between 800 and 1400 ym. ;The device is supplied with 350 g of the minigranules of ketoprofen. ;A solution prepared with: ;39 g of the copolymer of polysiloxane and poly-L-lactic acid, 707 ml of dichloro-1,2-ethane PROLABO RECTAPUR is atomized.;The atomization conditions are as follows: ;air flow during fluidization: 72 m< *>/h,

air temperature during fluidization: 40°C,

air pressure when atomizing: 1.5 bar,

air temperature when atomizing: ambient temperature, flow of coating solution: 3 ml/min.

Samples of coated granules are taken from the apparatus after atomization times which respectively correspond to calculated coating quantities from 3.6 to 10% (sample A, B, C).

b) - Release kinetics for ketoprofen in buffer solution ( pH = 6.6) at 37°C: These three samples are subjected to the following

release test:

Description of the test: In a glass reactor of 1 liter equipped with a stirrer and heated in a thermostatically controlled water bath at 37°C, 6 g of the granules and 1 liter of solution with pH = 6.6 are introduced.

The buffer solution used is prepared as follows:

- solution of 68 g potassium dihydrogen phosphate (KH2PO4) in

10 liters of demineralized water,

- adjusting the pH to 6.6 by adding an IN NaOH solution.

Kinetic curves are plotted from determinations of ketoprofen at 260 nm on samples from the liquid phase with a spectrophotometer UV/visible PHILIPS of the type PYE UNICAM PU 8600.

The stirring speed for the suspension of granules is 300 rpm.

The results of these tests are set out below

table 2.

Claims (12)

1. Block copolymer of diorganopolysiloxane polyester with from 1 to 99% by weight of diorganopolysiloxane units of average formula: and from 99 to 1% by weight polyester unit of average formula: characterized by: the radicals R, which are the same or different, are monova lean organic radicals, Y is a divalent organic radical attached to the silicon atom with SiC bond, Z is a divalent hydrocarbon radical with formula: wherein W is selected from a straight chain, branched or cyclic divalent hydrocarbon radical having from 1 to 8 carbon atoms and a covalent bond, m is an integer between 1 and 500, p1, p<2>,r<1>and r<2> are whole numbers between 0 and 10,000 and extensive that r1+r2+p1+p<2>is greater than 1 and less than 10,000, units (1) and (2) are bound to each other by a bridge with formula: in which B is a divalent organic or organosilicon radical which optionally comprises a diorganopolysiloxane unit of intermediate formula (1') in which r! has the same meaning as R and n has the same meaning as m, since R and R<1>, m and n can be the same or different. 2. Copolymer as stated in claim 1, characterized in that the radicals R are chosen from the methyl radicals, W is a covalent bond and in that the copolymer comprises from 10 to 90% by weight of diorganopolysiloxane units and from 90 to 10% by weight of polyester units and in that r1+r2+ p1+p<2> is between 10 and 200. 3. Copolymer as stated in claim 1 or 2, characterized in that it does not comprise the unit of formula (1) when B is a unit of formula (l<1>). 4. Process for producing a block copolymer as stated in claim 1 or 2, characterized by reacting: a) - a starting diorganopolysiloxane oligomer with general formula: in which the symbols Y, which are the same or different, are a divalent organic radical which is bound to the silicon atom by means of a SiC bond and R and m have the same meaning as indicated above, b) - a starting polyester oligomer of medium general formula in which Z, p<1>, p<2>, r-*- and r<2> are as indicated above for formula (2), c) - a diisocyanate compound of formula: wherein B is a divalent organic or organosilicon radical which may comprise a unit of formula (l<1>) as indicated above. 5. Process for producing a copolymer with alternating blocks as stated in claim 3, characterized in that: - in the first step, a polyester oligomer b) of formula (5) is reacted with a molar excess of an olefin compound bearing an isocyanate group, preferably with the general formula: wherein R<2>is an alkyl radical of 1 to 6 carbon atoms, E is a hydrocarbon radical without olefinic unsaturation, of from 1 to 20 carbon atoms, and which may contain at least one heteroatom selected from 0 and Si, preferably in an organic solvent in the presence of a tin catalyst as dibutyltin dilaurate, - in a second step, a polyester (bis-a,w-vinyl) oligomer obtained in the first step is reacted with a diorganopolysiloxane of average formula: wherein R<1> and n are as indicated above for formula (1'), in the presence of an effective catalytic amount of a hydrosilylation catalyst, preferably a platinum catalyst with a molar ratio between SiH and between 0.9 and 1.5. 6. Process as stated in claim 5, characterized in that the product with formula (7) is an allyl isocyanate with formula: 7. Block copolymer, is characterized in that it can be achieved by using the method as stated in claims 4-6. 8. Objects that can be broken down by hydrolysis, characterized in that they are at least partially made up of a copolymer as specified in claims 1 - 3 and 7. 9. Items as specified in claim 8, characterized in that they also include an active substance. 10. Articles as stated in claim 9, characterized in that the active substance is encapsulated by means of the copolymer. 11. Articles as stated in claim 9, characterized in that the active substance is dispersed in a matrix of the copolymer. 12. Items as specified in claims 9-11, characterized in that the active substance is selected from among a drug, a pesticide, vegetable sprouts, vegetable seeds, a catalyst and a cosmetic product.