AU630925B2

AU630925B2 - Hydrolytically degradable polyester-silicone block copolymer DO NOT SEAL CASE WITHDRAWN DO NOT SEAL

Info

Publication number: AU630925B2
Application number: AU50602/90A
Authority: AU
Inventors: Gerard Helary; Rafael Jorda; Hugues Porte; Christian Prud'homme; Georges Sauvet; Ghislaine Torres
Original assignee: Rhone Poulenc Chimie SA
Current assignee: Rhodia Chimie SAS
Priority date: 1989-03-02
Filing date: 1990-03-01
Publication date: 1992-11-12
Anticipated expiration: 2010-03-01
Also published as: HUT53920A; FR2643906B1; JPH0320320A; ZA901569B; BR9000993A; EP0389386A1; CA2011246A1; NO900943D0; NO900943L; PT93315A; HU901251D0; FR2643906A1; FI901054A0; AU5060290A

Description

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Sgaue of Declarant(s) (io -6 atWitation required).

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is this 24 day of Janury 1990 Jean-Louis v Fo d degg qVi A V1 6 35w 9 2 0 00b *0 V COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952 C1Q4PLETE SPECIFICATION NAME ADDRESS OF APPLICANT: Rhone-Poulenc Chimie quai Paul Doumer 92408 Courbevoie France NAME(S) OF INVENTOR(S): Gerard HELARY Rafael JORDA Hugues PORTE Christian PRUD'HOMME Georges SAUVET Ghislaine TORRES ADDRESS FOR SERVICE: DAVIES COLLISON Patent Attorneys I Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR '~iE INVENTION ENTITLED: 0 0 0 00$ 00 0 *0 0 0~ O 0 0 0 O 0 a..0 H-ydrolytically degradable polyester-silicone block copolymer The following statement is a full description of this invention, including the best method of performing it known to me/us:rt 2 00 0 o o 03 0000 0 00 o oo 0700 0 00 o o 0 o300 0 00 S0 o 0000 0000 00 0 00 0 0 e S00 0 0 The present invention relates to a polyester-silicone block copolymer, its preparation and its use as a matrix or as a skin of a capsule containing an active substance with a view to the controlled release of the active substance by simple hydrolytic erosion of this matrix or capsule and/or by diffusion of the active substance through the matrix or capsule before or during its erosion.

10 In a controlled release system of this type the release of the active substance which is an inorganic, organic or vegetable substance is a function of the nature of the active substance, of the matrix and of the erodible nature of the matrix, which determine the release profile of 15 the active substance.

Hydrolytically degradable, in particular biodegradable, polymers already described in the literature are chiefly cyanoester polyethylenes, polyamides, polyurethanes, polyacetates, polylactones, polyanhydrides, polyorthoesters and polyesters.

Silicone polymers have been employed for a long time, in crosslinked form, as a matrix within which an active substance is dispersed or as a constituent material of a capsule, that is to say of a coating encapsulating an active substance.

There are very many patents describing matrix systems (for example US-A-4,053,580 and FR-A-2,560,768) and systems 3 using encapsulation (for example EP-A-171,907, US-A-4,011,312 and US-A-4,273,920).

In this type of application silicones are not hydrolytically degradable and are therefore not erodible.

Moreover, the crosslinking of these silicone polymers takes place in the presence of the active substance. This crosslinking is generally produced by an organometallic curing catalyst, by heating, or by radiation (ultraviolet, infrared, electron beam, gamma), or by a combination of these ,oo, 10 means. Since this crosslinking involves chemical or photochemical reactions in the presence of the active substance, it can therefore have a detrimental effect on this active substance.

Furthermore, the intrinsic physicochemical properties of the active substance can disturb or even completely Sinhibit the crosslinking process.

Moreover, in pharmaceutical and biological applications, the biocompatible nature of the polymer is of fundamental importance.

For these applications it is very difficult, and sometimes impossible, to remove from the crosslinked silicone ipolymer undesirable products such as residual catalysts and silicone polymers which are not integral with the crosslinked polymer. Lastly, the use of a nondegradable crosslinked silicone does not permit the release of a macromolecular active substance.

I_ 4 The use of degradable polyesters of the polylactic or polyglycolic type and their copolymers was originally described for the production of biodegradable surgical suture threads (US-A-2,703,316, US-A-2,758,987 and FR-A-1,425,333).

These polyesters have also been described as a matrix for the controlled release of active substance (EP-A-171,907, US-A-4,011,312 and US-A-4,273,920).

Degradable polyesters exhibit great advantages in the 0 00 case of controlled release applications: 10 they are nontoxic, as are their degradation products 0 0 °generated by hydrolysis, 0 o0 S0 the duration, the release profile of the active o o 0 0 0 0 substance and the kinetics of hydrolysis can be adapted to a certain extent, especially through the choice of the starting monomers, of the length of the 0 0 0 chain, its crystallinity, and the like.

However, they exhibit a glass transition temperature 0a 00 Sowhich is too high to permit the diffusion of a large number of active substances.

o.0 o 20 They frequently require high processing temperatures which can be incompatible with the thermal stability of a large number of active substances.

The object of the present invention is to provide a thermoplastic, erodible, hydrolytically degradable copolymer which can exhibit sufficient mechanical properties and easy shaping properties, I Another object of the present invention is to provide a copolymer which offers at the same time the advantageous properties of silicones and of degradable polyesters, without exhibiting their disadvantages or, at the very least, only in a highly attenuated form.

This objective is met by the present invention which provides diorganopolysiloxane-polyester block copolymers having from 1 to 99 preferably from 10 to 90 by weight o of diorganopolysiloxane blocks of average formula: 0 00 o R R( °0 00 10 I I (1) Y -Y 0i-- Si Y 0o00 R

R

S 00 000 0 and from 99 to 1 by weight of polyester block of average formula: oc 0 00 °0 0° -CH 0---CH C Z 0 C CH- 0 C CH (2) 0.0 H 0 CH3 0 CH 3 0 H 1 P 2 -r 1 2 the blocks and being linked together by an organic or organosilicon bridge having a urethane bond at each end.

In formula the radicals R, which are identical or different, are monovalent organic radicals. They are preferably C 1

-C

6 alkyl, phenyl, vinyl or 3,3,3trifluoropropyl radicals.

The diorganosiloxyl units which are preferred because 6 of their industrial availability are the dimethylsiloxy, methylphenylsiloxy and diphenylsiloxy units.

m is a whole or fractional number of between 1 and 500, preferably between 5 and 200, Y denotes a divalent organic radical linked to the silicon atom via an SiC bond.

In the formula of block pl, P2, r 1 and r 2 are whole or fractional numbers of between 0 and 10,000 inclusive 0 o0 o0' 10 (rl r2 PI P2) is greater than 1 and smaller ooo than 10,000, preferably between 10 and 200 inclusive, 0 0 and 0 0 Z is a divalent hydrocarbon radical of formula:

-CH

2

-W-CH

2 in which W is a linear, branched or cyclic, divalent, saturated or unsaturated hydrocarbon radical containing from 0 0 0 0. 0 1 to 8 carbon atoms, or a divalent bond.

°0 0° Within the polyester block of formula the lactic and glycolic blocks can be distributed in random, alternating 20 or block fashion.

o 0 The contents by weight of blocks and are calculated relative to the total weight of the blocks and The bridge linking the blocks and corresponds to the formula: 7 0 0 -0-C-NH-B-NH-C-O- (3) where B is a divalent organic or organosilicon radical which can optionally contain a diorganopolysiloxane block of average formula: i R (1 b) SSiO Si Ri n R1 o, o in which R 1 has the same meaning as R and n has the same meaning as m, which are given above in the case of formula In the case where the copolymer according to the 6oo 10 invention contains both the blocks of formulae and (1 b), 0 00 R and R 1 m and n can obviously have identical or different meanings.

The copolymers according to the invention are .0 prepared from the following starting materials b) and c): 000 S" 15 a) a starting diorganopolysiloxane oligomer o corresponding to the average general formula: R R HO Y iO Si Y OH R R -m in which the symbols Y, which are identical or different, denote a divalent organic radical linked to the silicon atom by an SiC bond and R and m have the same meaning as above.

The chain unit Y preferably denotes an inclusively

I

8 CI-C18, linear or branched alkylene chain unit, optionally extended by a polyether chain unit chosen from polyethylene oxide, polypropylene oxide and mixtures thereof and comprising from 1 to 50, preferably from 5 to 30 ethylene oxide and/or propylene oxide units.

As examples of chain units Y there may be mentioned:

-CH

2

-(CH

2 2

-(CH

2 3

(OCH

2

-CH

2 29

-(CH

2 3

-(CH

2 3

-[O-CH

2

-CH(CH

3 15

-(CH

2 3 -0-(CH 2

-CH

2 0o -(CH 2

)-CH(CH

3

)-CH

2

-(CH

2 12 S 10 b) a starting polyester oligomer corresponding to o o. the average general formula: o o o 0o HO CH C 0- CH C- 0 Z 0 -CH 0- CH o a H 0 CH3 0 CH3 0 H SP2 P 1 r r2 o no in which Z, pi, P2, rl and r 2 have the same meaning as in formula above.

oo^ 15 W is therefore a single covalent bond, or an alkylene or cycloalkylene chain unit, tor example: S- CH2 (CH2)2 CH(CH3)-, The processes for obtaining the polyester of formula are of two types: using polycondensation or using ringopening polymerization.

Processes of this type are described in the following ll n m 1,.1111 _ilu Cs- ra C 9 patents: US-A-2,676,945, US-A-4,273,920, FL-A-1,425,333, FR-A-2,086,047, EP-A-171,907 and EP-A-172,636.

Depending on the polycondensation process, lactic acid, glycolic acid or a mixture of the two monomers is placed in a closed reactor in the presence of the diol of formula HO-CH 2

-W-CH

2

-OH.

The polycondensation is carried out, preferably without any catalyst, by raising the temperature and by t decreasing the pressure simultaneously. The reaction time can o o4 o°°oo 10 range, for example, from 5 to 120 hours; the temperature can oo ooo be changed from 20 to 220*C and the pressure can be 0o o0 o0° simultaneously reduced from atmospheric pressure to 0.02 kPa con o or less.

According to a preferred way of operating the polymerization process of the present invention, cyclic dimers of lactic or glycolic acids, called lactides or 4 0 glycolides, or mixtures thereof, are employed in the presence S0 of the diol.

The lactide employed may be optically pure °oO 20 lactide or racemic DL lactide.

This determines the stereoregularity of the polylactic obtained. Thus, in the case of the lactide, a semicrystalline polymer is obtained, whereas with the DL lactide, an amorphous polymer is obtained.

The polymerization is performed in bulk in the presence of a catalyst.

10 The reaction time, temperature and pressure conditions are the following: reaction time of between 3 and 120 hours, temperature of between 110 and 180*C, and pressure below 0.02 kPa.

The molecular weight, polydispersity and crystallinity characteristics of the polymer obtained according to either process are controlled by the Sexperimental conditions and the composition of the starting monomers.

c) a diisocyanato compound of formula: S" O=C=N-B-N=C=0 (6) in which B symbolizes a divalent organic or organosilicon radical, which may contain a block of formula (1 b) above.

In the case where B is a divalent organic radical, it o contains from 3 to 30 carbon atoms, preferably from 4 to S carbon atoms.

As organic diisocyanato compounds it is possible to employ, in particular: 1,2-diisocyanatopropane, o- 1 1,2-diisocyanatobutane, 1,3-diisocyanatobutane, 1,6-diisocyanatohexane, 1,3-diisocyanatobenzene, 1,4-diisocyanatobenzene, 2,4-diisocyanatotoluene, 11 1. a 2, 6-diisocyanatotoluene, 2, 4-diisocyanatoxylene, 2, 6-diisocyanatoxylene, 3,3 '.-diisocyanatobiphenyl, 4,4 '-diisocyanatobiphenyl, 3,3' -diisocyanatodiphenylmethane, 4,4 '-diisocyanatodiphenylmethane, 4,4 '-diisocyanato-3 ,3 '-dimethyldiphenyl, 4,4' -diisocyanato-3 -dimethyldiphenylmethane, 4,4' -diisocyanatodiphenylethane, 3, 3 -diisocyanatodiphenyl ether, 4, 4 -diisocyanatodiphenyl ether, 33'-diisocyanatodiphenyl suiphone, -4,4 '-diisocyanatodiphenyl suiphone, -diisocyanatobenzophenone, -4,4 '-diisocyanatobenzophenone, -3,3 '-diisocyanatodicyclohexylmethane, -4,4 '-diisocyanatodicyclohexylmethane, -4,4 '-diisocyanato-3 ,3-dichiorobiphenyl, -diisocyanato-3, 3 -dimethoxybiphenyl.

The diisocyanates which are preferably employed are the following: 1, 6-diisocyanatohexane, 2, 4-diisocyanatotoluene, 2, 6-diisocyanatotoluene, a~ I a I I a Ia I I I

I

14I4 20

I

12 2,4-diisocyanatoxylene, 4,4'-diisocyanatobiphenyl, 4,4'-diisocyanatodiphenylmethane, 4,4'-diisocyanatodiphenyl ether, 4,4'-diisocyanatodiphenyl sulphone, 4,4'-diisocyanatobenzophenone, 4,4'-diisocyanatodicyclohexylethane, o The copolymer according to the invention is obtained .o 10 by polyaddition, preferably in an organic solvent, of the o starting materials b) and c) in quantities such that the So°o molar ratio of the isocyanate groups to OH groups is between 0 aoo 0.95 and 1.05.

The preferred solvents are aliphatic or aromatic o"°o 15 halogenated hydrocarbons. Among these, it is recommended to 000 o employ o-dichlorobenzene or tetrachloroethane. The o 0 polyaddition reaction can be carried out in the absence or in 0 0 o the presence of catalyst. Dialkyltin dicarboxylates like dibutyltin dilaurate can be mentioned as recommended catalysts.

The polyaddition reaction is carried out simply by heating the reactants to a temperature which is generally between 100 and 180 0

C.

According to a preferred embodiment, the polyester b) is introduced into a solvent fraction which is heated to a temperature of between 100 and 180 0 C, and the catalyst and 13 the starting materials a) and c) are added with the remainder of the solvent. The end of the reaction is checked by chemical determination of the residual isocyanate functional groups. The copolymer is recovered after solvent removal.

In the case where in the compound B is an organosilicon radical, B may comprise a diorganosiloxane block of formula (1 In this case, the copolymer according o0 o to the invention may comprise no diorganopolysiloxane block S o of formula 0o° 0 The compounds comprising a block of formula (1 b) can be obtained by a hydrosilylation reaction between an a,- (dihydro)polydiorganosiloxane with an olefinic compound bearing an isocyanate group. Such compounds are described in particular in EP-A-77,744, mentioned as reference.

.00 15 Since the corpound contains a diorganopolysiloxane block, it is therefore not necessary to employ 8 8. the starting material a).

In this case, it is recommended to employ the following process for preparing the alternating block copolymers according to the invention: during a first stage, the polyester oligomer b) ot formula is reacted with a molar excess of an olefinic compound bearing an isocyanate group, particularly described in European Patent EP-A-77,744, preferably corresponding to the general formula:

CH

2 =C-E-NCO (7)

I-,

1. i: 14 in which R 2 is chosen from a hydrogen atom and a C:-C6 alkyl radical, E is a hydrocarbon radical free from olefinic unsaturation, containing from 1 to 20 carbon atoms and capable of containing at least one heteroatom chosen from 0 and Si, preferably in an organic solvent in the presence of a tin catalyst such as dibutyltin dilaurate.

The most preferred compounds of formula (7) correspond to the formula: 0 CH 2

=CH-CH

2

-NCO

CH

2

=C(CH

3

)-CH

2

-NCO

CH

2

=CHQNCO

CH

2 =CH-Si(CH 3 2

-CH

2 -0 -NCO o o 0 0 S0 0 o0o 4 0000 o p 0 Q 0 0 0.00 0 40 0 0 0 00 0 00 0 0 0 0000 o o o o o o 1 during a second stage the (bis-a,o-vinyl) polyester 15 oligomer obtained during the first stage is reacted with a diorganopolysiloxane of formula: R1 P H SiO-- Si H RI Ri in in which R 1 and n have the meaning given in formula (1 b) above, in the presence of a catalytically effective quantity of a hydrosilylation Italyst. preferably a platinum catalyst 15 according to a molar ratio SiH of between 0.9 and

CH

2

=C-

R

2 The platinum catalysts employed for carrying out the hydrosilylation reaction of the polymers of formula with the derivative of formula are abundantly described in the literature; among them, there may be mentioned in particular the complexes of platinum and of an organic product described in US Patents US-A-3,159,601, US-A-3,159,602, US-A-3,220,972 O. 10 and European Patents EP-A-57,459, EP-A-188,978 and EP-A-190,530 and the complexes of platinum and of vinylated S. organopolysiloxane which are described in US Patents US-A-3,419,593, US-A-3,715,334, US-A-3,377,432 and US-A-3,814,730.

15 To react the polymer containing SiH of formula (8) with the derivative of formula use is generally made of a quantity of platinum catalyst, calculated as weight of platinum metal, of between 5 and 600 ppm, preferably between and 200 ppm, based on the weight of polymer containing SiH of formula The hydrosilylation reaction can take place 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 60 to 120*C for the time needed for the reaction to be complete. Furthermore, it is desirable -i c; I: i 16 o <t o 4o o 4 4 4444 4 4 445.

44t o 4 4 44 4 ooe o000 ttl

I~

to add the polymer containing SiH dropwise to the derivative of formula in solution in an organic solvent.

The degree of progress of the reaction is checked by determining the residual SiHs with alcoholic potassium hydroxide, and the solvent is then removed, for example by distillation under reduced pressure.

The crude oil obtained can be purified, for example, by a pass on a silica absorbent column.

The copolymers according to the invention are 10 thermoplastic and hydrolytically degradable and may form the whole or part of hydrolytically degradable objects.

They have sufficient mechanical properties to exist at room temperature in the form of hydrolytically degradable objects of any shape containirg an active substance, 15 generally in a concentration of between 0.1 and 40 by weight, which can be especially a medicinal active substance, a plant-protection product (such as a fertilizer, an insecticide, a pesticide, a fungicide or a herbicide), a plant embryo, a plant seed, a catalyst, a cosmetic product, and the like.

In the case where the active substance is encapsulated, this concentration can range f-Jd 0.1 to 99 by weight, depending on the encapsulation process employed.

Among the medicinal active substances there may be ae o 0 4 I t 44444I Is tt mentioned: antiinflammatory agents such as: i 17 ketoprofen, ibuprofen, indomethacin, hormonal agents such as: steroids, pept.de hormones, antitumour agents, antibacterials such as: penicillins, cephalosporins, Sstreptomycins.

The copolymers according to the invention therefore exhibit sufficient mechanical properties for controlled release applications. Furthermore, they are very easy to 15 shape at low temperature. They can be employed for the controlled release of macromoletular active substances, which is not possible by means of simple silicone polymers.

Another advantage of the copolymer according to the invention is that it makes it possible to encapsulate an S' 20 active substance by successive skin formations employing a process comprising at least one stage of spraying a skinforming composition containing the copolymer in solution in an organic solvent or in the form of an aqueous emulsion or dispersion, followed by at least one drying, that is to say evaporation of the organic solvent and/or of water. In this case, the concentration of active substance in the capsule 18 may range from 40 to 99 by weight relative to the total weight of the object.

An example of such a process is the process known by the name of "spray coating", according to which the particles to be encapsulated are stirred (fluidized) by a gaseous stream which also ensures the drying, that is to say the evaporation of the organic solvent and/or of water.

The skin-forming composition is sprayed by one or 0@ more nozzles situated in different regions of the reactor, depending on the type of process employed, for example above, inside or at the base of the cloud of particles.

Thus, this spraying is at the base of the fluidized bed of particles in the Wurster process. The Wurster spraying technique is described in detail in Patents US-A-2,799,241, 15 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 S. EP-A-188,953.

Accordinc to other processes which can be employed within the scope of the present invention, the stirring of the particles of active substance is produced mechanically, for example by means of a rotary drum or tray, and the gaseous stream serves only for drying.

To obtain an effective encapsulation it is recommended that the coating skin should have a mean thickness of between 1 and 200 Am, preferably between 5 and 100 Am.

II~__

19 A person skilled in the art, using routine tests can, of course, easily adapt the thickness of the coating to the nature of the active substance, to its surface state, to the nature of the copolymer employed, to the desired kinetics of release of the active substance, and so on.

It is also possible to encapsulate the particles, for example, by a first copolymer capsule according to the invention and then to produce a second layer of different oo nature and by a different process, for example made of a 0000 10 natural or synthetic wax.

0The medicinal active substances encapsulated by the said copolymers also form part of the invention. They exhibit highly advantageous release kinetics when administered to man.

S 15 The majority of the medications have an "in vivo" a0ooo :0:o activity profile and for this profile to be attained it 0000 requires a specific pharmaceutical formulation, particularly ~Og 0o when a carefully controlled plasma concentration is sought after. The availability of the medication over long periods 20 and the ease of ambulatory treatment also introduce requirements with regard to the nature of the excipients of formulation. Every patient prefers to take his medication once daily rather than a number of times over the same period. In addition, the release of the active substance must take place as uniforr-ly as possible, especially in the case of analgesics, to protect the patient from painful crises 20 during the latency periods when the active substance is not active. The encapsulated active substances of the invention meet this objective.

The following examples illustrate the invention: GPC means gas permeation chromatography, DSC means differential calorimetry, Mn means number-average molecular mass, Mw means weight-average molecular mass, SIp means polydispersity index.

0 00 ooo 10 The tensile strength is measured in MPa 00 according to AFNOR standard T 46 002.

0ooo ooo The elongation at break E/B is measured in per cent .0 0 according to AFNOR standard T 46 002.

Tg is the glass transition temperature.

25 Mp is the melting point.

o oo 00 4f denotes the phenyl radical.

SDL PLA: racemic polylactic.

o o° Reference will be made to the attached drawing in which Figure 1 shows, as ordinate, the of ketoprofen 20 released as a function of time (as abscissa and in days) in 0 0 the case of Examples 13 and 14, Figure 2 shows the of nicergolin released in the case of Examples 16, 17 and 18 and Figure 3 gives the of bovalbumin released in the case of Examples 19, 20 and 21.

i. 'ii~ a~-**"rr&Y~L(SLU~ ~ii r;u~x~ Pna~xl-il---- 21 EXAMPLE 1: la. Preparation of a polyester of formula: HO CH C 0 CH 2 CH 0 C CH OH I t CH3 0 0 CH 3 Lpl Jrl 291 g of lactide freshly recrystallized from ethyl acetate, 8.2 ml of ethylene glycol distilled under vacuum and 0.510 g of tin octanoate are charged into a 1-litre reactor. A vacuum of less than 0.02 kPa is o oo o0 established in the reactor and heating to 120*C is then applied for 48 hours.

After cooling, the reaction product is dissolved in 500 ml of CH 2 Cl1 and is then purified by running this solution into water at 65"C with vigorous stirring. After solvent evaporation, 268 g of polymer, dried under vacuum, are recovered, exhibiting the following characteristics: Tg: Mp: 78*C, Mn: 2010, OH functional group content- 0.97 equivalents per kg.

lb. Preparation of the diisocyanate bridge of formula: ABA with A: CH3 OC OCH2 Si CH2 CH 2 CH3 Processes of this type are described in the following 22 and B: Si 0 Si CH3 H3 The following are charged into a 500-ml glass reactor fitted with a stirrer and a reflux condenser: 40 ml of toluene, 38.7 g (0.166 moles) of an isocyanatosilane of So 0 0000 o oO 0 00 oo o a oa o oo 0 0 0 000 0 formula:

CH

3 CH2 CH Si CH 2 0 CO

CH

3 0000 oo 0 000ao 0 6 0 a i t whose preparation is described in Example 8 of US-A-4,088,670, 10 mg (calculated as platinum metal) per 1 kg of reactant of chloroplatinic acid in solution in 2-ethylhexanol.

The mixture is stirred and heated to 70"C and 75 g of an a,-(dihydro)polymethylphenylsiloxane of formula: H Si 0 Si H CH3 CH3 Sn Mn 900 in solution in toluene are run in over 35 minutes. The 23 mixture is then stirred and heated to 90°C for 4 hours. The reaction mass is then devolatilized at 120°C under reduced pressure (0.07 kPa).

The fluid obtained is clear and colourless. A chemical determination of the isocyanate functional groups enables a mass Mn of 1515 g/mole to be calculated, that is 1.32 equivalents of isocyanate functional groups/kg.

Ic. Preparation of the copolymer: o °o 15.2 g of oligomer obtained in Example lb., 20.6 g of 10 the polyestar obtained in Example la. and 45 ml of odichlorobenzene are charged into a 100 ml glass reactor fitted with a stirrer and a reflux condenser.

0 00 0 0 0 .0 0. The polyester is charged first with a part of the solvent. The mixture is stirred and heated until a homogeneous solution is obtained. The silicone oil, 00e previously diluted with the remainder of the solvent, is then 00 0 added to the mixture. 18 mg of di-n-butyltin dilaurate are 0 00 then introduced to catalyse the reaction. Stirring at 125°C is maintained for 5 hours 10 minutes. A check is made by 20 chemical determination that the reaction mixture no longer contains any detectable isocyanate functional groups. The solvent is removed in a rotary evaporator at 130°C under a pressure of 0.133 kPa.

34.35 g c2 copolymer are obtained and are redissolved in 40 ml of dichloromethane and are precipitated in 500 ml of hexane cooled to 24 The copolymer is separated off and then dried in the oven at 100"C at reduced pressure.

The dry product is reground to give a fine powder which gives a rigid and transparent solid when it is compression moulded.

The qcantity of powder obtained represents a mass of 30.8 g.

Characterization of the purified copolvmer: 0 0 0 o 0 C inherent viscosity (in chloroform at 10 C 3 g/dl): 0.17 dl/g, o a molecular masses (by GPC, polystyrene calibration): o Mn: 4620 g/mole; Mw: 16,400 g/mole, glass transition temperature (by DSC at after a first heating to 180*C: Tg 15 EXAMPLE 2: o The following are charged into a 100-ml glass reactor fitted with a stirrer and a reflux condenser: o o 10.3 g of the polyester of Example la., 5.4 g of functionalized polymethylphenylsiloxane o 0 20 oil of formula: HO(CH2)3 Si 0 Si (CH2)3--OH CH3 LH3 exhibiting an OH functional group content equal to 1.84 equivalents/kg, ,U i i, i iii.. i r Mi M i iil-lii>M-iw -i t rf^ t i tr i~ i fT-" r^ l fT-f 25 1.7 g of 1,6-diisocyanatohexane of formula:

OCN-(CH

2 6

-NCO

25 ml of o-dichlorobenzene.

The polylactic diol is charged first with a part of the solvent. The mixture thus formed is stirred and heated using an oil bath until the polyester has dissolved completely and a homogeneous solution has been obtained. The functionalized silicone oil and 1,6-diisocyanatohexane, mixed 0° 0 beforehand and diluted with the remainder of the solvent, are U 00 0°0° 10 then added to the reactor in their turn.

0 00 o° o The mixture is finally catalysed by introducing 12 mg St4 6 0 o of dibutyltin dilaurate.

After 6 hours 15 minutes' stirring at 120'C a check is made by a chemical determination that the reaction mixture 15 no longer contains any detectable isocyanate functional 0 0 oo groups.

After removal of the solvent in a rotary evaporator r0 (at 130*C, at a pressure of 0.133 kPa), 17.3 g of a flexible and transparent, almost colourless material are obtained.

20 Characteristics: inherent viscosity (in chloroform, at C 3 g/dl): 0.30 dl/g molecular masses (by GPC, polystyrene calibration): Mn: 4870 g/mole; Mw: 38,210 g/mole, glass transition temperature (by DSC) 10 softening temperature: 60/70°C (Kofler bench) -26mechanical properties at 20'C: the copolymer was placed in a mould and compressed to 100 kPa at 80*C. A moulded plaque 1 mm in thickness was obtained, from which type H 3 test specimens were cut out.

Measurements of mechanical properties were carried out with an instrument of Instron 1 026 type on 9 H 3 test specimens: tensile strength: 1.17 0.25 MPa, elongation at break: 360 76 EXAMPLE 3: The following are charged into a 100-ml glass reactor fitted with a stirrer and a reflux condenser: 10.3 g of polyester obtained in Example la.

13.0 g of a functionalized polydimethylsiloxane oligomer corresponding to the following formula: 40'4

C

H3 CH 3 HO -(CH2)3 Si 0 Si (CH 2 )3-OH I I CH3 CH 3 and characterized by an OH functional group content equal to: 0.77 equivalents per kg, 1.7 g of 1,6-diisocyanatohexane, 27 ml of o-dichlorobenzene.

The polylactic diol is charged first with a part of the solvent. The mixture is stirred and heated with the aid I t~ -i ii~~~

~J

27 o 0 o o +O a 0 fl0 D y o i of an oil bath until the polyester has dissolved and a homogeneous solution has been obtained.

The polysiloxane oligomar and tne diisocyanate, which are premixed and diluted with the remainder of the solvent are then introduced in their turn into the reactor.

Lastly, 12 mg of dibutyltin dilaurate (catalyst) are added. Heating to 120*C is maintained with stirring for 6 hours 15 minutes.

After having checked that the reaction mixture no 10 longer contains any detectable isocyanate functional groups, the solvent is evaporat.d off in the rotary evaporator (130-C, 0.133 kPa), 22.4 g of a very flexible (elastomeric), opaque, slightly coloured material are thus obtained.

15 Characterization: inherent viscosity (in chloroform, at C 3 g/dl): 0.33 dl/g molecular masses (by GPC, polystyrene calibration): Mn: 4330 g/mole; Mw: 44,770 g/mole, 20 softening temperature: approximately 60*C (on a Kofler bench) EXAMPLE 4: The fo'lowing are charged into a 100-ml glass reactor fitted with a stirrer and a reflux condenser: 15.79 g of the polyester prepared in Example la.

8.25 g of a functionalized polymethylphenylsiloxane 0 490 04 01 0 0 1..

0 1 of a hydrosilylation italyst, preferably a platinum catalyst 28 corresponding to the following formula: HO -(CH2)3 Si 0 -Si (CH2) 3

OH

I I CH3 CH3 -m and characterized by a hydroxyl functional group content equal to: 1.82 equivalents per kg, 2.55 g of 1,6-diisocyanatohexane, 30 g of ortho-dichlorobenzene.

o o0 The polyester is charged first into the reactor with o 0 o, 0 a part of the solvent. The mixture thus formed is stirred and o000 0 0 0 S0 heated with the aid of a thermostated oil bath. A homogeneous o o, solution is obtained.

000 0 The functionalized polysiloxane and the 1,6diisocyanatohexane, which are premixed and diluted with the °0000 remainder of the 30 g of solvent are then introduced.

090 0"0. Lastly, the temperature of the reaction mixture being 0000 about 110*C, 0.0132 g of dibutyltin dilaurate (catalyst) are added.

The progress of the reaction is followed by 0 o 0 determining the isocyanate functional groups.

After two hours' heating at 120°C, the reaction medium is placed in a rotary evaporator at 130-140 0 C under a pressure of 0.133 kPa to remove the solvent.

The product obtained is dissolved in dichloromethane, precipitated in hexane and dried in the oven for 15 hours.

l~

I

29 21.0 g of a transparent and thermoplastic (fairly stiff), slightly coloured material are obtained.

Characterizations: inherent viscosity (in chloroform, at 25 0

C,

C 1.5 g/dl): 0.49 dl/g molecular masses (by GPC, polystyrene calibration): Mn: 7550 g/mole; Mw: 61,720 g/mole, softening temperature: 60-70C (on the Kofler bench), o 10 mechanical properties at the product was placed in a mould heated to 170"C and compressed to 80 MPa.

A moulded plaque 0.5 mm in thickness was thus obtained, from which type H 3 test specimens were cut out.

Mechanical properties were determined with the aid of an Instron 1 026 model apparatus: tensile strength: 9.7 MPa, elongation at break: 87 S EXAMPLE The following are charged into a 100-ml glass reactor 0 fitted with a stirrer and a reflux condenser: 4 4 6.27 g of the polyester prepared in Example la.

13.21 g of a functionalized polymethylphenylsiloxane oligomer corresponding to the following formula: 4-~~9i HO -(CH 2 3 Si 0 i (CH 2 3

-OH

CH

3 CH 3 -m and characterized by a hydroxyl functional group content of: 1.82 equivalents per kg, 2.55 g of 1,6-diisocyanatohexane, 25 g of ortho-dichlorobenzene.

The polyester is charged first into the reactor, with 1 a part of the solvent. The mixture thus formed is stirred and o heated with the aid of a thermostated oil bath. A homogeneous S solution is obtained.

i' The functionalized polysiloxane and the Sceo 10 1,6-diisocyanatohexane, which are premixed and diluted with 0 I 0" the remainder of the solvent are then introduced in their turn into the reactor.

0.010 g of dibutyltin dilaurate (catalyst) are then 0000 added, while the temperature of the mixture is approximately 110*C.

0 The progress of the reaction is followed by determining NCO functional groups.

The reaction mixture is thus stirred at 120"C for 1 0 0 hour 30 minutes.

The solvent is then removed in a rotary evaporator at 130-140*C at a pressure of 0.133 kPa.

The polymer is then redissolved in 25 ml of dichloromethane and precipitated, with energetic stirring, in ~---tn;z~s~iaarwra- I- I 31 250 ml of hexane.

The copolymer collected is then dried in the oven, under reduced pressure (13.3 kPa), at 19.9 g of dry product are thus obtained.

It is a very flexible and thermoplastic, transparent, slightly coloured material.

Characterizations: inherent viscosity (in chloroform, at C 1.5 g/dl): 0.27 dl/g 10 molecular masses (by GPC, polystyrene calibration): Mn: 7570 g/mole; Mw: 33,890 g/mole, mechanical properties at the product was placed in a mould heated to 150°C and compressed to 80 MPa.

A moulded plaque 0.8 mm in thickness was thus obtained, from which type H 3 test specimens were cut out.

4 0 0 Mechanical properties were determined with the aid of an Instron 1 026 model apparatus: tensile strength: 0.4 MPa, elongation at break: 1375 EXAMPLE 6: e a The operating procedure of Example 5 is reproduced precisely, except that the following are charged into the reactor: polylactic diol: 10.75 g NCO-functionalized polymethylphenyl 32 siloxane: 10.88 g 1,6-diisocyanatohexane: 2.55 g ortho-dichlorobenzene: 30 g dibutyltin dilaurate (catalyst): 0.012 g.

22.2 g of dry product, reprecipitated in hexane, are obtained.

Characteristics of the copolymer: same measurement conditions as in the case of Example inherent viscosity (in chloroform, at 10 C 1.5 g/dl): 0.30 dl/g, molecular masses (by GPC, polystyrene calibration): 0 S® Mn 7610 g/mole; Mw 36,660 g/mole, S o mechanical properties at a 6 the product was placed in a mould heated to 170°C and compressed to 80 MPa.

A moulded plaque 0.5 mm in thickness war thus obtained, from whict H 3 type test specimens were cut out.

Mechanical properties were determined with the aid of an Instron 1 026 model apparatus: tensile strength: 7.5 MPa, elongation at break: 212 EXAMPLE 7: 7a. Preparation of a bis(a,o-vinyl) polyester: 165g of the polyester prepared in Example la, 450 g of toluene and 56 g of allyl isocyanate are charged into a 1-litre reactor.

33 The reaction mixture is heated to 70 0 C for 2 hours 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 an alternating block copolvmer: 35.3 g of an a,,-dihydropolysiloxane of formula:

CH

3 CH 3 H SiO Si H

CH

3

CH

3 S-32 S' in 200 g of toluene are introduced into a dropping funnel.

25 g of bis(a,--vinyl) polyester prepared in Example 10 7a., 200 g of toluene and 49 mg of platinum catalyst

(H

2 PtC16), calculated as platinum metal, are introduced into a i-litre reactor.

0 0 The solution in the reactor is heated to the reflux temperature of toluene, while the c.otents of the dropping 15 funnel are introduced dropwise over a time t.

The disappearance of the SiH functional groups in the 00...0 course of reaction is followed by IR spectrum (characteristic o 0 absorption band at 2100 cm~l).

The reaction is stopped when the SiH functional group concentration remains substantially constant.

The toluene is removed in a rotary evaporator at at a pressure of 0.133 kPa.

a 0 o 4 34 g of block copolymer are obtained and are redissolved in 600 ml of tetrahydrofuran and are precipitated in 5000 ml of distilled water.

The copolymer is separated of f and then dried in the oven at 100 0 C under reduced pressure.

The dry product is reground to give a fine powder exhibiting the following characteristics: Mn 25,100 q/mole, Ip 2.2.

0 EXAM"PLES 8 TO 11: The operating procedure of Example 7 is repeated precisely, except that the quantity Q (in mg) of platinum catalyst and/or the reaction time t (in h an~d min) are modified.

The results obtained are collated in Table 1 below: TABLE 1 Example Q t Mn Ip (mg) min) g/mole 0 7b. 49 30 min 25,100 2.2 8 21 30 min 20,600 1.7 9 12 1 hour 15,000 1.85 6 4 hours 11,000 1.6 11 6 25 hours 14,800 1.7 *000 4040 8000 0 0 0 00 00 0 0 *4100* 0 0 I 35 EXAMPLE 12: synthesis of a silicone/lactic copolymer: A The following are charged into a 100-ml glass reactor fitted with stirring and a condenser: 16.84 g of functionalized polylactic corresponding to the formula and to the characteristics which follow: HO CH C 0 CH2-C2 O-C-CH OH CH3 0 CH y Tg Mn 2000 OH functional group content: 0.95 equivalents per kg 10 g of functionalized polydimethylsiloxane 10 corresponding to the formula and to the characteristics which follow: CH3 CH3

HO-(-CH

2 0-Si (CH2-)30H CH3 CH 1 t i l 44 e 1001 0S 4 0040 o 'o 44 i 0 4 0 o 04 4 4 4o~ 00 00 OH functional group content: 1.6 equivalents per kg 2.7 g of 1,6-diisocyanatohexane, 30 ml of o-dichlorobenzene.

15 The polylactic diol is charged first with a part of the solvent. The mixture is stirred and heated with the aid of an oil bath until the polyester has dissolved and a homogeneous solution has been obtained.

The polysiloxane oligomer and the diisocyanate, which are premixed and diluted with the remainder of the solvent, -36are then introduced in their turn into the reactor.

Lastly, 12 mg of dibutyltin dilaurate (catalyst) are I added. Heating is maintained at 120*C with stirring for 4 hours 30 minutes.

After checking that the reaction mixture no longer contains any detectable isocyanate functional groups the solvent is evaporated off in the rotary evaporator (130°C, 0.133 kPa).

28.2 g of a very flexible (elastomeric), transparent, slightly yellow material are thus obtained.

The product obtained is dissolved in 30 ml of methylene chloride and the polymer is precipitated in 300 ml of hexane at 10*C. After recovery and drying in the rotary evaporator (35°C, 0.133 kPa), 24.6 g of copolymer are recovered.

Characteristics: 20 inherent viscosity (in chloroform, at 25*C, C 3 g/dl): 0.21 dl/g, molecular masses (by GPC, polystyrene calibration): Mn 6000 g/mole; Mw 22,000 g/mole, Tg -120*C; Tg 2 (Tg 1 relates to the silicone portion and Tg 2 to the lactic portion'.

EXAMPLE 13: Release of ketoprofan A solution is prepared, containing: 1~i 37 o~ Q o a.

*044 a, a I 4 1 25 ml of chloroform, 1.7 g of Ketoprofen 4.1 g of copolymer A obtained in Example 12.

The solvent is evaporated off and the residue is dried under vacuum. The product is then recovered and compacted at 70°C to obtain a film 1.5 mm in thickness. The latter is placed in a vessel thermostated at 37°C, containing 1 litre of buffer solution of the following composition:

KH

2

PO

4 6.8 g 0 H 2 0 1000 g NaOH (4N) to pH 7 and with gentle stirring.

The kinetics of elution of the ketoprofen are followed by UV determination at 261. nm.

5 The results obtained and plotted in Figure 1 show a release of diffusion-controlled type during 15 days, followed 0 by a release of the remainder of ketoprofen by erosion of the copolymer.

In Figure 1, curve relates to Example 13.

.44* EXAMPLE 14: 0 Release of ketoprofen The procedure is as in Example 13, but with the copolymer A replaced with an amorphous polylactic DL-PLA of following characteristics: Mn 18,300 Mw 39,800 I rz~- r-;r :i 38 Tg The release of the ketoprofen produced in the conditions of Example 13 shows, in Figure 1, a slow release of the ketoprofen at the beginning (latency period), which accelerates after 15 days' elution under the effect of the erosion of the polylactic.

In Figure 1, the plotted curve relates to Example 14.

In contrast to Example 13, no release of the diffusion-controlled type is observed here. 10 o 0 0 r 0 000 0 6 0 0B S000 B a o o O 00 00 s6 66 0 0 00.006 0 -39- EXAMPLE Release of ketoprofen The procedure is as in Example 13, but with the copolymer A replaced with a silicone elastomeric composition capable of being crosslinked by polyaddition reaction using platinum and marketed by Rh6ne-Poulenc under the trade name Rhodorsil RTV 141.

The presence of ketoprofen inhibits the crosslinking of the silicone and does not make it possible to obtain a finished product in the solid state after heating to 100°C for several hours.

i Comparison of Examples 13, 14 and 15 shows that the copolymer A makes it possible to obtain the advantages of the silicone (release of ketoprofen by diffusion) and of the polylactic (release by erosion of the material), while avoiding the disadvantages linked with problems of crosslinking of the silicone and of the latency period of the

DL-PLA.

EXAMPLE 16: Release of Nicerqolin S' The procedure is identical with that of Example 13, the ketoprofen being replaced with Nicergoline to obtain a film 1.5 mm in thickness.

200 mg of this film are taken and are placed in a vessel thermostated at 37°C, in the absence of light, containing 1 litre of buffer solution of the following i 40 composition: Na 2

HPO

4 .12H 2 0 8.05 g NaH 2

PO

4 .2H 2 0 2.03 g

H

2 0 1000 g NaOH 4N to pH and with gentle stirring.

The kinetics of release of the Nicergolin® are followed by UV determination at 288 nm.

The results obtained [curve and plotted in Figure 2 show that the release of the Nicergolin takes place over 70 days, completely and at an apparently constant rate.

EXAMPLE 17: Release of Nicercolin The procedure is as in Example 16, but with the copolymer A replaced with an amorphous polylactic DL-PLA which has the following characteristics: Mn 29800 Mw 84700 Tg The elution of the Nicergolin performed in the conditions of Example 16 shows, in Figure 2 [curve a very slow release during a latency period of 21 days. This is characteristic of the thorough degradation of the DL-PLAs.

After that, the Nicergolin is released much more quickly.

EXAMPLE 18: Release of Nicerqolin 41 The procedure is as in Example 16, but with the copolymer A replaced with a silicone elastomeric composition capable of being crosslinked by polyaddition reaction using platinuam and marketed by Rh6ne-Poulenc under the trade name RhodorsiP RTV 141.

The crosslinking of RTV 141 is performed at 120*C for one hour, and no compacting is needed to obtain a film 1.5 mm in thickness.

0o 0° The elution of Nicergolin performed in the 0 oo 10 conditions of Example 16, shows in Figure 2 [curve an 0 01 o apparently constant release of Nicergolin during at least o oo days, but at a slow rate.

Comparison of Examples 16, 17 and 13 shows that, in the same conditions, the copolymer A permits the total release of the active substance and at a much 'ister rate 0 00 0 oo.. than that permitted by a pure silicone elastomts..

00 0 Furthermore, the latency period linked with the use 00 00 0 of DL-PLA is avoided.

EXAMPLE 19: 20 Release of Bovalbumin (BSA): The procedure is identical with that of Example 13, the ketoprofedr being replaced with ground BSA with a mean particle size equal to 35 Am. The film obtained after compacting at 70°C is placed in a vessel thermostated at 37 0 C, containing 500 ml of buffer solution of the following composition: 1111 -42 H20 1000 g Na 2

HPO

4 .12H 2 0 8.05 g NaH2PO4.2H20 2.03 g NaOH, 4N to pH 7.4 and with gentle stirring.

The kinetics of release of the BSA are followed by UV determination at 278 nm.

The results obtained and plotted in Figure 3 [curve ooo show that more than 80 of the BSA is released in the S 1 0 space of a few days.

o EXAMPLE 0000 S0 0 Release of BSA: 0o0. The procedure is identical v th that of Example 19, but with the copolymer A replaced with an amorphous polylactic DL-PLA which has the following characteristics: ao Mn 29,800 o Mw 84,700 Tg The elution of BSA, performed in the conditions of 20 Example 1. shows, in Figure 3 [curve a fast release of 0 0 the latter over 6 days. The release profile obtained is like that obtained with the copolymer A.

EXAMPLE 21: Release of BSA: The procedure is as in Example 19, but with the copolymer A replaced with the silicone elastomeric 43 composition employed in Example 18. The crosslinking takes place at 120*C for 1 hour and the film obtained is not compacted.

The elution of BSA, performed in the conditions of Example 19, shows, in Figure 3 [curve that the latter is not released. In fact, the BSA, which is a macromolecule (molecular weight 63,000) cannot diffuse through the crosslinked silicone elastomer.

o Comparison of Examples 19, 20 and 21 sho w that, in 10 contrast to a crosslinked silicone elastomer, the copolymer A 0 49 permits the release of macromolecules of the BSA type, with o0 release profiles close to those obtained with a commercial 0Q 0 lactic solution.

EXAMPLE 22: o0 15 Use of a membrane made of polysiloxane/poly-L-lactic acid multiblock thermoplastic copolymer for the controlled release of ketoprofeng ?a 1. Preparation of the copolymer: an a,-hydroxylated poly- L-lactic oligomer prepared in the following conditions is 20 employed: The following are charged into a 1-litre reactor fitted with stirring and a reflux condenser and purged with a stream of nitrogen: 288 g of crystallized L-lactic dimer, 9 g of distilled ethylene glycol, 500 ml of distilled toluene, 44 0.5 g of stannous octoate.

This mixture is heated under gentle reflux, with stirring, for 5 hours.

It is then concentrated under reduced pressure, at about 80-90 C, in a rotary evaporator.

After dilution with 150 ml of dichloromethane, the solution is precipitated in 2 litres of demineralized water at 65"C. After filtration and drying overnight, under reduced o o pressure, at 45°C, 297 g of a white solid are collected.

0o0 10 Characterization of the product: 0000 S. determination of the (total) OH functional groups: o 124.8 milliequivalents/100 g, a 00 oo00 determination of the C02H functional groups: 7.6 milliequivalents/100 g.

The copolymer is then prepared in the following Souoo 0 manner: The following are charged into a 500-ml three-necked glass reactor fitted with a stirrer, a reflux condenser and a dropping funnel: S20 130 g of the poly-L-lactic oligomer described 060000 0 a0 above, 94.7 g of an a,--hydroxypropylated poly(dimethylsiloxane) oligomer containing 161 OH milliequivalents/100 g, 25.62 g of 1,6-hexane diisocyanate, 230 ml of ortho-dichlorobenzene.

-s~-3qaolp 45 The mixture is stirred and heated. At about 110"C, 0.125 ml of Stavinor 1200 SN (catalyst) is added. The heating is then continued with stirring, at 120*C, for 6 hours. Part of the solvent is then removed in the rotary evaporator at 120-130*C, at 2 mm Hg. The rest is then diluted with 250 ml of 1,2-dichloroethane, and is precipitated in 3 litres of hexane. After drying in the oven, under reduced pressure, a white solid is obtained (233.6 g).

The product was characterized by gel permeation chromatography (GPC): Mn 12,250 g/mole, Mw 37,990 g/mole (polystyrene calibration).

a) Skin-forming conditions: a Uni-Glatt fluidizedbed skinning apparatus, equipped with a Wurster system, is oo° employed.

350 g of Ketoprofen obtained in the following S° manner, are prepared: Raw materials: 20 Avicel PH 101, FMC (US), Courlose, Courtaulds Acetate Ltd (GB).

ketoprofen Rh6ne-Poulenc Ltd (GB).

The granules were prepared according to an extrusionspheronization process. 3 kg of ketoprofen were mixed with 965.6 g of Avicel PH 101 in a Hobart planetary mixer at a speed of 1. This powder mixture was granulated with 2363 g of -i Y~UY~ F -i*~u-~iri"m~ (4 4 6 4a 44 4 t 4 t

II

*It 4( I 44 440004 46 a solution of Courlose at a concentration of 1.5 for 2 minutes. The wet mass was extruded in a Fuji Paudal AXDCS-700 apparatus, marketed by Russel Finex. This apparatus was fitted with a grid pierced with holes 1 mm in diameter and 1 mm in thickness. The cylindrical extruded bodies were introduced into a machine for rolling spherical granules (JP Caleva Spheronizer) for 3 minutes and at a speed of 500 revolutions per minute. They were then screened in an apparatus of the Fritsch Sieve Analyser type, so that their size would be between 800 and 1400 gm.

The apparatus is charged with 350 g of ketoprofen minigranules.

A solution prepared with the following is sprayed: 39 g of copolymer of polysiloxane and of poly-L-lactic acid, 707 ml of 1,2-dichloroethane Prolato Rectapur-.

The spraying conditions are as follows: fluidization air flow rate: 72 m 3 /h, fluidization air temperature: 20 spraying air pressure: 1.5 bar, spraying air temperature: room, flow rate of coating solution: 3 ml/min.

Samples of coated granules are taken from the apparatus after spraying periods corresponding respectively to the calculated proportions of coating material of 3.6 to (tests A, B, C).

i -1 1 47 b) Kinetics of release of ketoprofen in a buffer medium (pH at 37°C: These three samples were subjected to the following release test: Description of the test: 6 g of granules and 1 litre of pH 6.6 solution are charged into a 1-litre glass reactor fitted with a stirrer and heated with a water bath thermostated at 37"C.

The buffer solution employed was prepared in the following 0 manner: 0 00 ao 4 a.

a a aa 1 4 9 a a a a I 1 o I dissolving 68 g of potassium dihydrogen phosphate

(KH

2

PO

4 in 10 litres of demineralized water, adjustment of the pH to 6.6 by running in a N sodium hydroxide solution.

The kinetic curves were plotted from ketoprofenB determinations performed at 260 nm on samples of the liquid phase, with a Philips UV/visible spectrophotometer of the Pye Unicam PU 8600 type.

The rate of stirring of the granule suspension was 300 rev/min.

The results of these tests are presented in Table 2 below.

4* I, 48 COATING OF KET0PR0FEN(D Kinetics at pH 6.6 and 37*C KETOPROFENO released 00 0 o 0 0 o 00 0000 o 0 0000 0 0~ 0 #4 0 0 0 *00 I GRANULE UNCOATED A B C Coating ratio 0 1.5 4.6 9.2% minutes 42.0 1 hour 55.0 7.5 3.9 2 hours 70.5 14.2 8.3 4.8% 3 hours 80.0 21.1 12.4 7.1% 4 hours 85.0 28.1 15.6 10.0 5 hours 32.6 21.4 11.9 6 hours 37.6 24.3 14.1 7 hours 96.0 43.2 28.2 16.8 8 hours 47.6 32.6 18.8 16 hours 73.7 54.4 38.5 18 hours 79.3 58.9 43.5 hours 82.1 62.8 46.7 22 hours 87.6 67.5 51.0 24 hours 89.7 70.7 52.5 26 hours 92.8 77.3 55.6 28 hours 94.0 78.6 58.8% hours 94.0 81.2 62.0% 32 hours 94.0 84.2 63.9 hours 98.5 89.9 75.8% 42 hours 90.5 44 hours 92.3 46 hours 94.1 48 hours 94.6% 50 hours 93.7% 52 hours 96.7% 54 hours 0000 0 4 0140 0410

Claims

1. Diorganopolysiloxane-polyester block copolymer having from 1 to 99 by weight of diorganopolysiloxane blocks of average formula: -Y--Si-o Si Y (1) R Jm R and from 99 to 1 by weight of polyester blocks of average formula: -CH C- 0---CH C Z 0 C- CH- (2) H 0 CH3 0 CH 0 o a p °2 P1 r2 in which: 0 0 •O the radicals R, which are identical or different, are monovalent organic radicals, Y denotes a divalent organic radical linked to the silicon o o atom via an Sic bond, o 0 o Z is a divalent hydrocarbon radical of formula: -CH 2 -W-CH 2 o B in which W is a linear, branched or cyclic divalent hydrocarbon radical containing from 1 to 8 carbon atoms or a covalent bond, m is an integer from 1 to 500, Pl, P2, rl and r 2 are each an integer from 0 to 10,000 50 inclusive, such that r 2 P1 P2) is greater than 1 and smaller than 10,000, and the blocks and are joined together by a bridge of formula: 0 0 -0-C-NH-B-NH-C-O- (3) where B is a divalent organic or organosilicon radical which can optionally contain a diorganopolysiloxane block of average formula (ib): C R 1 R 1 I 1 (1 b) ,iO Si R I R 1 Gnun in which R 1 has the same meaning as R and n has the same meaning as m, it being possible for R and RI, and m and n to have identical or different meanings.

2. Copolymer according to Claim 1, in which the radicals R are methyl radicals, W is a covalent bond, which contains from 10 to 90 by weight of diorganopolysiloxane blocks and from 90 to 10 by weight of polyester blocks, and in which (rl r 2 PI P2) is from 10 to 200 inclusive.

3. Modification of a copolymer according to Claim 1 or 2, in which, in the bridge of formula B contains a diorganopolysiloxane block of formula (1 and the diorganopolysiloxane blocks of formula are absent.

4. Process for the preparation of a block copolymer as 51 51 defined in Claim 1 or 2, which comprises reacting together: a) a starting diorganopolysiloxane oligomer of the general formula: R R I I HO Y SiO- Si Y OH (4) im in which the symbols Y, which are identical or different, o"o each denote a divalent organic radical linked to the silicon o c o o° atom by an SiC bond and R and m have the same meanings as in claim 1 or 2. b) a starting polyester oligomer of the average general formula: HO CH C -CH C Z 0 C H 0 C CH -OH o H CH3 CH3 0 H 2oo P 1 2i 00 00 o in which Z, P1, P2, rl and r 2 have the same meaning as in formula and 0 c) a diisocyanato compound of formula: O=C=N-B-N=C=O (6) in which B represents a divalent organic or organosilicon radical which may contain a block of formula (1 b). Process for the preparation of block copolymer as defined in Claim 3, which comprises: in a first stage, reacting a polyester oligomer b) in a second stage reacting the (bis-~a,-vinyl) polyester oligomer obtained during the first stage with a diorganopolysiloxane of average formula: RI RI H SiO- Si H(8) o 0o in which R 1 and n have the meaning given in formula (1 b) above, in the presence of a catalytically effective quantity of a hydrosilylation catalyst, according to a molar ratio SiH of between 0.9 and CH 2 =CH- R 2

6. Process according to claim 5 in which the olefinic compound bearing an isocyanate group has the formula: carbon atoms and capable of containing at least one heteroatom chosen from O and si.

7. Process according to Claim 6, in which the compound of formula is allyl isocyanate. I- I 7 53

8. Process according to claim 5, 6 or 7 in which the reaction between the polyester oligomer and olefinic compound is effected in an organic solvent in the presence of a tin catalyst.

9. Process according to any one of claims 5 to 8 in which the reaction between the (bis-a,c-vinyl) polyester oligomer and the diorganopolysiloxane of formula is effected in the presence of a platinum catalyst. o0 o 10. Process for the preparation of a block copolymer as o defined in claim 1 substantially as described in any one of Examples 1 to 12.

11. A block copolymer obtainable by a process as defined in any one of Claims 4 to

12. A hydrolytically degradable object comprising a Scopolymer as defined in any one of Claims 1 to 3 and 11.

13. An object according to Claim 12, which additionally Scomprises an active substance.

14. An object according to Claim 13, in which the active substance is encapsulated by the copolymer. An object according to Claim 13, in which the active substance is dispersed in a matrix of the copolymer.

16. An object according to any one of Claims 13 to 15, in which the active substance is a medicinal active substance, a plant-protection product, a plant embryo, a plant seed, a catalyst or a cosmetic product. II-- composition: -54-

17. An object according to claim 12 substantially as described in any 3ne of Examples 13 to 22. 04 4 4 4 "4 2, 4 04 4 24 o a 24 2, 2, ,3 a. 24 4 2,2,2,2,2,4 2, 6 4 I 55 3. The steps, features, eempesitienJndcrpud----- disclosed herein or referred to or indica he specification and/or clai is application, individua collectively, and any and all combinations oaytw~o or more of sa-id-s-teps or featura C o o o ~4C o 4 44 I 1 I o oo I I Ito I DATED this FIRST day of MARCH 1990 Rhone-Poulenc Chimie by DAVIES COLLISON Patent Attorneys for the applicant(s) 0010 0 0 4040 0 I I 41 1 01 44 0 4 I I 044004 0 4