FR2661683A1 - MATERIAL CONTROLLED DELIVERY SYSTEM COMPRISING A DISPERSE HYDROSOLUBLE ACTIVE PRINCIPLE IN A MATRIX CONSISTING OF A THERMOPLASTIC SILICONE COPOLYMER - Google Patents

Abstract

The invention relates to a composition characterized in that it is comprised of (A): at least one thermoplastic silicone copolymer non degradable by hydrolysis, (B): one or a plurality of compounds of which at least one is hygroscopic, and dispersed within (A). Utilization of the composition for making matrix systems with controlled release in aqueous media or in humid atmosphere.

Description

MATERIAL SYSTEM OF CONTROLLED RELEASE
COMPRISING AN ACTIVE WATER-SOLUBLE PRINCIPLE DISPERSE IN
A MATRIX CONSISTING OF A THERMOPLASTIC SILICONE COPOLYMER
The present invention relates to a matrix system for controlled release of a water-soluble active principle in an aqueous medium or in a humid atmosphere, comprising said active ingredient dispersed in a matrix consisting of a thermoplastic silicone copolymer that is not degradable by hydrolysis.

 The French patent application No. 89.07831, filed on June 8, 1989 in the name of the Applicant, aims at a matrix system based on thermoplastic silicone whose active principle is an iodine compound.In the context of the present invention, the water-soluble active principles based on iodine, which are otherwise those described in EP-A-0,284,521 or EP-A-0,283,408 are excluded.

 The French patent application No. 89.02995 filed March 2, 1989 in the name of the Applicant aims at a matrix system based on thermoplastic silicone degradable by hydrolysis The thermoplastic silicones degradable by hydrolysis are excluded from the present invention.

In addition, silicone polymers have long been used in crosslinked form as a matrix within which an active ingredient is dispersed. To illustrate this prior art, US-A-4,53,580, EP-A-0,284,521, EP-A-0,283,408,
EP-A-0,285,525 and EP-A-0,283,407.

 These matrices of silicone elastomers have, in certain cases, the advantage of releasing the water-soluble active principle according to a diffusion kinetics of order O (see EP-A-0,284,521 and EP-A-0,283,408 mentioned above). However, the crosslinking of the silicone elastomer compositions is done in the presence of the active ingredient, generally by means of an organometallic catalyst for curing, heating or radiation (UV, IR, etc.). This crosslinking, involving chemical or photochemical reactions in the presence of the active ingredient, can be generated by the active ingredient (inhibition of the catalyst by the active ingredient, possible reaction between the active ingredient and the chemical functions present in the elastomer composition, etc.). ....).

 The main object of the present invention is precisely to provide a polymer that can be used to form the basis of a controlled release matrix system which can be easily shaped according to conventional methods into objects of various shapes and which have sufficient mechanical properties for intended application without having to undergo a crosslinking step.

 Another object of the present invention is to provide a controlled release system in aqueous medium or in a wet atmosphere of a water-soluble active ingredient that is released for all or part of a kinetics substantially O-order with respect to time.

 Another aim is to propose a composition making it possible to produce such matrix systems, this composition possibly containing only a polymer and the water-soluble active ingredient.

 Another object of the present invention is to obtain such compositions in which the polymer can be purified before it is shaped, for example by solubilization in organic solvents and then reprecipitation (in a non-solvent), before being mixed with water-soluble active ingredient.

 Another object of the present invention is a composition in which the polymer used with the water-soluble active principle is soluble in certain organic solvents.

 Another object of the present invention is a composition in which the water-soluble active principle can be distributed homogeneously, by stirring, in a solution of the polymer used.

 Another object of the present invention is to obtain compositions allowing the easy preparation of shaped articles, in particular by molding, by extrusion, or by spinning under the action of temperature.

 Another object of the present invention is the preparation of shaped articles obtained from such compositions, these articles, once in an aqueous medium or in a humid atmosphere, releasing all or part of the active ingredient according to a substantially O-order kinetics. with respect to time and continuously until preferably 80% by weight and more of the active ingredient is released.

These and other objects are attained by the present invention which relates to a composition that can be shaped in particular by molding, extrusion or spinning under the action of heat characterized in that it comprises
A: at least one non-thermoplastic silicone copolymer
degradable by hydrolysis,
B: a water-soluble active ingredient dispersed in a
substantially homogeneous within A.

The thermoplastic silicone copolymers that can be used in the context of the present invention are chosen from block copolymers
- or multi-sequenced linear, including the polymer chain
substantially linear principal is constituted by a
alternation of polydiorganosiloxane segments or blocks and
organic segments or blocks,
- either grafted, consisting of a polydiorgano chain
siloxane on which are grafted organic chains.

 The organic radicals of the diorganosiloxyl units are preferably C 1 -C 4 alkyl radicals, in particular methyl radicals, 3,3,3-trifluoropropyl radicals and phenyl radicals.

 The thermoplastic copolymers which can be used in the context of the present invention are, in addition, polymers which soften under the effect of heat, which are soluble in certain organic solvents and whose shaping involves reversible physical processes.

 Preferred thermoplastic copolymers are those having a Tg (glass transition temperature) or melting temperature (for semi-crystalline copolymers) above room temperature (25 ° C) and preferably above 40 ° C and generally below at 200 ° C.

 The thermoplastic silicone copolymers that can be used in the context of the present invention are advantageously soluble in at least one of the organic solvents or a mixture of organic solvents chosen from chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, dichloroethane, tetrachloroethane, carbon tetrachloride, trichlorethylene, hexane, heptane, methanol, ethanol, isopropanol, toluene and N-methyl pyrrolidone.

The organic segments, blocks or grafts of the thermoplastic silicone copolymers can be in particular
polyurethanes (see, for example, the Canadian patent
CA-A-1,072,241, US Patents US-A-4,145,508,
US-A-4,180,515 and US-A-4,518,758),
polysilarylenes (see for example US-A-4,233,427,
FR-A-2 407 950 and FR 1 299 160),
polystyrenes (see for example US-A-4,263,401),
polyesters (see for example US-A-3,701,815),
polyethers,
polycarbonates (see for example J. Polym Sci.
Polymer Letters ed. 7, p. 569-577) (1969),
polyamides,
polyimides,
polyimides / amides,
polysulfones,
polyacrylates,
polymethacrylates, and generally the thermoplastic silicone copolymers described on pages 181 to 198 of the 1988 edition of INORGANIC and
ORGANOMETALLIC POLYMERS.

 Thus, the thermoplastic silicone copolymers according to the present invention may especially be those described in the patents cited above, cited as references in the present application.

By way of illustration, these copolymers may especially be those taught by US-A-4,233,427 cited as a reference, that is to say those having a plurality of repeating units corresponding to one and / or the other of the two formulas F1 and F'1

<tb> F1 <SEP>: - <SEP> ASiRz (GSiR2) aASiR2G'SiR2JAp <SEP> siR2 (GSiR2) aASiR2 (0SiR2) n <SEP> - <SEP>
<tb>F'1<SEP>:<SEP> E <SEP><SEP> A <SEP> SiR2GtSiR2AsiR2 (GSiR2) ai <SEP> p <SEP>SiR2G'SiR2ASiR2 (0SiR2: <SEP>
<tb> in which the different symbols have the following meaning - the symbols A, identical, represent alkylene radicals,
linear or branched, having from 2 to 6 carbon atoms,
cyclohexylenes radicals; the symbols R, identical or different, represent
alkyl and haloalkyl radicals having from 1 to 5
carbon atoms,
cycloalkyl and halogenocycloalkyl radicals having
from 3 to 8 carbon atoms,
aryl and haloaryl radicals having from 6 to 8
carbon atoms,
cyanoalkyl radicals having 3 to 4 carbon atoms
carbon - the symbols G, identical, represent
. alkylene radicals, linear or branched, having 1
at 8 carbon atoms,
divalent organic radicals having the formula
F2: - (CH2) xQTQ (CH2) x- in which
+ the symbols Q, identical, represent one of the groups
-O-, -OCO - (- OCO-being linked to T by the radical -CO-),
+ the symbol T represents a divalent hydrocarbon radical,
monocyclic, having 6 to 8 carbon atoms, or a
divalent organic radical having from 10 to 22 carbon atoms
carbon consisting of 2 hydrocarbon cycles welded one to
the other or linked by a valid link or by one
groups of formulas -O-; -CH2-; -C (CH3) 2
-Si (R ') - 2, R' being an alkyl radical having from 1 to 3
carbon atoms
+ the symbols x, identical, represent 1, 2 or 3, or
divalent hydrocarbon radicals responding to the
formula F3: (CH2) bT (CH2) b in which the symbol T has the
meaning given in formula F2, and symbols
b, identical, represent 0 or 1 - the identical symbols G 'have the meaning given for G except
that they do not answer the formula F2; the symbols a, identical, represent 0 or 1; the symbol p represents any number ranging from 1 to 120; the symbol n represents any number ranging from 1 to 1500;

 In the compositions according to the present invention, the organic segments, blocks or grafts are present in a weight content of 10 to 60%, preferably 10 to 40% relative to the total weight of the thermoplastic silicone copolymer.

 Hydrolytically degradable thermoplastic silicone copolymers are excluded from the scope of the present invention.

 The water-soluble active principle must have a solubility in water preferably greater than 500 mg / l, preferably greater than 5 g / l.

 This active ingredient can be a medicinal active ingredient, a phytosanitary product (such as a fertilizer, an insecticide, a pesticide, a fungicide, a herbicide), a disinfectant, a catalyst, a veterinary active ingredient, a cosmetic product, etc. ..

 Mention may be made more particularly of aluminum ethylphosphite, dipotassium phosphite, copper sulphate, potassium sulphate, potassium nitrate, ammonium nitrate, pefloxaxine methanesulphonate, sodium ketoprofen, potassium chloride, iron fumarate, ferrous chloride, lysine hydrochloride.

 The active ingredient is dispersed substantially homogeneously within the polymer matrix. This does not exclude from the field of the invention a shaped object consisting of several zones having different levels of active ingredient but dispersed homogeneously in each of the zones.

 This active ingredient is preferably in the form of a powder at room temperature (25 ° C) which is dispersed homogeneously by any appropriate means within the polymer.

 It is then desirable that the powder has a particle size of between 1 and 200 μm, preferably between 2 and 100 μm.

It is desirable that the amount of powder homogeneously distributed in the polymer is below the percolation threshold. To fix the ideas especially in the case where the active ingredient is in the form of powder, is used from 5 to 100 parts by volume, preferably from 10 to 50 of B per 100 parts by volume of
AT.

 Matrix systems for the controlled release of a water-soluble active ingredient exhibit a diffusion of the active principle normally governed by the FICK law, that is to say by a diffusion kinetics of order 1/2 for only 60% by weight active ingredient. Beyond 60% there is depletion of the matrix and the diffusion fluxes are greatly diminished. Surprisingly and unexpectedly, it has been found that the matrix system with a thermoplastic silicone copolymer in accordance with the invention releases the active principle according to a kinetics of substantially zero order with respect to time and in a continuous manner and that until 80% by weight and more of the active ingredient is released.

 By the expression "substantially 0 order according to the invention means 0 or a value close to 0.

 The considerable advantage provided by the thermoplastic silicone copolymer matrix is therefore that it is very easy to extrapolate the continuous diffusion of the active principle after a measurement of the quantity released after a certain time since it is known that the diffusion kinetics is of order 0 with respect to time and that at least 80% of the active ingredient will be released according to this kinetics.

In order to control the release of the active ingredient, it is advantageous to present the thermoplastic silicone copolymer matrix in the form of modules or elementary articles of various shapes such as cubes, rectangular parallelepipeds, cylinders, spheres. The fundamental parameters governing the release of the active principle are as follows
- the nature of the active ingredient,
the granulometry of the particles of the active principle in the preferred case where the latter is a solid,
the content t of active principle within the matrix,
the ratio R of the surface to the volume of the module.

 The nature of the active ingredient and its particle size define, among other things, its diffusion rate v through the matrix.

 Plus g is small and v is slow and vice versa.

 The greater the t, the greater the flow of active ingredient and vice versa.

 The larger the R, the greater the flow of active ingredient, and vice versa.

 The person skilled in the art, by routine experiments, can without difficulty quickly reach the desired result by extrapolating from the first elution times, the theoretical elution time and the product flow which will correspond to the real time of diffusion of the active ingredient.

 It is also necessary that the active ingredient is dispersed homogeneously within the matrix. To do this, in a (or a mixture of) suitable organic solvent (s) chosen from among those mentioned above, the thermoplastic silicone copolymer is solubilized, optionally by heating, and then when the solution is dissolved. The active ingredient, which is homogeneously distributed in the solution, is added with stirring. The organic solvent is then evaporated and the composition obtained is then shaped by heating and, for example, by molding or by extrusion, articles containing the composition according to the present invention are obtained.

 Possibly these articles of various shapes (cubes, pellets, spheres, cylinders etc ...) can be obtained by heating, for example by molding or by extrusion, after the composition has been prepared directly by mixing the finely divided thermoplastic silicone copolymer with the active ingredient, until a homogeneous mixture is obtained. It is then not necessary to solubilize the thermoplastic silicone copolymer.

The compositions according to the invention can in particular be used in the following fields of application
- Release of therapeutically active molecules in the digestive tract or by transdermal application,
- Release of active molecules in veterinary health by "bolus" systems,
- Release of phytosanitary active ingredients by incorporation into the soil, or by making collars arranged around the trunks of trees and strips placed over crops (for example son loaded with copper sulphate over vine crops).

Without wishing to limit the invention to a scientific theory, it is thought that the release of the active principle can be explained by the following mechanism
the silicone part being very permeable to water vapor, this water vapor penetrates into the material and solubilizes the active ingredient. At the same time, swelling of the matrix, made possible by the elasticity of the material, is observed. When the osmotic pressure generated at the interface between the elastomeric material and the active ingredient solution becomes greater than the tear resistance of the material, there is a rupture of the network and creation of micropores which allow the release of the active principle solution. .

In what follows or the foregoing, the% and parts are by weight unless expressly stated otherwise.

 The examples below illustrate the invention.

EXAMPLE 1 1.1 Preparation of Copolymer Thermoplastic Silicone
A thermoplastic polyblock copolymer, the preparation of which is described in Example 4 of US Pat. No. 4,233,427, employs a dihydrogenpolydimethylsiloxane used having a number-average molecular weight of 4760 g / mol, determined by assaying the SiH functions.

This copolymer is formed by an alternation of polydimethylsiloxane segments and poly [(dimethylsilylene) phenylene (dimethylsilylene) -1,2-ethanediyl]] segments corresponding to the average general formula

 The proportion of polydimethylsiloxane segments in this copolymer is 80% by weight.

 The inherent viscosity of this copolymer is 0.39 dl / g (measured at 25 ° C on a chloroform solution having a concentration of 1 g / dl).

1.2 - Preparation of a Composition According to the Present Invention with
the DréDaré copolvère above
20 g of the copolymer are melted in a reactor at a temperature in the region of 1800 ° C. When the viscosity of the product is sufficiently low, 4 g of dipotassium phosphite of average particle size less than 50 μm are added. The mixture is stirred for a few minutes to disperse the active ingredient.

The mixture is then poured into a mold preheated to 1800C having the following dimensions
L = 5 cm
1 = 2.5 cm
e = 0.2 cm
The whole is then returned to the study at 1800C for 15 minutes, then cooled to room temperature.

1.3 - Experimental protocol of measurement of elution kinetics.

Two in vitro release tests are performed
. a release in water
. a release in a humid atmosphere
1.3.1. Protocol in the water
A matrix having the following dimensions (L = 2.5 cm 1 = 2.5 cm e = 0.2 cm) is placed in a 100 ml container of distilled water, thermostated at 20 ° C.

 The container is equipped with a magnetic stirring system, driven by a slow rotation movement (100 rpm) ensuring the homogeneity of the solution. It is covered with a lid to minimize evaporation of water.

 Samples of 2 ml are made regularly: every day during the first elution time, then 3 times a week and finally every week.

 The concentration of dipotassium phosphite is determined by atomic absorption assay of potassium.

 In Table 1 are collected the results of the kinetics of elution. The times indicated are the sampling times.

Q is the amount of active ingredient released at each sampling time relative to the initial quantity Qo of active ingredient.

TABLE 1

<tb> Time <SEP> Q / Qo
<tb> (days) <SEP> (%)
<tb><SEP> 1 <SEP> 23.67
<tb><SEP> 2 <SEP> 24.67
<tb><SEP> 7 <SEP> 34.59
<tb><SEP> 9 <SEP> 38.70
<tb><SEP> 12 <SEP> 49.38
<tb><SEP> 15 <SEP> 59.88
<tb><SEP> 22 <SEP> 66.64
<tb><SEP> 29 <SEP> 72.71
<Tb>
1.3.2. Protocol in humid atmosphere
In order to verify that the active ingredient incorporated in the copolymer can be dispensed into the ambient humid medium, a matrix identical to that of Example 1.3.1 is suspended. using a stainless steel nacelle in a confined environment where an atmosphere of 100% relative humidity maintained. The release is monitored by assaying the potassium (by atomic absorption) in the aqueous phase (100 ml) contained in said container.

 In Table 2 are collected the results of the kinetics of elution.

TABLE 2

<tb> Time
<tb> (days) <SEP> (%) <SEP>
<tb><SEP> 1 <SEP> 13.22
<tb><SEP> 2 <SEP> 13.35
<tb><SEP> 7 <SEP> 17.13
<tb><SEP> 9 <SEP> 17.74
<tb><SEP> 12 <SEP> 22.56
<tb><SEP> 15 <SEP> 25.44
<tb><SEP> 22 <SEP> 30.57
<tb><SEP> 29 <SEP> 38.08
<tb><SEP> 36 <SEP> 42.92
<tb><SEP> 43 <SEP> 45.80
<tb><SEP> 50 <SEP> 53.41
<Tb>
EXAMPLE 2 2.1 - The copolymer prepared above in 1.1 is used.

2.2 - Preparation of a Composition According to the Present Invention with
the copolvère prepared above
20 g of the copolymer are melted in a reactor at a temperature in the region of 1800 ° C. When the viscosity of the product is sufficiently low, 6 g of potassium sulphate of average particle size less than 50 μm are added. The mixture is stirred for a few minutes to disperse the active ingredient.

The mixture is then poured into a mold preheated to 1800C having the following dimensions
L = 5 cm
1 = 2.5 cm
e = 0.2 cm
The whole is then returned to the oven at 1800C for 15 minutes, then cooled to room temperature.

2.3 - Kinetics of elution
2.3.1. In water
We proceed as in 1.3.1. The dosage of the active ingredient is carried out by assaying potassium by atomic absorption.

 The results of the kinetics of elution in water are summarized in Table 3 below.

TABLE 3

<tb> Time <SEP> Q / Qo
<tb> (days) <SEP> (%)
<tb><SEP> 1 <SEP> 3.28
<tb><SEP> 2 <SEP> 4.71
<tb><SEP> 7 <SEP> 10.23
<tb><SEP> 9 <SEP> 11.85
<tb><SEP> 12 <SEP> 14.44
<tb><SEP> 15 <SEP> 16.91
<tb><SEP> 22 <SEP> 20.93
<tb><SEP> 29 <SEP> 24.95
<tb><SEP> 36 <SEP> 27.96
<tb><SEP> 43 <SEP> 29.64
<tb><SEP> 50 <SEP> 35.00
<Tb>
2.3.2. In humid atmosphere
We proceed as in 1.3.2.

 The results of the elution kinetics in a humid atmosphere are summarized in Table 4 below.

TABLE 4

<tb> Time <SEP> Q / Qo
<tb> (days) <SEP> (%)
<tb><SEP> 1 <SEP> 0.05
<tb><SEP> 2 <SEP> 0.08
<tb><SEP> 7 <SEP> 3.35
<tb><SEP> 9 <SEP> 4.41
<tb><SEP> 12 <SEP> 5.71
<tb><SEP> 15 <SEP> 6.10
<tb><SEP> 22 <SEP> 8.95
<tb><SEP> 29 <SEP> 11.21
<tb><SEP> 36 <SEP> 11.39
<tb><SEP> 43 <SEP> 12.83
<tb><SEP> 50 <SEP> 15.02
<Tb>
EXAMPLE 3 3.1 - The copolymer prepared above in 1.1 is used.

3.2 - Preparation of a Composition According to the Present Invention with
the copolymer prepared above
20 g of the copolymer are melted in a reactor at a temperature in the region of 1800 ° C. When the viscosity of the product is sufficiently low, 6 g of lysine hydrochloride of average particle size less than 50 μm are added. The mixture is stirred for a few minutes to disperse the active ingredient.

The mixture is then poured into a mold preheated to 180 ° C. having the following dimensions
L = 5 cm
1 = 2.5 cm
e = 0.2 cm
The whole is then returned to the oven at 1800C for 15 minutes, then cooled to room temperature.

3.3 - Kinetics of elution
In water
We proceed as in 1.3. The dosage of the active ingredient is carried out by determination of chloride ion by argentimetry.

 The results of the kinetics of elution in water are summarized in Table 5 below.

TABLE 5

<tb> Time <SEP> Q / Qo
<tb> (days) <SEP> (%)
<tb><SEP> 1 <SEP> 25.91
<tb><SEP> 2 <SEP> 38.72
<tb><SEP> 7 <SEP> 70.01
<tb><SEP> 9 <SEP> 74.27
<tb><SEP> 12 <SEP> 74.72
<tb><SEP> 15 <SEP> 81.96
<Tb>
In humid atmosphere
We proceed as in 1.3.2.

 The results of the elution kinetics in a humid atmosphere are summarized in Table 6 below.

TABLE 6

<tb> Time <SEP> Q / Qo
<tb> (days) <SEP> (%)
<tb><SEP> 1 <SEP> 10.96
<tb><SEP> 2 <SEP> 21.59
<tb><SEP> 7 <SEP> 60.56
<tb><SEP> 9 <SEP> 62.36
<tb><SEP> 12 <SEP> 67.57
<tb><SEP> 15 <SEP> 66.10
<tb><SEP> 22 <SEP> 78.08
<tb><SEP> 29 <SEP> 82.52
<Tb>

Claims (11)

 1. - Composition that can be shaped in particular by molding, extrusion or spinning under the action of heat characterized in that it comprises  A: at least one non-thermoplastic silicone copolymer  degradable by hydrolysis including segments, blocks or  organic grafts are present according to a certain  weight of 10 to 60%, preferably 10 to 40% by  relative to the total weight of the silicone copolymer  thermoplastic,  B: a water-soluble active ingredient dispersed in a  substantially homogeneous within A.  2. - Composition according to claim 1, characterized in that the thermoplastic silicone copolymer is chosen from block copolymers  - or multi-sequenced linear, including the polymer chain  substantially linear principal is constituted by a  alternation of polydiorganosiloxane segments or blocks and  organic segments or blocks,  - either grafted, constituted by a chain  polydiorganosiloxane on which are grafted chains  organic.  3. - Composition according to claim 1 or 2, characterized in that the blocks, blocks or grafts of the thermoplastic silicone copolymer are chosen from polyurethanes, polysilarylenes, polystyrenes, polyesters, polyethers, polycarbonates, polyamides, polyimides, polyimides / amides, polysulfones, polyacrylates and polymethacrylates.  4. - Composition according to any one of the preceding claims, characterized in that the thermoplastic silicone copolymer has a glass transition temperature or a melting temperature greater than 40 C.  5. - Composition according to any one of the preceding claims, characterized in that the thermoplastic silicone copolymer consists of a plurality of repeating units responding to one and / or the other of the two formulas F1 and F'1

<tb> F1 <SEP>: [- <SEP> A [SiR2 (GSiR2) aAsiR2clsiR2A)] pSiR2 (GSiR2) aASiR2 (OSiR2) n] <tb> F'1 <SEP> :: - <SEP> [-A [SiR2G'SiR2ASiR2 (GSiR2) aA] p <SEP> SiR2G'SiR2ASiR2 (0SiR2) n -] - <SEP> <tb> in which the different symbols have the following meaning - the symbols A, identical, represent alkylene radicals,  linear or branched, having from 2 to 6 carbon atoms,  cyclohexylene radicals - the symbols R, which are identical or different, represent  . alkyl and haloalkyl radicals having from 1 to 5  carbon atoms,  . cycloalkyl and halogenocycloalkyl radicals having  from 3 to 8 carbon atoms,  . aryl and haloaryl radicals having from 6 to 8  carbon atoms,  . cyanoalkyl radicals having 3 to 4 carbon atoms  carbon - the symbols G, identical, represent  . alkylene radicals, linear or branched, having 1  at 8 carbon atoms,  . divalent organic radicals having the formula  F2: - (CH2) xQTQ (CH2) x- in which  + the symbols Q, identical, represent one of the groups  -O-, -OCO - (- OCO-being linked to T by the radical -CO-),  + the symbol T represents a divalent hydrocarbon radical,  monocyclic, having 6 to 8 carbon atoms, or a  divalent organic radical having from 10 to 22 carbon atoms  carbon consisting of 2 hydrocarbon cycles welded one to  the other or linked by a valid link or by one  groups of formulas -0-; -CH2-; -C (CH3) 2  -Si (R ') - 2, R' being an alkyl radical having from 1 to 3  carbon atoms  + the symbols x, identical, represent 1, 2 or 3, or  divalent hydrocarbon radicals responding to the  formula F3: (CH2) bT (CH2) b in which the symbol T has the  meaning given in formula F2, and symbols  b, identical, represent 0 or 1 - the identical symbols G 'have the meaning given for G except  that they do not correspond to the formula F2 - the symbols a, identical, represent 0 or 1 - the symbol p represents any number ranging from 1 to 120 - the symbol n represents any number ranging from 1 to 1500.  6. - Composition according to claim 6 characterized in that the thermoplastic silicone copolymer consists of a plurality of repeating units corresponding to the formula

 7. - Composition according to any one of the preceding claims, characterized in that the active ingredient has a solubility in water greater than 500 mg / l.  8. - Composition according to any one of the preceding claims, characterized in that it contains from 5 to 100 parts by volume, preferably from 10 to 60 parts by volume of B per 100 parts by volume of A.  9. - Composition according to any one of the preceding claims, characterized in that the active ingredient is selected from aluminum ethylphosphite, dipotassium phosphite, copper sulfate, potassium sulfate, potassium nitrate, ammonium nitrate, pefloxaxine methanesulfate, sodium ketoprofen, potassium chloride, iron fumarate, ferrous chloride, lysine hydrochloride.  10. - Composition according to any one of the preceding claims, characterized in that B is powdered at room temperature distributed in the polymer at a content below the percolation threshold.  he. - Controlled release matrix system prepared by shaping a composition as defined in any one of claims 1 to 10.  12. - Process for the controlled release of an active ingredient with a release kinetics of substantially order 0 with respect to time by immersion in an aqueous medium or in a humid atmosphere of a matrix system as defined in claim 11.