MXPA00012749A - A membrane or matrix for controlling the permeation rate of drugs - Google Patents

Abstract

The invention relates to a membrane or matrix for controlling the permeation rate of a drug, wherein said membrane or matrix comprises a siloxane-based elastomer composition which comprises at least one elastomer and possibly a non-crosslinked polymer. The elastomer composition comprises poly(alkylene oxide) groups, and the poly(alkylene oxide) groups are present in the elastomer or the polymer as alkoxy-terminated grafts of polysiloxane units, or as blocks, the said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms. The invention also relates to methods for the preparation of the elastomer composition to be used in said membrane or matrix.

Description

A MEMBRANE OR MATRIX FOR CONTROLLING THE DRUG IMPREGNATION RATE This invention relates to a membrane or matrix intended to control the rate of impregnation of a drug, wherein the membrane or matrix comprises a siloxane-based elastomer composition, and a method for the preparation of this elastomer composition. STATUS OF THE TECHNOLOGY Polysiloxanes, in particular poly (dimethyl siloxane) (PDMS) are highly suitable to be used as a membrane or shade to regulate the rate of impregnation of drugs in different forms of drugs, in particular in implants and in IU systems . The polysiloxanes are physiologically inert, and a broad group of drugs have the ability to penetrate polysiloxane membranes that also have the required potency properties. It is known from the literature that adding groups of poly (ethylene oxides), ie PEO groups, to a PDMS polymer can increase the rate of drug impregnation. The publication by KL Yll et al., Journal of Controlled Relay 10 (1989) 251-260, discloses membranes prepared from a block copolymer containing PEO and PDMS and the penetration of various steroids through these membranes. It is noted in the publication that an increasing amount of PEO in the block polymer has to increase the penetration of hydrophilic steroids, while the penetration of lipophilic steroids decreases. The block copolymer described in the publication is very complicated in its structure and penetration and therefore is not easy in a more extensive technical production. OBJECTIVE OF THE INVENTION The objective of the invention is to provide an elastomer composition that is easy to prepare, through which a drug migrates at the desired rate and which provides the membrane with the required mechanical properties. The object of the invention is in particular to provide an elastomer composition through which the rate of impregnation of drugs with hormonal action can be controlled. SUMMARY OF THE INVENTION Thus, the invention relates to a membrane or matrix intended to control the rate of impregnation of a drug, wherein said membrane or matrix comprises a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer. The invention is characterized in that the elastomer composition comprises poly (alkylene oxide) groups and that the polyalkylene oxide groups are present in the elastomer or polymer as finished alkoxy grafts or grafts of polysiloxane units, or as blocks, where these blocks or grafts are linked to the polysiloxane units through silicone-carbon bonds, or as a mixture of these forms. The invention also relates to a method for the preparation of a siloxane-based elastomer comprising poly (alkylene oxide) groups and which is intended for use in a membrane or matrix to control the drug impregnation rate. . The method is characterized in that a) a functional vinyl polymer component and a functional hydride component are crosslinked in the presence of a catalyst, or that b) a polymer component is crosslinked in the presence of a peroxide catalyst. DETAILED DESCRIPTION OF THE INVENTION General description of the composition of the elastomer The term "elastomer composition" can mean a single elastomer, in which case the polysiloxane units containing polyalkylene oxide groups are present in the elastomer. According to another embodiment, the composition of the elastomer can be formed of up to two elastomers that are entangled, one inside the other. In this case, the first elastomer comprises poly (alkylene oxide) groups for which polyalkylene oxide groups are present in the elastomer either as finished alkoxy grafts or polysiloxane units or as blocks, these grafts or block are linked to the polysiloxane units through the polysiloxane units by silicone-carbon bonds. The poly (alkylene oxide) groups can, of course, also be present in the polymer as a mixture of the mentioned forms. In this embodiment, also the siloxane-based elastomer may comprise poly (alkylene oxide) groups, in which case these polyalkylene oxide groups are present in the elastomer either as finished alkoxy grafts of the polysiloxane units or as blocks, these blocks or grafts are linked to the polysiloxane units through silicone-carbon bonds.The poly (alkylene oxide) groups can also be present as a mixture of the forms mentioned. , the elastomer composition can also be formed of two elastomers intertwined one inside the other, as mentioned above, and at least one straight chain of polysiloxane copolymer comprising poly (alkylene oxide) groups. alkylene oxide) of the elastomer composition may be suitable, for example, poly (ethylene oxide) groups (PEO groups). of polysiloxane in the elastomer composition are preferably groups having the formula: - (SiR'R 'O) qSiR'R "- where R' and R" are -partially free groups, which are the same or different and which are a lower alkyl group, or a phenyl group, in which case alkyl or phenyl groups can be substituted or unsubstituted, or terminated alkoxy polyalkylene oxide groups having the formula R -R3-0- (CH-) CH2-0) m-al, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl, m is 1 ... 30, and R3 is an alkyl group C2-C6 straight or branched, partial bonds, formed from the groups of hydrogen or alkylene, to other polymer chains in the elastomer, and - possibly partially unreacted groups, such as hydrogen, vinyl or vinylene-terminated alkylene, and - which is 1 ... 3000. The term "lower alkyl" means here and generally in the description of the present invention C2-C6 alkyl groups. The above-mentioned free R 'and R "groups are suitably a lower alkyl group, preferably methyl. The term "poly (alkylene oxide) group" means that the group comprises at least two alkyl ether groups successively connected to each other. According to a preferred embodiment, the poly (alkylene oxide) groups are present in the elastomer in the form of poly (alkylene oxide) blocks having the formula R - (CH2) and O (CHCH20) m (CH2)? -, O Ri R Ri -CH2 C IHCOO (CIHCH 20) m COC IHCH2 - where R is hydrogen, a lower alkyl or a phenyl, Ri is hydrogen of a lower alkyl, and is 2 ... 6 , and m is 1 ... 30. The elastomer composition suitably contains a filler, such as silica, in order for the membrane to obtain sufficient strength. The word "membrane" means the same movie. The general description of the method for the preparation of the elastomer composition. According to a preferred embodiment, the innovative elastomer that prepares when crosslinking, in the presence of a catalyst, a functional vinyl polymer component and a functional hydride siloxane component. In order to crosslink, the additional reaction of a functional hydride component with a carbon-carbon double bond of the functional vinyl polymer component is desired. According to another embodiment, the elastomer is prepared by crosslinking the polymer in the presence of a peroxide catalyst. In this case the vinyl and methyl groups react with each other and form carbon-carbon bonds. A crosslinking between two methyl groups or between two vinyl groups can also be formed. For crosslinking, the amounts of the components are preferably selected such that the ratio of the molar amounts of the hydrides and the double bonds is at least 1. The functional vinyl polymer component can be a) a vinyl polysiloxane functional which has the formula R'-Sir'R'O (SiR'R'O) rSIR'R '' R 'where R' and R "are the same or different, and are a lower alkyl group, or a phenyl group , in which case the alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents of R 'and / or R "have been replaced by vinyl groups, and r is 1 ... 27000, or b) a block copolymer based on polyalkylene terminated polysiloxane having the formula T (AB) XAT (I), where A = - (Sir'R'O) g SiR'R "-, where R 'and R" they are the same or different and are a lower alkyl group, or a phenyl in which case the alkyl or phenyl group may have the formula R R1 -) - (CH2CH20) m-R2 where R1 and R2 are C2-C6 alkyl groups of straight or branched chain the same or different, R is a hydrogen or lower alkyl, and m is 1 ... 30, or e) A mixture of at least two of the aforementioned components a) -d). If the functional vinyl polysiloxane copolymer formula is, according to the above description R '-SiR'R "0 (SiR'R" 0) r (SiR'R "0) pSiR # R" -R ', it should be noted that the formula is a type of gross formula, where blocks in successive parentheses can appear in any order in relation to - the other. In addition, it is preferable that both vinyl groups and the alkoxy terminated polyalkylene oxide group do not bind to each other on the same Si atom. The functional hydride component may be a) a functional hydride siloxane, which may be a straight, star-shaped, branched or cyclic chain, or b) a block copolymer based on a hydride-terminated siloxane having the formula T (BA XBT (II), where T = H-SiR'R 'O (SiR'R' O) qSiR'R '' -, some of the substituents R 'and / or R "have been replaced by vinyl groups, yr is 1 ... 27000, and - wherein in the second block R 'is a lower alkyl group, or a group of alkoxy terminated polyalkylene oxide having the formula R' -SiR'R "O (Sir'R 'O) r ( SiR'R 'O) PSIRR' '-R' - where in the first block of R 'and R "are the same or different and are a lower alkyl group, or a phenyl group, in which case the group alkyl or phenyls can be substituted or unsubstituted and where some of the substituents R 'and / or R "have been replaced by vinyl groups, and r is 1 ... 27000, and - wherein the second block of R 'is a lower alkyl group, or a poly (alkylene oxide) terminated alkoxy group of the formula RI -R3-0- (CH-CH2-0) m-ALK, where alk is a lower alkyl group, a suitable methyl, R is hydrogen or a lower alkyl group, R3 is a straight or branched C2-C6 alkyl, and m is 1 ... 30, or R 'is a phenyl group, in which case the group alkyl or phenyl can be substituted or unsubstituted, and R "is a lower alkyl or phenyl group, in which case the alkyl or phenyl group can be substituted or unsubstituted, and p is 1 ... 5000, or d) a,? - dialkenyl poly (alkylene oxide) having the formula R I R1-0- (CH2CH20) m-R2 where R1 and R2 are identical or different straight or branched chain C2-C6 alkyl groups, R is a hydrogen or lower alkyl, and m is 1 ... 30, oe) A mixing of at least two of the aforementioned components a) -d). If the formula of the functional vinyl polysiloxane copolymer is, according to the above description R'-SiR'R''0 (SiR'R''0) r (SiR'R'O) pSiR'R '' - R ' , it should be noted that the formula is a type of gross formula, where the blocks in successive parentheses can appear in any order in relation to the other. In addition, it is preferable that both vinyl groups and the alkoxy terminated polyalkylene oxide group do not bind to each other on the same Si atom. The functional hydride component can be a) a functional hydride siloxane, which may be a straight, star-shaped, branched or cyclic chain, or b) a block copolymer based on hydride-terminated siloxane having the formula T (BA ) XBT (II), where T = H-SiR'R '' O (SiR'R '' 0) qSiR'R '' -, A = -SiR'R '' O (SiR'R 'O) qSiR' R "-, wherein R 'and R" are the same or different and are a lower alkyl group or a phenyl group, in which case the alkyl or phenyl group may be substituted or unsubstituted; B is a poly (alkylene oxide) having the formula R -R3-0 (CHCH20) mR4-, O -CH2CHCOO (CHCH20) mCOCHCH2- where R is hydrogen, a lower alkyl or a phenyl, Ri is hydrogen or a lower alkyl, R3 and R4 are the same or different and are straight or branched chain C2-Cs alkyl groups, m is 1 ... 30, q is 1 ... 3000, and x is 0 .. 100, or c) a mixture of the aforementioned components a) and b). According to one embodiment, the functional hydride siloxane copolymer can be a straight chain, in which case its formula is R '-SiR'R' 'O (SiR'R' '0) rSiR'R' ' R 'wherein R' and R "are the same or different and are a lower alkyl group, or a phenyl group, in which case the alkyl or phenyl group may be substituted or unsubstituted, and wherein the substituents R 'and / or R' 'have been replaced by hydrogen, and r is 1 ... 27000. The functional vinyl polymer component may contain a filler, suitably silica. The catalyst to be used in the crosslinking is suitably a noble metal catalyst, more commonly a platinum complex in alcohol, xylene, divinyl siloxane or cyclic vinyl siloxane. A particularly suitable catalyst is a Pt (0) -divinyl-tetramethyl disiloxane complex. The elastomer composition formed of two elastomers is prepared so that initially an elastomer is formed, where a second elastomer is formed upon being crosslinked in the presence of the first elastomer. This is how the second elastomer will penetrate through the first elastomer. The elastomer composition comprising an elastomer and a straight chain polymer is prepared, for example, by mixing a functional vinyl polymer component, a functional hydride component, and a polymer having either vinyl or hydride groups. In crosslinking the functional vinyl polymer component and the functional hydride component form an elastomer, but the polymer component that does not contain the functional groups will not take part in the crosslinking reaction but will remain in a straight chain form, inside the elastomer. EXPERIMENTAL SECTION The invention is described below in greater detail with the help of the examples. The elastomer compositions of different types (A-J) were prepared. From most types of composition there were different prepared compositions that differ from one another with respect to the amount of PEO. The elastomer membranes representing the different compositions were tested with respect to the impregnation rates of various drugs. Prepared Elastomer Compositions In the elastomer compositions A-H described below, an addition reaction was used between the vinyl groups and the silyl hydride groups for crosslinking, ie, to produce a network structure. The functional hydride siloxane polymer serving as the crosslinked agent contained at least two Si-H groups, which reacts with the carbon-carbon double bond of the polymer to be cross-linked. The membranes made of the elastomer compositions I and J were prepared using peroxide as the catalyst for the crosslinking, in which case the vinyl or methyl groups reacted, forming carbon-carbon bonds In all types of composition except the types of composition A, D, F, "H, sß first prepared a basic polymer mixture and the fillers, or the vinyl content polymers containing a filler, were mixed together. The filler used was silica. Composition types A, D, F and H only had one polymer with vinyl content, each, and that is how these are basic polymers. The basic polymer mixture was divided into portions I and II. The catalyst was added to portion I and the crosslinking agent and the inhibitor to portion II. Portions I and II were combined immediately before crosslinking. The mixture obtained was crosslinked at a temperature above the decomposition temperature of the inhibitor and to which the crosslinking reaction was carried out at the desired rate. A mixture of the compositions can also be formed directly in step one, in which case the ingredients can be added in the following order: polymers containing vinyl, inhibitor, catalyst and cross-linking agent. The following table describes the elastomer membranes with different types of composition and their main components. Table 1 Type of Polymers Containing Crosslinking Agent Groups Vinyl composition in the basic polymer mixture A a,--divinyl either poly (ethylene hydride siloxane - (functional poly (dimethyl) siloxane) multiple block copolymer (PEO- (PDMS-PEO) n) And a siloxane polymer PEO-Siloxane hydride (PDMS-PE?) N containing a functional filler PEO- (PDMS-PEO) n together or separately with a polymer of a,? - bis (siloxane hydride containing and not silyl dimethyl) - contains a poly (dimethyl siloxane) multiple block copolymer (PDMS. (PEO-PDMS) n) together or separately with a functional hydride siloxane a, ? -divinyl of Siloxane hydride poly (ethylene oxide) (PEODIVI) functional PEODIVI and a siloxane polymer Siloxane hydride EXAMPLE 1 Elastomer membrane prepared from a Type A composition Ingredients used for the preparation of the elastomer membrane: - Copolymer of the PEO-PDMS block of ether -a,? -divinil where the amount of PEO was 27.0% by weight and vinyl content was 0.186 nmol / g. - Platinum Catalyst Silopren U Katalysatoren Pt-D (Bayer AG), with a platinum-siloxane complex in a siloxane matrix with vinyl content. The platinum content was 1% by weight and the vinyl content was 0.5 mmol / g. The crosslinking agent of the copolymer oc,? -di- (trimethyl silyl) dimethyl siloxane-hydromethyl siloxane (DMS-HMS) Silopren U Vernetzer 730 (Bayer AG) has a Si-H content of 7.1 mmol / g, and a mass molecular weight of 2800 g / mol and a ratio of the DMS group to a HMS group of 1: 1. 1-ethynyl-1-cyclohetanol inhibitor (ETCH, Aldrich) with a decomposition temperature of +40 ° C. - The PEO (-PDMS-PEO) n that was used as the starting substance was prepared as follows: 50 g of poly (ethylene oxide) ether (PEODIVI) -divinil anhydride was weighed with a mass molecular weight of 268 g / mol in a bottle with three mouths. Additionally, 129.87 g of α, β-bis (dimethyl silyl hydride) poly (dimethyl siloxane) (PDMSDIH, Mn = 717 g / mol) and 30% by weight of dry toluene were weighed out by distillation in the same container. Since the vinyl groups were present in excess (3%) in the reaction, vinyl groups were obtained at both ends of the final product, which were essential for subsequent cross-linking. The reaction solution was emptied into a magnetic stir plate at 200 rpm, and dry oxygen was directed through the solution in order to avoid deactivation of the catalyst. The reaction solution was heated to 50 ° C, where after the catalyst (Pt (0) divinyl-tetramethyl disiloxane complex) was added to the solution via packing. The amount of platinum was 30 ppm, calculated from the amount of reagents. From then on, the polymerization was monitored by means of Ir until the reactions were finished (loss of Si-H with a peak at 2130 cm1), which took approximately 4 hours. After polymerization, the toluene was distilled out of the solution by raising the temperature to 65 ° C and the pressure to 5 mbar for a period of 1 hour. In the preparation of the elastomer, two mixtures, portions I and II, were first prepared. Portion I contained PEO- (PDMS-PEO) n and the platinum catalyst. Portion II contained PEO- (PDMS-PEO) n, the cross-linking agent and the inhibitor. Portions I and II were combined by mixing immediately before crosslinking.

The quantities of ingredients in the example of the composition in the final mixture to be crosslinked were as follows .- Basic polymer PEO- (PDMS-PEO) n 94.87% by weight - Platinum catalyst 0.1% by weight - Crosslinking agent 5.00 % by weight - Inhibitor 0.03% by weight Portion I was prepared using a mixing chamber. 5.489 g of the basic polymer and 0.011 g of the platinum catalyst were weighed in the mixing chamber. The ingredients were stirred until the mixture was homogeneous. The crosslinking agent and the inhibitor were combined before being mixed with portion II. The mixture of the crosslinking agent and the inhibitor were prepared by weighing 0.059 of ERTCH and 9,941 g of Silopren U Vernetzer 730 in a glass container and by stirring the mixture in a water bath of + 37 ° C until the ETCH completely dissolved in the crosslinking agent. The amount of the inhibitor in the mixture was 0.59% by weight. Portion II was prepared using a mixing chamber. The mantle of the mixing chamber was cooled by circulating water to a point below room temperature, where the temperature was increased because the friction did not raise the temperature to the decomposition temperature in the inhibitor. 4.947 g of PEO-PDMS block copolymer and 0.553 g of the mixture of the crosslinking agent and the inhibitor were weighed into the mixing chamber. The ingredients were stirred until the mixture was homogeneous. Portions I and II were combined immediately before crosslinking, by adding 5 grams of portion I and 5 grams of portion II inside the mixing chamber of the mixing chamber. The ingredients were stirred until the mixture became homogeneous. The mixture was recovered and poured into a vacuum to remove the air bubbles. Four batches of 2 g of the mixture were weighed and crosslinked successively in a hot dam. The heavy mixture was placed between two FEP release membranes in the center of a round shaped metal having a thickness of 0.4 mm and an inner diameter of 8 cm. The mixture, together with the shapes and the FEP membranes, were placed between the compression surfaces of the hot press, whose surfaces were heated up to +115 | C. The surfaces were pressed together and kept pressed at a pressure of 200 bar for 5 minutes.

The pressure was released and the membrane was allowed to settle at room temperature for 24 hours. Round test pieces having a diameter of 22 mm were cut out of the membranes by a perforator. EXAMPLE 2 Elastomer membrane prepared from the type B composition The ingredients used for the preparation of the elastomer membrane: - The PEO (-PDMS-PEO) n was the same as in Example 1, except that the amount of PEO it was increased to 28.0% by weight and the vinyl content to 0.23 mmol / g by increasing the proportion of PEODIVI in the synthesis of the block copolymer. The catalyst, the crosslinking agent and the inhibitor were the same as in Example 1. The siloxane polymer containing the filler was a copolymer (DMS-VMS) dimethyl siloxane-vinyl methyl siloxane containing a silicon filler and having a molecular mass of Mn = 400,000 mmol / g. 36% by weight of silica was mixed in the polymer, and the silica was surface treated with α, β-bis (dimethyl hydroxysilyl) poly (dimethyl siloxane) (M = 520 g / mol), which was present in a 12% by weight in the mixture. The amounts of the ingredients in the example of the composition were as follows: - 32.8% by weight of PEO (-PDMS-PEO) n - DMS-VMS copolymer containing 60.9% by weight of the silica filler, - 0.1% by weight of platinum catalyst - 6.19% by weight of crosslinking agent - 0.03% by weight of inhibitor. First the first basic polymer mixture was prepared in a mixing chamber. 4.2 grams of PEO block copolymer (-PDMS-PEO) n and 7.8 grams of the DMZ-VMS copolymer containing a silica filler that were weighed into the mixing chamber. The ingredients were stirred until the mixture was homogeneous. Portion I was prepared as in Example 1. The combination of the cross-linking agent and the inhibitor was performed, as in Example 1, before mixing with portion II, except that ETCH was weighed in an amount of 9,952 g. The amount of the inhibitor in the mixture was 0.48% by weight. Portion II was prepared as in Example 1, except that the mixture of the basic polymer was weighed in an amount of 4.816 grams and the mixture of the crosslinking agent and the inhibitor in an amount of 0.684 grams. Portions I and II were combined as in Example 1. Four batches of 2.1 g of the mixture were weighed and crosslinked successively in a hot press, as in Example 1. EXAMPLE 3 Elastomer membrane prepared from the composition of the Type C. Ingredients to be used for the preparation of the elastomer membrane: - The PEO (-PDMS-PEO) n was the same as in Example 2. The catalyst and the inhibitor were the same as in Examples 1 and 2. The dimethyl siloxane-vinyl methyl siloxane copolymer (DMS-VMS) containing a silica filler was the same as in Example 2. The crosslinking agent used was a PDMS- (-PEO-PDMS) n copolymer having a Si-H content of 0.26 mmol / g, and the amount of PEO in this was 23.6% by weight. The crosslinking agent was prepared in the following manner: 40 g of a poly (ethylene oxide) α-dibinyl ether (EODIVI) anhydride having a molecular mass of 246.3 g / mol was weighed into a three-neck flask. Additionally, 129.4 g of,? -bis (dimethyl silyl hydride) poly (dimethyl siloxane) (PDMSDIH, Mn = 717 g / mol) and 30% by weight of toluene were weighed out by distillation into the same container. Since the dimethyl silyl hydride groups were present in excess (10%) in the reaction, the dimethyl silyl hydride groups were obtained at both ends in the final product. The reaction solution was stirred on a magnetic stir plate at 200 rpm, and the dried oxygen was directed through the solution to avoid deactivation of the catalyst. The reaction solution was heated to 50 ° C, where after the catalyst was added (Pt (0) livinyl-tetramethyl siloxane complex) was added to the solution through the packing. The amount of platinum was 30 ppm, calculated from the amount of the reagents. From that moment, the polymerization was monitored through IR elements until the reactions were finished (loss of the vinyl peak at 1600 cm1), which took approximately 4 hours. After polymerization, the toluene was removed from the solution by distillation through the raising of the temperature of 65 ° C and by lowering the pressure to 5 mbar over a period of 1 hour.

The amounts of the ingredients in the example of the composition were as follows: - 1.10% by weight of PEO (-PDMS-PEO) n - 85.50% by weight of DMS-VMS containing a silica filler, - 0.10% by weight of platinum catalyst - 13.27% crosslinking agent a, β-bis- (dimethyl silyl hydride) PEO-PDMS. - 0.03% by weight of the inhibitor. First, the basic polymer mixture was prepared in a mixing chamber. 0.15 degrees a,? - divinyl either in PEO-PDMS copolymer block and 11.-85 grams of DMS-VMS copolymer containing a silica filler were weighed into the mixing chamber. The ingredients were stirred until the mixture was homogeneous. Portion I was prepared as in Example 1. The combination of the crosslinking agent and the inhibitor was performed, as in Example 1, before being mixed with portion II, except that ETCH was weighed in an amount of 0.022 g and the block PDMS- (PEO-PDMS) copolymer n in an amount of 9,978 g instead of Vernetzer 730. The amount of the inhi-bidor _ in the mixture was 0.22% by weight. Portion II was prepared as in Example 1, except that the basic polymer mixture * was weighed in an amount of 4.04 grams and the mixture of the crosslinking agent and the inhibitor in an amount of 1.46 grams. Portions 1 I and ti were combined as in Example 1. Four batches of 2.1 g of the mixture were weighed and successively crosslinked in a hot press, as in Example 1. EXAMPLE 4 - Elastomer membrane prepared from the Type D composition. The ingredients used for the preparation of the elastomer membrane were: a,? -divinyl ether poly (ethylene oxide) (PEODIVI) (polyethylene glycol divinyl ether Adrich, Mn = 240 g / mol). The amount of vinyl obtained by fragmentation was 7.4 mmol / g. Gelest SIP 6831.0 catalyst, platinum complex - siloxane in a content of 2.25% by weight of xylene, platinum. The crosslinking agent and the inhibitor were the same as in Example 1. The amounts in the ingredients in the composition of the example were as follows: - 52.231% by weight of PEODIVI - 0.045% by weight of platinum catalyst - 47.694% by weight of crosslinking agent - 0.030% by weight of inhibitor First a mixture of the crosslinking agent and the inhibitor was prepared as in Example 1, except that the inhibitor was weighed in an amount of 0.0063 grams and the crosslinking agent in an amount of 9.9937 grams. The amount of the inhibitor in the mixture was 0.063% by weight. 5.2231 grams of PEODIVI and 0.0045 grams of platinum catalyst were mixed together in a glass container. 4.772 grams of the mixture of the crosslinking agent and the inhibitor were mixed therein. Eight batches of 0.8 g of the mixture were weighed in flat bottom aluminum shapes with a diameter of 5 cm and having an FEP membrane in the bottom. The forms were placed under a vacuum of 100 mbar at + 115 C over a period of 15 minutes. The test pieces were cut out of the obtained elastomer. EXAMPLE 5 Elastomer membrane prepared from the type E composition Ingredients used for the preparation of the elastomer membrane: - PEODIVI, as in Example 4. - DMS-VMS copolymer, same as in Example 2. The catalyst, the crosslinking agent and the inhibitor were the same as in Example 1. The amounts of the ingredients in the example of the composition were as follows: - 11.37% by weight of PEODIVI - 64.46% by weight of the copolymer DMS-VMS - 0.1 % by weight of platinum catalyst - 24.03% by weight of crosslinking agent - 0.03% by weight of inhibitor First, a mixture of the crosslinking agent and the inhibitor was prepared, as in Example 1, except that the inhibitor was weighed in a amount of 9.9875 grams. The amount of the inhibitor in the mixture was 0.125% by weight. 1,138 grams of PEODIVI and 6,446 grams of DMS-VMS copolymer were mixed together in a mixing chamber. 0.01 grams of platinum catalyst was added, and the mixture was stirred until homogeneous. 2.406 grams of the mixture of the crosslinking agent and the inhibitor were added and the mixture was stirred until it was homogeneous. Four batches of 2.1 grams of the mixture were weighed and crosslinked successively in a hot press, as in Example 1. EXAMPLE 6 Elastomer membrane prepared from the type F composition Ingredients used for the preparation of the elastomer membrane: PDMS-PEO graft copolymer having a vinyl concentration of 0.0743 mmol / g and a PEO content of 1.28% by weight. The catalyst, the crosslinking agent and the inhibitor were the same as in composition A. The copolymer of the PDMS-PEO graft used was prepared as follows: 600 grams of octamethyl cyclotetrasiloxane (D4), 9.28 grams of graft copolymer of poly (dimethyl siloxane) -poly (ethylene oxide) (Gelest, DBE-821), which contains 80% by weight of PEO), 6 18 grams of PDMS end-blocked silyl vinyl dimethyl (end blocker, Bayer Silopren U2), and 3.1 grams of tetramethyl tetravinyl cyclotetrasiloxane were weighed. The reactor was nitrogen-free, the heavy chemicals were emptied inside and stirring started. The internal temperature of the reactor was raised to 135 ° C, and the catalyst (potassium siloxane, 0.9 ml, 20 ppm K +) was added to the reaction solution. The viscosity of the reaction solution started to increase vigorously, and at 1 hour from the addition of the catalyst, it was possible to deactivate the catalyst by increasing the reactor pressure to 2 bar over a period of 15 minutes by means of dioxide carbon. From this, the light cyclic compounds (13% by weight) were removed from the reaction solution by distillation (10 mbar, 30 min, 135 ° C). Product Mn = 190,000 g / mol. The amounts of the ingredients in the example of the composition were as follows: - 96.10% by weight of basic polymer PDMS-PEO graft copolymer - 0.5% by weight of platinum catalyst - 3.06% by weight of crosslinking agent - 0.34% by weight of inhibitor The combination of the crosslinking agent and the inhibitor was performed as in Example 1, except that ETCH was weighed in an amount of 1.0 g and Silopren U Vernetzer 730 in an amount of 9.0 g. The amount of the inhibitor in the mixture was 10% by weight. 9.61 grams of PDMS-PEO graft copolymer and 0.05 grams of platinum catalyst were mixed together. 0.34 grams of the crosslinking agent and the inhibitor mixture was added and the mixture was stirred until homogeneous. Four batches of 2.1 g of the mixture were weighed and subsequently cross-linked in a hot press, as in Example 1. EXAMPLE 7 Elastomer membrane prepared from the composition of type G Ingredients used for the preparation of the membrane elastomer: - The PDMS-PEO graft copolymer was the same as in Example 6. - The DMS-VMS copolymer was the same as in Example 2. The catalyst, the cross-linking agent and the inhibitor were the same as in Example 1. The amounts of the ingredients in the composition example were as follows: - 26.75% by weight of PDMS-PEO graft copolymer - 72.32% by weight of DMS-VMS copolymer - 0.10% by weight of platinum catalyst - 0.81% by weight of crosslinking agent - 0.03% by weight of inhibitor The combination of the crosslinking agent and the inhibitor was carried out as in Example 1, except that the ETCH was weighed in an amount of 0.36 g of Silopren U Vernetzer 730 in an amount of 9.64 g. The amount of the inhibitor in the mixture was 3.6% by weight. 2675 grams of injunction copolymer ~ PDMS-PEO and 7,231 grams of DMS-VMS copolymer containing a filler were mixed together. 0.01 grams of platinum catalyst was added and the mixture was stirred until it was homogeneous. 0.084 grams of the mixture of the crosslinking agent and the inhibitor was added and the mixture was stirred until homogeneous. Four batches of 2.1 g of the mixture were weighed and successively crosslinked in a hot press, as in Example 1. EXAMPLE 8 Elastomer membrane prepared from the H type composition Ingredients used for the preparation of the elastomer membrane: - APEO- (-PDMS -APEO) n, where the amount of PEO was 10.3% by weight and the vinyl content was 0.063 mmol / g. The catalyst was the same as in Example 4 - the inhibitor was the same as in Example 1.

The crosslinking agent was a DMS-HMS copolymer containing 22.5% by weight of the siloxane methyl hydride groups (Gelest). The APEO- (-PDMS-APEO) n used was prepared in the following manner: α, β-diallyl anhydride (ethylene oxide) (PEODIAL) having a molecular mass of 520 g / mol and which was prepared by adapting the procedure disclosed in the Mei-Hui, Yang, Laing-Jong, Li, and Tsang-Feng, Ho, Synthesis and Characterization of Polymethylsiloxane / Poly (ethylene glycol) monomethyl ether copolymers, J. Ch. Colloid & amp;; Interface Soc. 3 (17), 1994. 19-28 and a,? -bis (dimethyl silyl hydride) poly (dimethyl siloxane) (PDMSDIH, Mn = 6000 g / mol) were weighed in a three-neck flask. The mass of the PEODIAL was 1.38 g (Mn = 520 g / mol, 5.28 mmol of allyl groups) and the mass of PDMSDIH was 12 g (4.8 mmol of hydride groups) the amount of the allyl groups were 10% higher than that of the hydride groups. This is how a final product of a,? -dialilo-final blocked was assured. Additionally, the toluene was weighed into the reaction vessel in an amount of 45% by weight (7.2 g). The reaction mixture was stirred on a magnetic stir plate at 200 rpm, and the dried oxygen was bubbled through the mixture in order to avoid deactivation of the catalyst. The temperature of the reaction mixture was raised to 60 ° C. From this the catalyst was added to the reaction solution (Pt (0) divinyl tetramethyl disiloxane complex) through packing, with caution one drop at a time. The amount of platinum was 50 ppm, calculated from the reagents. The polymerization was allowed to proceed for about 6 hours, where from the termination of the polymerization it was confirmed by IR (loss of Si-H peak at 2130 cm "1). For the removal of toluene by distillation, the temperature was it rose to 65 ° C and the pressure was lowered to 5 mbar over a period of 30 minutes The amounts of the ingredients of the composition of the example were as follows: - 94.68% by weight of APEO- (-PMDS -APEO) n - 0.5% by weight of platinum catalyst - 4.7% by weight of crosslinking agent - 0.12% by weight of inhibitor 3.0 grams of APEO- (PMDS-APEO) n, 0.0158 grams of the catalyst, 0.0038 g of the inhibitor, and 0.1489 g of the agent The air bubbles were removed from the mixture, and the mixture was reticulated in a hot press at 100 ° C for 14 minutes and cured at 110 ° C for 15 minutes EXAMPLE 9 Elastomeric membrane prepared at 100 ° C. from the composition of type I Ingred used for the preparation of the elastomer membrane: PEO- (PDMS-PEO) n, where the amount of PEO was 5.0% by weight and the vinyl content was 0.04 mmol / g. The DMS-VMS copolymer containing a silica filler was the same as in Example 2. - Dichlorobenzoyl peroxide (Perkadox PD50 S, Nusil). The PEO- (PDMS-PEO) n used was prepared as follows .- 0.528 g of ether anhydride of α, β-divinyl poly (ethylene oxide) (PEODIVI) having a molecular mass of 240 g / mol Weighed in a bottle of three mouths. lOg of α, β-bis (dimethyl silyl hydride) poly (dimethylsilyl siloxane) (PHMSDIH) having a molecular mass of 6000 g / mol was weighed into the same container. The PDMSDIH contained hydride groups in an amount of 0.04% by weight, and in this way the amount of hydride groups in 10 grams was 4 mmol and the amount of the PEODIVI vinyl groups was 4.4 mmol. Since the vinyl groups were present in excess (10%) in the reaction, the vinyl groups were obtained at both ends of the final product, an essential fact for the subsequent cross-linking. Additionally, to facilitate the mixing and to prevent the reaction from occurring too vigorously, toluene was added by distillation to the reaction mixture so that the proportion of toluene was 30% by weight (4.5 g). The reaction solution was stirred on a magnetic stir plate at 200 rpm, and the dried oxygen was directed through the solution; this prevented the catalyst from becoming a metallic form and thus deactivation of the catalyst was prevented. The reaction solution was heated to 50 ° C, where the catalyst (Pt (0) divinyl tetramethyl disiloxane complex) was subsequently added to the mixture through packing. The amount of platinum was 50 ppm, calculated from the amount of the reagents. The catalyst was added by dripping, where the hot spots in the reactor were avoided. After adding the catalyst, the reaction was allowed to proceed for 2 hours. From this the termination of the reaction by IR was confirmed (loss of the peak of Si-H at 2130 cm "1) After the polymerization the reaction mixture was heated to 65 ° C and the toluene was distilled off under vacuum (5 mbar) in the course of 30 minutes. example of the composition were the following: - 4.9% by weight of PEO- (PDMS-PEO) n of basic polymer - 93.9% by weight of full DMS-VMS copolymer - silica 1. 2% by weight of dichlorobenzoyl peroxide (Perkadox PD50 S, Nusil) 0.5 g of PEO- were mixed together. (PDMS-PEO) n and 9.5 g of a DMS-VMS copolymer containing a filler. 0.12 g of the peroxide catalyst was mixed with the homogeneous mixture, and the mixture was cured at a temperature of +115 ° C and a pressure of 200 bar for 5 minutes and cured at +150 ° C for 2 hours. EXAMPLE 10 Elastomer membrane prepared from the type J composition Ingredients used for the preparation of the elastomer membrane: - The PDMS-PEO graft copolymer is the same as in Example 6 - Perkadox PD50 S dichlorobenzoyl peroxide, Nusil The amounts of the ingredients in the composition example were as follows: - 98.8% by weight of graft copolymer PDMS-PEO - 1.2% by weight of Dichlorobenzoyl peroxide Perkadox PD50 S 10 grams of the PDMS graft copolymer were mixed together -PEO and 0.12 grams of Perkadox PD 50 S. The mixture was hardened at a temperature of + 115 ° C and a pressure of 200 bar for 5 minutes and cured at + 150 ° C for 2 hours. Impregnation Tests Various compositions were prepared, in which the amount of the PEO groups varied from the composition of types A-J. The composition of types A-G was tested for impregnating rates of various drugs. The test apparatus described in the publication by Yie W. Chien, Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York and Basel 1987, page 173. The fluxes (impregnations) of the drugs were measured in the test. of the membranes with a two compartment diffusion cell at 37 ° C (side-by-side diffusion cells, Crown Glass Company). The apparatus consists of two concentric cells (donor and receptor compartments) that were separated by the membrane of the elastomer to be investigated. The donor and receiver compartments were jacketed and a thermostat was placed through an external circulating bath and each of the compartments has a magnetic stirrer. A solution of the drug and the solvent (without the drug) were added in the donor and receptor compartments. At each predetermined time interval, the samples were taken out of the receiver compartment and replaced with the same volume of solvent. The amount of the drug that was impregnated through the membrane was measured by HPLC. in all measurements, the thickness (0.4 mm) of the membrane and the surface area of the membranes was constant. In the tests described below, the rates of impregnation of two different drugs were measured through an elastomer membrane 0.4 mm thick when using the assay apparatus described above. The tables below show the effect of the concentration of the PEO groups (% by weight of said compositions) on the impregnation rates of the different drugs for the elastomers prepared from different types of composition. The tables show the "relative impregnation compared to a cross-linked commercial elastomer of dimethyloxy siloxane-methyl siloxane (Mn about 400,000 g / mol) containing a silica filler." Drug 1: Levonorgestrel Type of Impregnation Concentration PEO Composition by Weight% Relative comparison 0 1 A 28.0 14.5 B 3.8 1.5 B 4.1 2.0 B 5.0 2.3 Drug 2: 17-ß-Estradiol Type of Concentration of Compound Composition PEO by% of weight Relat comparison 0 1 A 11.6 21.3 A 26.4 110 B 7.8 13.3 B 9.8 24.4 C 3.4 4.6 D 52.3 90.4 E 11.4 7.7 F 1.3 2.4 G 0.5 1.4 The impregnation tests carried out showed that an increased concentration of PEO in the membrane increased the impregnation rate for each of the types of composition and for each of the proven drugs, regardless of whether the drug concerned was hydrophilic or lipophilic. An elastomer composition according to the invention is, for example, highly suitable for controlling, in implants and intravaginal intrauterine devices, the impregnation rates of drugs that have a hormonal action. The most important drugs that have a hormonal action include antiprogestins, estradiol progestins and androgens. In the above embodiments of the invention are only examples of the implementation of the idea of the invention. For a person skilled in the art it is clear that the different embodiments of the invention may vary within the framework of the claims presented below.

Claims (22)

1. CLAIMS 1. A membrane or matrix for controlling the rate of impregnation of a drug, wherein the membrane or matrix comprises a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer, characterized in that the elastomer composition comprises polyalkylene oxide groups, and in that the polyalkylene oxide groups are present in the elastomer or the polymer as finished alkoxyl grafts of polysiloxane units, or as blocks, the grafts or blocks are linked to the polysiloxane units through silicone-carbon bonds, or a mixture of these forms.
2. 2. The membrane or matrix according to the Claim 1, characterized in that in the composition of the elastomer there is an elastomer formed by polysiloxane units comprising polyalkylene oxide groups 3. The membrane or matrix according to Claim 1 or 2, characterized in that the polyalkylene oxide groups are poly (ethylene oxide) groups (PEO groups). The membrane or matrix according to Claim 2 or 3, characterized in that the formula of the polysiloxane groups is - (SiR'R '' 0) qSiR'R "- where R 'and R" are partially groups free, which are the same or different, which are a lower alkyl group, or a phenyl group, in which case the alkyl or phenyl group may be substituted or unsubstituted, or terminated alkoxy poly (alkylene oxide) groups having the formula - R3-0- (CH-CH2-0) m-alk, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl, R3 is a straight or branched chain C2-C6 alkyl group and m is 1 ... 30, - partial bonds formed from the hydrogen or alkylene groups to other polymer chains in the elastomer, and - possibly partially unreacted groups, such as hydrogen, vinyl, or vinyl-terminated alkene, and - which is 1 ... 3000. 5. The membrane or matrix according to the Claim 4, characterized in that the free groups of R 'and R "are a lower alkyl group, preferably methyl. The membrane or matrix according to Claim 2 or 3, characterized in that the poly (alkylene oxide) groups are present in the elastomer in the form of poly (alkylene oxide) blocks having the formula R-R30 (CHCH20) mR4-, or JX R. Ri -CH2CHCOO (CHCH20) mCOCHCH2-, where R is hydrogen, a lower alkyl or phenyl, Rx is hydrogen or a lower alkyl, R3 and R4 are the same or different and are straight or branched chain C-C6 alkyl groups, and m is 1 ... 30. The membrane or matrix according to claim 1, characterized in that the composition of the elastomer is formed of two elastomers intertwined one inside the other, in which case - the first elastomer comprises poly (alkylene oxide) groups, and that the Poly (alkylene oxide) groups are present in the elastomer as finished alkoxyl grafts of the polysiloxane units, or as blocks, in which case the grafts or blocks are linked to the polysiloxane units through silicone-carbon bonds , or as a mixture of these forms, and that - the second elastomer is a siloxane-based elastomer. The membrane or matrix according to Claim 7, characterized in that the second elastomer is an elastomer based on a poly (dimethyl siloxane) that possibly comprises polyalkylene oxide groups 9. The membrane or matrix according to Claim 8, characterized in that the possible poly (alkylene oxide) groups of the second elastomer based on poly (dimethyl siloxane) are present in the form of finished alkoxy grafts of poly (siloxane dimethyl) units or as blocks, where the grafts or blocks are linked to the poly (dimethyl siloxane) units through silicone-carbon bonds, or as a mixture of these forms. 10. The membrane or matrix according to the Claim 1, characterized in that the composition of the elastomer is a mixture comprising - a siloxane-based elastomer and - a straight chain of the polysiloxane copolymer comprising poly (alkylene oxide) groups, in which case the poly (oxide) groups alkylene) are present in the polymer as finished alkoxyl grafts of the polysiloxane units, or as blocks, where the grafts or blocks are linked to the polysiloxane units through carbon-silicone bonds, or a mixture of these forms. The membrane or matrix according to Claim 10, characterized in that the polyalkylene oxide groups are poly (ethylene oxide) groups (PEO groups). The membrane or matrix according to Claim 10 or 11, characterized in that the formula of the polysiloxane groups is - (SiR'R'O) g SiR'R "- _ where R 'and R" are the same or different and are a lower alkyl group, or a phenyl group, in which case the alkyl or phenyl group can be substituted or unsubstituted, or the polyalkylene oxide groups terminated by alkoxy have the formula RI -R3 -O- ( CH-CH-0) m alk, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl, R3 is straight or branched C2-Cs alkyl group, m is 1 ... 30, and q is 1 ... 3000 The membrane or matrix according to Claim 12, characterized in that the free groups of R 'and R "are lower alkyl groups, preferably methyl. 14. The membrane or matrix according to Claim 10 or Claim 11, characterized in that the polyalkylene oxide groups are present in the straight chain polysiloxane polymer in the form of poly (alkylene oxide) blocks having the formula R-R30 (CHCH20) mR4 -, or Ri R Ri -CH2CHCOO (CHCH20) mCOCHCH2-, where R is hydrogen, a lower alkyl or a phenyl, Ri is hydrogen or a lower alkyl, R3 and R4 are the same or different and are C2-C6 alkyl groups of straight or branched chain, and m is 1 ... 30. 15. The membrane or matrix according to Claim 10, characterized in that the elastomer based on siloxane is formed of poly (dimethyl siloxane). The membrane or matrix according to any of Claims 1 - 15, characterized in that the siloxane-based elastomer comprises poly (alkylene oxide) groups, and that the polyalkylene oxide groups are present in the elastomer or the polymer as finished alkoxy grafts of polysiloxane units, or as blocks, the grafts or blocks are linked to the polysiloxane units through silicone-carbon bonds, or a mixture of these forms. The membrane or matrix according to any of Claims 1-16, characterized in that it contains a filler, suitably silica. 18. A method for the preparation of a siloxane-based elastomer comprising the poly (alkylene oxide) groups and is intended for use in a membrane or matrix to control the rate of drug impregnation, characterized in that a) a Functional vinyl polymer component and a functional hydride component are crosslinked in the presence of a catalyst, or b) a polymer component is crosslinked in the presence of a peroxide catalyst. The method according to claim 18, characterized in that the amounts of the functional vinyl component and the functional hydride component are selected so that the ratio of the molar amount of the hydride to the molar amount of the double bonds is at least 1. 20. The method according to Claim 18 or Claim 19, characterized in that I) the functional vinyl polymer component is a) a functional vinyl polysiloxane having the formula R '-SiR'R "O (SiR) 'R' O) r SiR'R''R 'where R' and R "are the same or different and are a lower alkyl group or a phenyl group, in which case the alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R 'and / or R "have been substituted by vinyl groups, and r is 1 ... 27000, or b) a finished alkylene of block copolymer based on polysiloxane having the formula T (AB) XAT (I), where A = - (SiR'R '' =) qSiR'R '' -, where R 'and R' 'are equal or different and are a lower alkyl group or a phenyl group, in which case the alkyl or phenyl group may be substituted or unsubstituted; B is a poly (alkylene oxide) having the formula R I -R30 (CHCH20) mR4-, or R-i R R-i I I I -CH2CHC00 (CHCH20) mCOCHCH2-, and T is R-RxO (CHCH20) mR3-, or Ji R. Ri -CH2 = CCOO (CHCH20) mCOCHCH2-, where R is hydrogen, a lower alkyl or phenyl, Rx is hydrogen or a lower alkyl, R3 and R4 are the same or different and are straight or branched chain C2-Ce alkylene groups, R1 is a straight or branched chain C2-C6 alkylene group, m is 1 ... 30, q is 1 ... 3000, and x is 1 ... 100, or c) a functional vinyl polysiloxane copolymer having the formula R '-SiR'R "O (SiR'R" O) r (SiR'R' O) pSiR 'R "-R' - where, in the first block, R 'and R "are the same or different and are a lower alkyl group, or a phenyl group, in which case the alkyl or phenyl group can be substituted or unsubstituted, and where some of the substituents R 'and / or R' 'have been replaced by vinyl groups, and r is 1 ... 27000, and - where, in the second block, R' is a lower alkyl group, or a poly (alkylene oxide alkoxy) group finished that has the formula R -R -O- (CH-CH2-0) m-alk, where alk is an alkyl group lower ilo, suitably methyl, R3 is a straight or branched C2-C6 alkyl group, R is hydrogen or a lower alkyl, m is 1 ... 30, or e) a mixture of at least two of the aforementioned components in a) - d), and that II) the functional hydride component is a) a functional hydride siloxane which may be a straight chain, in the form of a star, branched or cyclic, or b) a block copolymer based on siloxane of finished hydride having the formula T (BA) XBT (II), where T = H-SiR'R '' O (SiR'R 'O) qSiR'R' '-, A = -SiR'R' 'O ( SiR'R 'O) qSiR'R' '-, where R' and R "are the same or different and the lower alkyl group or a phenyl group, in which case the alkyl or phenyl group can be substituted or unsubstituted, -B is a poly (alkylene oxide) having the formula RI -R30 (CHCH20) mR4-, or Ri R i - | | I-CH2CHCOO (CHCH20) raCOCHCH2-, where R is hydrogen, a lower alkyl or phenyl, Rx is hydrogen or a lower alkyl, R3 and R are the same or different and are straight or branched chain C2-Cg alkyl groups, 1 ... 30, q is 1 ... 3000, and x is o ... loo, or c) a mixture of components a) and b) mentioned above. The method according to claim 20, characterized in that the functional hydride siloxane copolymer is a straight chain and that its formula is R '-SiR'R "O (SiR'R" 0) rSiR'R "R 'where R' and R '' are the same or different and are a lower alkyl group or a phenyl group, in which case the alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R 'and / or R' 'have been replaced by hydrogen, and r is 1 ... 27000. 22. The method according to any of Claims 18-21, characterized in that the functional vinyl polymer component contains a filler, suitably silica.