WO2000000550A1 - A membrane or matrix for controlling the permeation rate of drugs - Google Patents

A membrane or matrix for controlling the permeation rate of drugs Download PDF

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Publication number
WO2000000550A1
WO2000000550A1 PCT/FI1999/000511 FI9900511W WO0000550A1 WO 2000000550 A1 WO2000000550 A1 WO 2000000550A1 FI 9900511 W FI9900511 W FI 9900511W WO 0000550 A1 WO0000550 A1 WO 0000550A1
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WO
WIPO (PCT)
Prior art keywords
groups
poly
lower alkyl
alkylene oxide
sir
Prior art date
Application number
PCT/FI1999/000511
Other languages
French (fr)
Inventor
Harri Jukarainen
Tommi Markkula
Juha Ala-Sorvari
Matti Lehtinen
Jarkko Ruohonen
Original Assignee
Leiras Oy
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE69923992T priority Critical patent/DE69923992T2/en
Priority to HU0102600A priority patent/HU229159B1/en
Application filed by Leiras Oy filed Critical Leiras Oy
Priority to NZ508275A priority patent/NZ508275A/en
Priority to DK99931285T priority patent/DK1124902T3/en
Priority to EP99931285A priority patent/EP1124902B1/en
Priority to BRPI9911140-3A priority patent/BR9911140B1/en
Priority to EEP200000788A priority patent/EE04685B1/en
Priority to CA002336149A priority patent/CA2336149C/en
Priority to AU47839/99A priority patent/AU752895B2/en
Priority to AT99931285T priority patent/ATE290049T1/en
Priority to SK1894-2000A priority patent/SK285325B6/en
Priority to PL99345103A priority patent/PL193485B1/en
Priority to JP2000557307A priority patent/JP2002519467A/en
Priority to UA2001010652A priority patent/UA71566C2/en
Publication of WO2000000550A1 publication Critical patent/WO2000000550A1/en
Priority to NO20006581A priority patent/NO327955B1/en
Priority to HK02100469A priority patent/HK1038939A1/en
Priority to US10/298,197 priority patent/US6887948B2/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L83/00—Compositions of macromolecular compounds obtained by reactions forming in the main chain of the macromolecule a linkage containing silicon with or without sulfur, nitrogen, oxygen or carbon only; Compositions of derivatives of such polymers
    • C08L83/10—Block- or graft-copolymers containing polysiloxane sequences
    • C08L83/12—Block- or graft-copolymers containing polysiloxane sequences containing polyether sequences
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
    • A61K9/0039—Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception

Definitions

  • the invention relates to a membrane or matrix intended for controlling the permeation rate of a drug, wherein said membrane or matrix comprises a siloxane-based elastomer composition, and to a method for the preparation of said elastomer composition.
  • Polysiloxanes in particular pol (dimethyl siloxane) (PDMS), are highly suitable for use as a membrane or matrix regulating the permeation rate of drugs in various drug forms, in particular in implants and IU systems.
  • PDMS dimethyl siloxane
  • Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required strength properties .
  • the object of the invention is to provide an elastomer composition which is easy to prepare, through which a drug migrates at the desired rate, and which gives the membrane the required mechanical properties.
  • the object of the invention is in particular to provide an elastomer composition through which the permeation rate of drugs with hormonal action can be controlled.
  • the invention thus relates to a membrane or matrix intended for controlling the permeation rate of a drug, said membrane or matrix comprising 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 poly(alkylene oxide) groups are present in the elastomer or polymer as alkoxy-terminated grafts of polysiloxane units, or as blocks, the said blocks or grafts being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.
  • the invention also relates to a method for the preparation of a siloxane-based elastomer which comprises poly(alkylene oxide) groups and is intended for use in a membrane or matrix for controlling the permeation rate of drugs .
  • the method is characterized in that a) a vinyl-functional polymer component and a hydride-functional component are crosslinked in the presence of a catalyst, or that b) a polymer component is crosslinked in the presence of a peroxide catalyst.
  • elastomer composition may stand for one single elastomer, in which case the polysiloxane units which contain poly(alkylene oxide) groups are present in the said elastomer .
  • the elastomer composition may be made up of two elastomers which are interlaced, one inside the other.
  • the first elastomer comprises poly(alkylene oxide) groups so that the poly(alkylene oxide) groups are present in the said elastomer either 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.
  • the pol (alkylene oxides) may also be present as a blend of the options mentioned.
  • the second elastomer may be a siloxane-based elastomer, suitably a poly(dimethyl siloxane ) -based elastomer.
  • the said second elastomer may possibly also comprise poly(alkylene oxide) groups. These poly(alkylene oxide) groups may also be present either as alkoxy-terminated grafts of poly(dimethyl siloxane) units or as blocks, the said grafts or blocks being linked to the poly(dimethyl siloxane) units by silicon-carbon bonds.
  • the poly(alkylene oxides) may also in this elastomer be present as a blend of the options mentioned above.
  • the elastomer composition may be a blend which comprises a siloxane-based elastomer, which is, for example, made up of PDMS, and at least one straight-chain polysiloxane copolymer which comprises poly(alkylene oxide) groups.
  • the poly(alkylene oxide) groups are present in the said polymer either 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.
  • the poly(alkylene oxide) groups may, of course, also be present in the polymer as a blend of the forms mentioned.
  • the siloxane-based elastomer may comprise poly(alkylene oxide) groups, in which case these poly(alkylene oxide) groups are present in the elastomer either as alkoxy-terminated grafts of polysiloxane units or as blocks, the said blocks or grafts being linked to the polysiloxane units by silicon-carbon bonds.
  • the poly(alkylene oxide) groups may also be present as a blend of the forms mentioned.
  • the elastomer composition may also be made up of two elastomers interlaced one inside the other, as above, and at least one straight-chain polysiloxane copolymer which comprises poly(alkylene oxide) groups.
  • the poly(alkylene oxide) groups of the elastomer composition may suitably be, for example, poly(ethylene oxide) groups (PEO groups).
  • the polysiloxane units of the elastomer composition are preferably groups having the formula
  • R' and R' ' are - partly free groups, which are the same or different and which are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl groups may be substituted or unsubstituted, or alkoxy-terminated poly(alkylene oxide) groups having the formula R
  • alk is a lower alkyl group, suitably methyl
  • R is hydrogen or a lower alkyl
  • m is 1...30
  • R 3 is a straight or branched C 2 - C 6 alkyl group, - partly bonds, formed from the hydrogen or alkylene groups, to other polymer chains in the elastomer, and
  • lower alkyl stands here and generally in the description of the present invention for C 2 - C 6 alkyl groups.
  • R' and R' ' groups are suitably a lower alkyl group, preferably methyl.
  • poly(alkylene oxide) group means that said group comprises at least two alkyl ether groups successively connected to each other.
  • the poly(alkylene oxide) groups are present in the elastomer in the form of poly(alkylene oxide) blocks having the formula
  • R is hydrogen, a lower alkyl or a phenyl
  • Ri is hydrogen or a lower alkyl
  • y is 2...6, and m is 1...30.
  • the elastomer composition suitably contains a filler, such as silica, in order that the membrane should obtain a sufficient strength.
  • membrane means the same as film.
  • the novel elastomer is prepared by crosslinking, in the presence of a catalyst, a vinyl-functional polymer component and a hydride-functional siloxane component.
  • crosslinking is meant the addition reaction of the hydride-functional siloxane component with the carbon- carbon double bond of the vinyl-functional polymer component .
  • the elastomer is prepared by crosslinking the polymer in the presence of a peroxide catalyst.
  • a peroxide catalyst In this case the vinyl and methyl groups react with each other and form carbon-carbon bonds.
  • a crosslink may also be formed between two methyl groups or between two vinyl groups .
  • the amounts of the components are preferably selected so that the ratio of the molar amounts of the hydrides and the double bonds is at least 1.
  • the vinyl-functional polymer component may be any vinyl-functional polymer component.
  • R' and R' ' are the same or different, and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsub- stituted, and where some of the substituents R' and/or R' ' have been substituted for by vinyl groups, and r is 1...27000, or
  • A -(SiR'R' '0) q SiR'R' '-, where R' and R'' are the same or different and are a lower alkyl group, or a phenyl, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
  • B is a poly(alkylene oxide) having the formula R
  • R is hydrogen, a lower alkyl or phenyl
  • Rj is hydrogen or a lower alkyl
  • R 3 and R A are the same or different and are straight-chain or branched C 2 - C 6 alkylene groups
  • R 1 is a straight-chain or branched C 2 - C 6 alkenyl group
  • m is 1...30
  • q is 1...3000
  • x is 0...100, or
  • R' and R' ' are the same or different and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R'' have been substituted for by vinyl groups, and r is 1...27000, and
  • R' is a lower alkyl group, or an alkoxy-terminated poly(alkylene oxide) group having the formula R -R -0-(CH-CH 2 -0) m -alk, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl group, R 3 is a straight or branched C 2 - C 6 alkyl, and m is 1...30, or R' is a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and R' ' is a lower alkyl or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and p is 1...5000, or
  • R 1 and R 2 are the same or different straight-chain or branched C 2 - C 6 alkenyl groups, R is hydrogen or a lower alkyl, and m is 1...30, or
  • the formula of the vinyl-functional polysiloxane copolymer is, in accordance with the above description, R'-SiR'R"0(SiR'R"0) r (SiR'R"0) p SiR'R"-R' f it should be noted that the formula is a kind of gross formula, in which the blocks in successive parentheses may appear in any order in relation to one another. Furthermore, it is preferable that both a vinyl group and the above-mentioned alkoxy-terminated poly(alkylene oxide) group are not bonded to one and the same Si atom.
  • the hydride-functional component may be
  • a hydride-functional siloxane which may be straight- chain, star shaped, branched or cyclic, or
  • R' and R" are the same or different and are a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
  • B is a poly(alkylene oxide) having the formula R -R 3 -0(CHCH 2 0) m R*-, or
  • R is hydrogen, a lower alkyl or a phenyl
  • R l is hydrogen or a lower alkyl
  • R 3 and R 4 are the same or dif- ferent and are straight-chain or branched C 2 - C 6 alkyl groups
  • m is 1...30
  • q is 1...3000
  • x is 0...100, or
  • the hydride-functional siloxane copolymer may be straight-chain, in which case its formula is
  • R' and R' ' are the same or different and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsub- stituted, and where some of the substituents R' and/or R' ' have been substituted for by hydrogen, and r is 1...27000.
  • the vinyl-functional polymer component may contain a filler, suitably silica.
  • the catalyst to be used in the crosslinking is suitably a noble metal catalyst, most commonly a platinum complex in alcohol, xylene, divinyl siloxane or cyclic vinyl siloxane.
  • a noble metal catalyst most commonly a platinum complex in alcohol, xylene, divinyl siloxane or cyclic vinyl siloxane.
  • An especially suitable catalyst is a Pt ( 0 )-divinyl- tetramethyl disiloxane complex.
  • the elastomer composition made up of two elastomers is prepared so that initially a first elastomer is formed, whereafter a second elastomer is formed by crosslinking in the presence of the first elastomer. Thus the second elastomer will penetrate through the first elastomer.
  • the elastomer composition which comprises an elastomer and a straight-chain polymer is prepared, for example, by blending a vinyl-functional polymer component, a hydride- functional component, and a polymer which has no vinyl or hydride groups.
  • the vinyl-functional polymer component and the hydride-functional component form an elastomer, but the polymer component which does not contain the said functional groups will not take part in the crosslinking reaction but will remain, in a straight- chain form, inside the elastomer.
  • Elastomer compositions of different types were prepared. Of most composition types there were prepared different compositions which differed one from another with respect to the PEO amount. Elastomer membranes representing the different compositions were tested with respect to the permeation rates of various drugs . Elastomer compositions prepared
  • elastomer compositions A - H described below, an addition reaction between vinyl groups and silyl hydride groups was used for the crosslinking, i.e. for producing a network structure.
  • the hydride-functional siloxane polymer serving as the crosslinking agent contained at least two Si-H groups, which reacted with the carbon-carbon double bond of the polymer to be crosslinked.
  • Membranes made from elastomer compositions I and J were prepared by using peroxide as the catalyst for crosslinking, in which case the vinyl or methyl groups reacted, forming carbon-carbon bonds.
  • composition types A, D, F and H there was first prepared a basic polymer blend, in which case all of the vinyl-containing polymers and the fillers, or vinyl-containing polymers which contained a filler, were mixed together.
  • the filler used was silica.
  • Composition types A, D, F and H had only one vinyl-containing polymer each, and thus they themselves were basic polymers .
  • the basic polymer blend 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 the crosslinking.
  • the obtained blend was crosslinked at a temperature which was higher than the decomposition temperature of the inhibitor and at which the crosslinking reaction took place at the desired velocity.
  • a blend can be made of the compositions also directly in one step, in which case the ingredients can be added in the following order: vinyl-containing polymers, inhibitor, catalyst and crosslinking agent.
  • Composition Polymers containing vinyl groups Crosslinking type in the basic polymer blend agent ⁇ , ⁇ -divinyl ether poly(ethylene Hydride-functional oxide)-poly(dimethyl siloxane) siloxane multi-block copolymer (PEO- (-PDMS-PE0) n )
  • PEO- (PDMS-PEO) n together or ⁇ , ⁇ -bis(dimethyl silyl separately with a siloxane polyhydride ) -poly(dimethyl mer which does or does not siloxane ) -poly( ethylcontain a filler ene oxide) multi- block copolymer (PDMS- (PE0-PDMS) n ) together or separately with a hydride-functional siloxane .
  • PEODIVI poly(ethylene Hydride-functional oxide
  • PDMS-PEO graft copolymer and a Hydride-functional siloxane polymer which does or siloxane does not contain a filler ⁇ , ⁇ -diallyl ether poly(ethylene Hydride-functional oxide) -poly(dimethyl siloxane) siloxane multi-block copolymer APEO- (-PDMS-APEO) n )
  • PEO- (PDMS-PEO) n PEO- (PDMS-PEO) n and a siloxane Peroxide polymer which does or does not contain a filler
  • DMS-HMS crosslinking agent , ⁇ -di( trimethyl silyl) dimethyl siloxane-hydromethyl siloxane copolymer Silopren U Vernetzer 730 (Bayer AG) having a Si-H content of 7.1 mmol/g, a molar mass of 2800 g/mol and a DMS group to HMS group ratio of 1:1.
  • the PEO( -PDMS-PEO) n which was used as the initial substance was prepared as follows:
  • the reaction solution was stirred over a magnetic stirring plate at 200 rpm, and dry oxygen was directed through the solution in order to prevent the deactivation of the catalyst.
  • the reaction solution was heated to 50 °C, whereafter the catalyst (Pt(0) divinyl- tetramethyl disiloxane complex) was added to the solution through the septum.
  • the amount of platinum was 30 ppm, calculated from the amount of reactants .
  • the polymerization was monitored by means of IR until the reactions were complete (loss of the Si-H peak at 2130 cm 1 ), which took approximately 4 h.
  • the toluene was distilled off from the solution by raising the temperature to 65 °C and by lowering the pressure to 5 bar for a period of 1 h.
  • Portion I contained PEO- (PDMS- PEO ) n and the platinum catalyst.
  • Portion II contained PEO- (PDMS-PEO) n , the crosslinking agent and the inhibitor. Portions I and II were combined by mixing immediately before the crosslinking.
  • Portion I was prepared using a chamber mixer. 5.489 g of the basic polymer and 0.011 g of the platinum catalyst were weighed into the mixing chamber. The ingredients were agitated until the blend 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 was prepared by weighing 0.059 g of ETCH and 9.941 g of Silopren ⁇ Vernetzer 730 into a glass vessel and by stirring the mixture in a water bath of +37 °C until ETCH had dissolved completely in the crosslinking agent.
  • the amount of inhibitor in the mixture was 0.59 % by weight.
  • Portion II was prepared using a chamber mixer.
  • the mantle of the chamber mixer was cooled by water circulation to a point below room temperature, whereupon the temperature increase due to friction did not raise the temperature to the decomposition temperature of 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 agitated until the blend was homogeneous .
  • Portions I and II were combined immediately before the crosslinking, by adding 5 grams of portion I and 5 grams of portion II into the mixing chamber of the chamber mixer. The ingredients were agitated until the blend was homogeneous . The blend was recovered and was drawn into vacuum to remove air bubbles . Four batches of 2 g of the blend were weighed and crosslinked successively in a hot- press .
  • the weighed blend was placed between two FEP release membranes in the center of a round metal form having a thickness of 0.4 mm and an inner diameter of 8 cm.
  • the blend, together with the forms and the FEP membranes, was placed between the compression surfaces of the hot-press, which surfaces had been heated in advance to +115 °C.
  • the surfaces were pressed together and were kept pressed at a pressure of 200 bar for 5 minutes.
  • the pressure was released and the membrane was allowed to set at room temperature for 24 hours.
  • Round test pieces having a diameter of 22 mm were cut out from the membranes by means of a puncher.
  • the PEO ( -PDMS-PEO ) n was the same as in Example 1, except that the amount of PEO had been increased to 28.0 % by weight and the vinyl content to 0.24 mmol/g by increasing the proportion of PEODIVI in the synthesis of the block copolymer.
  • the vinyl content of the blend was
  • the basic polymer blend was prepared in a chamber mixer. 4.2 grams of the PEO ( -PDMS-PEO ) n block copolymer and 7.8 grams of the DMS-VMS copolymer containing a silica filler were weighed into the mixing chamber. The ingredients were agitated until the blend was homogeneous.
  • Portion I was prepared as in Example 1.
  • the combining of the crosslinking agent and the inhibitor was done, as in Example 1, before mixing with portion II, except that ETCH was weighed in an amount of 0.048 g and Silopren U Vernetzer 730 in an amount of 9.952 g.
  • the amount of inhibitor in the blend was 0.48 % by weight.
  • Portion II was prepared as in Example 1, except that the basic polymer blend 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.
  • the dimethyl siloxane-vinyl methyl siloxane (DMS-VMS) copolymer containing a silica filler was the same as in
  • 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 it was 23.6 % by weight.
  • the said crosslinking agent was prepared as follows:
  • the basic polymer blend was prepared in a chamber mixer. 0.15 grams of the , ⁇ -divinyl ether PEO-PDMS block copolymer and 11.85 grams of the DMS-VMS copolymer containing a silica filler were weighed into the mixing chamber. The ingredients were agitated until the blend was homogeneous .
  • Portion I was prepared as in Example 1. The combining of the crosslinking agent and the inhibitor was done, as in Example 1, before mixing with portion II, except that ETCH was weighed in an amount of 0.022 g and PDMS- ( PEO-PDMS ) n block copolymer in an amount of 9.978 g instead of Vernetzer 730. The amount of inhibitor in the blend was 0.22 % by weight.
  • Portion II was prepared as in Example 1, except that the basic polymer blend 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.
  • the vinyl amount obtained by titration was 7.4 mmol/g.
  • Example 2 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 inhibitor in the mixture was 0.063 % by weight.
  • the catalyst, the crosslinking agent and the inhibitor were the same as in Example 1.
  • the amounts of the ingredients in the composition example were as follows:
  • 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 0.0125 grams and the crosslinking agent in an amount of 9.9875 grams. The amount of inhibitor in the mixture was 0.125 % by weight.
  • the catalyst, the crosslinking agent and the inhibitor were the same as in composition A.
  • the PDMS-PEO graft copolymer used was prepared as follows:
  • the inside temperature of the reactor was raised to 135 °C, and the catalyst (potassium siloxanolate, 0.9 ml, 20 ppm K + ) was added to the reaction solution.
  • the viscosity of the reaction solution began to increase vigorously, and at 1 h from the adding of the catalyst it was possible to deactivate the catalyst by increasing the reactor pressure to 2 bar for a period of 15 minutes by means of carbon dioxide. Thereafter the light cyclic compounds (13 % by weight) were removed from the reaction solution by distillation (10 mbar, 30 in, 135 °C).
  • Product M Clear 190,000 g/mol.
  • the combining of the crosslinking agent and the inhibitor was done 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 inhibitor in the mixture was 10 % by weight.
  • Example 6 The PDMS-PEO graft copolymer was the same as in Example 6. - The DMS-VMS copolymer was the same as in Example 2.
  • the combining of the crosslinking agent and the inhibitor was done as in Example 1, except that ETCH was weighed in an amount of 0.36 g and Silopren U Vernetzer 730 in an amount of 9.64 g. The amount of inhibitor in the mixture was 3.6 % by weight.
  • the crosslinking agent was a DMS-HMS copolymer which contained 22.5 % by weight methyl hydride siloxane groups (Gelest) .
  • the APEO-(-PDMS-APEO) n used was prepared as follows:
  • toluene was weighed into the reaction vessel in an amount of 45 % by weight (7.2 g). The reaction mixture was stirred over a magnetic stirring plate at 200 rpm, and dry oxygen was bubbled through the mixture in order to prevent the deactivation of the catalyst. The temperature of the reaction mixture was raised to 60 °C.
  • the DMS-VMS copolymer containing a silica filler was the same as in Example 2.
  • the PEO- ( PDMS-PEO ) n used was prepared as follows:
  • PEODIVI anhydrous ⁇ , ⁇ -divinyl ether poly(ethylene oxide)
  • PDMSDIH ⁇ -bis (dimethyl silyl hydride)poly(dimethyl silyl siloxane)
  • the PDMSDIH contained hydride groups in an amount of 0.04 % by weight, and thus the amount of hydride groups in 10 grams was 4 mmol and the amount of PEODIVI vinyl groups was 4.4 mmol.
  • the amount of platinum was 50 ppm, calculated from the amount of the reactants.
  • the catalyst was added dropwise, whereby hot spots in the reactor were avoided. After the adding of the catalyst the reaction was allowed to proceed for 2 h. Thereafter the completion of the reaction was confirmed by IR (loss of the Si-H peak at 2130 cm "1 ). After the polymerization the reaction mixture was heated to 65 °C and the toluene was removed by vacuum distillation (5 mbar) in the course of 30 minutes.
  • the amounts of ingredients in the composition example were as follows:
  • compositions in which the amount of PEO groups varied, were prepared of the above-mentioned composition types A - J.
  • Composition types A - G were tested for the permeation rates of various drugs .
  • the drug fluxes (permeations) through membranes were measured with a two-compartment diffusion cell at 37 °C (side-by-side diffusion cell, Crown Glass Company).
  • the apparatus consisted of two concentric cells (donor and receptor compartments) that were separated by the elastomer membrane to be investigated.
  • the donor and receptor compartments were both jacketed and thermostated by an external circulating bath and each compartment had a magnetic stirrer.
  • a drug solution and solvent (without drug) was added into the donor and the receptor compartments .
  • samples were withdrawn from the receptor compartment and replaced with the same volume of solvent.
  • the amount of the drug that permeated 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 were constant.
  • An elastomer composition according to the invention is, for example, highly suited for controlling, in implants and in intrauterine and intravaginal devices, the permeation rates of drugs having hormonal action.
  • the most important drugs having hormonal action include antiprogestins, progestins, estradiols and androgens .

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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 PERMEATION RATE OF DRUGS
The invention relates to a membrane or matrix intended for controlling the permeation rate of a drug, wherein said membrane or matrix comprises a siloxane-based elastomer composition, and to a method for the preparation of said elastomer composition.
STATE OF THE ART
Polysiloxanes, in particular pol (dimethyl siloxane) (PDMS), are highly suitable for use as a membrane or matrix regulating the permeation rate of drugs in various drug forms, in particular in implants and IU systems.
Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required strength properties .
It is known from the literature that the adding of poly- (ethylene oxide) groups, i.e. PEO groups, to a PDMS polymer may increase the permeation rate of drugs . Publication KL Ullman et al., Journal of Controlled Release 10 (1989) 251- 260, describes membranes prepared from a block copolymer which contains PEO and PDMS and the penetration of various steroids through these membranes. It is noted in the publication that an increasing PEO amount in the block polymer tends 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 preparation, and would therefore not be facile in more extensive technical production .
OBJECT OF THE INVENTION
The object of the invention is to provide an elastomer composition which is easy to prepare, through which a drug migrates at the desired rate, and which gives the membrane the required mechanical properties.
The object of the invention is in particular to provide an elastomer composition through which the permeation rate of drugs with hormonal action can be controlled.
SUMMARY OF THE INVENTION
The invention thus relates to a membrane or matrix intended for controlling the permeation rate of a drug, said membrane or matrix comprising 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 poly(alkylene oxide) groups are present in the elastomer or polymer as alkoxy-terminated grafts of polysiloxane units, or as blocks, the said blocks or grafts being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.
The invention also relates to a method for the preparation of a siloxane-based elastomer which comprises poly(alkylene oxide) groups and is intended for use in a membrane or matrix for controlling the permeation rate of drugs . The method is characterized in that a) a vinyl-functional polymer component and a hydride-functional 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 elastomer composition
The term "elastomer composition" may stand for one single elastomer, in which case the polysiloxane units which contain poly(alkylene oxide) groups are present in the said elastomer .
According to another embodiment, the elastomer composition may be made up of two elastomers which are interlaced, one inside the other. In this case the first elastomer comprises poly(alkylene oxide) groups so that the poly(alkylene oxide) groups are present in the said elastomer either 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. The pol (alkylene oxides) may also be present as a blend of the options mentioned. The second elastomer may be a siloxane-based elastomer, suitably a poly(dimethyl siloxane ) -based elastomer. The said second elastomer may possibly also comprise poly(alkylene oxide) groups. These poly(alkylene oxide) groups may also be present either as alkoxy-terminated grafts of poly(dimethyl siloxane) units or as blocks, the said grafts or blocks being linked to the poly(dimethyl siloxane) units by silicon-carbon bonds. The poly(alkylene oxides) may also in this elastomer be present as a blend of the options mentioned above.
According to a third embodiment, the elastomer composition may be a blend which comprises a siloxane-based elastomer, which is, for example, made up of PDMS, and at least one straight-chain polysiloxane copolymer which comprises poly(alkylene oxide) groups. In this case the poly(alkylene oxide) groups are present in the said polymer either 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. The poly(alkylene oxide) groups may, of course, also be present in the polymer as a blend of the forms mentioned. In this embodiment, also the siloxane-based elastomer may comprise poly(alkylene oxide) groups, in which case these poly(alkylene oxide) groups are present in the elastomer either as alkoxy-terminated grafts of polysiloxane units or as blocks, the said blocks or grafts being linked to the polysiloxane units by silicon-carbon bonds. The poly(alkylene oxide) groups may also be present as a blend of the forms mentioned.
Of course, the elastomer composition may also be made up of two elastomers interlaced one inside the other, as above, and at least one straight-chain polysiloxane copolymer which comprises poly(alkylene oxide) groups.
The poly(alkylene oxide) groups of the elastomer composition may suitably be, for example, poly(ethylene oxide) groups (PEO groups).
The polysiloxane units of the elastomer composition are preferably groups having the formula
-(SiR'R' '0)qSiR'R' '-
where R' and R' ' are - partly free groups, which are the same or different and which are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl groups may be substituted or unsubstituted, or alkoxy-terminated poly(alkylene oxide) groups having the formula R
-R3-0-(CH-CH2-0)m-alk, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl, m is 1...30, and R3 is a straight or branched C2 - C6 alkyl group, - partly bonds, formed from the hydrogen or alkylene groups, to other polymer chains in the elastomer, and
- possibly partly unreacted groups, such as hydrogen, vinyl or vinyl-terminated alkene, and
- q is 1...3000.
The term "lower alkyl" stands here and generally in the description of the present invention for 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 said 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)yO(CHCH20)m(CH2)y-, or
Rx R R,
/ i i
-CH2CHC00 ( CHCH20 )mC0CHCH2-
where R is hydrogen, a lower alkyl or a phenyl, Ri is hydrogen or a lower alkyl, y is 2...6, and m is 1...30.
The elastomer composition suitably contains a filler, such as silica, in order that the membrane should obtain a sufficient strength.
The word "membrane" means the same as film.
General description of the method for the preparation of the elastomer composition
According to a preferred embodiment, the novel elastomer is prepared by crosslinking, in the presence of a catalyst, a vinyl-functional polymer component and a hydride-functional siloxane component.
By crosslinking is meant the addition reaction of the hydride-functional siloxane component with the carbon- carbon double bond of the vinyl-functional polymer component .
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 crosslink may also be formed between two methyl groups or between two vinyl groups .
For crosslinking, the amounts of the components are preferably selected so that the ratio of the molar amounts of the hydrides and the double bonds is at least 1.
The vinyl-functional polymer component may be
a) a vinyl-functional polysiloxane having the formula
R'-SiR'R' '0(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 said alkyl or phenyl group may be substituted or unsub- stituted, and where some of the substituents R' and/or R' ' have been substituted for by vinyl groups, and r is 1...27000, or
b) an alkenyl terminated polysiloxane-based block copolymer having the formula
T(AB)χAT (I), where
A = -(SiR'R' '0)qSiR'R' '-, where R' and R'' are the same or different and are a lower alkyl group, or a phenyl, in which case the said alkyl or phenyl group may be substituted or unsubstituted; B is a poly(alkylene oxide) having the formula R
I
-R30 ( CHCH20 )mR4- , or
Figure imgf000009_0001
H2- ,
and T is
R
R1 i0 ( C 'HCH20 )mR ,3- , or
R, R R,
/ ' / CH2=. CCOO ( CHCH20 )mCOCHCH2-
where
R is hydrogen, a lower alkyl or phenyl, Rj is hydrogen or a lower alkyl, R3 and RA are the same or different and are straight-chain or branched C2 - C6 alkylene groups, R1 is a straight-chain or branched C2 - C6 alkenyl group, m is 1...30, q is 1...3000, and x is 0...100, or
c) a vinyl-functional polysiloxane copolymer having the formula
R'-SiR'R' '0(SiR'R' '0)r(SiR'R' '0)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 said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R'' have been substituted for by vinyl groups, and r is 1...27000, and
- where in the second block R' is a lower alkyl group, or an alkoxy-terminated poly(alkylene oxide) group having the formula R -R -0-(CH-CH2-0)m-alk, where alk is a lower alkyl group, suitably 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 said alkyl or phenyl group may be substituted or unsubstituted, and R' ' is a lower alkyl or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and p is 1...5000, or
d) ,ω-dialkenyl poly(alkylene oxide) having the formula R R1-0-(CH2CH20)m-Rz
where R1 and R2 are the same or different straight-chain or branched C2 - C6 alkenyl groups, R is hydrogen or a lower alkyl, and m is 1...30, or
e) a blend of at least two of the above-mentioned components a) - d) .
If the formula of the vinyl-functional polysiloxane copolymer is, in accordance with the above description, R'-SiR'R"0(SiR'R"0)r(SiR'R"0)pSiR'R"-R'f it should be noted that the formula is a kind of gross formula, in which the blocks in successive parentheses may appear in any order in relation to one another. Furthermore, it is preferable that both a vinyl group and the above-mentioned alkoxy-terminated poly(alkylene oxide) group are not bonded to one and the same Si atom.
The hydride-functional component may be
a) a hydride-functional siloxane, which may be straight- chain, star shaped, branched or cyclic, or
b) a hydride-terminated siloxane-based block copolymer having the formula
T(BA)XBT (II), where
T = H-SiR'R' '0(SiR'R' '0)qSiR'R' '-,
A = -SiR'R"0(SiR'R"0)qSiR'R"-, where R' and R" are the same or different and are a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
B is a poly(alkylene oxide) having the formula R -R3-0(CHCH20)mR*-, or
Ri R R, / I I
-CH2CHC00(CHCH20)raC0CHCH2-
where R is hydrogen, a lower alkyl or a phenyl, Rl is hydrogen or a lower alkyl, R3 and R4 are the same or dif- ferent and are straight-chain or branched C2 - C6 alkyl groups, m is 1...30, q is 1...3000, and x is 0...100, or
c) a blend of the above-mentioned components a) and b).
According to one embodiment, the hydride-functional siloxane copolymer may be straight-chain, in which case its formula is
R'-SiR'R' '0(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 said alkyl or phenyl group may be substituted or unsub- stituted, and where some of the substituents R' and/or R' ' have been substituted for by hydrogen, and r is 1...27000. The vinyl-functional polymer component may contain a filler, suitably silica.
The catalyst to be used in the crosslinking is suitably a noble metal catalyst, most commonly a platinum complex in alcohol, xylene, divinyl siloxane or cyclic vinyl siloxane. An especially suitable catalyst is a Pt ( 0 )-divinyl- tetramethyl disiloxane complex.
The elastomer composition made up of two elastomers is prepared so that initially a first elastomer is formed, whereafter a second elastomer is formed by crosslinking in the presence of the first elastomer. Thus the second elastomer will penetrate through the first elastomer.
The elastomer composition which comprises an elastomer and a straight-chain polymer is prepared, for example, by blending a vinyl-functional polymer component, a hydride- functional component, and a polymer which has no vinyl or hydride groups. In the crosslinking, the vinyl-functional polymer component and the hydride-functional component form an elastomer, but the polymer component which does not contain the said 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 examples.
Elastomer compositions of different types (A - J) were prepared. Of most composition types there were prepared different compositions which differed one from another with respect to the PEO amount. Elastomer membranes representing the different compositions were tested with respect to the permeation rates of various drugs . Elastomer compositions prepared
In the elastomer compositions A - H described below, an addition reaction between vinyl groups and silyl hydride groups was used for the crosslinking, i.e. for producing a network structure. The hydride-functional siloxane polymer serving as the crosslinking agent contained at least two Si-H groups, which reacted with the carbon-carbon double bond of the polymer to be crosslinked. Membranes made from elastomer compositions I and J were prepared by using peroxide as the catalyst for crosslinking, in which case the vinyl or methyl groups reacted, forming carbon-carbon bonds. In all the composition types except composition types A, D, F and H, there was first prepared a basic polymer blend, in which case all of the vinyl-containing polymers and the fillers, or vinyl-containing polymers which contained a filler, were mixed together. The filler used was silica. Composition types A, D, F and H had only one vinyl-containing polymer each, and thus they themselves were basic polymers . The basic polymer blend 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 the crosslinking. The obtained blend was crosslinked at a temperature which was higher than the decomposition temperature of the inhibitor and at which the crosslinking reaction took place at the desired velocity.
A blend can be made of the compositions also directly in one step, in which case the ingredients can be added in the following order: vinyl-containing polymers, inhibitor, catalyst and crosslinking agent.
The following table describes elastomer membranes of different composition types and their initial components. Table 1
Composition Polymers containing vinyl groups Crosslinking type in the basic polymer blend agent α,ω-divinyl ether poly(ethylene Hydride-functional oxide)-poly(dimethyl siloxane) siloxane multi-block copolymer (PEO- (-PDMS-PE0)n)
PE0-(PDMS-PE0)n and a siloxane Hydride-functional polymer containing a filler siloxane
PEO- (PDMS-PEO)n together or α,ω-bis(dimethyl silyl separately with a siloxane polyhydride ) -poly(dimethyl mer which does or does not siloxane ) -poly( ethylcontain a filler ene oxide) multi- block copolymer (PDMS- (PE0-PDMS)n) together or separately with a hydride-functional siloxane . α,ω-divinyl ether poly(ethylene Hydride-functional oxide (PEODIVI) siloxane
PEODIVI and a siloxane polymer Hydride-functional which does or does not contain siloxane a filler
PEO-grafted dimethyl siloxane- Hydride-functional methyl vinyl siloxane copolysiloxane mer (PDMS-PEO graft copolymer)
PDMS-PEO graft copolymer and a Hydride-functional siloxane polymer which does or siloxane does not contain a filler α,ω-diallyl ether poly(ethylene Hydride-functional oxide) -poly(dimethyl siloxane) siloxane multi-block copolymer (APEO- (-PDMS-APEO)n)
PEO- (PDMS-PEO)n and a siloxane Peroxide polymer which does or does not contain a filler
PDMS-PEO graft copolymer together Peroxide or separately with a siloxane polymer which does or does not contain a filler EXAMPLE 1
Elastomer membrane prepared from composition type A
Ingredients used for the preparation of the elastomer membrane :
- ,ω-divinyl ether PEO-PDMS block copolymer where the amount of PEO was 27.0 % by weight and the vinyl content was 0.186 mmol/g.
- Platinum catalyst Silopren U Katalysatoren Pt-D (Bayer AG), which had a platinum-siloxane complex in a vinyl- containing siloxane matrix. The platinum content was 1 % by weight and the vinyl content was 0.5 mmol/g.
- Crosslinking agent ,ω-di( trimethyl silyl) dimethyl siloxane-hydromethyl siloxane (DMS-HMS) copolymer Silopren U Vernetzer 730 (Bayer AG) having a Si-H content of 7.1 mmol/g, a molar mass of 2800 g/mol and a DMS group to HMS group ratio of 1:1.
- Inhibitor 1-ethinyl-l-cyclohexanol (ETCH, Aldrich) having a decomposition temperature of +40 °C.
The PEO( -PDMS-PEO)n which was used as the initial substance was prepared as follows:
50 g of anhydrous ct,ω-divinyl ether poly(ethylene oxide) (PEODIVI) having a molar mass of 268 g/mol was weighed into a three-necked flask. In addition, 129.87 g of ,ω- bis (dimethyl silyl hydride) pol (dimethyl siloxane) (PDMSDIH, M„ = 717 g/mol) and 30 % by weight of toluene dried by distillation were weighed into the same vessel. Since vinyl groups were present in excess (3 %) in the reaction, in the final product vinyl groups were obtained at both ends, which was essential for the subsequent crosslinking. The reaction solution was stirred over a magnetic stirring plate at 200 rpm, and dry oxygen was directed through the solution in order to prevent the deactivation of the catalyst. The reaction solution was heated to 50 °C, whereafter the catalyst (Pt(0) divinyl- tetramethyl disiloxane complex) was added to the solution through the septum. The amount of platinum was 30 ppm, calculated from the amount of reactants . Thereafter the polymerization was monitored by means of IR until the reactions were complete (loss of the Si-H peak at 2130 cm1), which took approximately 4 h. After the polymerization, the toluene was distilled off from the solution by raising the temperature to 65 °C and by lowering the pressure to 5 bar for a period of 1 h.
In the preparation of the elastomer, two blends were first prepared, portions I and II. Portion I contained PEO- (PDMS- PEO )n and the platinum catalyst. Portion II contained PEO- (PDMS-PEO)n, the crosslinking agent and the inhibitor. Portions I and II were combined by mixing immediately before the crosslinking.
The amounts of the ingredients in the composition example in the final blend 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 chamber mixer. 5.489 g of the basic polymer and 0.011 g of the platinum catalyst were weighed into the mixing chamber. The ingredients were agitated until the blend 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 was prepared by weighing 0.059 g of ETCH and 9.941 g of Silopren ϋ Vernetzer 730 into a glass vessel and by stirring the mixture in a water bath of +37 °C until ETCH had dissolved completely in the crosslinking agent. The amount of inhibitor in the mixture was 0.59 % by weight.
Portion II was prepared using a chamber mixer. The mantle of the chamber mixer was cooled by water circulation to a point below room temperature, whereupon the temperature increase due to friction did not raise the temperature to the decomposition temperature of 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 agitated until the blend was homogeneous .
Portions I and II were combined immediately before the crosslinking, by adding 5 grams of portion I and 5 grams of portion II into the mixing chamber of the chamber mixer. The ingredients were agitated until the blend was homogeneous . The blend was recovered and was drawn into vacuum to remove air bubbles . Four batches of 2 g of the blend were weighed and crosslinked successively in a hot- press .
The weighed blend was placed between two FEP release membranes in the center of a round metal form having a thickness of 0.4 mm and an inner diameter of 8 cm. The blend, together with the forms and the FEP membranes, was placed between the compression surfaces of the hot-press, which surfaces had been heated in advance to +115 °C. The surfaces were pressed together and were kept pressed at a pressure of 200 bar for 5 minutes. The pressure was released and the membrane was allowed to set at room temperature for 24 hours. Round test pieces having a diameter of 22 mm were cut out from the membranes by means of a puncher. EXAMPLE 2
Elastomer membrane prepared from composition type B
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 had been increased to 28.0 % by weight and the vinyl content to 0.24 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 which contained filler was a dimethyl siloxane-vinyl methyl siloxane (DMS-VMS) copolymer containing a silica filler and having a molar mass of M„ = 400,000 g/mol. The vinyl content of the blend was
0.011 mmol/g. There was 36 % by weight of silica mixed in the polymer, and the silica was surface-treated with α,ω- bis (dimethyl hydroxysilyl ) poly(dimethyl siloxane) (M = 520 g/mol), which was present in an amount of 12 % by weight in the blend.
The amounts of ingredients in the composition example were as follows:
- PEO ( -PDMS-PEO )n 32.8 % by weight
- DMS-VMS copolymer containing a silica filler, 60.9 % by weight
- Platinum catalyst 0.1 % by weight
- Crosslinking agent 6.19 % by weight
- Inhibitor 0.03 % by weight
First the basic polymer blend was prepared in a chamber mixer. 4.2 grams of the PEO ( -PDMS-PEO )n block copolymer and 7.8 grams of the DMS-VMS copolymer containing a silica filler were weighed into the mixing chamber. The ingredients were agitated until the blend was homogeneous.
Portion I was prepared as in Example 1.
The combining of the crosslinking agent and the inhibitor was done, as in Example 1, before mixing with portion II, except that ETCH was weighed in an amount of 0.048 g and Silopren U Vernetzer 730 in an amount of 9.952 g. The amount of inhibitor in the blend was 0.48 % by weight.
Portion II was prepared as in Example 1, except that the basic polymer blend 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 blend were weighed and were crosslinked successively in a hot-press, as in Example 1.
EXAMPLE 3
Elastomer membrane prepared from composition type C
Ingredients 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 (DMS-VMS) copolymer 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 it was 23.6 % by weight.
The said crosslinking agent was prepared as follows:
40 g of an anhydrous α,ω-divinyl ether poly(ethylene oxide) (PEODIVI) having a molar mass of 246.3 g/mol was weighed into a three-necked flask. In addition, 129.4 g of α,ω- bis (dimethyl silyl hydride) poly(dimethyl siloxane) (PDMSDIH, M-, = 717 g/mol) and 30 % by weight of toluene dried by distillation were weighed into the same vessel. Since dimethyl silyl hydride groups were present in excess (10 %) in the reaction, dimethyl silyl hydride groups were obtained at both ends in the final product. The reaction solution was stirred over a magnetic stirring plate at 200 rpm, and dry oxygen was directed through the solution to prevent the deactivation of the catalyst. The reaction solution was heated to 50 °C, whereafter the catalyst
(Pt(0) divinyl-tetramethyl siloxane complex) was added to the solution through the septum. The amount of platinum was 30 ppm, calculated from the amount of the reactants. Thereafter the polymerization was monitored by means of IR until the reactions were complete (loss of the vinyl peak at 1600 cm1), which took approximately 4 h. After the polymerization, the toluene was removed from the solution by distillation by raising the temperature to 65 °C and by lowering the pressure to 5 mbar for a period of 1 h.
The amounts of the ingredients in the composition example were as follows:
- PEO ( -PDMS-PEO )n 1.10 % by weight
- DMS-VMS containing a silica filler, 85.50 % by weight
- Platinum catalyst 0.10 % by weight - Crosslinking agent ,ω-bis- (dimethyl silyl hydride) PEO- PDMS 13.27 % by weight
- Inhibitor 0.03 % by weight
First the basic polymer blend was prepared in a chamber mixer. 0.15 grams of the ,ω-divinyl ether PEO-PDMS block copolymer and 11.85 grams of the DMS-VMS copolymer containing a silica filler were weighed into the mixing chamber. The ingredients were agitated until the blend was homogeneous .
Portion I was prepared as in Example 1. The combining of the crosslinking agent and the inhibitor was done, as in Example 1, before mixing with portion II, except that ETCH was weighed in an amount of 0.022 g and PDMS- ( PEO-PDMS )n block copolymer in an amount of 9.978 g instead of Vernetzer 730. The amount of inhibitor in the blend was 0.22 % by weight.
Portion II was prepared as in Example 1, except that the basic polymer blend 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 I and II were combined as in Example 1. Four batches of 2.1 g of the blend were weighed and were successively crosslinked in a hot-press, as in Example 1.
EXAMPLE 4
Elastomer membrane prepared from composition type D
Ingredients used for the preparation of the elastomer membrane :
- ,ω-divinyl ether poly(ethylene oxide) (PEODIVI) (polyethylene glycol divinyl ether, Aldrich, M„ = 240 g/mol). The vinyl amount obtained by titration was 7.4 mmol/g.
- Catalyst Gelest SIP 6831.0, platinum-siloxane complex in xylene, platinum content 2.25 % by weight.
- The crosslinking agent and the inhibitor were the same as in Example 1. The amounts of the ingredients in the composition example were as follows:
- PEODIVI 52.231 % by weight
- Platinum catalyst 0.045 % by weight - Crosslinking agent 47.694 % by weight
- Inhibitor 0.030 % by weight
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 inhibitor in the mixture was 0.063 % by weight.
5.2231 grams of PEODIVI and 0.0045 grams of the platinum catalyst were mixed together in a glass vessel. 4.772 grams of the mixture of the crosslinking agent and the inhibitor was mixed into it.
Eight batches of 0.8 g of the blend were weighed into flat- bottomed aluminum forms having a diameter of 5 cm and having a FEP membrane on the bottom. The forms were placed under a 100 mbar vacuum at +115 °C for a period of 15 minutes. Test pieces were cut out from the elastomer obtained .
EXAMPLE 5
Elastomer membrane prepared from composition type E
Ingredients used for the preparation of the elastomer membrane:
- PEODIVI , the same as in Example 4.
- DMS-VMS copolymer, the 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 composition example were as follows:
- PEODIVI 11.37 % by weight
- DMS-VMS copolymer 64.46 % by weight - Platinum catalyst 0.1 % by weight
- Crosslinking agent 24.03 % by weight
- Inhibitor 0.03 % by weight
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 0.0125 grams and the crosslinking agent in an amount of 9.9875 grams. The amount of 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 chamber mixer. 0.01 grams of platinum catalyst was added, and the blend was agitated until homogeneous. 2.406 grams of the mixture of the crosslinking agent and the inhibitor was added and the blend was agitated until homogeneous .
Four batches of 2.1 g of the blend were weighed and were successively crosslinked in a hot-press, as in Example 1.
EXAMPLE 6
Elastomer membrane prepared from composition type F
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 PDMS-PEO graft copolymer used was prepared as follows:
600 g of octamethyl cyclotetrasiloxane (DA), 9.28 g of poly- (dimethyl siloxane) -poly(ethylene oxide) graft copolymer (Gelest, DBE-821, containing 80 % by weight PEO), 6.18 g of dimethyl vinyl silyl end-blocked PDMS (end-blocker, Bayer Silopren U2 ) , and 3.1 g of tetramethyl tetravinyl cyclotetrasiloxane were weighed. The reactor was nitrogenated, the weighed chemicals were poured in, and stirring was started. The inside temperature of the reactor was raised to 135 °C, and the catalyst (potassium siloxanolate, 0.9 ml, 20 ppm K+) was added to the reaction solution. The viscosity of the reaction solution began to increase vigorously, and at 1 h from the adding of the catalyst it was possible to deactivate the catalyst by increasing the reactor pressure to 2 bar for a period of 15 minutes by means of carbon dioxide. Thereafter the light cyclic compounds (13 % by weight) were removed from the reaction solution by distillation (10 mbar, 30 in, 135 °C). Product M„ = 190,000 g/mol.
The amounts of the ingredients in the composition example were as follows:
- Basic polymer PDMS-PEO graft copolymer 96.10 % by weight
- Platinum catalyst 0.5 % by weight
- Crosslinking agent 3.06 % by weight - Inhibitor 0.34 % by weight
The combining of the crosslinking agent and the inhibitor was done 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 inhibitor in the mixture was 10 % by weight.
9.61 grams of the PDMS-PEO graft copolymer and 0.05 grams of the platinum catalyst were mixed together. 0.34 grams of the mixture of the crosslinking agent and the inhibitor was added and the blend was stirred until homogeneous.
Four batches of 2.1 g of the blend were weighed and were successively crosslinked in a hot-press, as in Example 1.
EXAMPLE 7
Elastomer membrane prepared from composition type G
Ingredients used for the preparation of the elastomer membrane :
- 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 crosslinking agent and the inhibitor were the same as in Example 1.
The amounts of the ingredients in the composition example were as follows:
- PDMS-PEO graft copolymer 26.75 % by weight
- DMS-VMS copolymer 72.31 % by weight
- Platinum catalyst 0.10 % by weight
- Crosslinking agent 0.81 % by weight
- Inhibitor 0.03 % by weight
The combining of the crosslinking agent and the inhibitor was done as in Example 1, except that ETCH was weighed in an amount of 0.36 g and Silopren U Vernetzer 730 in an amount of 9.64 g. The amount of inhibitor in the mixture was 3.6 % by weight.
2.675 grams of the PDMS-PEO graft copolymer and 7.231 grams of the DMS-VMS copolymer containing a filler were mixed together. 0.01 grams of the platinum catalyst was added and the blend was stirred until homogeneous. 0.084 grams of the mixture of the crosslinking agent and the inhibitor was added and the blend was stirred until homogeneous.
Four batches of 2.1 g of the blend were weighed and were successively crosslinked in a hot-press, as in Example 1.
EXAMPLE 8
Elastomer membrane prepared from composition type H
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 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 which contained 22.5 % by weight methyl hydride siloxane groups (Gelest) .
The APEO-(-PDMS-APEO)n used was prepared as follows:
Anhydrous ,ω-diallyl poly(ethylene oxide) (PEODIAL) which had a molar mass of 520 g/mol and which was prepared by adapting the procedure disclosed in the publication Mei- Hui, Yang, Laing-Jong, Li, and Tsang-Feng, Ho, Synthesis and Characterization of polymethylsiloxane/poly( ethylene glycol )monomethyl ether copolymers, J. Ch. Colloid & Interface Soc . 3(17), 1994, 19-28 and , ω-bis (dimethyl silyl hydride) poly(dimethyl siloxane) (PDMSDIH, M„ = 6000 g/mol) were weighed into a three-necked flask. The mass of the PEODIAL was 1.38 g (M„ = 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 allyl groups being 10 % greater than that of hydride groups. Thus an α,ω-diallyl- end-blocked final product was ensured. In addition, toluene was weighed into the reaction vessel in an amount of 45 % by weight (7.2 g). The reaction mixture was stirred over a magnetic stirring plate at 200 rpm, and dry oxygen was bubbled through the mixture in order to prevent the deactivation of the catalyst. The temperature of the reaction mixture was raised to 60 °C. Thereafter the catalyst (Pt(0) divinyl tetramethyl disiloxane complex) was added to the reaction solution through the septum, cautiously one drop at the time. The amount of platinum was 50 ppm, calculated from the reactants. The polymerization was allowed to proceed for approximately 6 h, whereafter the completion of the polymerization was confirmed by IR (loss of the Si-H peak at 2130 cm"1). For the removal of the toluene by distillation, the temperature was raised to 65 °C and the pressure was lowered to 5 mbar for a period of 30 min.
The amounts of the ingredients of the composition example were as follows:
- APE0-(-PMDS-APE0)n 94.68 % by weight - Platinum catalyst 0.5 % by weight
- Crosslinking agent 4.7 % by weight
- Inhibitor 0.12 % by weight
3.0 grams of the APEO-(-PMDS-APEO)n, 0.0158 grams of the catalyst, 0.0038 g of the inhibitor, and 0.1489 g of the crosslinking agent were mixed together. The air bubbles were removed from the mixture, and the mixture was crosslinked in a hot-press at 110 °C for 15 minutes and was cured at 110 °C for 15 minutes.
EXAMPLE 9
Elastomer membrane prepared from composition type I
Ingredients used for 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 anhydrous α,ω-divinyl ether poly(ethylene oxide) (PEODIVI) having a molar mass of 240 g/mol was weighed into a three-necked flask. 10 g of ,ω-bis (dimethyl silyl hydride)poly(dimethyl silyl siloxane) (PDMSDIH) having a molar mass of 6000 g/mol was weighed into the same vessel. The PDMSDIH contained hydride groups in an amount of 0.04 % by weight, and thus the amount of hydride groups in 10 grams was 4 mmol and the amount of PEODIVI vinyl groups was 4.4 mmol. Since the vinyl groups were present in excess (10 %) in the reaction, vinyl groups were obtained at both ends of the final product, a fact essential for the subsequent crosslinking. In addition, to facilitate mixing and to prevent the reaction from occurring too vigorously, toluene dried by distillation was added to the reaction mixture so that the proportion of toluene was 30 % by weight (4.5 g). The reaction solution was stirred over a magnetic stirring plate at 200 rpm, and dry oxygen was directed through the solution; this prevented the catalyst from converting to metallic form and thus prevented the deactivation of the catalyst. The reaction solution was heated to 50 °C, whereafter the catalyst (Pt(0) divinyl tetra ethyl disiloxane complex) was added to the mixture through the septum. The amount of platinum was 50 ppm, calculated from the amount of the reactants. The catalyst was added dropwise, whereby hot spots in the reactor were avoided. After the adding of the catalyst the reaction was allowed to proceed for 2 h. Thereafter the completion of the reaction was confirmed by IR (loss of the Si-H peak at 2130 cm"1). After the polymerization the reaction mixture was heated to 65 °C and the toluene was removed by vacuum distillation (5 mbar) in the course of 30 minutes. The amounts of ingredients in the composition example were as follows:
- PEO- (PDMS-PEO )n, 4.9 % by weight
- silica-filled DMS-VMS copolymer, 93.9 % by weight - dichlorobenzoyl peroxide (Perkadox PD50 S, Nusil), 1.2 % by weight .
0.5 g of PEO- (PDMS-PEO )n and 9.5 g of a DMS-VMS copolymer containing a filler were mixed together. 0.12 g of the peroxide catalyst was mixed with the homogeneous blend, and the blend was hardened at a temperature of +115 °C and a pressure of 200 bar for 5 minutes and was cured at +150 °C for 2 hours .
EXAMPLE 10
Elastomer membrane prepared from composition type J
Ingredients used for the preparation of the elastomer:
- PDMS-PEO graft copolymer the same as in Example 6
- Dichlorobenzoyl peroxide Perkadox PD50 S, Nusil
The amounts of the ingredients in the composition example were as follows:
- PDMS-PEO graft copolymer 98.8 % by weight
- Dichlorobenzoyl peroxide Perkadox PD50 S 1.2 % by weight
10 grams of the PDMS-PEO graft copolymer and 0.12 grams of Perkadox PD50 S were mixed together. The blend was hardened at a temperature of +115 °C and a pressure of 200 bar for 5 minutes and was cured at +150 °C for 2 hours.
Permeation tests
Various compositions, in which the amount of PEO groups varied, were prepared of the above-mentioned composition types A - J. Composition types A - G were tested for the permeation rates of various drugs .
The assay apparatus described in the publication Yie W. Chien, Transdermal Controlled Systemic Medications, Marcel Dekker Inc., New York and Basel 1987, page 173, was used in the tests.
The drug fluxes (permeations) through membranes were measured with a two-compartment diffusion cell at 37 °C (side-by-side diffusion cell, Crown Glass Company). The apparatus consisted of two concentric cells (donor and receptor compartments) that were separated by the elastomer membrane to be investigated. The donor and receptor compartments were both jacketed and thermostated by an external circulating bath and each compartment had a magnetic stirrer. A drug solution and solvent (without drug) was added into the donor and the receptor compartments . At each predetermined time interval , samples were withdrawn from the receptor compartment and replaced with the same volume of solvent. The amount of the drug that permeated 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 were constant.
In the tests described below, the permeation rates of two different drugs through a 0.4-mm-thick elastomer membrane were measured by using the assay apparatus described above. The tables below show the effect of the concentration of PEO groups (% by weight of the said compositions) on the permeation rates of the different drugs for elastomers prepared from different composition types. The tables show the relative permeation as compared with a commercial crosslinked dimethyl siloxane-vinyl methyl siloxane elastomer (M,, approximately 400,000 g/mol) containing a silica filler. Drug 1: Levonorgestrel
Composition type PEO concentration Relative
% by weight permeation 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-β-Estradiol Composition type PEO concentration Relative
% by weight permeation 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 permeation tests performed showed that an increasing concentration of PEO in the membrane increased the permeation rate for each composition type and for each drug tested, regardless of whether the drug concerned was hydrophilic or lipophilic.
An elastomer composition according to the invention is, for example, highly suited for controlling, in implants and in intrauterine and intravaginal devices, the permeation rates of drugs having hormonal action.
The most important drugs having hormonal action include antiprogestins, progestins, estradiols and androgens .
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

1. A membrane or matrix for controlling the permeation rate of a drug, said membrane or matrix comprising a siloxane- based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer, charac- terized in that the elastomer composition comprises poly(alkylene oxide) groups, and that the poly(alkylene oxide) groups are present in the elastomer or 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.
2. The membrane or matrix according to Claim 1, characterized in that the elastomer composition is an elastomer made up of polysiloxane units which comprise poly(alkylene oxide) groups.
3. The membrane or matrix according to Claim 1 or 2 , characterized in that the poly(alkylene oxide) groups are polyethylene oxide) groups (PEO groups).
4. The membrane or matrix according to Claim 2 or 3 , char- acterized in that the formula of the polysiloxane groups is
-(SiR'R' '0)qSiR'R' '-
where R' and R' ' are
- partly free groups, which are the same or different and which are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, or alkoxy-terminated poly(alkylene oxide) groups having the formula
R -R-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-chain or branched C2 - C6 alkyl, and m is 1...30,
- partly bonds formed from the hydrogen or alkylene groups to other polymer chains in the elastomer, and - possibly partly unreacted groups, such as hydrogen, vinyl or vinyl-terminated alkene, and
- q is 1...3000.
5. The membrane or matrix according to Claim 4 , characterized in that the free R' and R' ' groups are a lower alkyl group, preferably methyl.
6. 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
-R3-0(CHCH20)mR*-, or
R, R R,
-CH2C 'HC00(CLHCH20)mC0*CHCH2-
where R is hydrogen, a lower alkyl or phenyl, R, is hydrogen or a lower alkyl, R3 and R4 are the same or different and are straight-chain or branched C2 - C6 alkyl groups, and m is 1...30.
7. The membrane or matrix according to Claim 1, characterized in that the elastomer composition is made up of two elastomers interlaced 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 said elastomer as alkoxy-terminated grafts of polysiloxane units, or as blocks, in which case the said grafts or blocks are linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms, and that
- the second elastomer is a siloxane-based elastomer.
8. The membrane or matrix according to Claim 7 , characterized in that the second elastomer is a poly(dimethyl siloxane) -based elastomer which possibly comprises poly(alkylene oxide) groups.
9. The membrane or matrix according to Claim 8 , characterized in that the possible poly(alkylene oxide) groups of the second poly(dimethyl siloxane) -based elastomer are present in the form of alkoxy-terminated grafts of poly(dimethyl siloxane) units, or as blocks, the said grafts or blocks being linked to the poly(dimethyl siloxane) units by silicon-carbon bonds, or as a mixture of these forms.
10. The membrane or matrix according to Claim 1, characterized in that the elastomer composition is a blend which comprises
- a siloxane-based elastomer and
- a straight-chain polysiloxane copolymer which comprises poly(alkylene oxide) groups, in which case the poly(alkylene oxide) groups are present in the said 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 a mixture of these forms.
11. The membrane or matrix according to Claim 10, characterized in that the poly(alkylene oxide) groups are polyethylene oxide) groups (PEO groups).
12. The membrane or matrix according to Claim 10 or 11, characterized in that the formula of the polysiloxane groups is
-(SiR'R' '0)qSiR'R' '- where R' and R' ' are the same or different and are a lower alkyl group, or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, or alkoxy-terminated poly(alkylene oxide) groups having the formula R -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 C2 - C6 alkyl group, m is 1...30, and q is 1...3000.
13. The membrane or matrix according to Claim 12, characterized in that the free R' and R' ' groups are lower alkyl groups , preferably methyl .
14. The membrane or matrix according to Claim 10 or 11, characterized in that the poly(alkylene oxide) groups are present in the straight-chain polysiloxane polymer in the form of poly(alkylene oxide) blocks having the formula
R -R30(CHCH20)ffiR-, or
R, R R,
/ I I
-CH2CHC00 (CHCH20 )mCOCHCH2-
where R is hydrogen, a lower alkyl or phenyl, R: is hydrogen or a lower alkyl, R3 and R are the same or different and are straight-chain or branched C2 - C6 alkyl groups, and m is 1...30.
15. The membrane or matrix according to Claim 10, characterized in that the siloxane-based elastomer is made up of poly(dimethyl siloxane).
16. The membrane or matrix according to any of Claims 10 - 15, characterized in that the siloxane-based elastomer comprises poly(alkylene oxide) groups, and that the poly(alkylene oxide) groups are present in the elastomer or 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.
17. 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 which comprises poly(alkylene oxide) groups and is intended for use in a membrane or matrix controlling the permeation rate of drugs , characterized in that
a) a vinyl-functional polymer component and a hydride- functional component are crosslinked in the presence of a catalyst, or b) a polymer component is crosslinked in the presence of a peroxide catalyst.
19. The method according to Claim 18, characterized in that the amounts of the vinyl-functional component and the hydride-functional component are selected so that the ratio of the molar amount of hydrides to the molar amount of double bonds is at minimum 1.
20. The method according to Claim 18 or 19, characterized in that
I ) the vinyl-f nctional polymer component is
a) a vinyl-functional polysiloxane having the formula
R'-Sir'R' '0(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 said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R' ' have been substituted for by vinyl groups, and r is 1...27000, or
b) an alkenyl terminated polysiloxane-based block copolymer having the formula
T(AB)χAT (I), where
A = -(SiR'R' '0)qSiR'R' '-, where R' and R' ' are the same or different and are a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
B is a poly(alkylene oxide) having the formula
R -R30(CHCH20)mRi-, or
R, R Ri
-CH2CHCOO(CHCH20)mCOCHCH2- and T is
R
R10(CHCH20)mR3, or
R! R Ri CH2=aCCOO(CHCH20)mCOCHCH2-
where R is hydrogen, a lower alkyl or phenyl, Rl is hydrogen or a lower alkyl, R3 and R4 are the same or different and are straight-chain or branched C2 - C6 alkylene groups, R1 is a straight-chain or branched C2 - C6 alkenyl group, m is 1...30, q is 1...3000, and x is
0...100, or
c) a vinyl-functional polysiloxane copolymer having the formula
R'-SiR'R' '0(SiR'R' '0)r(SiR'R' '0)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 said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R' ' have been substituted for by vinyl groups, and r is 1...27000, and
- where, in the second block, R' is a lower alkyl group, or an alkoxy-terminated poly(alkylene oxide) group having the formula
R
-R3-0-(CH-CH2-0)m-alk, where alk is a lower alkyl group, suitably methyl, R3 is a straight or branched C2 - C5 alkyl group, R is hydrogen or a lower alkyl group, and m is 1...30, or R' is a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and R' ' is a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted, and p is 1...5000, or
d) α,ω-dialkenyl poly(alkylene oxide) having the formula
R R1-0-(CH2CH20)m-R2
where R is hydrogen or a lower alkyl, R1 and R2 are the same or different straight-chain or branched C2 - C6 alkenyl groups, and m is 1...30, or
e) a blend of at least two of the above-mentioned components a) - d), and that I) the hydride-functional component is
a) a hydride-functional siloxane which may be straight- chain, star shaped, branched or cyclic, or
b) a hydride-terminated siloxane-based block copolymer having the formula
T(BA)XBT (II), where
T = H-SiR'R' '0(SiR'R' O)qSiR'R"-,
A = -SiR'R"0(SiR'R' '0)qSiR'R' '-, where R' and R' ' are the same or different and are a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted;
B is a poly(alkylene oxide) having the formula
R /
-R3-0(CHCH20)mRA-, or
R, R R,
-CH2C iHCOO(CHCH20)mC0C 'HCH2-
where R is hydrogen, a lower alkyl or phenyl, R, is hydrogen or a lower alkyl, R3 and R4 are the same or different and are straight-chain or branched C2 - C6 alkyl groups, m is 1...30, q is 1...3000, and x is 0...100, or
c) a blend of the above-mentioned components a) and b) .
21. The method according to Claim 20, characterized in that the hydride-functional siloxane copolymer is straight- chain, and that its formula is
R'-SiR'R' '0(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 said alkyl or phenyl group may be substituted or unsubstituted, and where some of the substituents R' and/or R' ' have been substituted for by hydrogen, and r is 1...27000.
22. The method according to any of Claims 18 - 21, characterized in that the vinyl-functional polymer component contains a filler, suitably silica.
PCT/FI1999/000511 1998-06-30 1999-06-11 A membrane or matrix for controlling the permeation rate of drugs WO2000000550A1 (en)

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CA002336149A CA2336149C (en) 1998-06-30 1999-06-11 A membrane or matrix for controlling the permeation rate of drugs
NZ508275A NZ508275A (en) 1998-06-30 1999-06-11 A membrane or matrix containing siloxane based elastomer for controlling the permeation rate of drugs
DK99931285T DK1124902T3 (en) 1998-06-30 1999-06-11 Diaphragm or matrix for controlling the degree of permeation of drugs
EP99931285A EP1124902B1 (en) 1998-06-30 1999-06-11 A membrane or matrix for controlling the permeation rate of drugs
BRPI9911140-3A BR9911140B1 (en) 1998-06-30 1999-06-11 membrane or matrix for controlling the rate of drug permeation and method for preparing an elastomer.
EEP200000788A EE04685B1 (en) 1998-06-30 1999-06-11 The rate-controlling membrane or matrix of the drug
DE69923992T DE69923992T2 (en) 1998-06-30 1999-06-11 Membrane or matrix for controlling the permeation rate of an active substance
AU47839/99A AU752895B2 (en) 1998-06-30 1999-06-11 A membrane or matrix for controlling the permeation rate of drugs
SK1894-2000A SK285325B6 (en) 1998-06-30 1999-06-11 A membrane or matrix for controlling the permeation rate of drugs
AT99931285T ATE290049T1 (en) 1998-06-30 1999-06-11 MEMBRANE OR MATRIX FOR CONTROLLING THE RELEASE RATE OF DRUGS
PL99345103A PL193485B1 (en) 1998-06-30 1999-06-11 A membrane or matrix for controlling the permeation rate of drugs
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UA2001010652A UA71566C2 (en) 1998-06-30 1999-11-06 A membrane for controlling the permeation rate of drugs
NO20006581A NO327955B1 (en) 1998-06-30 2000-12-21 Diaphragm or matrix for regulating the permeation rate of drugs
HK02100469A HK1038939A1 (en) 1998-06-30 2002-01-21 A membrane or matrix for controlling the permeation rate of drugs.
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Cited By (16)

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WO2001047490A1 (en) * 1999-12-23 2001-07-05 Leiras Oy Devices for the delivery of drugs having antiprogestinic properties
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US9452082B2 (en) 2008-09-17 2016-09-27 Bayer Oy Inserter
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Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101239998B1 (en) * 2004-08-25 2013-03-06 유니온 카바이드 케미칼즈 앤드 플라스틱스 테크날러지 엘엘씨 Polymeric film
US8044161B2 (en) 2007-03-12 2011-10-25 Bayer Shering Pharma Oy Use of tocopherol
CN102068914B (en) * 2010-12-13 2012-10-10 大连欧科膜技术工程有限公司 Preparation method of gas separation composite film
CN102008909B (en) * 2010-12-13 2012-10-10 大连欧科膜技术工程有限公司 Preparation method for gas separation composite membrane
ES2834450T3 (en) * 2018-03-05 2021-06-17 Evonik Operations Gmbh Cross-linked polyether-siloxane block copolymers and their use for the production of polyurethane foams

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0882753A1 (en) * 1997-06-02 1998-12-09 Dow Corning Corporation Thickening solvents with elastomeric silicone polyethers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0882753A1 (en) * 1997-06-02 1998-12-09 Dow Corning Corporation Thickening solvents with elastomeric silicone polyethers
US5889108A (en) * 1997-06-02 1999-03-30 Dow Corning Corporation Thickening solvents with elastomeric silicone polyethers

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 1 January 1900, Columbus, Ohio, US; abstract no. 126:200090, HU YUNHUA, ZHOU RENXI: "Synthesis and Drug Release Property of Polysiloxane Containing Pendant Long Alkyl Ether Group" XP002921044 *
ULMAN KATHERINE L. ET AL: "Drug Permeability of Modified Silicone Polymers. I.Silicone-Organic Block Copolymers", JOURNAL OF CONTROLLED RELEASE, vol. 10, 1989, THE NETHERLANDS, pages 251 - 260, XP002921045 *

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US6476079B1 (en) 1999-12-23 2002-11-05 Leiras Oy Devices for the delivery of drugs having antiprogestinic properties
WO2001047490A1 (en) * 1999-12-23 2001-07-05 Leiras Oy Devices for the delivery of drugs having antiprogestinic properties
WO2002032433A1 (en) * 2000-10-20 2002-04-25 Leiras Oy Drug delivery system
WO2004064912A1 (en) * 2003-01-17 2004-08-05 Schering Oy An otorhinological delivery device
US7294345B2 (en) 2003-01-17 2007-11-13 Schering Oy Otorhinological delivery device
US7862552B2 (en) 2005-05-09 2011-01-04 Boston Scientific Scimed, Inc. Medical devices for treating urological and uterine conditions
EP2905014A1 (en) 2008-07-03 2015-08-12 Bayer Oy An intrauterine delivery system for contraception
EP2140860A1 (en) 2008-07-03 2010-01-06 Bayer Schering Pharma Oy An improved method of contraception
US10532025B2 (en) 2008-07-03 2020-01-14 Bayer Oy Intrauterine delivery system for contraception
US9999592B2 (en) 2008-07-03 2018-06-19 Bayer Oy Intrauterine delivery system for contraception
US9615965B2 (en) 2008-09-17 2017-04-11 Bayer Oy Inserter
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US10149784B2 (en) 2010-10-29 2018-12-11 Bayer Oy Inserter for an intrauterine system
WO2013160213A1 (en) 2012-04-23 2013-10-31 Bayer Pharma Aktiengesellschaft Intrauterine application of 18-methyl-15ss,16ss-methylene-19-nor-20-spirox-4-en-3-one systems, intrauterine systems containing 18-methyl-15ss,16ss-methylene-19-nor-20-spirox-4-en-3-one, as well as the use thereof in contraception and gynaecological therapy
WO2013160200A1 (en) 2012-04-23 2013-10-31 Bayer Pharma Aktiengesellschaft Application of 18-methyl-15ss,16ss-methylene-19-nor-20-spirox-4-en-3-one systems in the treatment of menorrhagia, as well as intrauterine systems containing 18-methyl-15ss,16ss-methylene-19-nor-20-spirox-4-en-3-one for treating uterine bleeding disorders
EP3057573A1 (en) * 2013-10-18 2016-08-24 Bayer Oy Intrauterine delivery system
WO2016180764A1 (en) 2015-05-13 2016-11-17 Bayer Oy A long acting drug delivery device and its use in contraception
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WO2019119059A1 (en) 2017-12-22 2019-06-27 Alyra Biotech Pty Ltd Treatment of pain and/or pain related symptoms associated with dysmenorrhea

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