WO2002032433A1

WO2002032433A1 - Drug delivery system

Info

Publication number: WO2002032433A1
Application number: PCT/FI2001/000879
Authority: WO
Inventors: Harri Jukarainen; Timo Haapakumpu; Juha Ala-Sorvari; Jarkko Ruohonen; Matti Lehtinen
Original assignee: Leiras Oy; Lehtinen, Pirkko
Priority date: 2000-10-20
Filing date: 2001-10-11
Publication date: 2002-04-25
Also published as: AU2002210580A1

Abstract

The object of the invention is a delivery system for the controlled release of a therapeutically active agent 11b-(4-Acetylphenyl)-17β-hydroxy-17α-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one over a prolonged period of time, said system comprising a core comprising at least said therapeutically active agent, and a membrane encasing said core wherein said membrane is made of an elastomer chosen from the group consisting of a siloxane-based elastomer and a composition comprising at least a siloxane-based elastomer. The invention is characterized in that the release rate of said therapeutically active agent is 0,1-200 νg/day.

Description

DRUG DELIVERY SYSTEM

FIELD OF THE INVENTION

This invention relates to a drug delivery system, particularly to a system intended for administration of llβ-(4-Acetylphenyl)-17β-hydroxy-17α- (l,l,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one, at a substantially constant rate for a prolonged period of time.

BACKGROUND OF THE INVENTION

The publications and other materials used herein to illuminate the background of the invention, and in particular, the cases to provide additional details respecting the practice, are incorporated by reference.

Polysiloxanes, such as poly(dimethylsiloxane) (PDMS), are highly suitable for use as a membrane or a matrix regulating the permeation of drags in various drug forms, in particular in implants and intra-uterine systems (IUS), also known as intra-uterine devices (IUD). Polysiloxanes are physiologically inert, and a wide group of drugs are capable of penetrating polysiloxane membranes, which also have the required mechanical 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 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.

Contraceptive subcutaneous implants are known in the art and they are described e.g. in US patents 4,957,119, 5,088,505, 5,035,891, 5,565,443 and 5,633,000.

The commercially available NORPLANT ® system is an implant having a core containing the synthetic progestin, levonorgestrel as the active substance, and where the core is surrounded by a membrane of a siloxane elastomer of poly(dimethylsiloxane). A special preparation of this kind is JADELLE ® in which the core is a poly(dimethylsiloxane) based matrix with levonorgestrel dispersed therein. The membrane is an elastomer made from PDMS and silica filler, which, besides giving necessary strength properties to the membrane, also retards the permeation of the active agent through the membrane.

OBJECTS AND SUMMARY OF THE INVENTION

The object of this invention is to provide a drug delivery system, particularly a system intended for administration of llβ-(4-Acetylphenyl)-17β-hydroxy- 17 -(l,l,2,2,2-ρentafluoroethyl)estra-4,9-dien-3-one, at a substantially constant rate for a prolonged period of time.

The object is particularly to provide a system with which the drug release rate can easily be adjusted.

Thus, the invention concerns a delivery system for the controlled release of the therapeutically active agent llβ-(4-Acetylphenyl)-17β-hydroxy-17α- (l,l,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one, over a prolonged period of time, said system comprising a core comprising at least said therapeutically active agent, and a membrane encasing said core wherein said membrane is made of an elastomer chosen from the group consisting of a siloxane-based elastomer and a composition comprising at least a siloxane-based elastomer.

.

According to the invention, the release rate of said therapeutically active agent is 0,1-200 μg/day.

In this specification, except where the context requires otherwise, the words "comprise", "comprises" and "comprising" means "include", "includes" and "including", respectively. That is, when the invention is described or defined as comprising specified features, various embodiments of the same invention may also include additional features.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 shows the daily in vitro release of l lβ-(4-Acetylphenyl)-17β- hydroxy- 17α-( 1 , 1 ,2,2,2-pentafluoroethyl)es tra-4,9-dien-3-one from the implants described in Example 1.

Figure 2 shows the daily in vitro release of llβ-(4-Acetylphenyl)-17β- hydroxy- 17(X-( 1 , 1 ,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one from the intrauterine systems described in Example 2. DETAILED DESCRIPTION OF THE INVENTION

The system according to the invention can for example be an implant, an intrauterine system, an intravaginal system or an intracervical system. According to one embodiment of the invention, the release rate of the active agent in an intrauterine system is 0,1-200 μg/day, preferably 0,5-50 μg/day, more preferably 1-30 μg/day and most preferably 0,5-20 μg/day. According to another embodiment of the invention, the release rate of the active agent in an implant is 0,1-200 μg/day, preferably 1-200 μg/day.

Description of the elastomer

The elastomer suitable for use in the system according to this invention, particularly for use in the membrane of the system, is chosen from the group consisting of a siloxane-based elastomer and a composition comprising at least a siloxane-based elastomer.

The term "siloxane-based elastomer" shall be understood to cover elastomers made of poly(disubstituted siloxanes) where the substituents mainly are lower alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or phenyl groups, wherein said alkyl or phenyl can be substituted or unsubstituted. A widely used and preferred polymer of this kind is poly(dimethylsiloxane) (PDMS).

According to an embodiment of the invention, said elastomer is a composition comprising poly(alkylene oxide) groups which are present in the elastomer as alkoxy-terminated grafts of polysiloxane units, or as blocks, said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.

According to another embodiment, the composition comprising at least a siloxane-based elastomer may be made up of two networks that are interlaced, one inside the other. In this case the first network comprises poly(alkylene oxide) groups so that the poly(alkylene oxide) groups are present in the said network 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 oxides) may also be present as a blend of the options mentioned. The second network may be a siloxane-based elastomer, suitably a poly(dimethyl siloxane)-based elastomer. Said second network 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 composition comprising at least a siloxane-based elastomer may be a blend which comprises a siloxane-based elastomer, which is, for example, made up of PDMS, and at least one linear 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 ρoly(alkylene oxide) groups, in which case these ρoly(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 ρoly(alkylene oxide) groups may also be present as a blend of the forms mentioned.

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'RO)_qSiR'R"-

where some of the substituents R' and R" are

- 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 ρoly(alkylene oxide) groups having the formula R₃-0-(CRH-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 linear or branched C₂ - C₆ alkylene group,

-bonds, formed from the hydrogen or alkenyl groups, to other polymer chains in the elastomer, and -optionally unreacted groups, such as hydrogen, vinyl or vinyl-terminated alkenyl, and

q is 1-3000.

The term "lower alkyl" stands here and generally in the description for - C₆ alkyl groups.

The above-mentioned 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

-(CH₂)_yO(CRHCH₂0)_m(CH₂)_y-, or

-CH₂CR₁HCOO(CRHCH₂0)_mCOCR₁HCH₂-

where R is hydrogen, a lower alkyl or a phenyl, R_! is hydrogen or a lower alkyl, y is 2-6, and m is 1-30.

The elastomer should preferably comprise a filler, such as amorphous silica, in order to give a sufficient strength for the membrane made from said elastomer. The word "membrane" means the same as film.

General description of the method for the preparation of the elastomer composition comprising at least a siloxane-based elastomer

According to a preferred embodiment, the novel elastomer composition comprising at least a siloxane-based 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. For crosslinking, the amounts of the components are preferably selected so that the ratio of the molar amounts of the reactive hydrides and the reactive double bonds is at least 1.

According to another embodiment, the elastomer composition comprising at least a siloxane-based 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.

The vinyl-functional polymer component may be

a) a vinyl-functional polysiloxane having the formula

R'-SiRRO(SiRRO)_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)_XAT, where

- A = -(SiR'R'O)_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

-R₃0(CRHCH₂0)_mR4-, or

-CH₂CR₁HCOO(CRHCH₂0)_mCOCR₁HCH₂-

and

- T is

R^πO(CRHCH₂0)_mR₃-, or

CH₂=CR₁COO(CRHCH₂0)_mCOCR₁HCH₂-

where R is hydrogen, a lower alkyl or phenyl, Ri is hydrogen or a lower alkyl, R₃ and R are the same or different and are linear or branched C₂ - C₆ alkylene groups, R¹¹ is a linear 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 random or block copolymer having the formula

R'-SiR'RO(SiR'RO)_r(SiR'RO)_pSiR^JR"-R'

- where in the first repeat unit 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 repeat unit R' is a lower alkyl group, or an alkoxy- terminated poly(alkylene oxide) group having the formula

-R₃-0-(CRH-CH₂-0)_m-alk, where alk is a lower alkyl group, suitably methyl, R is hydrogen or a lower alkyl group, R is a linear or branched

C₂ - C₆ alkylene, 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

R¹¹-0-(CRHCH₂0)_m-R¹²

where R¹¹ and R¹² are the same or different linear 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'RO(SiRRO)_r(SiR'RO)_pSiR'R"-R', it should be noted that the formula is a kind of gross formula, in which the repeat units in successive parentheses may appear in any order in relation to one another. The hydride-functional component may be

a) a hydride-functional siloxane, which may be linear, star shaped, branched or cyclic, or

b) a hydride-terminated siloxane-based block copolymer having the formula T(BA)_XBT, where

T = H-SiR'RO(SiRRO)_qSiR'R"-,

A = -SiR'R"0(SiRR"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

-R₃-0(CRHCH₂0)_raR₄-, or

(CRHCH₂0)_mCOCRιHCH₂-

whe e R is hydrogen, a lower alkyl or a phenyl, Ri is hydrogen or a lower alkyl, R₃ and R₄ are the same or different and are linear 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 linear, in which case its formula is

R'-SiR'RO(SiR'RO)_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.

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, vinyl siloxane or cyclic vinyl siloxane. An especially suitable catalyst is a Pt(0)-divinyl- tetramethyl disiloxane complex. The elastomer composition comprising at least a siloxane-based elastomer made up of two networks is prepared so that initially a first network is formed, whereafter a second network is formed by crosslinking in the presence of the first network. Thus the second network will penetrate through the first network, forming an interpenetrating network.

The elastomer composition comprising at least a siloxane-based elastomer which comprises an elastomer and a linear 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 non-crosslinked form, inside the elastomer.

Manufacture of the implants

The implants according to this invention can be manufactured in accordance with standard techniques. The therapeutically active agent is mixed with the core matrix polymer, processed to the desired shape by moulding, casting, extrusion, or other appropriate methods. The membrane layer can be applied onto the core according to known methods such as by mechanical stretching, swelling or dipping. Reference is made to the US-patents US 3,832,252, US 3,854,480, US 4,957,119. An especially suitable method for preparation of the implants is disclosed in the Finnish patent FI 97947. This patent discloses an extrusion technology where prefabricated rods containing the active ingredient are coated by an outer membrane. Each such rod is, for example, followed by another rod without any active ingredient. The formed string is cut at the rods that contain no active agent. In this way, no special sealing of the ends of the implant is necessary.

Manufacture of the intra-uterine, intra-vaginal and intra-cervical systems

The intra-uterine system can be made according to well-known technology. A preferable intra-uterine system (IUS, intrauterine system), intra-vaginal system or intra-cervical system in common use is a T-shaped body made of plastic material such as polyethylene. The body consists of an elongate member (stem) having at one end a transverse member comprising two wings. The elongate member and the transverse member form a substantially T- shaped piece when the system is positioned in the uterus. The system has an attached thread long enough to protrude out of the cervical canal when the system is in position in the uterus. IUS:s releasing drugs have a drug reservoir adjusted around the elongate member. This drug reservoir is preferably a matrix that consists of the elastomer matrix with the active agent(s) dispersed therein. Preferably, the matrix is encased in a membrane. The membrane is usually made of an elastomer.

The drug reservoir adjusted around the stem of the T-shaped body can be manufactured as the implant as described above. Alternatively, the matrix can first be applied onto the step after which the matrix is encased by a membrane.

It is clear that also other forms of IUS, known by the skilled person er se, are possible.

The matrix and membrane of the drag reservoir on the IUS can be made of the same elastomer as the implants described above.

EXPERIMENTAL SECTION

The invention is described below in greater detail in the following, non- limiting examples.

In this section, the therapeutically active agent l lβ-(4-Acetylphenyl)-17β- hydroxy- 17α-( 1 , 1 ,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one is called "drug". Further, "parts" stand for parts per weight.

The release rate of the drug from the implants and the IUS were measured in vitro as follows: the implants/IUS were attached into a stainless steel holder in vertical position and the holders with the implants were placed into glass bottles containing 75 ml of a dissolution medium. The glass bottles were shaked in shaking waterbath 100 rpm at 37 °C. The dissolution medium was withdrawn and replaced by a fresh dissolution medium at predetermined time intervals, and the released drug was analysed by HPLC. The concentration of the dissolution medium and the moment of change (withdrawal and replacement) of medium were selected so that sink-conditions were maintained during the test. Example 1

a) Drug containing implant based on the use of PDMS

Membrane:

The siloxane membrane corresponds to a commercial silica-filled poly(dimethylsiloxane) membrane and it was prepared as follows:

99 parts of silica-filled poly(dimethylsiloxane-co-vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species) and 0,03 parts of inhibitor (ethynyl cyclohexanol) and approx. 0,6 parts of poly(hydrogenmethylsiloxane-co- dimethylsiloxane) crosslinker were mixed in a 2-roll mill. The mixture was extruded to a tube-like form with a wall thickness of 0,2 mm and cured in an oven at a temperature of approximately 200 °C. The tube-shaped membrane was cut to 50 mm pieces.

Core:

49,4 parts (by weight) of commercial poly(dimethylsiloxane-co- vinylmethylsiloxane), 0,4 parts of poly(hydrogenmethylsiloxane-co- dimethylsiloxane) crosslinker, 0,02 parts of ethynyl cyclohexanol inhibitor and 10 ppm Pt-catalyst (of the reaction species) in vinyl-methyl-siloxane were mixed in a two-chamber mixer. 50 parts of the drag were added and the mixture was mixed in a two-chamber mixer. The mixture was casted to a PTFE-coated stainless steel mold, which was heated at +115° C for 30 minutes. The cores were removed, cooled and cut to desired length (40 mm). The content of the drug was 50 % (weight/weight), based on HPLC (high performance liquid chromatography) assay.

Preparation of the implant:

The membrane tubes (length 50 mm) were swelled with cyclohexane and the cores were inserted into the membrane. Cyclohexane was allowed to evaporate and ends were closed with a silicone adhesive. After 24 hours the ends were cut to give 2 mm end-caps. This implant corresponds to system 1 in

Figure 1. b) Drug containing implant based on the use of PEO-PDMS

Membrane:

9 parts of ,ω-divinylether poly(ethylene oxide)-b-poly(dimethylsiloxane) multiblock copolymer, 89 parts of silica-filled poly(dimethylsiloxane-co- vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0,03 parts inhibitor (ethynyl cyclohexanol), and approximately 2 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. The mixture was extruded to a tube-like form with a wall thickness of 0,2 mm and cured by heat at approximately 200 °C.

Core:

29 parts of α,ω-divinylether ρoly(ethylene oxide)-b-poly(dimethylsiloxane) multiblock copolymer, 29 parts of poly(dimethylsiloxane-co- vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0,02 parts inhibitor (ethynyl cyclohexanol), and approximately 2,4 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill and 39 parts of drug were added. The mixture was casted to a PTFE-coated stainless steel mold, which was heated at +115° C for 30 minutes. The cores were removed, cooled and cut to desired length (40 mm). The content of the drag was 40 % (weight/weight), based on HPLC assay.

The implant was prepared as in Example 1 a) and corresponds to system 2 in Figure 1.

c) Drug containing implant based on the use of PEO-PDMS

Membrane:

29 parts of α, ω-divinyl ether polyethylene oxide b-polydimethylsiloxane multiblock copolymer, 69 parts of silica-filled poly(dimethylsiloxane-co- vinylmethylsiloxane), 10 ppm Pt-catalyst (of the reaction species), 0,03 parts inhibitor (ethynyl cyclohexanol), and approximately 2 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker were mixed in a two-roll mill. The mixture was extruded to a tube-like form with a wall thickness of 0,2 mm and cured by heat at approximately 200 °C.

The core was prepared as in Example 1 b). The implant was prepared as in Example 1 a) and corresponds to system 3 in Figure 1. Example 2

The intrauterine system (IUS) described in this Example consists of three parts: a core with the drug in a polymer matrix, a membrane covering the core and a T-shaped body of polyethylene onto which the core surrounded by the membrane is applied.

a) Drug containing IUS based on the use of PDMS

Membrane:

The membrane was the same as described in Example 1 a) above.

Core:

49,4 parts of commercial poly(dimethylsiloxane-co-vinylmethylsiloxane), 0,4 parts of poly(hydrogenmethylsiloxane-co-dimethylsiloxane) crosslinker, 0,02 parts of ethynyl cyclohexanol inhibitor and 10 ppm of Pt-catalyst (of the reaction species) in vinyl-methyl-siloxane were mixed in a two-chamber mixer. 50 parts of the drag were added and the mixture was mixed in a two- chamber mixer. The mixture was extraded to a tube-like form with a wall thickness of 0,8 mm and cured by heat. The tube-like form was then heated at +115° C for 30 minutes, cooled and cut to desired length (19 mm). The content of the drug was 50 % (weight/weight), based on HPLC assay.

IUS:

The membrane tubes (length 25 mm) and the cores were swelled with cyclohexane and applied onto the polyethylene T-shaped body of the system. Cyclohexane was allowed to evaporate. This IUS corresponds to system 4 in Figure 2.

b) Drug containing IUS based on the use of PEO-PDMS

The IUS contains two different elastomer composition types. The partial amounts of the different elastomer composition types of the membrane and the core were the same as in Example lb). The content of the drag was 40 % (weight/weight), based on HPLC assay. The IUS was prepared as in Example 2 a) and corresponds to system 5 in Figure 2. c) Drug containing IUS based on the use of PEO-PDMS

The IUS contains two different elastomer composition types. The partial amounts of different composition types of the membrane and the core were the same as in Example 1 c). The content of the drag was 40 % (weight/weight), based on HPLC assay. The IUS was prepared as in Example 2 a) and corresponds to system 6 in Figure 2.

The Examples explained above, illustrated in Figures 1 and 2, clearly show the impact of the membrane and core compositions on the release rate of the drug. It is evident to a person skilled in the art, that the desired drag release rate is obtainable for example by varying the dimensions, for example, the length of the system.

Claims

1. A delivery system for the controlled release of a therapeutically active agent llβ-(4-Acetylρhenyl)-17β-hydroxy-17 -(l,l,2,2,2-pentafluoroethyl)- estra-4,9-dien-3-one over a prolonged period of time, said system comprising a core comprising at least said therapeutically active agent, and a membrane encasing said core wherein said membrane is made of an elastomer chosen from the group consisting of a siloxane-based elastomer and a composition comprising at least a siloxane-based elastomer, characterised in that the release rate of said therapeutically active agent is 0,1-200 μg/day.

2. The system according to Claim 1, characterised in that the release rate of the therapeutically active agent is 0,5-50 μg/day.

3. The system according to Claim 1, characterised in that the release rate of the therapeutically active agent is 1-30 μg/day.

4. The system according to Claim 1, characterised in that the release rate of the therapeutically active agent is 0,5-20 μg/day.

5. The system according to Claim 1, characterised in that said composition comprising at least a siloxane-based elastomer is a composition comprising poly(alkylene oxide) groups which are present in the elastomer as alkoxy- terminated grafts of polysiloxane units, or as blocks, said grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.

6. The system according to Claim 1, characterised in that it is an implant.

7. The system according to Claim 6, characterised in that the release rate of the therapeutically active agent is 0,1-200 μg/day.

8. The system according to Claim 6, characterised in that the release rate of the therapeutically active agent is 1-200 μg/day.

9. The system according to Claim 1, characterised in that it is an intrauterine system.

10. The system according to Claim 9, characterised in that the release rate of the therapeutically active agent is 1-30 μg/day.

11. The system according to Claim 1, characterised in that it is an intravaginal system.

12. The system according to Claim 1, characterised in that it is an intracervical system.

13. The system according to Claim 1, characterised in that the elastomer contains a filler.

14. The system according to Claim 13, characterised in that the filler is amorphous silica.