WO2001085132A1

WO2001085132A1 - Drug delivery device, especially for the delivery of levonorgestrel

Info

Publication number: WO2001085132A1
Application number: PCT/FI2001/000406
Authority: WO
Inventors: Tommi Markkula; Juha Ala-Sorvari; Harri Jukarainen; Jarkko Ruohonen; Matti Lehtinen
Original assignee: Leiras Oy; Lehtinen, Pirkko
Priority date: 2000-05-10
Filing date: 2001-04-27
Publication date: 2001-11-15
Also published as: AU2001258442A1

Abstract

The invention relates to a delivery device for the controlled release of the therapeutically active agent levonorgestrel, over a prolonged period of time, at a release rate of 0,1-200 νg/day, said device comprising a core comprising at least said therapeutically active agent, and a membrane encasing said core wherein said membrane is made of an elastomer. According to the invention, the elastomer is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, and the release rate of said therapeutically active agent of said delivery device is regulated by the amount of said 3,3,3-trifluoropropyl groups.

Description

DRUG DELIVERY DEVICE, ESPECIALLY FOR THE DELIVERY OF LEVONORGESTREL

FIELD OF THE INVENTION

This invention relates to a drug delivery device, particularly to a device intended for administration of levonorgestrel, 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 drugs in various drug forms, in particular in implants and mtra-uterine systems (IUS). 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. It is further known that membranes based on modified PDMS polymers, in which a certain amount of the methyl substituents at the Si- atoms are replaced by trifluoropropyl groups, decrease the permeation of drugs. The publication Ying Sun et al, Journal of Controlled Release, 5 (1987) 69-78, describes the effect on membranes prepared from PDMS, trifluoropropyl substituted PDMS and PDMS/PEO/PMMA (where PMMA is poly(methylmethacrylate)) on the permeation of androgenic and progestenic steroids. The study shows that the permeation for both groups of steroids was lower for the membrane made of trifluoropropyl substituted PDMS than for that made of unmodified PDMS. The publication does not, however, disclose any elastomer made of trifluoropropyl substituted PDMS.

OBJECTS AND SUMMARY OF THE INVENTION

The object of this invention is to provide a drug delivery device, particularly a device intended for administration of levonorgestrel, at a substantially constant rate for a prolonged period of time.

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

Thus, the invention concerns a delivery device for the controlled release of the therapeutically active agent levonorgestrel, over a prolonged period of time, at a release rate of 0,1-200 μg/day, said device comprising

- a core comprising at least said therapeutically active agent, and

- a membrane encasing said core wherein said membrane is made of an elastomer.

According to the invention, the elastomer is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, and the release rate of said therapeutically active agent of said delivery device is regulated by the amount of said 3,3,3-trifluoropropyl groups.

DETAILED DESCRIPTION OF THE INVENTION

The device according to the invention can for example be an implant, an intrauterine device, an intravaginal device or an intracervical device. According to one embodiment of the invention, the release rate of the active agent in an intrauterine device is 0,1-200 μg/day, preferably 0,5-100 μg/day, more preferably 0,5-50 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 0,5-150 μg/day and more preferably 1-100 μg/day. Description of the elastomer

The elastomer suitable for use in the device according to this invention, particularly for use in the membrane of the device, is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units.

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 the invention, a certain amount of the substituents attached to the Si-atoms of the siloxane units in the elastomer shall be 3,3,3- trifluoropropyl groups. Such an elastomer can be achieved in different ways. According to one embodiment, the elastomer can be based on one single crosslinked siloxane-based polymer, such as a poly(dialkyl siloxane) where a certain amount of the alkyl groups at the Si-atoms are replaced by 3,3,3- trifluoropropyl groups. A preferred example of such polymers is poly(3,3,3- trifluoropropyl methyl siloxane) the structure of which is shown as Compound I below.

Compound I

A polymer of this kind, in which approximately 50 % of the methyl substituents at the Si-atoms are replaced by 3,3,3-trifiuoropropyl groups, is commercially available. The term "approximately 50 %" means that the degree of 3,3,3-trifluoropropyl substitution is in fact somewhat below 50 %, because the polymer must contain a certain amount (about 0.15 % of the substituents) of crosslinkable groups such as vinyl or vinyl-terminated groups. Similar polymers having lower substitution degree of 3,3,3-trifluoropropyl groups can easily be synthetised.

The retarding effect of the 3,3,3-trifluoropropyl groups on the permeation of drugs across a membrane of the elastomer is dependent on the amount of these groups. Furthermore, the effect is highly dependent on the drug used. If the elastomer is made of one single polymer only, it would be necessary to prepare and use polymers with different amounts of 3,3,3-trifluoropropyl groups for different drugs.

According to another embodiment, which is particularly preferred if suitable elastomers for several different drugs are needed, is to crosslink a mixture comprising a) a non-fluorosubstituted siloxane-based polymer and b) a fluorosubstituted siloxane-based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units. The first ingredient of the mixture, the non-fluorosubstituted polymer, can be any poly(disubstituted siloxane) 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. The substituents are most preferably alkyl groups of 1 to 6 carbon atoms. A preferred non-fluorosubstituted polymer is PDMS. The second ingredient of the mixture, the fluoro-substituted polymer, can for example be a poly(dialkyl siloxane) where a certain amount of the alkyl groups at the Si- atoms are replaced by 3,3,3-trifluoropropyl groups. A preferred example of such polymers is poly(3,3,3-trifluoropropyl methyl siloxane) as mentioned above. A particularly preferable polymer of this kind is a polymer having as high amount of 3,3,3-trifluoropropyl substituents as possible, such as the commercially available polymer, in which approximately 50 % of the methyl substituents at the Si-atoms are replaced by 3,3,3-trifluoropropyl groups. An elastomer with great permeation retarding effect can be achieved by using exclusively or mainly the aforementioned polymer. Elastomers with less retarding influence on the permeation of the drug can be obtained by using mixtures with increasing amounts of the non-fluorosubstituted siloxane-based polymer. 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.

General description of the method for the preparation of the elastomer

According to one embodiment, the elastomer is prepared by crosslinking, in the presence of a catalyst, a vinyl-functional polysiloxane component and a silicon hydride-functional crosslinking agent.

By crosslinking is meant the addition reaction of the silicon hydride- functional crosslinking agent with the carbon-carbon double bond of the vinyl-functional polysiloxane component.

According to another embodiment, the elastomer is prepared by crosslinking the polymer in the presence of a peroxide catalyst.

The term "vinyl-functionar polysiloxane shall be understood to cover polysiloxanes substituted with vinyl groups or with vinyl-terminated groups. The "vinyl-functional polysiloxane component" and the "polysiloxane component" to be crosslinked shall also be understood to cover copolymers with polysiloxanes having vinyl substituents or vinylterminated substituents.

For crosslinking, the amounts of the components are preferably selected so that the ratio of the molar amounts of the silicon hydrides to the double bonds is at least 1.

As stated above, the elastomer for use in this invention can be made by crosslinking one single fluorosubstituted siloxane-based polymer, or by crosslinking a mixture of a non-fluorosubstituted siloxane-based polymer and a fluorosubstituted siloxane-based polymer. The term "vinyl-functional polysiloxane component" can thus be a mixture comprising a non- fluorosubstituted siloxane-based polymer and a fluorosubstituted siloxane- based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units. Alternatively, the "vinyl- functional polysiloxane component" can be a single fluorosubstituted siloxane-based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units. Additionally, a so-called compatibiliser can be mixed with the above- mentioned components. The compatibiliser is typically a block copolymer of a non-fluorosubstituted polymer and a fluorosubstituted polymer.

The silicon hydride-functional crosslinking agent is preferably a hydride- functional polysiloxane that may be straight chain, branched or cyclic. The hydride-functional siloxane crosslinking agent may also contain trifluoropropyl groups.

The fluorosubstituted siloxane-based polymer is preferably a PDMS polymer where approximately 50 % of the methyl groups in said PDMS are replaced by 3,3,3-trifluoropropyl groups.

A filler, such as amorphous silica, is preferably added to the vinyl-functional component before the crosslinking.

In case the elastomer is made by crosslinking a polymer component in the presence of a peroxide catalyst, such a polymer component can be a mixture comprising a non-fluorosubstituted siloxane-based polymer and a fluorosubstituted siloxane-based polymer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units. Alternatively, this polymer component can be a single fluorosubstituted siloxane-based polymer, where said polymer comprises 3,3,3-trifluoropropyl groups attached to the Si- atoms of the siloxane units.

The catalyst to be used in the crosslinking is preferably 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 therapeutically active agent

The preferred therapeutically active agent used in the device according to the invention is levonorgestrel, (-)-13-Ethyl-17 hydroxy-18, 19-dinor-17α-pregn- 4-en-20-yn-3-one, the structure of which is shown as Compound II.

Compound II

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 molding, 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 devices

The intra-uterine device can be made according to well known technology, a preferable intra-uterine device (IUS, intrauterine system), intra-vaginal device or intra-cervical device in common use is a T-shaped body made of plastic material such as polyethene. 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 device is positioned in the uterus. The device has an attached thread long enough to protrude out of the cervical canal when the device 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 which 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.

The matrix and membrane of the drug 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.

The implants consisted of three parts: a core, a membrane and adhesive end- caps. The end-caps were inert and their function was only minimal in a sense of controlling the release of the active agent. The core consisted of elastomer mixed with the active agent. The membrane was made from elastomer that controlled the release rate of the active agent.

The therapeutically active agent used in the examples was levonorgestrel (LNG), of purity over 99 m-%, manufactured by Schering AG.

Example 1

In this example 50 % of the substituents of siloxane groups in the membrane were 3,3,3- trifluoropropyl groups.

Core preparation

50 parts by weight LNG and 50 parts by weight of poly(dimethylsiloxane-co- vinylmethylsiloxane) and 1,2 parts by weight of dibentsoylperoxide- polydimethylsiloxane paste (50 % of dichlorobenzoylperoxide) were mixed with a 2-roll mill. The mixture was casted to a polytetrafluoroethene-coated (PTFE-coated) stainless steel mold, which was heated at +150 °C for 30 minutes, during which crosslinking took place. The cores were removed, cooled and cut to desired length. The cured (crosslinkked) core was cut into 12 mm length.

Membrane preparation

100 parts by weight of silica-filled poly(trifluoropropylmethylsiloxane-co- vinylmethylsiloxane) (content of trifluoropropyl-rnethylsiloxane units 99,7 mol-%; i.e. degree of trifluoropropyl substitution 50 %) and 1.2 parts by weight of dibentsoylperoxide-polydimethylsiloxane paste (50 % of dichlorobenzoylperoxide) were mixed with a 2-roll mill. The mixture was extruded into a tube-like form with a wall thickness of 0,2 mm and cured by heat.

Implant preparation

25 mm membranes and 12 mm cores were swelled with cyclohexane and the ends were sealed into polyethylene end-caps to the implants. Cyclohexane was allowed to evaporate. The ends were closed with a silicone adhesive. After 24 hours the ends were cut to give 2 mm end-caps.

Drug release test

The release rate of the drug from the implant was measured in vitro as follows:

the implants 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.

The results are shown in Figure 1 as the daily in vitro release rate of levonorgestrel. Example 2

In this example 30% of the substituents of siloxane groups in the membrane were 3,3,3- trifluoropropyl groups.

The core and membrane were prepared according to the example 1, except that in the membrane, the content of trifluoropropyl-methylsiloxane units of poly(trifluoropropylmethylsiloxane-co-vinylmethylsiloxane) was 60 mol-%; i.e. the degree of trifluoropropyl substitution was 30 %. The implant was prepared according to example 1.

The drug release test was performed according to example 1 and the results are shown in Figure 1 as the daily in vitro release rate of levonorgestrel.

Comparative example 3

In this example the implant was made from PDMS and it did not contain 3,3,3- trifluoropropyl groups.

The core and membrane were prepared according to the example 1, except that in the membrane, silica-filled poly(dimethylsiloxane-co- vinylmeth lsiloxane) was used instead of silica-filled poly (trifluoropropylmethylsiloxane-co- vinylmethylsiloxane) . The implant was prepared according to example 1.

Discussion of the results

Figure 1 shows the daily in vitro release rate of levonorgestrel from the three implants according to examples 1-3. The square marked curve refers to example 1, the round marked curve to example 2 and the triangle marked curve to comparative example 3. The examples thus demonstrate clearly the retarding effect caused by the 3,3,3-trifluoropropyl substitution of the membrane polymer. It will be appreciated that the methods of the present invention can be incorporated in the form of a variety of embodiments, only a few of which are disclosed herein. It will be apparent for the specialist in the field that other embodiments exist and do not depart from the spirit of the invention. Thus, the described embodiments are illustrative and should not be construed as restrictive.

Claims

1. A delivery device for the controlled release of the therapeutically active agent levonorgestrel, over a prolonged period of time, at a release rate of 0,1- 200 μg/day, said device comprising

- a core comprising at least said therapeutically active agent, and

- a membrane encasing said core wherein said membrane is made of an elastomer, characterised in that the elastomer is a siloxane-based elastomer comprising 3,3,3-trifluoropropyl groups attached to the Si-atoms of the siloxane units, and the release rate of said therapeutically active agent of said delivery device is regulated by the amount of said 3,3,3-trifluoropropyl groups.

2. The device according to Claim 1, characterised in that it is an implant.

3. The device according to Claim 2, characterised in that the release rate of the therapeutically active agent is 0,5-150 μg/day.

4. The device according to Claim 1, characterised in that it is an intrauterine device.

5. The device according to Claim 4, characterised in that the release rate of the therapeutically active agent is 0,5-100 μg/day.

6. The device according to Claim 1, characterised in that it is an intravaginal device.

7. The device according to Claim 1, characterised in that it is an intracervical device.

8. The device according to Claim 1, characterised in that the elastomer is made of either

I) a mixture comprising a) a non-fluorosubstituted siloxane-based polymer and b) a fluorosubstituted siloxane-based polymer, said polymer comprising 3, 3, 3, -trifluoropropyl groups attached to the Si-atoms of the siloxane units, or

II) a single siloxane-based polymer comprising 3, 3, 3, -trifluoropropyl groups attached to the Si-atoms of the siloxane units, wherein said polymer or mixture of polymers are crosslinked to form the elastomer.

9. The device according to Claim 8, characterised in that the mixture of polymers is a mixture of a) poly(dimethylsiloxane) and b) poly(dimethylsiloxane) in which the methyl groups attached to the Si-atoms of the siloxane units to some extent have been replaced by 3,3,3,- trifluoropropyl groups.

10. The device according to Claim 9, characterised in that approximately 50 % of the methyl groups in the polymer b) have been replaced by 3,3,3,- trifluoropropyl groups.

11. The device according to Claim 1, characterised in that the elastomer contains a filler.

12. The device according to Claim 11, characterised in that the filler is amorphous silica.