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Title:  Devices for the delivery of drugs having antiprogestinic properties

United States Patent:  6,476,079

Issued:  November 5, 2002

Inventors:  Jukarainen; Harri (Turku, FI); Markkula; Tommi (Cheshire, GE); Ala-sorvari; Juha (Turku, FI); Lehtinen; Matti (Piispanristi, FI); Ruohonen; Jarkko (Vanhalinna, FI)

Assignee:  Leiras Oy (Turku, FI)

Appl. No.:  472126

Filed:  December 23, 1999

Abstract

A device for the controlled release over a prolonged period of time of a drug having antiprogestinic properties, the device including a core containing the drug, optionally a membrane encasing the core, where at least one of the core and membrane, when present, is made of a siloxane-based elastomer composition including at least one elastomer and optionally a non-crosslinked polymer. The device is characterized in that the elastomer composition includes 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 grafts or blocks being linked to the polysiloxane units by silicon-carbon bonds, or as a mixture of these forms.

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 poly(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 linear polysiloxane copolymer which comprises poly(alkylene oxide) groups. In his 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 linear 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"O)q SiR'R"--

where some of the substituents R' and R" are

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 R3 --O--(CRH--CH2 --O)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 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 of the elastomer composition for C1 -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

--(CH2)y O(CRHCH2 O)m (CH2)y--,

or

--CH2 CR1 HCOO(CRHCH2 O)m COCR1 HCH2 --

where

R is hydrogen, a lower alkyl or a phenyl,

R1 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 crosslinkig 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 reactive hydrides and the reactive double bonds is at least 1.

The vinyl-functional polymer component may be

a) a vinyl-functional polysiloxane having the formula

R'--SiR'R"O(SiR'R"O)r SiR'R"R'

where R' and R" are the same or different, and are a lower alkyl group, or a phenyl group, in which case the 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)x AT (I),

where

A=--(SiR'R"O)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

--R3 O(CRHCH2 O)m R4 --,

or

--CH2 CR1 HCOO(CRHCH2 O)m COCR1 HCH2 --

and T is

R11 O(CRHCH2 O)m R3 --,

or

CH2.dbd.CR1 COO(CRHCH2 O)m COCR1 HCH2 --

where

R is hydrogen, a lower alkyl or phenyl, R1 is hydrogen or a lower allyl, R3 and

R4 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'R"O(SiR'R"O)r (SiR'R"O)p SiR'R"--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 --O--(CRH--CH2 --O)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 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) .alpha.,.omega.-dialkenyl poly(alkylene oxide) having the formula

R11 --O--(CRHCH2 O)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'R"O(SiR'R"O)r (SiR'R"O)p SiR'R"--R', 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 linear, star shaped, branched or cyclic, or

b) a hydride-terminated siloxane-based block copolymer having the formula

T(BA)x BT (II),

where

T=H--SiR'R"O(SiR'R"O)q SiR'R"--,

A=--SiR'R"O(SiR'R"O)q SiR'R"--, where R' and R" are the same or different and are a lower alkyl group or a phenyl group, in which case the said alkyl or phenyl group may be substituted or unsubstituted;

B is a poly(alkylene oxide) having the formula

--R3 --O(CRHCH2 O)m R4 --,

or

--CH2 CR1 HCOO(CRHCH2 O)m COCR1 HCH2 --

where R is hydrogen, a lower alkyl or a phenyl, R1 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'R"O(SiR'R"O)r SiR'R"R'

where R' and R" are the same or different and are a lower alkyl group, or a phenyl group, in which case the 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, 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 crosslinkg 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 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.

Different Types of Devices

The device can be any device suitable for delivery of the active agent at a controlled rate over a prolonged period of time. Thus, the device can take a wide variety of shapes and forms for administering the active agent at controlled rates to different areas of the body. The invention includes external and internal drug delivery devices such as transdermal patches, implants for releasing a therapeutically active agent in the body tissues, intravaginal rings, intracervical and intrauterine devices.

According to a preferred embodiment, the device is an implant for subcutaneous use, an intravaginal ring or an intrauterine device (IUD). According to the most preferred embodiments, the device is an implant for subcutaneous use or an intrauterine device.

Construction of the Core

The core of the device can consist of the active antiprogestin as such, e.g. in liquid or crystallized form, optionally in combination with other therapeutically active agents. Alternatively, the core can consist of the active agent or agents in a mixture with pharmaceutically acceptable excipients.

Preferably, the core is an elastomer matrix in which the drug is dispersed.

According to a particularly preferable embodiment, the core is made of a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer. The elastomer composition comprises poly(alkylene oxide) groups where 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. The elastomer composition can also be a mixture of these forms.

Although the device, for example the implant, can be a plain core which consists of the elastomer matrix with the active agent(s) dispersed therein, the core is preferably encased in a membrane. The membrane is usually made of an elastomer.

According to a preferable embodiment, also the membrane is made of a siloxane-based elastomer composition comprising at least one elastomer and possibly a non-crosslinked polymer. The elastomer composition comprises poly(alkylene oxide) groups where 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 twits by silicon-carbon bonds. The elastomer composition can also be a mixture of these forms.

According to another alternative, the matrix can be made of the afore mentioned elastomer composition while the membrane is made of normal PDMS (i.e. PDMS containing no poly(alkylene oxide)). Alternatively, the membrane can be made of the afore mentioned elastomer composition while the matrix is made of normal PDMS.

Manufacture of 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 such as PDMS or the components forming the elastomer composition as defined above, 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 U.S. Pat. Nos. 3,832,252, 3,854,480 and 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.

Intrauterine and Intracervical Devices

The intrauterine device can be made according to well known technology. A preferable intrauterine device (IUD) or intracervical device 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 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. IUD: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 stem after which the matrix is encased by a membrane.

The matrix and membrane of the drug reservoir on the IUD can be made of the same elastomers as the implants described above.

Drugs

As antiprogestinic compounds useful in this invention shall be understood compounds which compete at least to a certain extent with progesterone for its receptor and which therefore counteract the effect of progesterone at the receptor level. These compounds may be relatively pure antiprogestins, i.e. compounds without any significant other hormonal activities. These compounds may also exert a certain degree of other hormonal activities, for instance antiandrogenic and/or antiglucocorticoid activity. Suitable for the purpose of his invention are also compounds with antiprogestinic properties which in itself incorporate some degree of gestagenic activity and which are characterized by intermediate McPhail scores between those for antiprogestins without inherent gestagenic activity and progestins. It is also known that compounds with antiprogestinic properties may inherently possess some estrogenic activity.

The antiprogestinic compounds useful in this invention may be of steroidal or non-steroidal origin.

Examples of antiprogestins which can be employed in this invention are

11beta-[(4-(Dimethylamino)phenyl]-17beta-hydroxy-17alpha-(1-propinyl)-4,9-e stradien-3-one (mifepristone)

11beta-[(4-(Dimethylamino)phenyl]-17beta-hydroxy-17alpha-(1-propinyl)-18-ho moestra-4,9-dien-3-one

11beta-[(4-(Dimethylamino)phenyl]-17beta-hydroxy-17alpha-(1-propinyl)-17a-h omoestra-4,9,16-trien-3-one

and other corresponding compounds described in U.S. Pat. Nos. 4,386,085, 4,447,424, 4,519,946 and 4,634,695;

11beta-[(4-Dimethylamino)phenyl]-17alpha-hydroxy-17beta-(3-hydroxypropyl)-1 3.alpha.-methyl-estra-4,9-dien-3-one (onapristone)

and the other compounds described in U.S. Pat. No. 4,780,461 and EP 129499;

(Z)-11beta-[(4-dimethylamino)phenyl)]-17beta-hydroxy-17alpha-(3-hydroxy-1-p ropenyl)estra-4,9-dien-3-one (lilopristone)

and the other compounds described in U.S. Pat. No. 4,609,651;

11beta-(4-Acetylphenyl)-17beta-hydroxy-17alpha-(1-propinyl)estra-4,9-dien-3 -one, (Z)-11beta-(4-acetylphenyl)-17beta-hydroxy-17alpha-(3-hydroxy-1-propenyl)e stra-4,9-dien-3-one

and the other compounds described in U.S. Pat. No. 5,089,635 and EP 190759;

11beta-(4-Methoxyphenyl)-17beta-hydroxy-17alpha-ethynyl-4,9-estradien-3-one

and the other compounds described in Steroids 37 (1981), 361-382;

(Z)-11beta-[(4-Dimethylamino)phenyl)]-17beta-hydroxy-17alpha-(3-hydroxy-1-p ropenyl)estr-4-en-3-one

and the other compounds described in EP 404283 and U.S. Pat. No. 5,728,689 as well as 11beta-aryl-estrene derivatives disclosed in e.g. U.S. Pat. Nos. 5,843,933 and 5,843,931

4-[17.beta.-Methoxy-17.alpha.-(methoxymethyl)-3-oxoestra-4,9-dien-11.beta.- yl]benzaldehyde-1-(E]-oxime,

4-[17.beta.-Hydroxy-17.alpha.-(methoxymethyl)-3-oxoestra-4,9-dien-11.beta.- yl]benzaldehyde-1-(E)-oxime,

and the other compounds described in U.S. Pat. No. 5,693,628 and EP 648778;

4-[17.beta.-Methoxy-17.alpha.-(methoxymethyl)-3-oxoestra-4,9-dien-11.beta.- yl]benzaldehyde-1-(E)-[O-(ethylamino)carbonyl]oxime,

4-[17.beta.-Methoxy-17.alpha.-(methoxymethyl)-3-oxoestra-4,9-dien-11.beta.- yl]benzaldehyde-1-(E)-[O-(ethoxy)carbonyl]oxime

and the other compounds described in U.S. Pat. No. 5,576,310 and EP 648779;

4-[17.beta.-Methoxy-17.alpha.-(methoxymethyl)-3-oxoestra-1,9-dien-11.beta.- yl]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime,

4-[17.beta.-Methoxy-17.alpha.-(ethoxymethyl)-3-oxoestra-4,9-dien-11.beta.-y l]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime,

4-[17.beta.-Hydroxy-17.alpha.-(methoxymethyl)-3-oxoestra-4,9-dien-11.beta.- yl]benzaldehyde-1-E)-[O-(n-propylthio)carbonyl]oxime

and the other compounds described in DE 19809845 and WO 99/45023;

(Z)-6'-(4-cyanophenyl)-9,11.alpha.-dihydro-17beta-hydroxy-17.alpha.-[4-(1-o xo-3-methylbutoxy)-1-butenyl]4'H-naphtho[3',2',1';10,9,11]estr-4-en-3-one,

(Z)6'-(4-cyanophenyl)-9,11.alpha.-dihydro-17beta-hydroxy-17.alpha.-[3-(1-ox o-3-methylbutoxy)-1-propenyl]4'H-naphtho[3',2',1'; 10,9,11]estra-4,15-dien-3-one,

and the other compounds described in DE 196 52 408 and WO98/24803 as well as in DE 4434488, DE 4216003 and DE 4216004;

(Z)-6'-(4-cyanophenyl)-9,11.alpha.-dihydro-17beta-hydroxy-17.alpha.-(3-hydr oxy-1-propenyl)-4'H-naphtho[3',2',1';10,9,11]estra-4,15-dien-3-one,

(Z)-6'-(3-pyridinyl)-9,11.alpha.-dihydro-17beta-hydroxy-17.alpha.-(3-hydrox y-1-propenyl)-4'H-naphtho[3',2',1';10,9,11]estra-4,15-dien-3-one,

11.beta.O-(4-acetylphenyl)-17.beta.-hydroxy-17.alpha.-(1,1,2,2,2-pentafluor oethyl)estra-4,9-dien-3-one,

6'-(Acetyloxy)-9,11.alpha.-dihydro-17.beta.-hydroxy-17.alpha.-(1,1,2,2,2-pe ntafluoroethyl)-4'H-naphth[3',2',1';10,9,11]estr-4-en-3-one,

9,11 .alpha.-Dihydro-17.beta.-hydroxy-6'-(hydroxymethyl)-17.alpha.-(1,1,2,2,2-p entafluoroethyl)-4'H-naphth[3',2',1';10,9,11]estr-4-en-3-one

and the other compounds described in WO 98/34947;

11beta-(4-Acetylphenyl)-19,24-dinor-17,23-epoxy-17alpha-chola-4,9,20-trien- 3-one,

11beta-(4-Methoxyphenyl)-19,24-dinor-17,23-epoxy-17alpha-chola-4,9,20-trien -3-one,

and the other compounds described in U.S. Pat. No. 5,292,878;

(Z)-11beta,19-[4-(3-Pyridinyl)-o-phenylene)-17beta-hydroxy-17.alpha.-[3-hyd roxy-1-propenyl]-4-androsten-3-one,

(Z)-11beta,19-[4-(4-Cyanophenyl-o-phenylene)]-17beta-hydroxy-17.alpha.-[3-h ydroxy-1-propenyl]-4-androsten-3-one

and the other compounds described in WO 93/23020 and U.S. Pat. No. 5,439,913;

11beta-[4-(1-methylethenyl)phenyl]-17.alpha.-hydroxy-17beta-(3-hydroxypropy l)-13.alpha.-estra-4,9-dien-3-one,

11beta-[4-(3-Furanyl)phenyl]-17.alpha.-hydroxy-17beta-(3-hydroxypropyl)-13. alpha.-estra-4,9-dien-3-one

and the other compounds described in EP 349481 and U.S. Pat. No. 5,446,036;

4',5'-Dihydro-11beta-[4-(dimethylamino)phenyl]-6beta-methylspiro[estra-4,9- dien-17beta,2'(3'H)-furan]-3-one,

4',5'-Dihydro-11beta-[4-(dimethylamino)phenyl]-7beta-methylspiro[estra-4,9- dien-17beta,2'(3'H)-furan]-3-one

and the other compounds described in U.S. Pat. No. 4,921,845 and EP 321010;

4-beta,17.alpha.-Dimethyl-17beta-hydroxy-3-oxo-4.alpha.,5-epoxy-5.alpha.-an drostan-2.alpha.-carbonitrile

7.alpha.-[9-(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-tri en-3,17beta-diol

Additional examples of drugs are

11-beta-aryl-estradienes disclosed e.g. in U.S. Pat. Nos. 4,829,060, 4,814,327, and 5,089,488;

11beta-aryl-4,9-gonadiens and 11-beta-aryl-13-alkyl-4,9-gonadiens disclosed e.g. in U.S. Pat. Nos. 5,739,125; 5,407,928 and 5,273,971.

11beta-aryl-6-alkyl (or alkenyl or alkinyl) steroids disclosed e.g. in EP 289073; 10beta, 11beta-bridged steroids disclosed e.g. in U.S. Pat. No. 5,093,507;

11beta-aryl-14beta-steroids disclosed e.g. in U.S. Pat. No. 5,244,886 and EP 277676;

19,11beta-bridged steroids disclosed e.g. in U.S. Pat. Nos. 5,095,129, 5,446,178, 5,478,956, 5,232,915, EP 559690, and EP 283428;

As examples of non steroidal compounds can be mentioned

1-arylsulphonyl, arylcarbonyl and 1-arylphosphonyl-3-phenyl-1,4,5,6-tetrahydropyridazines such as

3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-1,4,5,6-tet rahydropyridazine; (R,S) 3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulphonyl)-6-methyl-1 ,4,5,6-tetrahydropyridazine;

3-(3,4-dichlorophenyl)-1-(3,5-dichlorobenzoyl)-1,4,5,6-tetrahydropyridazine ;

3-(3,4-dichlorophenyl)-1-(2,5-dichlorobenzenesulphonyl)-1,4,5,6-tetrahydrop yridazine;

and the other compounds described in U.S. Pat. No. 5,684,151;

1-Arylsulphonyl, arylcarbonyl and arylthiocarbonyl pyridazino derivatives such as

7,8-Dibromo-3,4-diazo-1,2,3,10,10a-hexahydro-3-(4-iodobenzenesulphonyl)-phe nanthrene,

7-Chloro-3,4-diazo-1,2,3,9,10,10a-hexahydro-3-(2,5-dichlorobenzenesulphonyl )-phenanthrene,

and the other compounds described in U.S. Pat. No. 5,753,655;

non-steroidal compounds that are modulators (i.e. agonists and antagonists) of steroid receptors such as

1,2-dihydro-[1,2-g]quinoline derivatives

1,2-dihydro-chromeno-[3,4f]quinoline derivatives

and the compounds described in U.S. Pat. Nos. 5,688,808, 5,693,646, 5,693,647, 5,696,127, 5,696,130 and 5,696,133.

The most preferred compounds are those explicitly mentioned by name above.

Typical diseases or conditions to be treated by the compounds having antiprogestinic properties:

The compounds of formula I in WO 98/34947 are competitive progesteron antagonists, which prevent progesteron from binding to its receptor. At the same instant other endocrinic side effects such as e.g. androgen, estrogen or antiglucocorticoidal activity are non-existent or minimal. The compounds can be used for contraception, for treating hormonal irregularities, to start the menstrual cycle and to start the labor. Further indications are hormone replacement therapy (WO-A 94/18983), treating of the pain connected to dysmenorrhoea, endometriosis (EP-A 0 266 303) as well as treating of myomas.

The compounds described in this invention are also suitable for treating hormone dependent carcinomas. Furthermore, combined with other active substances such as antiestrogens the compounds described in this invention can be used for treating hormone dependent tumors (EP-A 0 310 542) and for contraception (WO 96/19997). Without limiting the scope of this invention, antiestrogen can be e.g. tamoxifen, ICI 182.780, antiestrogens described in PCT/EP97/04517 and aromatase inhibitors, such as fadrozol, formestan, letrozol, anastrozol or atamestan or any other therapeutically active substance with antiestrogenic properties.

Many antiprogestinic compounds are also useful for the prevention and or treatment of osteoporosis.

Antiprogestins combined with e.g: gonadotropin releasing hormone analog can be used for treating an ovarian estrogen dependent condition such as endometriosis, uterine leiomyomata, PMS (premenstrual syndrome) or DUB (dysfunctional uterine bleeding), a method without rapid loss of bone density as wit GnRH analogs alone (U.S. Pat. No. 5,681,817). Antiprogestins combined with progesterone synthesis inhibitors are suitable for treatment of endometriosis, dysmenorrhea and hormone dependent tumors (e.g. U.S. Pat. No. 5,795,881). Antiprogestins in combination with estrogens are useful in hormone replacement therapy in women.

Antiprogestins may also be used in combination with other hormones, progestins, mesoprogestins or other therapeutically active compounds such as flutamide, hydroxy-flutamide, prostaglandins, glucocorticoids etc.

The required dose of the antiprogestinic compounds is disclosed in the art. The suitable dose range will vary with the particular condition to be treated, the severity of the condition, the duration of the treatment, the administration route and the specific compound being employed.

As examples can be mentioned:

compounds of U.S. Pat. No. 5,753,655 for contraception, menopause, endometriosis, breast cancer, cycle synchrony, pregnancy termination, labor induction or osteoporosis, most likely contraception, endometriosis and osteoporosis: 1-500 mg/kg, preferably 10-100 mg/kg/day

mifepristone (0.05-10 mg/kg, pref. 0.5-5.0 mg/kg daily),

compounds U.S. Pat. No. 5,516,769 for fertility control, without preventing ovulation: oral, depot, 0.01-1 mg, 0.05-0.5 mg

compounds of U.S. Pat. No. 5,439,913 for contraception (by inhibiting the formation of endometrial glands and epithelium growth, the implantation of a fertilized egg in the uterus is rendered impossible, less than ovulation inhibiting and less than abortion inductive dose): 0.25-50 mg daily dose/implant vaginal ring.

The desired daily dosage of the drug in vivo for a defined condition to be treated, for a defined drug and administration route can be achieved with the device according to the invention particularly by varying the elastomer composition of the matrix or membrane or both so that it will contain a proper amount of poly(alkylene oxide) groups. An increasing concentration of such groups in the device will increase the drug permeation. In addition to the amount of poly(alkylene oxide) groups in the elastomer, other parameters such as the size and form of the device, the drug load, etc. will influence the daily dose released from said device. Some, but not undue, experimentation will be needed to find the most suitable parameters for each combination.

Claim 1 of 15 Claims

What is claimed is:

1. A device for the controlled release over a prolonged period of time of a drug having antiprogestinic properties, said device comprising a core comprising said drug and optionally a membrane encasing said core, said core and/or membrane being made of a siloxane-based elastomer composition comprising at least one elastomer and optionally a non-crosslinked polymer, wherein said elastomer composition comprises poly(alkylene oxide) groups and 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, said poly(alkylene oxide) groups having the formula

--R3 --O--(CHR--CH2 --O)m --

where R is hydrogen or lower alkyl, R3 is a linear or branched C2 -C6 alkylene group and m is from 1 to 3.

 


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