Devices for the delivery of drugs having antiprogestinic properties

• US 6,476,079 B1
• Filed: 12/23/1999
• Issued: 11/05/2002
• Est. Priority Date: 12/23/1999
• Status: Expired due to Term

• Current Assignee: Schering Corporation (Merck & Co., Inc.)
• Original Assignee: Leiras Oy (Bayer AG)
• Inventors: Markkula, Tommi, Ala-sorvari, Juha, Jukarainen, Harri, Lehtinen, Matti, Ruohonen, Jarkko
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): FUBARA, BLESSING M
• Application Number:
  US09/472,126
• Time in Patent Office: 1,048 Days
• Field of Search: 524/862, 524/865, 424/423, 424/424, 424/422, 424/473, 424/486, 424/449, 514/170, 514/772.4, 514/171, 514/179, 514/843, 514/899
• US Class Current: 514/772.4
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/277 having a ring, e.g. verapamil
• CPC Class Codes: A61K 31/4418 having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
• CPC Class Codes: A61K 31/50 Pyridazines; Hydrogenated pyridazines
• CPC Class Codes: A61K 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/569 substituted in position 17 alpha, e.g. ethisterone
• CPC Class Codes: A61K 31/575 substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0039 Devices retained in the uterus for a prolonged period, e.g. intrauterine devices for contraception
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/04 for inducing labour or abortion; Uterotonics
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 15/18 Feminine contraceptives
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: A61P 5/32 Antioestrogens
• CPC Class Codes: A61P 5/36 : Antigestagens
• CPC Class Codes: C08G 77/18 : to alkoxy or aryloxy groups
• CPC Class Codes: C08G 77/44 : containing only polysiloxane sequences
• CPC Class Codes: C08G 77/46 : containing polyether sequences
• CPC Class Codes: C08G 77/50 : by carbon linkages C08G77/485 takes precedence
• CPC Class Codes: C08G 77/70 : Siloxanes defined by use of the MDTQ nomenclature
• CPC Class Codes: C08L 2666/14 : Macromolecular compounds according to C08L59/00 - C08L87/00; Derivatives thereof
• CPC Class Codes: C08L 83/04 : Polysiloxanes
• CPC Class Codes: C08L 83/12 : containing polyether sequences

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.

Claims

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

2. The device according to claim 1, wherein the core is an elastomer matrix, optionally made of said elastomer composition.

3. The device according to claim 2, wherein the membrane or matrix is made of an elastomer based on polysiloxane units which comprise poly(alkylene oxide) groups.

4. The device according to claim 1, wherein in the elastomer composition the poly(alkylene oxide) groups are poly(ethylene oxide) groups (PEO groups).

5. The device according to claim 1, wherein the formula of the polysiloxane groups is

6. The device according to claim 5, wherein the free R′

and R″

groups are lower alkyl groups.

7. The device according to claim 1, wherein the poly(alkylene oxide) groups are present in the elastomer in the form of poly(alkylene oxide) blocks having the formula

8. The device according to claim 1, wherein 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 elastomer.

9. The device according to claim 8, wherein the second elastomer is a poly(dimethyl siloxane) elastomer which optionally comprises poly(alkylene oxide) groups.

10. The device according to claim 9, wherein said second poly(dimethyl siloxane) elastomer contains poly(alkylene oxide groups, which are present in the form of alkoxy-terminated grafts of poly(dimethyl siloxane) units, or as blocks in which case the said grafts or blocks are linked to the poly(dimethyl siloxane) units by silicon carbon bonds, or as a mixture of these forms.

11. The device according to claim 1, wherein the elastomer composition is a blend, which comprises

a siloxane elastomer and

a linear 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 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.

12. The device according to claim 2, wherein the matrix is encased in a membrane.

13. The device according to claim 12, wherein the matrix and the membrane both are made of an elastomer composition comprising 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.

14. The device according to claim 1, wherein the device is an implant, an intrauterine or intracervical device, an intravaginal device, or a transdermal patch.

15. The device according to claim 1, wherein the drug having antiprogestinic properties is a compound selected from a group consisting of

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

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

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

11beta-[(4-Dimethylamino)phenyl]-17alpha-hydroxy-17beta-(3-hydroxypropyl)-13α

-methyl-estra-4,9-dien-3-one (onapristone);

(Z)-11beta-[(4-Dimethylamino)phenyl)]-17beta-hydroxy-17alpha-(3-hydroxy-1-propenyl)estra-4,9-dien-3-one (lilopristone);

11beta-(4-Acetylphenyl)-17beta-hydroxy-17alpha-(1-propinyl)estra-4,9-dien-3-one;

(Z)beta-(4-Acetylphenyl)-17beta-hydroxy-17alpha-(3-hydroxy-1-propenyl)estra-4,9-dien-3-one;

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

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

4-[17β

-Methoxy-17α

-(methoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-oxime;

4-[17β

-Hydroxy-17α

-(methoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-oxime;

4-[17β

-Methoxy-17α

-(methoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-[O-(ethylamino)carbonyl]oxime;

4-[17β

-Methoxy-17α

-(methoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-[O-(ethoxy)carbonyl]oxime;

4-[17β

-Methoxy-17α

-(methoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime;

4-[17β

-Methoxy-17α

-(ethoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-[O-(ethylthio)carbonyl]oxime;

4-[17β

-Hydroxy-17α

-(methoxymethyl)-3-oxoestra-4,9-dien-11β

-yl]benzaldehyde-1-(E)-[O-(n-propylthio)carbonyl]oxime;

(Z)-6′

-(4-cyanophenyl)-9,11α

-dihydro-17beta-hydroxy-17α

-[4-(1-oxo-3-methylbutoxy)-1-butenyl]-4′

H-naphtho[3′

,2′

,1′

;

10,9,11]estra-4-en-3-one;

(Z)-6′

-(4-cyanophenyl)-9,11α

-dihydro-17beta-hydroxy-17α

-[3-(1-oxo-3-methylbutoxy)-1-propenyl]-4′

H-naphtho[3′

,2′

,1′

;

10,9,11]estra-4,15-dien-3-one;

(Z)-6′

-(4-cyanophenyl)-9,11α

-dihydro-17beta-hydroxy-17α

-(3-hydroxy-1-propenyl)-4′

H-naphtho[3′

,2′

,1′

;

10,9,11]estra-4,15-dien-3-one;

(Z)-6′

-(3-pyridinyl)-9,11α

-dihydro-17beta-hydroxy-17α

-(3-hydroxy-1-propenyl)-4′

H-naphtho[3′

,2′

,1′

;

10,9,11]estra-4,15-dien-3-one;

11β

-(4-Acetylphenyl)-17β

-hydroxy-17α

-(1,1,2,2,2-pentafluoroethyl)estra-4,9-dien-3-one;

6′

-(Acetyloxy)-9,11α

-dihydro-17β

-hydroxy-17α

-(1,1,2,2,2-pentafluoroethyl)-4′

H-naphth[3′

,2,′

,1′

;

10,9,11] estr-4-en-3-one;

9,11α

-(Dihydro)-17β

-hydroxy-6′

-(hydroxymethyl)-17α

-(1,1,2,2,2-pentafluoroethyl)-4′

H-naphth[3′

,2,′

,1′

;

10,9,11] estr-4-en-3-one;

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;

(Z)-11beta,19-[4-(3-Pyridinyl)-o-phenylene)]-17beta-hydroxy-17α

-[3-hydroxy-1-propenyl]-4-androsten-3-one;

(Z)-11beta,19-[4-(4-Cyanophenyl-o-phenylene)]-17beta-hydroxy-17α

-[3-hydroxy-1-propenyl]-4-androsten-3-one;

11beta-[4-(1-methylethenyl)phenyl]-17α

-hydroxy-17beta-(3-hydroxypropyl)-13α

-estra-4,9-dien-3-one;

11beta-[4-(3-Furanyl)phenyl]-17α

-hydroxy-17beta-(3-hydroxypropyl)-13α

-estra-4,9-dien-3-one;

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;

4-beta,17α

-Dimethyl-17beta-hydroxy-3-oxo-4α

,5-epoxy-5α

-androstan-2α

-carbonitrile;

7α

-[9-(4,4,5,5,5-Pentafluoropentyl)sulfinyl]nonyl]estra-1,3,5(10)-trien-3,17 beta-diol;

3-(4-chloro-3-trifluoromethylphenyl)-1-(4-iodobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine;

(R,S)3-(4-chloro-3-trifluoromethylphenyl)-1-(iodobenzenesulfonyl)-6-methyl-1,4,5,6-tetrahyropyridazine;

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

3-(3,4-dichlorophenyl)1-(2,5-dichlorobenzenesulfonyl)-1,4,5,6-tetrahydropyridazine;

7,8-Dibromo-3,4-diazo-1,2,3,10,10a-hexahydro-3-(4-iodobenzenesulfonyl)-phenanthrene; and

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