(19) & (11) EP 2 062 568 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 27.05.2009 Bulletin 2009/22 A61K 9/00 (2006.01) (21) Application number: 07397042.8 (22) Date of filing: 22.11.2007 (84) Designated Contracting States: • Hanes, Vladimir AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Tarrytown, NY 10591 (US) HU IE IS IT LI LT LU LV MC MT NL PL PT RO SE • Keinänen, Antti SI SK TR 20540 Turku (FI) Designated Extension States: • Holmberg, Svante AL BA HR MK RS 20900 Turku (FI) • Nikander, Hannu (71) Applicant: Bayer Schering Pharma Oy 21330 Paattinen (FI) 20210 Turku (FI) (74) Representative: Matilainen, Mirja Helena et al (72) Inventors: Oy Jalo Ant-Wuorinen AB, • Talling, Christine Iso Roobertinkatu 4-6 A 20610 Turku (FI) 00120 Helsinki (FI) (54) Vaginal delivery system (57) The present invention is related to an intravag- brane (3) encasing the core, said core and membrane inal delivery system for the controlled release of a pro- essentially consisting of a same or different polymer com- gestogen and an estrogen, comprising additionally a position, wherein at cast one of the cores comprises a therapeutically active or a health-promoting substance progestogen or a mixture of a progestogen and an es- (1) capable of giving and/or enhancing the protection trogen, and another core may comprise an estrogen or against bacterial and fungal infections, and/or enhancing a progestogen, and wherein the membrane or the surface the protection against sexually transmitted diseases. The of the membrane or at least one of the cores comprises delivery system consists of one or more compartments said therapeutically active or a health-promoting sub- (2,4,5), one of each comprising a core (7) and a mem- stance. EP 2 062 568 A1 Printed by Jouve, 75001 PARIS (FR) 1 EP 2 062 568 A1 2 Description vaginal ring. Such a crystallization of progestogen onto the skin of the device may lead to uncontrolled and high [0001] The present invention is related to an improved burst release. intravaginal delivery system for the controlled release of [0005] EP 836473 relates to a ring-shaped device a progestogen and an estrogen, additionally comprising 5 comprising a first compartment having a non-medicated a therapeutically active or a health-promoting substance core of ethylene-vinylacetate copolymer, encircled by a capable of giving and/or enhancing the protection against steroid hormone loaded ethylene-vinylacetate copoly- bacterial and fungal infections, and/or enhancing the pro- mer layer, and a non-medicated outer layer of ethylene- tection against sexually transmitted diseases. The deliv- vinylacetate copolymer; a second compartment compris- ery system consists of one or more compartments each 10 ing a core of ethylene-vinylacetate copolymer loaded with comprising a core and a membrane encasing the core, a steroid hormone and a non-medicated outer layer of said core and membrane essentially consisting of a same ethylene-vinylacetate polymer; and optionally placebo or different polymer composition, wherein at least one of compartments of a thermoplastic material separating the the cores comprises a progestogen or a mixture of a pro- first from the second compartment. In a preferred em- gestogen and an estrogen, and another core may com- 15 bodiment the invention is related to a two-compartment prise an estrogen or a progestogen, and wherein the vaginal ring with the first compartment comprising crys- membrane or the surface of the membrane or at least talline etonogestrel and the second compartment com- one of the cores comprises said therapeutically active or prising a (sub)-saturated mixture of etonogestrel and a health-promoting substance. ethinyl estradiol, both compartments optionally being 20 separated from each other by placebo compartments of Background high density polyethylene. [0006] WO 1995000199 is related to an intravaginal [0002] Vaginal delivery systems capable of releasing delivery system comprising a flexible support means, and two or more therapeutically active substances at a sub- a delivery means carried by the support means and con- stantially constant rate to one another over a prolonged 25 taining active agent. The support means consists of a period of time are extremely useful for certain applica- core member substantially in the form of an open ring, tions, for example contraception and hormone replace- and the delivery means consists of at least one sleeve- ment therapy. Extensive use has been made of the si- like polymer body which encircles the core member in a multaneous administration of an agent having a pro- belt wise manner along a part of the length of the core gestogenic activity and an agent having an estrogenic 30 member. activity, preferably in a substantially constant ratio. Con- [0007] WO 2005089723 relates to a drug delivery sys- traceptive reliability is mainly provided by the pro- tem consisting of one or more compartments and com- gestogenic component and the estrogen component acts prising a progestogenic compound dissolved in a ther- to increase the ovulation inhibitory effect of progestin and moplastic polyethylene vinylacetate copolymer whereby, to ensure cycle stability. 35 if the delivery system consists of one compartment, the [0003] A number of different constructions of vaginal compartment comprises (i) a core of a thermoplastic pol- rings are known from the literature, see for example US yethylene vinylacetate copolymer comprising the pro- 4,596,576 and in US 4,237,885. In basic solutions the gestogenic compound, such progestogenic compound delivery system is simply formed by a drug-containing being dissolved in the polyethylene vinylacetate copoly- polymer core in the form of a closed ring. A modification 40 mer up to a concentration below the saturation level at of this is a closed ring which comprises a drug-free core 25°C, and an estrogenic compound; and (ii) a skin of a surrounded by a drug matrix optionally containing a thermoplastic polyethylene vinylacetate copolymer cov- number of different drugs and in addition optionally an ering the core, said skin being permeable for both com- outermost polymer membrane. pounds;-if the delivery system consists of more than one [0004] EP 876815 relates to a preferably ring-shaped 45 compartment, only one compartment comprises (iii) the vaginal delivery system for the simultaneous release of progestogenic compound, such progestogenic com- a progestogenic steroid compound and an estrogenic pound being dissolved in a core of a thermoplastic poly- steroid compound in a fixed physiological ratio over a ethylene vinylacetate copolymer up to a concentration prolonged period of time. The delivery system comprises below the saturation level at 25°C, and an estrogenic at least one compartment comprising a thermoplastic pol- 50 compound; and (iv) a skin of a thermoplastic polyethylene ymer core containing the mixture of the progestogenic vinylacetate copolymer covering the core, said skin being and estrogenic compounds and a thermoplastic polymer permeable for both compounds. skin, the progestogenic compound being initially dis- [0008] EP 862396 relates to a vaginal ring containing solved in the polymer core material in a relatively low a body made of a first polymeric material having at least degree of supersaturation. The drug delivery device is 55 one hollow internal channel defining an opening to the physically stable only when stored below room temper- exterior of said body and which channel is adapted to ature. As indicated in EP 876815 the progestogen may receive a drug-containing core through said opening, and eventually crystallize out on the exterior surface of the a core containing at least one intravaginally administrable 2 3 EP 2 062 568 A1 4 drug dispersed in a second polymeric material disposed [0014] International patent application WO in the channel. The core is positioned in the vaginal ring 2002/15832 relates to a non-hormonal intravaginal de- body suitably prior to use in order to substantially avoid vice and the vagina is maintained at a pH of about 5-6 initial bursts of drug into the tissues of the subject and by the addition of ascorbic acid to the matrix hydrogel. resultant side effects such as nausea and vomiting. 5 WO 2006/17341 relates to a vaginal device partly or com- [0009] The advantage of vaginal rings in general is that pletely coated or covered by or combined with a mucoad- the woman is free from the necessity of having to take hesive composition containing a therapeutical agent and tablets daily. The ring-shaped structure is simple to apply, a health-promoting agent such as ascorbic acid. it is well tolerated and at any time the device can easily [0015] The delivery of biological substances such as be removed and reinserted by the woman herself. A sig- 10 probiotics and bacteria in general are described for ex- nificant drawback of these devices is that they do not ample in WO 2003/26687, US 20050152966 and US give any protection against bacterial and fungal infections 20030096002, based on a swellable polymer matrices, and/or against sexually transmitted diseases. in WO 2002/94224 based on biocompatible carbohy- [0010] Therefore there is still need for an improved in- drate polymers associated with milk protein, and in WO travaginal delivery system, which in addition to a suffi- 15 2005/74976 based on uncrosslinked starch. cient daily dosage of a progestogen and an estrogen needed for contraception or hormone replacement ther- OBJECT OF THE INVENTION apy, would release a sufficient amount of a therapeuti- cally active or a health-promoting substance capable of [0016] The object of the present invention is to provide giving and/or enhancing the protection against bacterial 20 an improved intravaginal delivery system for the control- and fungal infections, and/or enhancing the protection led release of progestogen and estrogen, and addition- against sexually transmitted diseases.