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(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 , 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 , 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 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 , 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. ally a therapeutically active or a health-promoting sub- [0011] The resident microorganisms are known to be stance capable of giving and/or enhancing the protection the main factors to maintain and stabilize the physiolog- against bacterial and fungal infections, and/or enhancing ical environment in the vagina. Lactobacilli are the pre- 25 the protection against sexually transmitted diseases. The dominant microorganisms in the vaginal bacteria, and delivery system consists of one or more compartments they play a major role in maintaining a healthy urogenital each comprising a core and a membrane encasing the tract. They are capable of preventing adhesion and core, said core and membrane essentially consisting of growth of pathogenic microorganisms through mecha- a same or different polymer composition, wherein at least nisms that appear to involve secretion of anti-adhesion 30 one of the cores comprises a progestogen or a mixture factors, hydrogen peroxide, bacteriocins lethal to patho- of a progestogen and an estrogen, or an estrogen, and gens and fermenting the glycogen derived from the de- wherein the surface of the membrane, the membrane or cline of the atrophic vaginal mucosa, to with at least one of the cores comprises said therapeutically release of hydrogen ions, the final result being the optimal active or health-promoting substance. pH value (Microb. Infect. 4, 319 324 (2002)). 35 [0017] The present invention especially provides an [0012] Vaginal pH undergoes physiologically changes intravaginal delivery system for the simultaneous admin- from birth to menopause, according to changes of ovar- istration of a sufficiently high daily dosage of dros- ian occurring during woman’s life. Adequate lev- pirenone (6β,7β;15β;16β-dimethylene-3-oxo-17α-preg- els of estrogens play a role in the trophism of vaginal 4-ene-21,17-carbolactone), an estrogen, preferably es- mucosa, and estrogens increase the cellular content of 40 tradiol, estradiol hemihydrate , an estradiol ester or ethi- glycogen. Several factors, such as sexual activity, oral nyl estradiol and a therapeutically active or a health-pro- contraceptives or systemic or local therapies may in- moting substance capable of giving and/or enhancing crease vaginal pH through different mechanisms. The the protection against bacterial and fungal infections change in the pH value may also be indicative to pres- and/or enhancing the protection against sexually trans- ence of disbalance in the vaginal environment such as 45 mitted diseases, preferably a representative of Lactoba- systemic diseases or vaginal infections. The increase of cillus species. vaginal pH above 4.0-4.5 is detrimental for the survival [0018] The drug delivery system according to the in- of Lactobacillus bacteria, but not for other micro organ- vention is especially suitable for use in the field of female isms, especially for the pathogenetic microorganisms, contraception and hormone replacement therapy. The whose replication on the contrary is favored by the ab- 50 delivery system can also be used for treating diseases, sence of contraction exerted by lactobacilli. disorders and symptoms associated for example with [0013] Probiotic agents have been used to adjust or to natural menopause, peri-menopause, post-menopause, maintain the normal vaginal pH value. For example, in- hypogonadism or primary ovarian failure in women, ternational patent application WO 2006/65873 relates to wherein the amount of estrogen is sufficient to treat dis- a fiber-reinforced composite ring containing ferrous glu- 55 eases, disorders and symptoms associated with deficient conate or ferrous ascorbate as an active agent and acids, endogenous levels of estrogen and the amount of dros- such as ascorbic and glycolic acids to maintain the vag- pirenone is sufficient to protect the endometrium from inal pH below 6 and preferably at 3-4.5. the adverse effects of estrogen. The delivery system can

3 5 EP 2 062 568 A1 6 further be used for the treatment of endometriosis and DETAILED DESCRIPTION uterine fibroids based on the suppression of endogenous sexual steroid production combined with exogenous pro- [0027] The advantages of the invention are obtained gestogene effects. Further, the invention provides a con- by the intravaginal delivery system consisting of one or venient and highly adaptable drug delivery system for 5 more compartments, one or each compartment compris- use in female animals, too. ing a core and a membrane encasing the core, said core [0019] In addition to contraception or hormone re- and membrane essentially consisting of a same or dif- placement therapy, the invention provides a method for ferent polymer composition, wherein at least one of said giving and/or enhancing the protection against bacterial compartments comprises a progestogen or a mixture of and fungal infections and/or enhancing the protection 10 a progestogen and an estrogen, and another core may against sexually transmitted diseases, which comprises optionally comprise an estrogen or a progestogen, and the steps of positioning the delivery system of the subject wherein at least one of the cores or the membrane or the invention within the female vaginal tract and retaining the surface of the membrane additionally comprises a ther- system a prolonged period of time within the vaginal tract. apeutically active or a health-promoting substance ca- Thus the present invention concerns a delivery system 15 pable of giving and/or enhancing the protection against and a method as described below in the independent bacterial and fungal infections and/or enhancing the pro- claims. tection against sexually transmitted diseases. [0028] According to an embodiment of the invention, BRIEF DESCRIPTION OF THE FIGURES the intravaginal delivery system consists of one compart- 20 ment comprising a core and a membrane encasing said [0020] The invention is further illustrated by the follow- core, said core and membrane essentially consisting of ing examples, describing various constructions of the in- a same or different polymer composition, wherein the travaginal delivery system according to the invention core comprises a mixture of progestogen and an estro- [0021] Figure 1 is an intravaginal delivery system com- gen and the membrane comprises a therapeutically ac- prising a supporting ring free of active agent or the first 25 tive or a health-promoting substance capable of giving compartment containing a therapeutically active agent and/or enhancing the protection against bacterial and (1), the second compartment (2) applied to the outer sur- fungal infections and/or enhancing the protection against face of 1 and containing a therapeutically active agent sexually transmitted diseases. and a membrane layer (3) encasing the whole delivery [0029] According to another embodiment of the inven- system or a part of it. The supporting ring or compartment 30 tion, the intravaginal delivery system consists of at least 1 may have a groove at least on the portion of the annular two compartments comprising a core and a membrane surface adapted to mate with corresponding compart- encasing said core, said core and membrane essentially ment 2. consisting of a same or different polymer composition, [0022] Figure 2 is an intravaginal delivery system com- wherein at least one of the cores comprises a mixture of prising two compartments 4 and 5 encased by a mem- 35 progestogen and an estrogen and one of the cores com- brane 3, the compartments being positioned next to each prises said therapeutically active or a health-promoting other substance. [0023] Figure 3 is an intravaginal delivery system com- [0030] According to a further embodiment of the inven- prising three compartments 4, 5 and 6 encased by a tion, the intravaginal delivery system consists of at least membrane 3, the compartment 4 is separated from other 40 two compartments each comprising a core and a mem- compartments by separation membranes a and b, while brane encasing said core, said core and membrane es- compartments 5 and 6 are positioned next to each other sentially consisting of a same or different polymer com- [0024] Figure 4 is an intravaginal delivery system com- position, wherein one of the cores comprises a pro- prising three compartments 4, 5 and 6 encased by a gestogen or a mixture of a progestogen and an estrogen, membrane 3. An inert placebo compartment c separates 45 another core comprises a progestogen or an estrogen, the compartments 4 and 6, the compartments 4 and 5 and the membrane or the surface of the membrane or at as well as 5 and 6 are positioned next to each other. In least one of the cores comprises a therapeutically active this design compartments 4, 5 or 6 may or may not con- or a health-promoting substance capable of giving and/or tain a therapeutically active substance, either the same enhancing the protection against bacterial and fungal in- or different. 50 fections and/or enhancing the protection against sexually [0025] Figure 5 is a general design of an intravaginal transmitted diseases. delivery system comprising a core 7 and a membrane 3 [0031] Any suitable design of the delivery system or encasing the core. any combination of structure is naturally possible and [0026] Figure 6 is another type of general design of an within the scope of the invention. intravaginal delivery system comprising a core 8, a mem- 55 [0032] The core consists essentially of an polymer brane 3 encasing the core and an inert supporting mem- composition, that is, the core is an elastomer matrix ber 9 wherein the therapeutically active substance or sub- stances are dispersed. Therefore, even if the membrane

4 7 EP 2 062 568 A1 8 encasing the core would be damaged, the therapeutically is such that it allows the pre-determined release rates of active substances would not be released in a completely the therapeutically active agents. uncontrolled manner causing side effects to the patient. [0036] Polymer compositions of the core, the mem- Thus the polymer composition of the core is preferably brane and the possible separation membrane or the inert chosen so that the membrane primarily regulates the re- 5 placebo compartment, can be the same or different and lease of the therapeutically active agent. The release may stand for one single polymer, a mixture of polymers rates in general can be controlled by the membrane alone or the polymer composition may be made up of polymers or by the membrane together with the core. It is also that are blended with each other. possible that the release rate is mainly controlled by the [0037] In principle any polymer, either biodegradable core. 10 or non-biodegradable, can be used as long as it is bio- [0033] According to the embodiment in which the de- compatible. As known in the art, the release kinetics of livery system consists of two or more compartments, said a therapeutically active agent from a polymer based de- compartments may be positioned next to each other. The livery system depends on the molecular weight, solubility, compartments may also be side-by-side or one on the diffusivity and charge of the therapeutically active agent other, for example as described in US 4,822,616 and US 15 as well as on the characteristics of the polymer, on the 4,012,496 by Schering AG, the upper compartment being percentage of the loading of the therapeutically active assembled on or encircling the surface of the lower com- agent, on the distance the therapeutically active agent partment or assembled in a groove on the surface of the must diffuse through the device body to its surface lower compartment. The length of the compartments may and on the characteristics of any matrix or membrane. be same or different. The compartments may or may not 20 [0038] Polysiloxanes, in particular poly (dimethyl si- be separated from each other by a separation membrane loxane) (PDMS), are highly suitable for use as a mem- or by an inert placebo compartment. An advantage of brane or matrix regulating the permeation rate of drugs. using several compartments separated from each other Polysiloxanes are physiologically inert, and a wide group by a membrane or an inert placebo compartment is that of drugs are capable of penetrating polysiloxane mem- the release rates are more easily controllable since there 25 branes, which also have the required strength properties. is no interaction between the active substances. The permeation rate of the drugs can be adjusted at a [0034] The membrane may cover the whole delivery desired level by modifying the polymeric material in a system or cover only a part of the system, whereby the suitable way, e.g. by adjusting hydrophilic or hydrophobic degree of extension can vary depending on a number of properties of the material. It is for example known from factors, for example such as the choice of materials and 30 the literature that addition of poly (ethylene oxide) groups the choice of active agents. The thickness of the mem- or trifluoropropyl groups to a PDMS polymer may change brane depends on materials and active agents used as the permeation rate of the drugs. well as on desired release profiles, but generally the thick- [0039] Further examples of suitable materials include, ness is smaller the thickness of the core member. The but are not limited to, copolymers of dimethylsiloxanes membrane may consist of more than one layer, in which 35 and methylvinylsiloxanes, ethylene/vinyl acetate copol- case one of the layers or several layers may comprise a ymers (EVA), polyethylene, polypropylene, ethylene/ therapeutically active or a health-promoting substance propylene copolymers, acrylic acid polymers, ethylene/ capable of giving and/or enhancing the protection against ethyl acrylate copolymers, polytetrafluoroethylene (PT- bacterial and fungal infections and/or enhancing the pro- FE), polyurethanes, polybutadiene, polyisoprene, poly tection against sexually transmitted diseases. Each layer 40 (methacrylate), polymethyl methacrylate, styrenebutadi- has a certain thickness, and the thickness of the layers ene-styrene block copolymers, poly(hydroxyethylmeth- may be the same or different. acrylate) (pHEMA), polyvinyl chloride, polyvinyl acetate, [0035] The outer surface or membrane may further polyethers, polyacrylonitriles, polyethylene glycols, have different designs, layers or holes , in which case polymethylpentene, polybutadiene, polyhydroxy al- one of the layers or holes may comprise a therapeutically 45 kanoates, poly(lactic acid), poly(glycolic acid), polyanhy- active or a health-promoting substance capable of giving drides, polyorthoesters, hydrophilic polymers such as the and/or enhancing the protection against bacterial and hydrophilic hydrogels , cross-linked polyvinyl alcohol, ne- fungal infections and/or enhancing the protection against oprene rubber, butyl rubber, hydroxyl-terminated organ- sexually transmitted diseases. Each layer has a certain opolysiloxanes of the room temperature vulcanizing type thickness, either the same or different, and each hole 50 which harden to elastomers at room temperature follow- may have certain depth. The combination of different ing the addition of cross-linking agents in the presence membrane layers either in design, thickness or in mate- of curing catalysts, one- or two-component dimethyl- rial or both, gives a further possibility for controlling the polysiloxane compositions cured by hydrosilylation at release rates of the active agents. The surface of at least room temperature or under elevated temperatures, as one of the membranes may also comprise a therapeuti- 55 well as mixtures thereof. cally active or a health-promoting substance in a form of [0040] The structural integrity of the material may be particles, crystals, microcrystals, powder, suspension or enhanced by the addition of a particulate material such a like. The polymer composition used in the membrane as silica or diatomaceous earth. The elastomers can also

5 9 EP 2 062 568 A1 10 be mixed with other additives to adjust elastomer’s hy- propyl substitution is in fact somewhat below 50 %, be- drophilic or hydrophobic properties while taking into ac- cause the polymer must contain a certain amount (about count that all additives need to be biocompatible and 0.15 % of the substituents) of cross-linkable groups such harmless to the patient. The core or membrane may also as vinyl or vinyl-terminated groups. comprise additional material to further adjust the release 5 [0046] According to an especially preferred embodi- rate of one or several of the therapeutic substances, for ment of the invention, the siloxane-based elastomer com- example complex forming agents such as cyclodextrin prises poly(alkylene oxide) groups so that the poly derivatives to adjust the initial burst of the substance to (alkylene oxide) groups are present in the said elastomer the accepted or desired level. Auxiliary substances, for either as alkoxy-terminated grafts of polysiloxane units example such as tensides, antifoaming agents, solubi- 10 or as blocks, the said grafts or blocks being linked to the lisers or absorption retarders, or a mixture of any two or polysiloxane units by silicon-carbon bonds. Preferably more of such substances, can also be added in order to the poly(alkylene oxide) groups mentioned above are po- impart the desired physical properties to the body of the ly(ethylene oxide) (PEO) groups. In the core or mem- delivery system. brane polymer composition the proportion of the polysi- [0041] According to an embodiment, the core and the 15 loxane comprising poly (alkylene oxide) groups, for ex- membrane are made of a siloxane based elastomer com- ample polydimethylsiloxane comprising poly(ethylene position comprising at least one elastomer and possibly oxide) groups as alkoxy-terminated grafts or as blocks a non-crosslinked polymer. that are linked to the polysiloxane units by silicon-carbon [0042] The term "elastomer composition" may stand bonds (PEO-b-PDMS copolymer) may vary from zero to for one single elastomer, the deformation of which 20 80 % of the total amount of polymers, but can naturally caused by the strain is reversible so that the elastomer’s be higher. shape recovers to a certain level after the strain. The [0047] The methods for the preparation of suitable elastomer composition may also be made up of two or elastomers are given for example in international patent more elastomers blended with each other. applications WO 00/00550, WO 00/29464 and WO [0043] The term "siloxane-based elastomer" shall be 25 99/10412 (each assigned to Leiras Oy). understood to cover elastomers made of poly (disubsti- [0048] When the therapeutically active or a health-pro- tuted siloxanes) where the substituents mainly are lower moting substance is relatively large molecule, such as alkyl, preferably alkyl groups of 1 to 6 carbon atoms, or for example Lactobacillus species, biodegradable poly- phenyl groups, wherein said alkyl or phenyl can be sub- mers, for example hydrogels, are especially suitable stituted or unsubstituted. A widely used and preferred 30 membrane or matrix materials. polymer of this kind is poly (dimethylsiloxane) (PDMS). [0049] Progestogen can be any therapeutically active [0044] The elastomer composition may also be select- substance having progestogenic activity enough to ed from the group consisting of achieve contraception or to be useful in hormone replace- ment therapy. Examples of suitable progestogenic com- - an elastomer composition comprising poly(dimeth- 35 pounds include compounds such as cyproterone ace- ylsiloxane) (PDMS), tate, desogestrel, etonogestrel, levonorgestrel, lynestre- - an elastomer composition comprising a siloxane- nol, medroxyprogesterone acetate, , based elastomer comprising 3,3,3-trifluoropropyl norethisterone acetate, norgestimate, gestodene or dro- groups attached to the silicon atoms of the siloxane spirenone. units, 40 [0050] In a particular embodiment the progestogenic - an elastomer composition comprising poly(alkylene compound is drospirenone. In place of the active sub- oxide) groups, said poly(alkylene oxide) groups be- stance itself, an ester or prodrug of drospirenone may be ing present as alkoxy-terminated grafts or blocks employed in the present composition, e.g. an oxyimino- linked to the polysiloxane units by silicon-carbon pregnane carbolactone as disclosed in WO 98/24801. bonds or as a mixture of these forms, and 45 [0051] Estrogen may be selected from the group con- - a combination of at least two thereof. sisting of estradiol, ethinyl estradiol, esters of estradiol such as estradiol valerate, estradiol benzoate and estra- [0045] According to a preferred embodiment of the in- diol succinate, estradiol hemihydrate, estradiol sulfa- vention, in the siloxane-based elastomer from 1 to ap- mates, , , estriol succinate and conjugated proximately 50 % of the substituents attached to the sil- 50 estrogens, including conjugated equine estrogens such icon atoms of the siloxane units are 3,3,3-trifluoropropyl as estrone sulfate, 17β-estradiol sulfate, 17α-estradiol groups. The percentage of the substituents that are 3,3,3- sulfate, sulfate, 17β-dihydroequilin sulfate, 17α- trifluoropropyl groups can be for example 5-40 %, 10-35 dihydroequilin sulfate, sulfate, 17β-dihy- %, 1-29 % or 15-49.5 %. One polymer of this kind, in droequilenin sulfate and 17α-dihydroequilenin sulfate or which approximately 50 % of the methyl substituents at 55 mixtures thereof. Particularly interesting estrogens are the silicon atoms are replaced by 3,3,3-trifluoropropyl those selected from the group consisting of estradiol, es- groups, is commercially available. The term "approxi- tradiol valerate, estradiol succinate, estradiol benzoate, mately 50 %" means that the degree of 3,3,3-trifluoro- estradiol hemihydrate, estradiol sulfamates, estrone, and

6 11 EP 2 062 568 A1 12 estrone sulfate or mixtures thereof. Most preferred com- [0055] The amount of the therapeutically active agent pounds are ethinyl estradiol, estradiol, estradiol hemihy- incorporated in the delivery system varies depending on drate, estradiol succinate, estradiol valerate or estradiol the particular therapeutically active agent, intended use benzoate. of the substance, expected release rate and the time for [0052] Other suitable therapeutically active substanc- 5 which the system is expected to provide therapy. Since es include, but not limited to, compounds which can be a variety of devices with varying sizes can be formulated used to treat and/or prevent bacterial or fungal infections for administering dosages, there is no critical upper limit and/or sexually transmitted diseases, for example anti- on the amount of therapeutically active agent incorporat- microbial agents, antibacterial agents, for example such ed in the device. The lower limit depends on the activity as , , ampicillin, amoxicillin, 10 of the therapeutically active agent and the expected re- , doxycycline, antiviral agents, for example lease time. A person skilled in the art is readily able to such as acyclovir, famciclovir, ganciclovir, saquinavir, va- determine the amount of the therapeutically active agent lacyclovir and AZT, various , agents, needed for each specific application of the delivery sys- for example such as conazole derivatives like itracona- tem. zole, , terconazole, , fenticona- 15 [0056] Preferably, the amount of therapeutically active zole, , , and eco- agent in the core varies between almost zero to 60 wt- nazole, , , metronidazole, clindamycin, and %, when it is mixed into the polymer, the preferred 5 fluoracil, anti-inflammatoric agents and the like.. amount being between 10-40 wt-%. Other possible rang- [0053] Term "health-promoting agent" means a health- es of the amount of the therapeutically active agent are sustaining agent or a health-enhancing agent or gener- 20 0.5-60 wt-%, 5-55 wt-%, 10-50 wt-%, 25-60 wt-%, 40-50 ally a substance or a combination of substances that are wt-% and 15-35 wt-%. The amount of the therapeutically or may be used for the purpose of maintaining and/or active or the health promoting agent in the membrane improving health or treating and/or preventing disease varies between almost zero to 20 wt-%, the preferred conditions. Such compounds broadly include, but are not amount being between 1-20 wt-%. Other possible ranges limited to, vitamins, minerals, enzymes, co-enzymes, co- 25 of the amount of the therapeutically active agent are factors, microorganisms, organic acids, spermicides, de- 0.5-15 wt-%, 1-10 wt-%, 5-20 wt-%, 8-15 wt-%. tergents, surfactants and a variety of molecules extracted [0057] The daily dosage of the therapeutically active from natural sources such as amino acids, polysaccha- substances for a defined condition to be treated and for rides, peptides, naturally occurring hormones and bio- a defined substance can be achieved with the delivery chemical intermediates, as well as naturally occurring 30 system according to the invention particularly by varying molecules synthesized by chemical or biological means the polymer composition of the matrix or membrane or [0054] Preferable substances, but not limited to, are both, for example so that the polysiloxane elastomer will the compounds which can especially be used to maintain contain a proper amount of poly(alkylene oxide) groups. and stabilize the physiological environment in the vagina, An increasing concentration of such groups in the elas- for example such as natural amino acids, lactic acid, poly- 35 tomer will increase the drug permeation. In addition to lactic acids, glycolic acid, polyglycolic acids, carbopol, modifying the elastomer, other parameters such as the polycarbophil, ascorbic acid, D-pantothenic acid, folic ac- size and form of the device, the drug load, etc. will influ- id and the reduced forms thereof, especially tetrahydro- ence the daily dose released from said device. Some, folates and metabolites of folic acid, preferably 5-methyl- but not undue, experimentation will be needed to find the 6(S)-tetrahydrofolic acid and its salts, especially its earth 40 most suitable parameters for each combination. alkaline salts, of these the calcium salt (Metafolin) being [0058] The daily dosage, i.e. the daily release rate preferred, fumaric acid, benzoic acid, p-aminobenzoic needed for contraception is in the range of 1-5 mg for acid, alginic acid, sorbic acid, tartaric acid, edetic acid, drospirenone, 0.005-0.050 mg for ethinyl estradiol, salts of these acids, niacinamide, Lactobacillus species, 0.050-0.200 mg for estradiol and, for example, for example such as Lactobacillus reuteri, Lactobacillus 45 0.040-0.080 mg for gestodene. A preferred daily release reuterii RC-14, Lactobacillus delbrueckii, Lactobacillus rate for drospirenone is 2.5-3.5 mg, and more preferred gasseri, Lactobacillus jensenii, Lactobacillus catena- release rate is 3 mg. For hormone therapy the corre- forme, Lactobacillus paracasei, Lactobacillus paracasei sponding values are in the range of 0.1-10 mg for dros- Lbp PB01, Lactobacillus casei, Lactobacillus acido- pirenone, 0.001-0.100 mg for ethinyl estradiol, philus, Lactobacillus acidophilus Lba EB01, Lactobacil- 50 0.010-0.500 mg for estradiol and, for example, lus crispatus, Lactobacillus crispatus CTV05, Lactoba- 0.005-0.200 mg for gestodene. cillus salivarius, Lactobacillus brevis, Lactobacillus fer- [0059] For lactobacillus species no official requirement mentum, Lactobacillus fermentum RC-14, Lactobacillus concerning the therapeutic cell counts for the urogenital fermentum B-54, Lactobacillus rhamnosus and Lactoba- application exists. In the vaginal applications the cell cillus rhamnosus GR-1, octoxynol-9, chlorhexidine, ben- 55 counts may vary from 106-109 cfu/product. zalkonium chloride, nonoxynol-9, carrageenan, cyanovi- [0060] Depending on the use of the device, the expect- rin-N, fuzeon, hydroxyethyl cellulose, menfegol, dextran ed release time of progestogens and estrogens varies sulfate and cyclodextrin derivatives, and the like. from one week to several months, for example from one

7 13 EP 2 062 568 A1 14 week to 12 months, preferably from one week to 6 months together to form a drug delivery device using a coupling and more preferably from 21 days to 3 months. The re- means, which can be any method, mechanism, device lease time of additional therapeutically active agents or or material known in the art for bonding or joining mate- health-promoting agents may be shorter and may vary rials or structures together. The coupling can for example from one day up to 3 months, preferably from one day to 5 include solvent bonding, adhesive joining, heat fusing, 1 month and more preferably from one day to three heat bonding, pressure, and the like. When a solvent is weeks. used, the ends of the segments are moistened with an organic solvent that causes the surfaces to feel tacky, Manufacture of the device and when placed in contact the surfaces then bond and 10 adhere in a fluid tight union. The ends of the fiber can be [0061] The drug delivery system according to this in- joined together by applying an adhesive or a sealant to vention can be manufactured by any known techniques. at least one end of a segment, and then contacting the The therapeutically active agent may be mixed within the ends, or by placing the fiber in a mould at an elevated core or membrane material, processed to the desired temperature (e.g. a temperature of above about 40°C), shape by moulding, injection moulding, casting, extru- 15 injecting molten high density polyethylene in between the sion, such as co-extrusion and/or blend-extrusion or oth- fiber ends and cooling the prepared ring, or by joining er appropriate methods. The membrane layer can be ap- the fiber ends together by welding. plied onto the core according to known methods, such [0065] Tubular compartments can also be joined into as by mechanical stretching or expanding a prefabricat- a closed system by using a plug or a stopper made of ed, tube formed membrane by pressurised gas, e.g. by 20 any inert, biocompatible material which does not permit air, swelling in a suitable solvent, for example such as the transport of active material. Examples of suitable im- cyclohexane, diglyme, propanol, isopropanol or a mix- permeable material are metals, such as gold, silver or ture of solvents, or by extrusion, moulding, spraying or silver alloys, glass or ceramic material and suitable pol- dipping. The surface of a membrane or one of the mem- ymers. If desired, a biocompatible adhesive can be used branes can be encased, coated or dusted by particles, 25 for better sealing or better adhesion of the plug or stopper crystals, microcrystals, powder or suspension of a ther- to the compartment. apeutically active or a health-promoting substance by us- [0066] The delivery system can also comprise a sub- ing known methods, for example by spraying the whole stantially inert supporting means made of a material delivery system or a part of it, i.e. a core or a compart- which is biologically compatible and remains unchanged ment, with a suspension of said substance in a suitable 30 for a sufficient period of time in the conditions prevailing solvent or by dipping the system in such a suspension. in the vagina. The term "substantially inert" means in this [0062] An especially suitable method for preparation connection that the active agent cannot, to any substan- is disclosed in the Finnish patent FI 97947. This patent tial degree, diffuse or in any other way migrate from the discloses an extrusion technology where prefabricated core into the support means. Suitable supporting mate- rods containing the active ingredient are coated by an 35 rials are for example cross-linked rubbers, such as e.g. outer membrane. A therapeutically active agent is mixed natural rubber, butyl rubber and polydimethylsiloxane within the core matrix polymer composition, and proc- elastomers, flexible thermoplastic resins, such as ethyl essed to the desired shape and size by using known ex- vinyl acetate (EVA), thermoplastic polymers, such as sty- trusion methods. The membrane layer may then be ap- rene copolymers, polyurethanes, thermoplastic polyole- plied onto the prefabricated cores by feeding the cores 40 fins and inert, biocompatible metals. to the extruder followed either by another core or a core [0067] The support means can be prepared in a sim- without any active ingredient, i.e. by a placebo compart- ple, known manner. A suitable polymeric material may ment, or by an empty space filled with air, which during for example be compressed in a mould, or extruded to the extrusion process will be filled with the membrane form a rod-like member with a suitable diameter, then material to form a separation membrane. The drug-load- 45 followed by cutting the extrudate to pieces of suitable ed core and the membrane layer can also be prepared length and by vulcanizing into the desired, substantially simultaneously by co-extrusion. annular shape. The supporting member can be of solid [0063] The fibers or strings thus obtained can be cut material or hollow. into pieces of the required length and each piece can be [0068] One or more ring sections, membranes or cores assembled in any suitable manner to form a device 50 may be assembled on the prefabricated closed, contin- shaped, sized and adapted for placing in the vagina. The uous supporting member in the form of layers or coatings. device can have many shapes, for example various con- Drug containing cores can for example be prepared by tinuous, curved shapes, such as annular, ring-shaped, incorporating the finely ground or even micronized active oval, spiral, ellipse, toroidal and the like. The cross sec- substance in the polymer composition to form a suspen- tion of the device can have almost any shape, and it can 55 sion, which is then applied as a layer on the supporting be for example circular, oval, flat, ellipse, star-shaped means by using known techniques, such as spraying, and the like. dipping or the multi-colour injection moulding technique, [0064] The ends of the fiber or segments can be joined and vulcanized by known methods. Membrane or mem-

8 15 EP 2 062 568 A1 16 branes can be assembled in a similar way. EXPERIMENTAL PART [0069] Alternatively the hollow, sleeve-like core or cores are mounted on the rod-like supporting means pref- Drug release test erably by first enlarging the diameter to some degree and thereafter by simply sliding them onto the supporting 5 [0073] The release rate of the drug from the device is means or inserting the supporting means into the hollow measured in vitro as follows: The delivery systems are cores. When the cores are of a silicone based polymer attached into a stainless steel holder in vertical position or a cross-linked rubber the enlargement can take place, and the holders with the devices are placed into glass for example, by swelling in a suitable organic solvent, bottles containing 250 ml or less of a medium. The glass whereafter the swollen body is mounted onto the sup- 10 bottles are shaken in shaking water bath 100 rpm at 37 porting means. When the solvent evaporates, the cores °C. The dissolution medium is withdrawn and replaced tighten onto the support means. As an alternative, the by a fresh dissolution medium at predetermined time in- tube-like core can be stretched mechanically with a suit- tervals, and the amount of the released drug is analysed able device or by using for example pressurized gas and by using standard HPLC methods. The concentration of threaded in the stretched state onto the support means. 15 the dissolution medium and the moment of change (with- When the stretching force is discontinued, the sleeve- drawal and replacement) of medium are selected so that like body is tightened onto the support means. Membrane sink-conditions are maintained during the test. Frequen- or membranes can be assembled by mounting a suitable cy of sampling is chosen to keep sink conditions in the polymer tube on an individual core or on a rod-like deliv- medium. ery system using for example solvent swelling or me- 20 [0074] The invention as well as measured release chanical stretching. Finally the ends of the rod or the rates, which were at the expected level, are further illus- string so obtained are joined by using known techniques. trated by the following, non-limiting examples. [0070] The delivery system according to the invention [0075] The delivery systems of the examples are man- can be manufactured in any size as required, the exact ufactured in accordance with standard techniques known size is being dependent on the mammal and particular 25 in the art and described in the patent application. The application. In practice, for a human female an outer ring therapeutically active agent is mixed within the core ma- diameter is typically from 35 to 70 mm, preferably from trix polymer composition, and processed to the desired 35 to 58 mm or from 45 to 65 mm and more preferably shape by using known methods. The membrane is made from 50 to 58 mm. The cross sectional diameter is typi- and assembled onto the cores according to known meth- cally from 1 to 10 mm. In a particular embodiment the 30 ods, such as by expanding the prefabricated, tube formed cross sectional diameter is between 2 and 6 mm, in a membrane in a suitable solvent, for example such as specific embodiment between about 3.0 and 5.5 mm and propanol, isopropanol, or by using a coextrusion method in another embodiment between about 3.5 and 4.5 mm described in the Finnish patent FI 97947. According to and in yet another embodiment is 4.0 or 5.0 mm. said method, each of the cores are fed to the extruder [0071] The lengths of the cores of the drug delivery 35 followed either by an empty space filled with air or by system are chosen to give the required performance. Ra- another core without any active ingredient. The ends of tios of the lengths of the cores will depend upon the par- the fabricated rods comprising the cores and the mem- ticular therapeutic application, including the desired ratio brane are joined together by using a plug or a sealant. and dosages of each drug to be delivered. The length of Silica is preferably used as a filler. the drug containing compartments can be for example 40 from 5 to 160 mm, or up to the total length of the delivery Example 1 system. The length of each placebo compartment sepa- rating the drug containing cores may generally vary be- A delivery system for simultaneous administration of dro- tween 2-110 mm and depends on the nature of the ma- spirenone, estradiol and lactic acid. terial and its capacity to prevent permeation of the active 45 materials. Most ideally the placebo compartment com- [0076] A device comprising drospirenone at a target pletely prevents mixing of the active substances, which release rate of 1.6 mg/day and estradiol at a target re- otherwise might disturb the release pattern. lease rate of 120 gg/day is prepared. The core containing [0072] The thickness of a separation membrane can drospirenone consists of the composition containing be about 0.2 to 5 mm. The layer containing the active 50 PEO-b-PDMS copolymer (25 wt-% of the total amount substance may have a thickness of 0.1 to 5.0 mm, and of polymers) and PDMS and the length of the core is 100 preferably 0.2 to 3.5 mm. The thickness of the membrane mm. The second core comprising estradiol consists of is from 0.1 to 1.0 mm, preferably 0.2 to 0.6 mm. PEO-b-PDMS copolymer (24 wt-% of the total amount of polymers) and PDMS and the length is 15 mm. The 55 outer diameter of the cores is 3.0 mm. Two placebo com- partments added to separate the drug containing cores consist of PDMS and their length is 20 and 35 mm. The content of drospirenone and estradiol in the core are 40

9 17 EP 2 062 568 A1 18 wt-% and 18 wt-%, respectively. The membrane com- Example 4 prising 5 wt-% of lactic acid is made of PEO-b-PDMS copolymer (15 wt-%) and PDMS (85 wt-%). The wall of A delivery system for simultaneous administration of lev- the membrane tube is 0.25 mm, inner diameter 2.85-2.9 onorgestrel, ethinyl estradiol and Lactobacillus mm and the outer diameter 3.35-3.4 mm. The cores and 5 the tube-formed membrane are made by extrusion. The [0079] A delivery system comprising levonorgestrel at core is coated by the membrane by first swelling the a target release rate of 50 Pg/day and ethinyl estradiol membrane in propanol. The ends of the delivery system at a target release rate of 20 Pg/day is prepared. The are joined into a ring by using a polyethylene plug. first core comprising levonorgestrel consists of PDMS 10 and the length of the core is 40 mm. The second core Example 2 comprising estradiol consists of PEO-b-PDMS (18 wt-% of the total polymer amount) and PDMS, and the length A delivery system for simultaneous administration of dro- of the core is 15 mm. The cores are separated by inert spirenone, estradiol hemihydrate and polylactic acid placebo cores consisting of a siloxane based elastomer 15 comprising 3,3,3-trifluoropropyl groups attached to the [0077] A device comprising drospirenone at a target siloxane silicon atoms (degree of trifluoropropyl substi- release rate of 5.0 mg/day and estradiol hemihydrate at tution is 49.5 %), the length of the cores are 10 mm and a target release rate of 150 gg/day is prepared. The first 100 mm. The outer diameter of the cores is 2.6-2.7 mm. core comprising drospirenone (38 wt-%) consists of The cores are encased in a membrane consisting of PEO-b-PDMS (41 wt-% of the total amount of polymers) 20 PEO-b-PDMS/PDMS in a ratio of 10:90. The thickness and PDMS and the length of the core is 130 mm. The of the membrane wall is 0.22 mm, inner diameter of the second core comprising estradiol (20 wt-%) consists of tube is 2.35 mm and the outer diameter approximately PEO-b-PDMS (40 wt-% of the total amount of polymers) 2.8 mm. The ends of the delivery system are sealed with and PDMS, and the length is 10 mm. The outer diameter silicon glue. The outer surface of the membrane is coated of the core is 3.6 mm. An inert core consisting of PDMS 25 with a thin layer of Lactobacillus rhamnosus. is added to give a rod having the total length of 180 mm. The core parts are encased in a membrane consisting Example 5 of PEO-b-PDMS/PDMS in a ratio of 20:80 and containing 10 wt-% of polylactic acid. The membrane layer is applied A delivery system for simultaneous administration of dro- onto the prefabricated cores by using coextrusion. An 30 spirenone, estradiol and carbopol empty space of 3 mm left between the drug containing cores is during the process filled by the membrane ma- [0080] A device comprising drospirenone at a target terial thus forming a separation membrane. The thick- release rate of 3.0 mg/day and estradiol at a target re- ness of the membrane wall is 0.3 mm, the inner diameter lease rate of 100 Pg/day is prepared. The first core com- of the tube 3.4 mm and the outer diameter 4.0-4.05 mm. 35 prising drospirenone (35 wt-%) consists of PEO-b-PDMS (41 wt-% of the total polymer amount) and PDMS, and Example 3 the length of the core is 130 mm. The second core com- prising estradiol (18 wt-%) consists of PEO-b-PDMS (25 A delivery system for simultaneous administration of wt-% of the total polymer amount) and PDMS, and the gestodene, estradiol and Carbopol 40 length of the core is 10 mm. The outer diameter of the core is 3.6 mm. An inert core consisting of PDMS is added [0078] A device comprising gestodene at a target re- to give a rod having the total length of 180 mm. The core lease rate of 60 Pg/day and estradiol at a target release parts are encased in a membrane consisting of PEO-b- rate of 20 Pg/day is prepared. The first part of the core PDMS/PDMS in a ratio of 10:90 and containing 5 wt-% consists of PDMS comprising gestodene and the length 45 of carbopol. The membrane layer is applied onto the pre- is 45 mm. The second part of the core consisting of PEO- fabricated cores by using coextrusion. An empty space b-PDMS (20 wt-% of the total amount of polymers) and of 3 mm left between the drug containing cores is during PDMS, comprises estradiol and the length is 30 mm. The the process filled by the membrane material thus forming outer diameter of the cores is 2.58 mm. Two 50 mm pla- a separation membrane. The thickness of the membrane cebo compartments consisting of PDMS are used to sep- 50 wall is 0.35 mm, the inner diameter of the tube is 3.45 arate the drug containing cores. The core parts are en- mm and the outer diameter is 4.15-4.2 mm. cased in a membrane consisting of PDMS and methyl- trifluoropropyl-methylvinyl siloxane in a ratio of 70:30. Example 6 The thickness of the membrane wall is 0.25 mm, inner diameter 2.40 mm and the outer diameter 2.9 mm. The 55 A delivery system for simultaneous administration of dro- ends of the delivery system are joined to a closed system, spirenone, ethinyl estradiol and polyglycolic acid and finally the system is dipped in Carbopol suspension to give a thin polymer coating. [0081] A device comprising drospirenone at a target

10 19 EP 2 062 568 A1 20 release rate of 2.5 mg/day and ethinyl estradiol at a target longed period of time, the system consisting of one release rate of 15 Pg/day is prepared. The first core com- or more compartments, which one or each comprise prising drospirenone (30 wt-%) consists of PEO-b-PDMS a core and a membrane encasing the core, said core (35 wt-% of the total polymer amount) and PDMS and and membrane consisting essentially of a same or the length of the core is 120 mm. The second core com- 5 different polymer composition, characterized in prising ethinyl estradiol (10 wt-%) consists of PDMS, and that the delivery system additionally comprises a the length is 10 mm. The outer diameter of the core is substance capable of giving and/or enhancing the 3.5 mm. Inert cores of 20 mm and 25 mm consisting of protection against bacterial and fungal infections PDMS are added to separate the drug containing cores. and/or enhancing the protection against sexually The core parts are encased in a membrane consisting 10 transmitted diseases. of PEO-b-PDMS/PDMS in a ratio of 33:67. The thickness of the membrane wall is 0.3 mm, the inner diameter of 2. An intravaginal delivery system according to claim 1 the tube is 3.35-3.4 mm and the outer diameter is 3.95-4.0 consisting of one compartment comprising a mixture mm. The ends of the delivery system are joined into a of a progestogen and an estrogen, characterized ring by using a polyethylene plug, and finally the delivery 15 in that the membrane comprises a substance capa- system is dipped in polyglycolic acid suspension to give ble of giving and/or enhancing the protection against a thin coating. bacterial and fungal infections, and/or enhancing the protection against sexually transmitted diseases. Example 7 20 3. An intravaginal delivery system according to claim 1 A delivery system for simultaneous administration of dro- consisting of one compartment comprising a mixture spirenone, estradiol valerate and Lactobacillus of a progestogen and an estrogen, characterized in that the core additionally comprises a substance [0082] A device comprising drospirenone at a target capable of giving and/or enhancing the protection release rate of 3 mg/day and estradiol valerate at a target 25 against bacterial and fungal infections, and/or en- release rate of 150 Pg/day is prepared. The first core hancing the protection against sexually transmitted comprising drospirenone (30 wt-%) consists of PEO-b- diseases. PDMS (45 wt-% of the total polymer amount) and PDMS, and the length of the core is 130 mm. The second core 4. An intravaginal delivery system according to claim 1 comprising estradiol valerate (10 wt-%) consist of PEO- 30 consisting of two or more compartments, wherein at b-PDMS (15 wt-% of the total polymer amount) and least one of the compartments comprises a pro- PDMS, and the length of the core is 20 mm. The outer gestogen and another compartment comprises an diameter of the core is 3.5 mm. Inert cores of 8 mm and estrogen or a mixture of a progestogen and an es- 10 mm consisting of PDMS are added to separate the trogen, characterized in that the membrane of at drug containing cores. The core parts are encased in a 35 least one of the cores comprises a substance capa- membrane consisting of PEO-b-PDMS/PDMS in a ratio ble of giving and/or enhancing the protection against of 20:80. The thickness of the membrane wall is 0.3 mm, bacterial and fungal infections, and/or enhancing the the inner diameter of the tube is 3.3-3.35 mm and the protection against sexually transmitted diseases. outer diameter is 3.9-3.95 mm. The ends of the delivery system are joined together into a closed system by using 40 5. An intravaginal delivery system according to claim 1 a glass plug, and finally the system is dipped in the sus- consisting of two or more compartments, wherein at pension of Lactobacillus reuterii RC-14 to give a thin coat- least one of the compartments comprises a pro- ing. gestogen and another compartment comprises an [0083] Although the invention has been described in estrogen or a mixture of a progestogen and an es- terms of particular embodiments and applications, one 45 trogen, characterized in that at least one of the of ordinary skill in the art can in the light of this teaching compartments comprises a substance capable of generate additional embodiments and modifications giving and/or enhancing the protection against bac- without departing from the spirit of or exceeding the scope terial and fungal infections, and/or enhancing the of the claimed invention. Accordingly, it is to be under- protection against sexually transmitted diseases. stood that the descriptions herein are offered by way of 50 example to facilitate comprehension of the invention and 6. An intravaginal delivery system according to any of should not be construed to limit the scope thereof. the claims 1-5, characterized in that the pro- gestogen is selected from the group of , desogestrel, etonogestrel, levonorgestrel, Claims 55 , medroxyprogesterone acetate, nore- thisterone, norethisterone acetate, norgestimate, 1. An intravaginal delivery system for the controlled re- gestodene, drospirenone or any other compound lease of a progestogen and an estrogen over a pro- having a progestogenic activity.

11 21 EP 2 062 568 A1 22

7. An intravaginal delivery system according to claim CTV05, Lactobacillus salivarius, Lactobacillus 6, characterized in that the progestogen or a drug brevis, Lactobacillus fermentum, Lactobacillus fer- having a progestogenic activity is drospirenone. mentum RC-14, Lactobacillus fermentum B-54, Lactobacillus rhamnosus and Lactobacillus rhamno- 8. An intravaginal delivery system according to any of 5 sus GR-1, octoxynol-9, chlorhexidine, benzalkonium the claims 1-7, characterized in that the estrogen chloride or nonoxynol-9. is selected from the group consisting of estradiol, ethinyl estradiol, estradiol esters, estradiol hemihy- 12. An intravaginal delivery system according to any of drate, estradiol sulfamates, estriol succinate and the claims 1-11, characterized in that said polymer , including conjugated equine 10 compositions are selected from the group consisting estrogens such as estrone sulfate, 17β-estradiol sul- of polydimethyl siloxanes, modified polydimethyl si- fate, 17α-estradiol sulfate, equilin sulfate, 17β-dihy- loxanes, ethylene/vinyl acetate copolymers (EVA), droequilin sulfate, 17α-dihydroequilin sulfate, polyethylene, polypropylene, acrylic acid polymers, equilenin sulfate, 17β-dihydroequilenin sulfate and polytetrafluoroethylene (PTFE), polyurethanes, poly 17α-dihydroequilenin sulfate or mixtures thereof. 15 (methacrylate), polymethyl methacrylate, poly(hy- droxyethylmethacrylate) (pHEMA), polyhydroxy al- 9. An intravaginal delivery system according to claim kanoates, poly(lactic acid), poly(glycolic acid), hy- 8, characterized in that the estrogen is estradiol, drophilic polymers such as the hydrophilic estradiol hemihydrate, estradiol valerate, estradiol hydrogels , cross-linked polyvinyl alcohol or a com- succinate, estradiol benzoate, ethinyl estradiol, or 20 bination thereof. estradiol sulfamate. 13. An intravaginal delivery system according to any of 10. An intravaginal delivery system according to any of the claims 1-11, characterized in that said elas- the claims 1-9, characterized in that the substance tomer compositions are selected from the group con- capable of giving and/or enhancing the protection 25 sisting of against bacterial and fungal infections and/or en- hancing the protection against sexually transmitted - an elastomer composition comprising poly diseases is selected from the group of antimicrobial (dimethylsiloxane), substances, antifungal substances, antibacterial - an elastomer composition comprising a si- substances, antiviral substances, vitamins, miner- 30 loxane-based elastomer comprising 3,3,3-trif- als, enzymes, co-enzymes, co-factors, microorgan- luoropropyl groups attached to the silicon atoms isms, organic acids and a variety of molecules ex- of the siloxane units, tracted from natural sources such as amino acids, - an elastomer composition comprising poly polysaccharides, peptides, naturally occurring hor- (alkylene oxide) groups, said poly(alkylene ox- mones and biochemical intermediates 35 ide) groups being present as alkoxy-terminated grafts or blocks linked to the polysiloxane units 11. An intravaginal delivery system according to claim by silicon-carbon bonds, or a mixture of these 10, characterized in that the substance capable of forms, and giving and/or enhancing the protection against bac- - a combination of at least two thereof. terial and fungal infections, and/or enhancing the 40 protection against sexually transmitted diseases is 14. An intravaginal delivery system according to claim lactic acid, polylactic acid, glycolic acid, polyglycolic 13, characterized in that in the polymer composi- acid, carbopol, polycarbophil, ascorbic acid, D-pan- tion the amount of polydimethylsiloxane comprising tothenic acid, folic acid and the reduced forms there- poly(alkylene oxide) groups is from 5 to 80 wt-% of of, especially tetrahydrofolates and metabolites of 45 the total amount of polymers. folic acid, preferably 5-methyl-6(S)-tetrahydrofolic acid and its salts such as earth alkaline salts, espe- 15. An intravaginal delivery system according to claims cially the calcium salt (Metafolin), fumaric acid, ben- 13 and 14, characterized in that the poly(alkylene zoic acid, p-aminobenzoic acid, alginic acid, sorbic oxide) groups are poly(ethylene oxide) groups. acid, tartaric acid, edetic acid or salts of the acids, 50 niacinamide, Lactobacillus species, for example 16. An intravaginal delivery system according to claim such as Lactobacillus reuteri, Lactobacillus reuterii 13, characterized in that in the siloxane-based RC-14, Lactobacillus delbrueckii, Lactobacillus gas- elastomer from 1 to approximately 50 % of the sub- seri, Lactobacillus jensenii, Lactobacillus catena- stituents attached to the silicon atoms of the siloxane forme, Lactobacillus paracasei, Lactobacillus pa- 55 units are 3,3,3-trifluoropropyl groups. racasei Lbp PB01, Lactobacillus casei, Lactobacillus acidophilus, Lactobacillus acidophilus Lba EB01, 17. An intravaginal delivery system according to any of Lactobacillus crispatus, Lactobacillus crispatus the claims 1-16, characterized in that in the system

12 23 EP 2 062 568 A1 24

comprising two or more compartments, at least two of said compartments are adjacent to each other.

18. An intravaginal delivery system according to any of the claims 1-16, characterized in that in the system 5 comprising two or more compartments, at least two of said compartments are separated by an inert space consisting essentially of a same or different polymer composition. 10 19. An intravaginal delivery system according to any of the claims 1-16, characterized in that in the system comprising two or more compartments, at least two of the said compartments are separated by a sepa- ration membrane consisting essentially of a same or 15 different polymer composition.

20. An intravaginal delivery system according to any of the claims 1-19, characterized in that the mem- brane comprises at least two layers, each consisting 20 of a same or different polymer composition.

21. An intravaginal delivery system according to any of the claims 1-20, characterized in that the surface of at least one membrane comprises a substance 25 capable of giving and/or enhancing the protection against bacterial and fungal infections, and/or en- hancing the protection against sexually transmitted diseases. 30 22. A method of giving and/or enhancing the protection for the female mammal against vaginal bacterial and fungal and/or enhancing the protection against sexually transmitted diseases by using an intravaginal delivery system intended for the control- 35 led release of progestogen and an estrogen at a level required for contraception or hormone replacement therapy, said method comprising the steps of posi- tioning the delivery system within the female vaginal tract and retaining the system a prolonged period of 40 time within the vaginal tract, preferably for at least approximately 21 days, characterized in that said delivery system additionally releases a sufficient amount of a substance capable of giving and/or en- hancing the protection against bacterial and fungal 45 infections and/or enhancing the protection against sexually transmitted diseases.

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REFERENCES CITED IN THE DESCRIPTION

This list of references cited by the applicant is for the reader’s convenience only. It does not form part of the European patent document. Even though great care has been taken in compiling the references, errors or omissions cannot be excluded and the EPO disclaims all liability in this regard.

Patent documents cited in the description

• US 4596576 A [0003] • US 20050152966 A [0015] • US 4237885 A [0003] • US 20030096002 A [0015] • EP 876815 A [0004] [0004] • WO 200294224 A [0015] • EP 836473 A [0005] • WO 200574976 A [0015] • WO 1995000199 A [0006] • US 4822616 A [0033] • WO 2005089723 A [0007] • US 4012496 A [0033] • EP 862396 A [0008] • WO 0000550 A [0047] • WO 200665873 A [0013] • WO 0029464 A [0047] • WO 200215832 A [0014] • WO 9910412 A [0047] • WO 200617341 A [0014] • WO 9824801 A [0050] • WO 200326687 A [0015] • FI 97947 [0062] [0075]

Non-patent literature cited in the description

• Microb. Infect., 2002, vol. 4, 319-324 [0011]

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