WO1997028826A2

WO1997028826A2 - Contraceptive release systems with antibacterial and/or antiviral effect

Info

Publication number: WO1997028826A2
Application number: PCT/DE1997/000321
Authority: WO
Inventors: Klaus Stöckemann; Arwed Cleve; Karin Hoffmann; Ulrich Koch
Original assignee: Schering Aktiengesellschaft
Priority date: 1996-02-12
Filing date: 1997-02-11
Publication date: 1997-08-14
Also published as: BR9707416A; CZ253298A3; CN1211193A; EP0880364A2; IS4802A; NO983672L; AU2379297A; PL328333A1; NO983672D0; AP9801306A0; EA199800714A1; HUP9901977A3; SK107098A3; EE9800239A; JP2000506515A; WO1997028826A3; BG102682A; DE19606355A1; CA2245920A1; TR199801551T2

Abstract

The invention relates to the combination of at least one compound with contraceptive effect and/or one compound with antibacterial and/or antiviral effect for incorporation/application to an intravaginal, intrauterine or intracervical release system. The invention also relates to the use of said release system.

Description

Contraceptive release systems with antibacterial and / or antiviral effects

The present invention relates to the combination of at least one compound having (a) contraceptive activity and / or a compound having (b) antibacterial and / or (c) antiviral activity, where a compound can also have all three properties for incorporation / application to a intravaginal, intrauterine or intracervical delivery system.

Sexually transmitted diseases (STD) are a serious medical and socio-economic problem.

A large number of different diseases can be transmitted during sexual intercourse. A distinction is made between bacterial (Chlamydia, Gonorrhea, Syphilis) and viral (Cytomegalvirus = CMV, Genital Herpes Simplex = HSV, Human Papillomavirus = HPV and Human Immunodeficiency = HIV / AIDS) diseases.

In the U.S., approximately 12 million people ages 15-29 are affected by STDs. In total, 56 million Americans have some type of STD except AIDS or HIV. New WHO research shows that under the term "major reproductive health concems", STDs with an estimated 315 million cases worldwide represent a significant health problem. In particular, the estimated 30-40 million HIV infections with expected 12-18 million AIDS (acquired immunodeficiency syndrome) diseases by the year 2000 (Achieving Reproductive Health for All. The role of WHO (WHO / FHE / 95,6, World Health Organization , Geneva, 1995)) pose a serious threat to world health. Particularly noteworthy are the skyrocketing numbers of new HIV infections in the countries of the less developed world, with a sharp rise in infections among the heterosexual population in these countries . Estimates suggest that 60% of HIV infections worldwide occur through heteresexual transmission. There is also a growing number of HIV infections in the United States, which are heterosexual, with transmission in most cases from male to female.

In addition to condoms, various antibacterial and antiviral substances (tetracyclines, chlorhexidine, sulfonamides, Interferons). ISIS2105 (an antisense oligonucleotide) is currently being tested in clinical studies for the treatment of HPV. The spermicide Nonoxynol-9 (N9) inhibits the transmission of gonorrhea and chlamydia. There are indications that N9 inhibits the transmission of HIV. The data published on this topic are contradictory, however, N9 can irritate the vaginal epithelium, which could favor the transmission of STDs.

Furthermore, the use of so-called aminosterols such as squalamine for the treatment of STDs has been described in the literature (Aminosteroi antibiotics, Current Opin. Ther. Pat. 3, 1369-1370, 1993; Cohen J. Women: Absent Term in the AIDS Research Equation. Science, 269, 777-780, 1995). Squalamine has broad antibiotic activity (Moore K, Wehrli S et al. Squalamine: An aminosteroi antibiotic from the shark. Proc. Natl. Acad. Sei. 90, 1354-1358, 1992).

In most cases, these substances are used shortly before intercourse in the form of suppositories which are inserted into the vagina.

Another approach is based on influencing the pH in the vagina. Studies have shown that HIV is inactivated in an acidic environment. With this approach, the increasing pH during ejaculation is kept at an acidic level. By inhibiting the sodium / hydrogen ion exchange on the cell surface, the pH value can be lowered. Inhibitors of the Na / H ion exchange would thus lead to a drop in the pH and prevent the possibility of infection by HIV without damaging the vagina or cells of the reproductive tract. Compounds that inhibit sodium / hydrogen ion exchange have been described in the literature as possible therapy for the treatment of cardiovascular diseases (Scholz, Albus U. Potential of selective sodium-hydrogen exchange inhibitors in cardiovascular therapy. Cardiovasc. Res. 29, 184 -188, 1995). Substances that have this effect are mentioned in DE 93-4318756 (Schwark Jan-Robert), DE 93-120374 (Weichert A), EP 93-110195 (Weichert A) and US4423069 (Zanverld L).

All of the previously described applications for the prevention of STDs only offer temporary one-off protection, which is to be used in each case before sexual intercourse. As with any single-use application, revenue errors and compliance issues can occur. In such a case, the risks of STD transmission and contraception remain. With purely contraceptive Methods are therefore long-lasting methods - such as lUDs, implants, vaginal rings, injectables - preferred by a large number of women. This is especially true for women in the less developed countries.

There is therefore an urgent need to provide a system that continuously offers combined protection against STDs and at the same time offers safe contraceptive protection.

It is an object of the present invention to provide a system which at the same time offers contraceptive protection, continuously prevents diseases transmitted by intercourse, and is used by women.

It has now been found that the combination of a compound having (a) contraceptive activity and / or a compound having (b) antibacterial and / or (c) antiviral activity, where a compound can also have all three properties, for incorporation / application an intravaginal, intrauterine, or intercervical delivery system provides contraceptive protection while preventing sexually transmitted diseases.

In a particularly preferred embodiment of the combination according to the invention, the compound (a) with contraceptive action is levonorgestrel and the compound with (b) antibacterial and / or (c) antiviral action squalamine and the release system is an IUD, an intracervical system or a vaginal ring.

In a further embodiment, the invention relates to the use of an intravaginal, interauterine or intracervical release system containing at least one compound with a contraceptive effect and / or a compound with an antibacterial and / or antiviral effect for the prevention of sexually transmitted diseases.

According to the present invention, release systems are lUDs (Figures 1 and 2), vaginal rings (Figure 3) and cervical systems (Figure 4).

Intrauterine contraceptives containing active substances are delivery devices with a reservoir from which active substances are released by diffusion. The devices comprise a core of a lipophilic drug permeable solid or liquid carrier in which an excess of drug is dispersed and a drug-permeable polymeric wall surrounding this core. The wall is less permeable to the drug than the carrier, so the wall determines the rate of release of the drug to the environment during use. A hydrophilic active ingredient can be partially applied to the device as a mixture with a polar polymer in order to achieve the desired release rates, or the surface of the device is coated with a mixture of the hydrophilic drug and soluble polymers such as polyvinyl alcohol, polyethylene oxide, hydroxypropylmethyl cellulose and / or carboxymethyl cellulose, partially coated in different layers, depending on which release rate is to be achieved. By means of such release systems as described above, the medicinal substances contained are released at an essentially constant rate.

The use of intrauterine devices (lUDs) for contraception has been described in the literature (Speroff L and Damey P. The intrauterine device (IUD). In a Clinical Guide for Contraception. Eds. M. Fisher, Wiliams & Wilkins, Baltimore, Maryland p157-185 , 1992). Likewise, gestagen-containing lUDs are already on the market in some countries (Luukkainen T, Allonen H, Haukkamaa M et al. Five years ^' experience with levonorgestrel-releasing lUDs. Contraception 33: 139-145, 1986). The contraceptive security of lUDs is high. However, increased menstrual blood loss may occur when using copper IUDs. There is also an increased risk of infection (Buchan H, Villard-Mackintosh L et al. Epidemiology of pelvic inflammatory disease in parous women with Special reference to intrauterine device use. Br. J. Obset. Gynecol. 97: 780-786, 1990) and that Occurrence of ectopic pregnancies described in the literature. lUDs loaded with a progestin appear to prevent and even significantly reduce the increased menstrual blood loss; in addition, they combine mechanical contraception with a hormonal component (eg thickening of the cervical mucus as a barrier for the sperm) which increases the contraceptive protection (Speroff L and Darney P. The intrauterine device (IUD). In a Clinical Guide for Contraception. Eds. M Fisher, Wiliams & Wilkins, Baltimore, Maryland p157-185, 1992).

According to the present invention, all compounds which are present in an intravaginal, interauterine or intracervical release system can be used and have antibacterial or antiviral effects.

In all embodiments of the invention, the antibacterial or antiviral compound from the group of the following compounds is preferred

Squalamine (3ß- [3 - [(4-aminobutyl) amino] propyl] amino] -5α-cholestan-7α, 24-diol-24-sulfate)

3-acetyl-4-hydroxybenzoylguanidine

Nonoxynol-9

Cytokines such as the interferons α, 7, β and others.

Peptide antibiotics such as magainin:

PGLa (Gly-Met-Ala-Ser-Lys -Ala-Gly-Ala-Ile-Ala-Gly-Lys-Ile-Ala- Lys -Val -Ala-Leu-Lys -Ala-Leu-NH2) magainin 2 and their Analogues:

(Gly-Ile-Gly-Lys-Phe-Leu-His-Ser-Ala-Lys-Lys-Phe-Gly-Lys-Ala- Phe-Val-Gly-Glu-Ile-Met-Asn-Ser-NH2)

1-aryl-2-imidazolyl-alkyl (thio) ether

C31G (mixture of alkyldimethylglycine and alkyldimethylamine oxide (US Pat. No. 5,314,917))

or a mixture of these.

In addition to the antibacterial and / or antiviral effect, some of the substances mentioned also have a spermicidal effect.

In a particular embodiment, the compound with antibacterial and / or antiviral activity is: squalamine (3β- [3 - [(4-aminobutyl) amino] propyl] amino] - 5α-cholestan-7α, 24-diol-24-sulfate) in an effective dosage of 0.01-1 g per release system.

In a further preferred embodiment, the connection is with antibacterial and / or antiviral effect interferon ß.

Gestagens, antigestagens and others such as e.g. Antiestrogens (raloxifene), aromatase inhibitors (fadrozole, atamestane), spermicides and cytokine antagonists (interleukins) come into question.

In all embodiments of the invention, the gestagen is preferably derived from the

Group of connections

Gestoden,

Progesterone,

Levonorgestrel,

Cyproterone acetate,

Chlormadinone acetate;

Drospirenone (dihydrospirorenone),

Norethisterone,

Norethisterone acetate,

Norgestimate

Desogestrel

3-ketodesogestrel or a mixture thereof selected.

In a particularly preferred embodiment, the gestagen is: gestodene, levonorgestrel or 3-ketodesogestrel.

In a further particularly preferred embodiment, the gestagen is levonorgestrel in a dosage of 0.01 g - 1.0 g per release system.

All compounds which themselves or their metabolic products block the action of the progesterone at its receptor are suitable as competitive progesterone antagonists according to the present invention. 17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dien-3-one may be mentioned here as typical competitive progesterone antagonists

11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one

(Z) -11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one 11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (RU 38 486)

(Z) -9, 11 α-dihydro-17β-hydroxy-17α- (3-hydroxy-1-propenyl) -6 '- (3-pyridinyl) -4Η- naphth [3 \ 2 \ 1': 10.9 , 11] estra-4,9 (11) -dien-3-one

(Z) -11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4- en-3-one

4 ', 5'-Dihydro-11β- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-diene-17ß, 2' (3'λ7) furan] -3-one

11β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one

4 ', 5'-Dihydro-11β- {4- (dimethylamino) phenyl] -7ß-methylspiro [estra-4,9-diene-17ß, 2' (3'H) -furan] -3-one

such as

19, 11 β-bridged steroids from EP-A-0 283 428 and

10β-H steroids from EP-A-0 404 283.

In a particularly preferred embodiment of the invention, the competitive progesterone antagonist is the compound (Z) -11β- [4- (dimethylamino) phenyl] -17β-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4-en- 3-one or a connection comparable in its profile.

This list is not exhaustive; other competitive progesterone antagonists described in the publications mentioned and those from publications not mentioned here are also suitable.

The combination of a contraceptive compound and / or an antiviral and / or antibacterial compound in a release system according to the invention effectively prevents the transmission of different STDs in addition to the highest level of contraceptive protection, since both active components are uniformly administered in a desired dose over a desired period of time locally ( Uterus, cervix, vagina) are released. By local Administration (IUD, vaginal ring, cervix system) has a local effect in the endometrium.

The combination according to the invention thus provides effective protection against pregnancy and the transmission of STDs, which acts continuously at the desired site of action over a certain period of time.

Examples

The invention is illustrated by the following non-limiting examples:

The relative proportions of active ingredient and polymer carrier in devices 1, 2 and 3 can vary within wide limits, depending on the effectiveness of the active ingredients and the speed at which they are released from the device and the duration of the release. The devices according to the invention are intended to release one or more active substances over a long period of time, therefore the proportion of active substance or active substances is generally considerable, i.e. it makes up approximately 40 to 70% by volume of the mixtures of carrier and active ingredient.

example 1

T-shaped IUD (Figure 2)

A dispenser for two drugs of the type shown in Figure 1 is made as follows:

0.075 g of levonorgestrel are processed with a silicone-based polymer by extrusion in such a way that the active ingredient is embedded in the plastic material and both form the core of the device. The levonorgestrel to silicone polymer mixture used is 70:30. In a further step, the core is coated with a silicone-based polymer wall and poured into the known T-shape. 0.1 g of squalamine is partially applied to the rod-shaped base body (1) as a mixture with 0.05 g of a polyacrylate-based polymer in a ratio of 40:60. The proportion of the polymer in the mixture is defined by the release rates to be achieved.

Such a tubular container usually has a diameter of a few millimeters and a length of a few centimeters.

Example 2

Ball-shaped IUD

All T-shaped intrauterine contraceptives can be used in

Period of application for undesirable side effects such as bleeding and Cause pain. A device that offers the possibility of avoiding these risk factors is described in laid-open specification No. 24 02 882.

The device consists of a round rod assembly of several balls made of plastic with high elasticity, tear resistance and medium hardness with a maximum weight of 0.5 g. It can contain one or more drugs.

Based on this basic idea, modified devices were produced which, in addition to a lipophilic drug, preferably a hormone with a gestagenic effect, contain a hydrophilic drug with an antiviral effect.

The form of application of the contraceptive according to the invention and the applicator are shown in Figure 1. With a total length of 3 to 4 cm, it shows a Y-like plan. Starting from a central ball (1) with a diameter of 2.5 to 3.0 mm, three round rods (2 - 4) of different lengths with a diameter of 1.0 to 1.5 mm are arranged in balls. The round rods (3) and (4) end in a length of 0.8 to 1, 2 cm (3) and 0.5 to 0.8 cm (4) in the balls (5) and (6) of 4 up to 5 mm (5) diameter or 1, 5 to 2.0 mm (6) diameter and are arranged at an obtuse angle to the third round bar (2). The third round rod (2) sits in the triple round rod assembly (7, 8, 9) from Kugein (10 - 13) with a diameter of 2 to 3 mm in a bean-like end piece (14) of 4 to 5 mm in length and 2 to 3 mm diameter with a central bore (15) from 0.5 to 1.5 mm in diameter. The eyelet is intended for fastening a thread (18) made of a suitable material, such as e.g. Nylon or polyester. This thread serves as an indicator thread for easy checking for the presence of the contraceptive.

For the production of the plastic body for the contraceptives according to the invention, plastics known per se are used which, on the one hand, release dispersed medicinal substances again, and on the other hand have sufficient mechanical properties such as tear resistance, elasticity and cold stretchability and can easily be brought into suitable shapes. Examples include polyethylene, polyethylene / vinyl acetate, ionomer resins derived from polyethylene, polyamides, polyether ester elastomers based on terephthalate, polyethylene glycol terephthalate and silicone rubber. The plastics can be used individually or in combination, for example by molding in layers. The medicinal substances included in the contraceptive agent which can be used intrauterine according to the invention are contained in the plastic base (lipophilic, for example levonorgestrel) or fixed on the surface of the plastic body (hydrophilic, for example squalamine).

Lipophilic drugs can be dispersed homogeneously in the plastic body, optionally also with the aid of auxiliary substances, or in individual parts of the contraceptive with or without these auxiliary substances, e.g. as a core in a part of the plastic body, be contained in a suitable amount. Auxiliaries are, for example, surfactants, highly disperse silicon dioxide, anti-foaming agents, solubilizers, absorption retarders.

For the application of these contraceptives, known insertion tubes made of suitable plastics can be used. The contraceptive is inserted up to the ball (5) with the thread (18) fastened in the eyelet (15) and the associated pull and push rod (17) under aseptic conditions. The ball (5) of the device forms a ball end for the application unit consisting of contraceptive and applicator. Since the edge of the insertion tube is covered, primary injuries during application are excluded. Furthermore, the spherical end with a diameter of 4 to 5 mm prevents the fundus uteri from being pierced during application. The application of the contraceptive is easy for the person skilled in the art to carry out. It can be performed under aseptic conditions without anesthesia or with the use of other drugs or dilation of the cervical canal, even in women who have not yet given birth, without triggering cramp-like pain.

Example 2.1

A mixture of 50.0 g micronized levonorgestrel and 49.1 g milk sugar with 0.1 g lubricant additive is used to press pellets with a diameter of 2 mm and a radius of curvature of 3 mm. The levonorgestrel pellets are brought as cores into the spherical parts (5) and alternately into the balls (10 - 13) of an intrauterine contraceptive, the basic body and dimensions of which are as in

Figure 1 look and which consists of a mixture of 5.0 g barium sulfate, 35.0 g highly disperse silicon dioxide and 60.0 g catalyzed low temperature vulcanizing-type (LTV) silicone rubber two-component mass vulcanization is carried out for one hour at 100 ° C. following the molding.

The surface of the spheres of the plastic body is partially and alternately coated with a mixture of 0.1 g squalamine and 0.05 g of a polyacrylate-based polymer (alternating with loading with levonorgestrel pellets) with the help of a primer, in order to achieve the desired release rates for this drug achieve.

Example 2.2

The device is manufactured as in Example 2.1.

The surface of the balls is coated with a mixture of 0.1 g squalamine and 0.06 g hydroxypropyl cellulose / carboxymethyl cellulose in different layers in order to achieve the required release rate for the drug.

The polymers used are in solid form before use and only dissolve in the body at body temperature and humidity and release the active ingredient in the desired time and dose.

Example 3

Vaginal ring (Figure 3)

Another variant is the vaginal ring, which is also modified, as shown in Figure 3. The vaginal ring consists of a supporting ring 1 without an active ingredient, a layer 2 which contains a lipophilic active ingredient, e.g. a steroid hormone, and is placed in a continuous groove of the supporting ring. This layer 2 is covered with an active substance-free third layer. All components are preferably made on a silicone basis. The ratio of the layer thicknesses of active substance-containing layer 2 to active substance-free layer 3 is approximately 5-50: 1. As a result, a long-lasting uniform release rate for the lipophilic drug can be achieved. This offers an advantage of the vaginal ring according to the invention over vaginal rings known to the person skilled in the art.

A hydrophilic drug can be applied as a mixture with a relatively polar polymer to layer 3, partially as the fourth layer. Example 3.1

The following components are mixed thoroughly to produce the supporting ring 1:

232.6 g vinyl polydimethylsiloxane, molecular weight M = 5854

17.4 g of tetramethyltetravinylcyclotetrasiloxane

25.0 mg platinum (mixture A1)

193.8 g vinyl polydimethylsiloxane

56.2 g polydimethylhydrosiloxane (mixture B1)

The two mixtures A1 and B1 are homogenized in a static mixer, placed in an injection molding machine and vulcanized into rings with a circular cross section over a period of 60 s at 100 ° C. The hardness is 45 and the elongation to break 50%.

To produce layer 2, which contains the lipophilic drug, the following components are mixed intensively:

49.9 g vinyl polydimethylsiloxane, M = 8170

0.1 g tetramethyltetravinylcyclotetrasiioxane

5.0 mg platinum

0.05 g levonorgestrel (mixture A2)

48.6 g vinyl polydimethylsiloxane, M = 8170

1.4 g polydimethylhydrosiloxane

0.05 g levonorgestrel (mixture B2)

The two mixtures A2 and B2 are homogenized in a static mixer, placed in an injection molding machine which contains the supporting ring 1 and vulcanized over a period of 60 s at 100 ° C. on the outer edge of the supporting ring 1.

The vaginal rings thus produced are in the region of layer 2, which contains the lipophilic drug, with a layer 3 based on silicone elastomer sprayed. The layer thickness of layer 3 is approximately 200 μm. This layer forms a mixed vulcanizate with layer 2, which is arranged below it.

The drug-free silicone elastomer mixture consists of:

42.5 g vinyl polydimethylsiloxane, M = 4561

5.7 g polydimethylhydrosiloxane

1.8 g tetramethyltetravinylcyclotetrasiloxane 50 ppm platinum

To produce layer 4, which contains the hydrophilic drug, the following components are mixed intensively and partially sprayed onto layer 3:

0.05g polyacrylate polymer

0.1g squalamine

Example 3.2

The vaginal ring is made as in Example 3.1.

The 4th layer is made from a mixture of squalamine and hydroxypropyimethyl cellulose / carboxymethyl cellulose and applied.

0.06g hydroxypropylmethyl cellulose / carboxymethyl cellulose

0.1g squalamine

Example 4

Cervical application system (Figure 4)

It is a two-layer mucosal adhesive system (see Figure 4), which controls a lipophilic drug from the core (1) and a hydrophilic drug from the outer layer (2).

For this purpose, a core is produced from a mixture of 0.025 g micronized levonorgestrel and a silicone-based polymer by extrusion. The mixture of levonorgestrel and silicone polymer used is 50:50. In a further step, a mixture of 0.1 g sqalamin and 0.05 g of a mucoadhesive polymer mixture based on carboxymethyl cellulose / polyacrylate or hydroxypropyl cellulose / carboxy vinyl polymer and other polymers is applied as a second layer in such a way that the desired release rates for these drugs can be obtained over the desired period. Such a container has a diameter of a few millimeters and a length of 1-2 centimeters.

Claims

Claims:

1. Combination of at least one compound with (a) contraceptive effect and / or a compound with (b) antibacterial and / or (c) antiviral effect, where a compound can also have all three properties, for incorporation / application to an intravaginal, intrauterine or intracervical delivery system.

2. Combination of at least one compound with (a) contraceptive effect and one compound with (b) antibacterial and / or (c) antiviral effect for incorporation / application to an intravaginal, intrauterine or intracervical release system.

3. The combination of claim 1, wherein the delivery system is an IUD, an intracervical system, or a vaginal ring.

4. The combination of claim 1, wherein the contraceptive compound is a progestogen and / or a competitive progesterone antagonist.

5. A combination according to claim 4, in which the contraceptive compound is a progestogen from the group of compounds

Gestoden,

Progesterone,

Levonorgestrel,

Cyproterone acetate,

Chlormadinone acetate,

Drospirenone (dihydrospirorenone),

Norethisterone,

Norethisterone acetate,

Norgestimate,

Desogestrel,

3-ketodesogestrel or a mixture thereof and the competitive progesterone antagonist from the group of the compounds:

17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dien-3-one

11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one

(Z) -11β- (4-acetylphenyl) -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estra-4,9-dien-3-one

11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (RU 38 486)

(Z) -9, 11 α-dihydro-17ß-hydroxy-17α- (3-hydroxy-1-propenyi) -6 '- (3-pyridinyl) -4' W-naphth [3 \ 2 ', 1': 10.9, 11] estra-4.9 (11) -dien-3-one

4 ' _I 5'-dihydro-11β- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-diene-17ß, 2 ^, (3 ^, H) -furan] -3-one

11β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-choia-4,9,20-trien-3-one

4 ', 5 ^, -Dihydro-11β- [4- (dimethyiamino) phenyl] -7ß-methylspiro [estra-4,9-diene-17ß, 2'(3'H) -furan] -3-one

or a mixture thereof is selected.

6. Combination according to claim 1, in which the compound having antibacterial and / or antiviral activity from the group of the compounds:

Squalamine (3ß- [3 - [(4-aminobutyl) amino] propyi] amino] -5α-cholestan-7α, 24-diol-24-sulfate)

3-acetyl-4-hydroxybenzoylguanidine

Nonoxynol-9

Cytokines

Peptide antibiotics

1-aryl-2-imidazoiyl-alky! (Thio) ether C31G (mixture of alkyldimethylglycine and alkyldimethylamine oxide or a mixture thereof is selected.

7. Combination according to claim 1, in which the compound (a) with contraceptive action is levonorgestrel and the compound with (b) antibacterial and / or (c) viral action squalamine (3ß- [3 - [(4-aminobutyl) aminojpropyl] amino] -5α-cholestan- 7α, 24-diol-24-sulfate) -7 and the release system is an IUD, a cervical system or a vaginal ring.

8. Use of an intravaginal, intrauterine or intracervical release system containing at least one compound with (a) contraceptive action and / or with (b) antibacterial and / or (c) antiviral action, wherein a compound can also have all three properties to prevent sexually transmitted diseases.

9. Use of an intravaginal, intrauterine or intracervical release system containing at least one compound with (a) contraceptive effect in combination with a compound with (b) antibacterial and / or (c) antiviral effect for the prevention of sexually transmitted diseases.

10. Use according to claim 8, in which the delivery system is an IUD, a cervical system or a vaginal ring.

11. Use according to claim 8, in which the contraceptive compound is a progestogen and / or a competitive progesterone antagonist.

12. Use according to claim 8, in which the contraceptive compound is a progestogen from the group of compounds

Gestoden,

Progesterone,

Levonorgestrel,

Cyproterone acetate, Chlormadinone acetate,

Drospirenone (dihydrospirorenone),

Norethisterone,

Norethisterone acetate,

Norgestimate,

Desogestrel,

3-ketodesogestrel or a mixture thereof is selected and the competitive progesterone antagonist from the group of the compounds:

17α-ethynyl-17β-hydroxy-11β- (4-methoxyphenyl) estra-4,9-dien-3-one

11β- (4-acetylphenyl) -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one

11β- [4- (dimethylamino) phenyl] -17ß-hydroxy-17α- (1-propynyl) estra-4,9-dien-3-one (RU 38486)

(Z) -9,11α-dihydro-17-hydroxy-17α- (3-hydroxy-1-propenyl) -6 '- (3-pyridinyl) -4Η- naphth ^[3, ^2, 1': 10, 9.11] estra-4.9 (11) -dien-3-one

(2) -11β- [4- (Dimethylamino) phenyl] -17ß-hydroxy-17α- (3-hydroxy-1-propenyl) estr-4- en-3-one

4 ', 5'-Dihydro-11β- [4- (dimethylamino) phenyl] -6ß-methylspiro [estra-4,9-dien-17ß, 2X3'H) -. T.ran] -3-one

11β- (4-acetylphenyl) -19,24-dinor-17,23-epoxy-17α-chola-4,9,20-trien-3-one

4 ', 5 ^, -Dihydro-11β- [4- (dimethylamino) phenyl] -7ß-methylspiro [estra-4,9-diene-17ß, 2'(3'H) -furan] -3-one

or a mixture thereof is selected.

13. Combination according to claim 8, in which the compound having antibacterial and / or antiviral activity from the group of the compounds: Squalamine (3ß- [3 - [(4-aminobutyl) amino] propyl] amino] -5α-cholestan-7α, 24-diol-24-sulfate)

3-acetyl-4-hydroxybenzoylguanidine

Nonoxynol-9

Cytokines

Peptide antibiotics

1-aryl-2-imidazolyl-alkyl (thio) ether

C31G (mixture of alkyldimethylglycine and alkyldimethylamine oxide or a mixture thereof is selected.

14. The combination of claim 8, in which the compound (a) with contraceptive action is levonorgestrel and the compound with (b) antibacterial and / or (c) viral action squalamine (3ß- [3 - [(4-aminobutyl) amino] propylJamino] -5α-cholestan- 7α, 24-diol-24-sulfate) and the release system is an IUD or a vaginal ring.