FI58053C - FOER MAENNISKOR AVSETT CONTRACEPTIONSMEDEL - Google Patents

Description

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Patent- och rejisterstyrelsen v 'AmöIcm utlagd oeh uti. $ Krlftm publlcurad 29-08.80 (32) (33) (31) Requested «uolkuu» —Begird prtorltet 06.12.73 l8.Ol.7U, Ol.06.7U Federal Republic of Germany-Förbundsrepubliken Germany (DE) P 236l206.8 p 2U02882.8, p 2U269UU.1 (71) Schering Aktiengesellschaft, Berlin / Bergkamen, DE; Miillerstrasse 170-172, Dl Berlin 65, Federal Republic of Germany-Förbundsrepubliken Tyskland (DE) (72) Istvan von Kesseru, Lima, Peru (PE), Gerhard Laudahn, Berlin, Barbara Miihe, Berlin, Gisela Schöpflin, Berlin, Federal Republic of Germany-Förbunds -republiken Tyskland (DE) (7U) Oy Kolster Ab (5U) Infertility prevention device for human use - För människor avsett kontraceptionsmedel

The invention relates to a contraceptive device for human use, consisting of a combination of a round rod and plastic balls coated alternately with copper and nickel or copper and silver or optionally containing steroidal active substances, and having a perforated end piece to which a plastic pull-out can be attached.

Steroid contraceptives have been developed for intrauterine use to provide effective contraceptives without inhibition of ovulation and with a small amount of effective steroids. The human body is burdened with only a minimal amount of drugs, thus avoiding both subjective and observable side effects.

The introduction of devices of different substance, shape and function into the uterus to prevent infertility has long been known per se. The mechanism of action of these intrauterine contraceptives against the wall has not been definitively elucidated.

As early as 1920, Gräfenberg developed an intrauterine device to prevent fertilization from copper-silver alloy wire.

Subsequently, various plastics such as nylon, polyethylene, and polyethylene / vinyl acetate neat or barium sulfate were molded into various 2,58053 cervical occluding and bulky intrauterine contraceptive devices such as Mareulis spiral (USP 3,15; Bow (USP 3,255,590), Saf-T-Coil (U, SP 3,234,938 and 3,374,788) and Lippes Loop (USP 3,250,271).

T-shaped contraceptives (U.S.P. 3,533,406), Daikon-Shield (DT OS 1,956,701), and Lippes Loop D came with smaller plastic contraceptives made of plastic materials for intrauterine use. The reliability of the effect of these contraceptives could be increased by coating the surface of the device with metallic copper (cf. Zipper, Amer, J. Obst. Gynec. 105, 1274-1278 (1969) and Jecht et al., Contraception, 7 (5), 381 (1973)). )) or by incorporating the active ingredients into a plastic material. As active pharmaceutical ingredients, copper powder or steroid hormones having an effect on pregnancy were added by dispersing in a plastic material. One embodiment of the Daikon Shield comprises, for example, a fine dispersion of copper divided into a plastic carrier. Copper-T and Copper-7 (USP 3,563,235) were partially wrapped with copper wire or Copper TCu 220 C (USP 3,533,406) was partially coated with copper sleeves (TJ.SP 3,563,235) · To increase the antifouling effect of intrauterine devices coated with copper in addition zinc or silver (USP 3,563,235; Zipper et al., Amer. J. Obst. Gynec. 105, 529-534 (1969a); Zipper et al., Human fertility control through the use of endouterine metal antagonism of trace elements in control of human fertility, Nobel 15, Almquist & Wiksell, Stockholm 1971, PP (199).

Intrauterine contraceptive devices comprising a plastic body and a silicone rubber capsule containing an active drug attached thereto are still known. Combined contraceptive devices of this kind have also been proposed for use in the cervix (int. J. Fert. 15 (1970) 210).

Both intrauterine contraceptives containing active drugs, as well as shape-barrier drug-free devices, lead to undesirable side effects such as bleeding and pain when used for a longer period of time (Fortier et al., J. Amere0bstet. Gynec. 115 (1973) 291; 1972) 179; Mishell et al., Amer. J. Obstet. Gynec. 116 (1973) 1092).

Known disadvantages of intrauterine contraceptive devices include spontaneous protrusions, the occurrence of pregnancy, or removals that become necessary for medical reasons. Deletions due to side effects come into question especially in the early stages of use (Avery, Rep. Polul. Family Pian 4,6: (1973) 139) ·

The most common side effects of known intrauterine contraceptives are bleeding and pain. Due to these disadvantages, the rate of removal of intrauterine contraceptives due to these disadvantages is higher for closure-shaped plastic devices than for less closure devices such as Dalkon-Shield, T-shaped contraceptives, or Lippes Loop, D.

These side effects and the consequent exits, as well as the spontaneous protrusion of intrauterine contraceptives made of plastic materials, are not only due to the improper design and sizing of these devices. Other essential factors for this are the flexibility and hardness of the plastic material. Devices made of a plastic material with low flexibility and high hardness often cause pain and distress. These instruments must be made to different sizes according to the dimensions of the cervix. Too soft contraceptive devices made of plastic can twist in the uterus and can often be spontaneously pushed out, or possibly also puncture the target musculature. The syringes or intact devices of such intrauterine fertility inhibitors penetrate the abdominal cavity after perforation of the uterine wall and lead to further injuries there.

Numerous fewer side effects and spontaneous protrusions are observed with less plastic, intrauterine contraceptive devices than with plastic closure devices. However, the absolute number of unwanted side effects and spontaneous protrusions is too high for both types of intrauterine contraception. Less occlusive intrauterine contraceptives also show side effects such as menstrual irregularities, heavy uterine bleeding during and between periods, and the occurrence of white discharge with persistent pain and occasional spasmodic pain (cf. e.g. Ostergard et al. 5) »Contraception 4 (Contraception 4). (1971); Portruff et al., Am. J. Obst. Gynec. 114 (7), 934-937 (1972); Taylor et al., Obst. Gynec. 41 (3), 404-413 (1973); Buchmann, Fert. Steril. 21 (4), 348-355 (1970)). The amount of variation calculated by the life-table method (Tietze, Intrauterine Contraception, Recommended Procedures for Data Analysis Studies in Family Planning, No. 18 (Suppl.), The Population Council, New York, 1967) is so high that its infertility whether 5,803,53 spawns are questioned (Fuchs et al., Contraception 5 (2), 119-127 (1972), Baeyertz, Austr.NZJObst.Gynec. 11, 117-121 (1971); Davis, Amer.

J. Obst. Gynec. 114 (1), 154-151 (1972)).

Eruptions of uterine walls are also frequently found with these types of contraceptives (Buchmann, Fert.Steril. 21 (4), 348-555 (1973)). Rigidly formed intrauterine contraceptives can rupture due to flexural stresses in the uterus. Fractures can unnoticed spontaneously protrude or, like undamaged devices, can puncture the uterine wall and penetrate the abdominal cavity (Last, J. Obst. Gynec. Brit. Commonw. 79, (2), 190-191 (1972));

Domany et al., Brit. Med. J. 1, 549, (1973)) · When using drug-containing intrauterine contraceptives such as TCu 200 or TCu C., contraceptives containing copper and zinc, progesterone (DT PS 2,247,949) or dl-11p-ethyl-17a -ethyl-17β'-hydroxy-gon-4-en-3-one, reduced variability readings are observed compared to intrauterine contraceptives made of plastics alone.

However, these drug-containing intrauterine contraceptives, as well as formal drug-free devices, lead over time to undesirable side effects such as bleeding and pain. (Fortier et al., J. Amer. Obst. Gynec. 115 (3), 291-297 (1973), Tatum, Contraception 6 (3), 179-189 (1972); Mishell et al., Amer. J. Obst. Gynec 116 (8), 1092-1096 (1973) ·

What all T-shaped devices have in common is that they cannot be sterilized in an applicator due to insufficient resilience of the plastic material. In addition, it is hardly possible to place the device in the applicator under aseptic conditions, since the device and the applicator are not suitable for each other.

The device and the applicator together can lead to damage, as the collapsed device and the upper edges of the insertion tube have sharp edges. The Dalkon shield and the applicator developed for this purpose must be handled in such a way that the insertion of the contraceptive device is possible only by vigorous application of the cervix.

In addition to the susceptibility of these fertilization inhibitors, spontaneous protrusions also result from side effects (Fortier et al., Amer. J. Obst. Gynec. 115 (3), 291-297), Johannisson, Contraception 8 (2), 99-112 (1973); Snowden et al., Contraception 7 (2), 91-104 (1973); Horowitz, Contraception 7 (l), 1-10 (1975)) · Spontaneous out- ✓ 5 58053 protrusions are observed with some of these devices (Daikon Shield: DT OS 1 * 956,701; Ostergard et al., Obst. Gynec. 41 (2) , 257-258 (1975)); With T-shaped contraceptives, Copper-7: Newton et al., Lancet 1972/11 Nr. 7784, 951-954; Bernstein et al., Contraception 6 (2), 99-107 (1972)), although they are designed to form a support against oncoming pushing. The supports should prevent the pushing movement of the device (Jones et al.,

Brit. Med. J., 5,145 (1975)) · In the Dalkon plate, these supports are attached as pins and barbs to the ring. The use of intrauterine contraceptives thus formulated naturally carries the risk of uterine damage during insertion, during a certain period of use (Koetsawang, Contraception 7 (4), 527-552 (1975); Johannisson, Contraception 8 (2), 99-112 (1975)) * Lehfeldt et al., Obst. Gynecol. 57 (6), 826-831 (1971); Brooks et al.,

Amer, J.Obst.Gynecol. 115 (l), 104-106 (1972); Sprague et al., Obst. Gynecol. 41 (1), 80-82 (1975); Rienprayura et al., Contraception, 7 (6), 515-521 (1975) and upon removal (Snowdon et al. Contraception 7 (2), 91-104 (1975) -Kamal et al. (Pert. Steril. 24> ( 5) »165-169 (1975)) show that minor damage to the uterine wall caused by both horizontal ends of the T-shaped contraceptive device (US 5,555,406) which attaches the device to the uterine wall may be both advantageous for the function and attachment of the contraceptive device.

With copper-containing intrauterine contraceptives such as Copper-T, the copper wire may break or partially detach from the plastic body under the resulting mechanical stress. Broken pieces of copper wire can lead to damage. They can penetrate the uterine wall into the abdominal cavity and are difficult to locate in crumbs. Copper-TCu220 Cs has a very high risk of puncturing the condensate wall and subsequently detaching the copper cylinder and leaving it in the abdominal cavity.

The contraceptive devices used so far have also had disadvantages in terms of their total weight or the internal weight distribution of the device, which promotes spontaneous ejection. Copper-TCu220C weighs 612 mg, one Lippes Loöp embodiment up to 665 mg. Metal-containing intrauterine contraceptives, such as those described in German Application 2,207,959, easily protrude spontaneously due to poor internal weight distribution (metal rings attached exclusively to the plastic arm).

For example, DT PS 1,441,559 or DT OS 2,207,959 contraceptive devices have an extended intrauterine helix extending from the uterine cavity through the cervix to the vagina. These devices are made homogeneously of plastic. However, the plastic suitable for shaping the coil is too rigid for the inner part of the cervix and the inner part of the vagina. For this reason, these intracervical contraceptives have been found to have a particularly high number of side effects, such as convulsive pain and bleeding (Willson, Amer. J. Obstet. Gynecol. 92 (1965) 62). Uterine spasms often result in inconspicuous spontaneous protrusions and subsequent pregnancies.

A further disadvantage of known drug-containing contraceptives is that the release of non-metallic active ingredients from them does not take place over time with the required efficacy for contraception on a regular basis and within certain predetermined limits. Moreover, the production of this type of anti-fertilization device in larger batches is technically difficult and can only be carried out with many precautions.

The amount of pregnancy calculated by the life-table method (Tietze, Intra-Uterine Contraception, Recommended Proc. For Data Analysis Studies in Family Planning No. 18 (Suppl.), The Population Council, New York, 1967) is and useful intrauterine contraceptives so high that they do not affect the reliability of known oral contraceptives containing hormones as active drugs (Davis, Amer. J. Obstet. Gynec. 114 (1972) 134; Fuchs et al., Contraception 5 ( 1972) 119).

It is an object of the invention to provide a general and complication-free intrauterine, reliable, active drug-containing contraceptive device suitable for human use. The contraceptive device must be able to be used without risk for several years without any physical or mental harm in all expected uterine duct abnormalities in the unborn, inexperienced, multiple births and frequently pregnant women. This must be done in such a way that, after its use, it does not prevent or adversely affect fertilization. The use of contraceptives containing active substances must not involve the risk of undesirable side effects such as dysfunctional bleeding, inflammation, convulsive pain, transitions such as onset and displacement, or the risk of spontaneous protrusions. The intrauterine contraceptive device, taking into account all expected cervical dimensional changes, must be designed so that it does not rotate in the uterus during the greatest uterine movement, the cervix rotates and does not settle in an undesired position, and is always simple and secure, X-ray locally, if necessary. has been designed in such a way that mechanical damage to the uterus cannot occur due to its balance and the required elasticity at its maximum in terms of insertion, use and removal in relation to the shape and the material used to make it. Insertion of the contraceptive device. to the uterus to be simple and painless without significant cervical dilation and without the need to use other drugs under aseptic conditions.

The intrauterine contraceptive device applicator should be designed with respect to the device so that the contraceptive device can be inserted under aseptic conditions.

Such active drug-containing contraceptives must be technically simple and safe to manufacture and sterilize in large batches. Above all, these types of contraceptives should be such that the probability of unwanted pregnancies during use is as close as possible = 0.

According to the invention, this object is achieved by having a Y-shaped round rod and a ball combination, the round ball leaving two round rods of different lengths and having balls at their ends, which form an obtuse angle with each other and the third round rod, whereby the third round rod continues as spheres and intermediate circular rods therebetween, and terminates via a circular rod in a bean-like end piece with a central hole for the pull-out thread.

The use of the contraceptive device and the applicator according to the invention is shown in Figure 1.

It shows a basic shape of Y in length of 3- ^ cm. Connected to the central sphere 1 with a diameter of 2.5-3.0 mm are 3 circular rods 2-h starting from the sphere, which are of different lengths and have a diameter of 1.0-1.5 mm. The circular rods 3 and 1+ end at a distance of 0.8-1.2 cm 3 or 0.5 "0.8 cm h into spheres 5 and 6 with a diameter of h-5 mm or 1.5-2, respectively, 0 mm 6, and are at an obtuse angle to the third rotary rod 2. The third circular rod 2 continues as a three-circular rod connection 7,8,9 of four spheres 10-13 with a diameter of 2-3 mm, to a bean-shaped end piece 1U long and up to 3 mm in diameter and with a hole 15 in the middle, 0.5-1 »5 mm.

The loop is intended for attaching a yarn 18 of a suitable material such as nylon or polyester. The purpose of this thread is simply to act as an indicator of the presence of a contraceptive device.

In a particular embodiment of the contraceptive means of the method according to the invention, in addition to the central wire 15, another plastic inner cervical hanger wire 19 passes through the central hole 15, which may likewise contain 58053 of active ingredient.

This particular embodiment is shown in Figure 2.

For the production of plastic bodies for the contraceptive devices according to the invention, plastics known per se are used, which dispense once-dispersed non-metallic active substances and which have sufficient mechanical properties, such as breaking strength, flexibility and cold stretchability, and which can be easily molded into the desired shape. Examples include polyethylene, polyethylene / vinyl acetate, polyethylene-derived ionomer resins, polyamide, terephthalate-based polyether ester elastomers, polyethylene glycol terephthalate, and silicone rubber. Plastics can be used singly or in combination, for example in layers. The active ingredients contained in intrauterine contraceptives are metals, metal alloys or non-metallic substances of natural or synthetic origin attached to the surface of the plastic body or to the plastic material itself.

Among the active metallic substances, mention may be made of metals such as copper, silver, nickel or combinations of these metals and combinations of pure metals with the corresponding alloys. Metals or alloys can be similarly applied to the entire plastic body or dispersed only in certain parts thereof, or also partially and alternately applied to the surface of the contraceptive means in a suitable manner.

The metallic active ingredients are introduced into the plastic bodies in a manner known per se, e.g. by galvanizing, vacuum metallization, reducing separation, possibly with the aid of adhesives or by dispersion. Efficiency is not in itself affected by the form in which the metal in the galvanic coating of the metal or metals is separated and if the layers of different metals are coated on top of each other. The layer thickness of the coating metal is dimensioned so that the metal is not detached from the plastic body in the uterus in the contraceptive means under high variable bending stress.

In a particular embodiment of the contraceptive device, the metallic active substance is placed in spheres (5), (6), (10), (11), (12), (13). The alternating order of copper and nickel is particularly preferred.

The non-metallic active ingredients contained in the contraceptive devices according to the invention are preferably compounds having a hormonal action, anesthetics and weakly basic buffers. Examples are N -pregnene-3,20-dione (progesterone), d-13-ethyl-? 58053 17α-Ethynyl-17 (3-hydroxy-4-Gonen-3-one (d-Norgestrel) and its esters, 17α-Ethynyl-19-nortestosterone (Norethisteron) and its esters, 6-chloro-17-hydroxy-ΐα , 2cr-methylene-pregna-4,6-diene-3,20-dione (Cyproteron) and its esters, 3-methoxy-19-nor ** 17α-pregna-1,3,5 (10) -trien-20- γ-17-ol (Mestranol), 18-methyl-19-nor-N-pregnen-17α-ol-3,20-dione-17α-capronate, 3-hydroxy-1 * 3, 5 (10) -trien -17-one (Estrone), 17-acetoxy-6- (3,7β-epoxy-1cc, 2a-methylene-4-pregnene-3,20-dione, 4,6-dichloro-17-acetoxy-16a- methyl 4,6-pregna-diene-3,20-dione, 17α-hydroxy-6-methyl-pregna-4,6-diene-3,20-dione acetate (Megestrolacetate), 19-nor-5a -pregnane-3,20-dione, 3β-hydroxy-19-nor-5α-pregnan-20-one, 19-norhydroxyprogesterone and its esters, 6-chloro-17-hydroxy-pregna-4,6-dien-3, 20-dione acetate (Chlormadinone acetate), 1,3,5 (10) -estratriene-3,17β-diol (estradiol), 1,3,5 (10) -estratriene-3,16a, 17d-triol (Estriol) , 17β-hydroxy-4-androsten-3-one (testosterone) and its esters, 21-hydroxy-5- (3-pregnane-3,20-dione and its esters, 17α-acetoxy-6α-methyl-progesterone (medroxy-progesterone acetate), 10α-pregna-4,6-diene-3,20-dione ( Dydrogesterone), 17 (3-estradiol and xylocaine and novocaine as well as triethanolamine, ethylenediaminetetraacetic acid disodium salt and phosphate buffer according to Sörensen.

The Si-metallic active ingredients can be homogeneously present in the plastic bodies, possibly also dispersed by the auxiliaries or in individual parts of the antifouling means, with or without these auxiliaries, e.g. as a core body of a part of the plastic body, in a suitable amount. Excipients include, for example, surfactants, finely divided silica, antifoams, solubilizers, absorption retardants, X-ray contrast agents, and ferromagnetic agents for locating the fertilization device.

A preferred embodiment of the contraceptive device comprises, homogeneously distributed, d-13-ethyl-17α-ethynyl-17H-hydroxy-4-gon-3-one (d-Norgestrel) vulcanized with finely divided silica with 5% barium sulphate at low temperature. Among other things, another infertility inhibitor according to the invention contains in the spheres (5) »(6), (10), (11), (12) and (13) the core moieties comprising 6-chloro-17-hydroxy-1α, 2α-methylene-pregna -4,6-diene-3,20-dione acetate (cypro-deronacetate) and milk sugar, wherein the plastic body of this contraceptive device consists of a polyethylene / vinyl acetate copolymer.

The active substances in the wire-like hangers (19) are released from the plastic carrier within certain prescribed limits of 10 to Ä Λ 58053 for a limited period of time, i.e. during the first months of use of the fertilizer,

The hanger (19) can be used as such, in particular, with all metal-containing intrauterine contraceptive devices which are suitably suitable for attachment to the intracervical intraocular carrier of the active substance, e.g. by bonding, gluing or jointing. Particular mention should be made of the infertility means disclosed in U.S. Patent 3,535,406, German Patent 1,956,701, U.S. Patent 3,563,235 and German Patent 2,207,939.

The dimensions of the wire are chosen so that the wire extends into the cervix just barely, but not into the vagina. This active ingredient-containing yarn has a diameter of 0.2 to 1.0 mm and a length of 1.0 to 5 cm. The active ingredient content of the yarn is between 10-70%.

The non-metallic active ingredients contained in the cervical pendants within the cervix are preferably compounds having a hormonal effect. Examples are N-pregnene-3,20-dione (progesterone), d-13-ethyl-17β-ethynyl-17β-hydroxy-4-hydroxy-4-one (d-Norgestrel) and its esters, 17α-ethynyl -19-nortestosterone (norethisterone) and its esters, 6-chloro-17-hydroxy-loc, 2a-methylenepregna-4,6-diene-3,20-dione (Cypro-Teron) and its esters, 3-methoxy-19-nor -17α-pregna-1,3,5 (10) -trien-20-yn-17-ol (mestranol), 18-methyl-19-nor-N-pregnen-17α-ol-3,20-dione- 17α-Capronate, 3-hydroxy-1,3,5 (10) -trien-17-one (estrone), 17-acetoxy-6β, 7β-epoxy-1α, 2α-methylene-4-pregnene-3, 20-dione, 4,6-dichloro-17-acetoxy-16β-methyl-4,6-pregnadiene-3,20-dione; 17α-hydroxy-6-methyl-pregna-4,6-diene-3,20-dione acetate (megestrolacetate), 19-nor-5α-pregnane-3,20-dione, 3β-hydroxy-19-nor-5α -pregnan-20-om, 19-norhydroxyprogesterone and its esters, 6-chloro-17-hydroxy * pregna-4,6-diene-3,20-dione acetate ("Chlormadinone acetate"), 15,16a and 15,16β-methylene-> 17β-hydroxy-18-methyl-17α-ethynyl-4-estron-3-one, 17β-hydroxy-4-androsten-3-one (testosterone) and its esters, 21β-hydroxy-5β -pregnane-3,20-dione and its esters, 17α-acetoxy-6α-methyl-progesterone ("Medroxy-progesterone acetate"), 10α-pregna-4,6-diene-3,20-dione (Dydrogesterone).

Preferred are gestational steroid hormones such as D-Nor-gestrel and Progesterone, Norethisteron, Cyproteronacetate, Norhydroxyprogesterone, 15,16a and 15,16β-methylene-D-Norgestrel.

11 58053

The non-metallic active ingredients are homogeneously dispersed in the yarns containing the active ingredients by manually adding excipients. Excipients include, for example, surfactants, antifoams, solubilizers and resorption retardants such as finely divided silica.

Suitable plastics for the production of active substance-containing hangers (19) are particularly known known LTV silicone rubber bicomponent masses, which can be prepared, for example, according to the method of U.S. Patent 2,823,218. Particularly suitable are pulps containing 99-91% linear, dimethylpolysiloxane containing up to 0.5 role-methyl vinylsiloxane units and dimethylpolysiloxane containing 9-11 $ Si-II compounds having a molecular weight of 500-1000 and which may contain 3 Si -H compounds and are catalyzed by platinum or platinum compounds such as hexachloroplatinic acid (elastomeric mass i) or those comprising 85-89% of dimethylpolysiloxane having not more than 0.5 molar methylmethylsiloxane units, 5 * 6 ° dimethylpolysiloxane are Si-H bonds, a 5-10 Ί ° crosslinking and reinforcing dimethylpolysiloxane resin having up to 1.2 mol-methyl vinylsiloxane units catalyzed by a platinum ethanol complex compound (elastomeric mass II).

The contraceptive devices according to the invention are superior in their long-term effects compared to known contraceptive devices in that the number of pregnancies reported according to the "life-table-method" is considerably lower when used and causes less spontaneous protrusions and other side effects.

The amount of protrusion of the contraceptive devices according to the invention is very small, even if the devices do not have an anti-protrusion support structure or their shape does not allow attachment to the uterine mucosa or uterine musculature. In contrast to non-active intrauterine contraceptives, a large contact surface between the device and the uterine mucosa can be avoided without adversely affecting efficacy, because the addition of active substances or combinations of active substances results in improved potency.

By using plastics known per se, but not hitherto used for the manufacture of intrauterine contraceptives, contraceptive contraceptives can be prepared, for example, which have the required dose of release active substance for months to years to prevent intrauterine contraception. These contraceptive devices are generally useful regardless of the size of the cervix. These devices are structured in such a way that they do not penetrate the uterine musculature, or even pierce it.

The advantage of the hanging contraceptive device according to the invention is that the calming effect preferably has a punishing effect! to the uterus exposed (UFER, J., Ilormontherapie in der Frauen-Heilkunde, Verlag Walter De Gruyter Berlin, 1972, p. 124). The physiological mobility of the uterine muscles caused by the introduction of a foreign object is then reduced. This also reduces the number of early expulsions and, as a result, the number of pregnancies that occur. This avoids the disadvantage of a high failure rate associated with all intrauterine contraceptives to date during the first months of use, i.e., avoiding the first critical step when using intrauterine pessaries.

The contraceptive devices containing the active ingredients according to the invention are designed for use. Suitable inlet pipes (16) with an inner diameter of 3.5 mm and a wall thickness of 0.5 mm and made of high-pressure polyethylene or other suitable plastics are suitable for the setting. The contraceptive means is inserted under the aseptic conditions by means of a detection wire (18) attached to the joint of the ball (5), to the loop (15) and to the pulling and pushing arm (17) connected thereto. The ball (5) of the device then forms a ball seal for the applicator unit, which consists of an infertility means and an applicator. Because the edge of the inlet pipe is coated, primary damage during setup is not possible. In addition, a spherical head with a diameter of 4-5 mra prevents the base of the uterus from bursting during the setting. The installation of a contraceptive device is an easy task for a person skilled in the art. It can occur under aseptic conditions without anesthesia or use of medication or cervical delivery without convulsive pain even in unborn women.

Example 1

One terephthalate-based thermoplastic polyetherester elastomer injection molded plastic body having the basic shape shown in Figure 1 has the following dimensions: total length 3.6 cm, sphere diameters (5) 4.8 mm, (6) 1.5 mm, (1), (10) -13) 2.8 mm, round rod diameters (4) 1.3 mm, (2-3), (7-9) 1.5 Dim, round rod (3) or (4) length 0.85 cm or 0.65 cm, loop length 4.5 mm, loop diameter 2.8 mm; total weight of plastic body: 220, mg.

15 58053

The surfaces of the plastic body spheres are partially galvanized with copper and nickel alternately using a mounting base. The spheres (5) »(6), (10), (li), (12), (13) are coated with nickel (coating layer 100 μm) and the spheres (5), (li), (13) are further coated with copper (coating thickness 100 μm). yum).

Example 2

A polyethylene-based thermoplastic material which, due to copolymerization in the polymer chain molecule, contains associated carboxyl groups and is crosslinked with sodium ions, is formed into plastic bodies of the dimensions given in Example 1.

The spheres (5-6), (10-13) of the plastic body are superficially chemically copperized by adding a finishing iron-containing fixing substrate (coating thickness: about 0.5 μm). Nickel (coating thickness: 80 yum) is galvanized on top of the chemically separated copper layer. The spheres (5), (li), (13) are further galvanically coated with copper (coating thickness: 60 μm).

Example 3 75.0 g of a finely divided terephthalate-based thermoplastic polyetherester elastomer are mixed homogeneously with 12.5 g of very fine copper powder and 12.5 g of very fine nickel powder. The mixture is molded with contraceptive devices according to the dimensions shown in Example 1.

Example 4 60.0 g of catalyzed silicone rubber bicomponent acetone, "Low Temperature Vulcanizing-Typ (TTV)", are mixed with 40.0 g of very fine silica. Plastic bodies are prepared from the suspension according to the dimensions shown in Example 1 by vulcanizing the molded mass for one hour at 110 ° C. The plastic bodies are galvanically coated, as described in Example 2, partially and alternately on the surface with copper and nickel.

Example 5

The intra-conditional contraceptive device, which partially and alternately contains copper and silver on its surface, is manufactured as follows: high-pressure polyethylene is used to make plastic bodies with the basic shape according to Figure 1 and the following individual dimensions: overall length 3.4 cm, spherical diameters (5) 4.6 mm, (6) 1 , 6 mm, (l), (10-13) 2.6 mm, round rod diameters (4) 1.2 mm, (2-3), (7-9) 1.6 mm, round rod lengths (3) 0.9 cm, 0.7 cm, loop length 4.5 mm, loop diameter 2.6 mm.

The surface of the spherically shaped parts (5-6) and (10-13) of the plastic body is separated from the reducing silver (layer thickness about 1 ^ groove). Copper (layer thickness about 90 μm) is galvanized on top of this silver layer. The surfaces of the spheres m 58053 (5) * (li) and (13) are further galvanically coated with silver (layer thickness 70 μm).

Example 6

The terephthalate-based thermoplastic polyetherester elastomer is sprayed with plastic bodies having the dimensions given in Example 5 and the basic shape shown in Figure 1. Partial metal coating of the plastic bodies, with copper and silver in alternating order, is performed as described in Example 2 using a mounting substrate and then galvanizing. In this case, the spheres (5-6) and (10-13) receive a 100-μm-thick cup of copper, in addition to the spheres (5), (II) and (13), a 75-μm-thick silver layer of 100 μm on top of the copper layer.

Example 7

Plastic bodies made of terephthalate-based thermoplastic polyetherester elastomers having the basic shape of Figure 1 and the dimensions of Example 1 are coated in their spherical portions (6), (10) and (12) with a plastic body after being coated with a 10 μm silver wire, with nickel (layer thickness 90 μm) and for the spheres (5), (li) and (13) likewise on a silver wire lacquer layer of about 10 μm with silver (layer thickness 80 μm) galvanically.

Example 8 35 * 0 g of micronized d-13-ethyl-17α-ethynyl-17β-hydroxy-4-gon-3-one and 5 * 0 g of very finely divided barium sulphate are mixed with 60.0 g of very finely granulated high-pressure polyethylene (grain size about 500 yum) homogeneously. The mixture is formed into intrauterine usable contraceptive devices having the shape of Figure 1 and the dimensions of Example 5.

Example 9 30.0 g of micronized d-13-ethyl-17α-ethynyl-17β-hydroxy-4-gonen-3-Oria (d-Norgestrel) are mixed thoroughly with a mixture of 5.0 g of very fine barium sulphate, 0 g of very fine silica and 45.0 g of catalyzed LTV silicone rubber bicomponent mass. The suspension is molded and vulcanized for one hour at 110 ° C into d-TCorgestrel-containing plastic bodies having the basic shape of Figure 1 and the dimensions shown in Example 1.

Example 10

From a mixture of 50.0 g of micronized progesterone and 49.1 g of milk sugar together with C.1 g of lubricant, extrudates with a diameter of 2 mm and a radius of curvature of 3 mm are prepared. The progesterone presses are introduced into cores in spherical particles (5) and (10-13) into an intrauterine contraceptive device having a body and dimensions as described in Figure 1 and Example 5 and consisting of a mixture of 5.0 g of bait. rium sulphate, 35.0 g of very fine silica and 60.0 g of catalysed LTV silicone rubber bicomponent mass, heated for one hour at 10 ° C during molding.

Example 11

A homogeneous mixture of 40.0 g of 6-chloro-17-hydroxy-1α, 2α-methylene-pregna-4,6-diene-3,20-dione acetate together with 59.2 g of milk sugar and With 0.2 g of lubricant mixture, is made into extrudates (diameter 2 mm, radius of curvature 5 mm). These extrudates are used as cores in spheres (5) and (ID-13) in an intrauterine contraceptive device, the basic shape of which is shown in Figure 1 and the dimensions in Example 5, and which is made of high pressure polyethylene by adding $ 5 of barium sulfate.

Example 12

From the mixture described in Example 9, plastic bodies containing the active ingredients are formed by vulcanization at 100 ° C for 2 hours, from which 10 ml of 96 .mu.l ethanol are successively extracted for 90 minutes, 70-, 50-, 30- and 10- ethanol for 30 minutes is used to prepare intrauterine contraceptives in which the core of the plastic body is enriched for d-Forgestrel.

Example 13 50.0 g of micronized 17α-ethynyl-19-nortestosterone entant are mixed with 10.0 g of finely divided silica, 5.0 g of barium sulphate and 35.0 g of catalysed LTV silicone rubber. -two-component mass homogeneously. The mixture is formed into a Y-like base body with a rod diameter of about 1 mm and a total length of about 3 cm, vulcanized for 10 hours at 60 ° C, and this is a core component in an intrauterine contraceptive device having the basic shape of Figure 1. This active substance-containing body is surrounded by high-pressure polyethylene so that the dimensions of the contraceptive device remain those given in Example 5.

Example 14 3 <0.0 g of d-β-ethyl-β-ethynyl-β-hydroxy-β-gonen-one is mixed with 10.0 g of barium sulphate and 60.0 g of very finely granulated polyethylene -vinyl acetate copolymer and formed into a Y-shaped body having a rod diameter of 1 mm and a total length of 3 cm. This active substance-containing body is surrounded by a mixture of 45.0 g of very finely divided silica, 10.0 g of barium sulphide 58053 fate and 45.0 g of catalyzed LTV silicone rubber bicomponent mass according to the dimension of Example 1 in the basic form of Figure 1 vulcanized for one hour. for 10 hours at 10 ° C.

Example 15

A terephthalate-guided thermoplastic polyetherester elastomer injection molded plastic body has the basic shape shown in Figure 1 and the following dimensions: total length 3.6 cm, spherical particle diameters (5) 4.8 mm, (6) 1.5 mm, (l), ( 10-13) 2.8 mm, round rod diameter (4) 1.3 mm, (2-3), (7-9) 1.5 mm, round rod length (3) or (4) 0.85 cm or 0, 65 cm, loop length 4.5 mm, loop diameter 2.8 mm; total weight of plastic body: 220 mg.

The surface of the spheres in the plastic body is galvanized with the aid of a mounting base in part and alternately with copper and silver. The spheres (5), (6), (10), (li), (12), (13) are galvanically plated with silver (layer thickness ICC yum) and the spheres (6), (10), (12) are further coated with copper (plating pack). -suus 100 yum).

Example 16

A polyethylene-guided thermoplastic thermoplastic having carbocolyl groups attached to it due to the copolymerization of the polymer chain molecule and which is a crosslinker of sodium ions is molded into plastic bodies having the dimensions given in Example 1.

The spherical particles (5-6), (10-13) of the plastic body are chemically coated with copper (layer thickness: about 0.5 yutn) using a fixing substrate containing a very fine iron. Silver (layer thickness: 80 ^ groove) is galvanized on the chemically separated copper layer. In addition, the spherical particles (6), (10), (12) are galvanically coated with copper (coating thickness: 80 μm).

Example 17 75.0 g of a very finely granulated terephthalate-based thermoplastic polyetherester elastomer are uniformly mixed with 12.5 g of a very fine copper powder and 12.5 g of a very fine silver powder. The mixture is molded with contraceptive devices having the dimensions given in Example 1.

Example 18 60.0 g of a catalyzed silicone rubber bicomponent mixture, "Low Temperature Vulcanizing-Typ (LTV)", is mixed with 40.0 g of very fine silica. Stomach bodies of the dimensions prepared in Example 1 are prepared from the suspension by vulcanizing the molded mass at 110 ° C for 17,58053 hours. The plastic bodies are galvanically coated as described in Example 2, partially and alternately on the surface with copper and silver. Example 19

The intrauterine contraceptive device, partially and alternately coated with copper and silver, is manufactured as follows: high-pressure polyethylene is used to make plastic frames with the basic shape according to Figure 1 and the following special dimensions: total length 3.4 cm, spherical part (5) diameter 4.6 mm, 6) 1.6 mm, (1), (10-13) 2, 6 mm, round rod wax diameter (4) 1.2 mm, (2-3), (7-9) 1.6 mm, round rod ( 3) length 0.9 cm, (4) 0.7 cm, loop length 4.5 n® and loop diameter 2.6 mm.

The surfaces of the spherically shaped portions (5-6) and (10-13) of the lattice body are activated by treating the plastic surface with an ionic palladium solution. A layer of about 1-2 yum of copper is chemically separated on this activated surface. Thereafter, according to the usual plastic electroplating methods, about 80 μm of copper is separated on the surface, and in addition to the μm particles (6), (lo) and (12), 100 μm of copper is electrolytically deposited.

Example 20

From the terephthalate-based thermoplastic polyetherester elastomer, plastic bodies of the dimensions of Example 5 are injected into the basic shape of Example 1. The partial metal coating of the plastic bodies comprising copper and silver in varying order is separated as described in Example 19 on the ionic palladium solution activated spherical surfaces (5-6) and (10-13) chemically and electrolytically. The layer thickness of the electrolytically separated silver layer is about 90 μm, and the electrolytically separated copper layer is about 60 μm.

Example 21

Semi-metallized plastic bodies made of terephthalate-based thermoplastic polyetherester elastomers, with copper and silver in alternating order according to the basic shape shown in Figure 1 and the dimensions given in Example 1, are chemically coated with copper ionic palladium solution (about) after activating the plastic surface. Thereafter, 100 .mu.m of silver and 80 .mu.m of copper are separated electrolytically in succession. Using a suitable topcoat, in a two-step process, the metal coating of the end piece (14) and the central ball part (l) of all round bars is removed, the metallization of the ball parts (5), (li) and (13) becomes complete, such as balls (6), (10) and ( 12) with aberrant 80 μm copper layers.

w 58053

Example 22 50.0 grat of micronized D-13-ethyl-17α-ethynyl-17β-hydroxy-4-goen-5-one (D-Norgestrel) and 70.0 grat of LTV silicone rubber two-component backbone (elastomer type i) are made air-free suspension. The suspension is formed into wires through a nozzle and vulcanized by heating at 100 ° C for 2 hours. A wire with a diameter of 0.5 mm is obtained, which is cut into 4 cm sections, whereby, after joining, the intrauterine contraceptive device according to Fig. 1 has a further free length of more than 2 cm. The yarn is sterilized together with an anti-fouling agent in superheated steam for 30 minutes and packaged sterile.

Example 23

In the same manner as in Example 22, a yarn of similar dimensions is prepared which contains 25 'fo 17 l; -acetoxy-17a-ethynyl-4-estren-3-one (Norethisteronacetat) as a steroid hormone affecting pregnancy.

Example 24

The cervical wire is prepared using 40 parts by weight of the finest micronized progesterone mixed with 60 parts by weight of catalyzed LTV silicone rubber bicomponent mass (elastomeric mass II), forming a progesterone suspension and then heating at 10 ° C for one hour. It is 2.5 cm long and 0.5 mm in diameter.

Example 25

In the same manner as in Example 22, a wire of the same length is prepared, but with a diameter of 0.4 mm, which contains 30 / '17α-hydroxy-19-norpregn-4-ene-3,20-dione ("Korhydroxyprogesterone") as a steroid hormone affecting pregnancy. ).