CS197289B2 - Vaginal ring - Google Patents

Abstract

The present invention provides in a composite vaginal ring containing a safe and effective amount of a pharmaceutically active medicament which includes: a) a major supporting medicament-free vaginal ring consisting essentially of a physiolocigally acceptable synthetic resin and having at least a portion of the annular surface thereof adapted to mate with a corresponding minor, medicament-containing vaginal ring segment; and b) at least one minor, medicament-containing vaginal ring segment adapted to mate with the modified annular surface of said major supporting vaginal ring and consisting essentially of a safe and effective amount of a pharmaceutically active non-ionic, lipophilic drug dissolved or uniformly suspended in an elastomeric, cross-linked LTV linear dimethylpolysiloxane resin, the improvement wherein: at least one of the major supporting vaginal ring and the minor vaginal ring segment has a reniform or ellipsoidal cross section; or the major supporting vaginal ring is formed as a closed or inwardly open hollow-profile ring, as a closed or inwardly open hollow ring, as a hollow ring having a circular or reniform cross section, as a core-encased composite ring or as a sandwich element.

Description

The subject of the invention is a vaginal ring.

In MS. In U.S. Patent No. 181,791, a vaginal ring has been described which consists of a support ring of synthetic material with one or two pocket-like recesses extending circumferentially to receive the base rings. elastomers containing the active drug and corresponding recesses.

In a further embodiment of the invention according to U.S. Pat. . No. 181,791, the support ring has a kidney-shaped or ellipsoidal cross-section or is formed as a closed or inwardly open hollow profile ring or as a closed or inwardly open hollow ring or as a hollow ring of circular or kidney cross-section or as a composite ring forming a sheath or as a sandwich. ,

Since the support ring essentially forms the shape of the vaginal ring, the external features thus also correspond to the vaginal ring of the invention.

Vaginal rings that contain progestogenic steroid hormones or a combination of progestogenic and estrogenic active drugs and prevent ovulation without inhibiting fertilization in conjunction with inhibiting ovulation, are offered if the oral formulations containing these active substances cannot be used from a wide variety of reasons, for example in the case of sustained resistance to taking tablets. Vaginal rings have the further advantage that a woman is exempted from having to take tablets daily. Going. o simply. Applicable annular formations that '' become. into the vagina. Women are 'good'. tolerated. In contrast to known intrauterine pessaries and capsules administered individually, it is further preferred that women can. at any time to remove and reintroduce. ' ^/:

Vaginal. rings of synthetic material, in particular vaginal rings on the rings. base. . the silicone elastomers obtainable therefrom _; of'. _and "two-component compositions based on silicone. room vulcanized rubber [Contraception 8. (1973) 651], or. on . þjazi silicone rubber vulcanized ^{^} and heat [Steroids 21 (1973) 325], containing the active drugs, such as steroid. . hormones are known per se [Fertil. . i ^J teril. . 21 (1970) 99; Amsr. JJ Obstet. Gyn · .col. 113 (1972) 927; Contraception '3 (6)' (li 73) 561; DOS 1 900196]. The effective treatment is released over a longer period of time from the synthetic carrier and is absorbed by the mucosa of the wagon.

The steroid hormones contained in known vaginal rings are. exclusively those having a gestagenic effect. Of the thread, rather on the dose of the active ingredient released from the vaginal ring ^{T is} reached with their use contraceptives by preventing ovulation or ovulation without hindrance.

However, the vaginal ring-shaped contraceptives known to date have drawbacks. Among other things, they manufacture on the basis of two-component compositions based on silicone rubber vulcanized at room temperature, whose poor mechanical properties are known. The mechanical properties of the vulcamzates obtained by vulcanization at room temperature need only be improved by the addition of fillers. However, these fillers may adversely affect the release of active substances from the vaginal ring. Some of the known vaginal rings are manufactured in the corresponding shape by vulcanizing suspensions of the medicaments in two-component sonicated rubber vulcanized at room temperature. Effective drugs are released from this type of vaginal ring during periods of use in amounts which, together with the time of use, decrease significantly. [Contraception 8 (1973) 561]

Significant differences in the dosage of active drugs necessarily result in qualitative and quantitative differences. in the biological and possibly the conceptual effect as well as in the type and extent of undesirable side effects during the use of the vaginal rings. Known vaginal rings containing a drug suspended in a synthetic backing having a total weight of about 6.0 to 15.0 g. If the active drug is to be released from the vaginal rings at the time of use in an amount sufficient to achieve the desired effect, then the ring must contain about 5 to 30 wt. % of active drug. That's proportional. the amount of active drug released at the time of use by the uneconomically high content of the active ingredient in the dosage form.

Furthermore it is not known until now no way to set the size of the required release rate effective léč'va * from such vaginal rings based ^powers: horse power elastomer.

Hitherto known vaginal rings are produced partly on the basis of not entirely physiologically acceptable synthetic materials. Thus, for the manufacture of vaginal rings, two-component compositions at room temperature vulcanized silicone rubber containing tin compounds are used as vulcanization accelerators. Vulcanization accelerators have a toxic effect on the living organism (Amer. J. Obstet. Gynecol. 113 (1972J 927)).

Also known are vaginal rings which, like those used to treat prolapse, are provided with a metal spring. These vaginal rings are relatively rigid. Their use may cause mucosal erosions in the posterolateral arch of the uterus (Amer. Med. Ass. 208 (1969) 949). V · brit. patent. sp ^; Having 1264732 describe systems which consist of a capsule comprising ^Prior: variables treatment of ^tumors; on the ring of synthetic material. However, such devices are unsuitable for series production due to their construction. These rings are also not practical for use.

It is an object of the present invention to provide vaginal rings containing an active drug which release the active ingredients for several weeks, for at least three weeks, regularly and consistently in an amount necessary to achieve the desired biological effect, and eliminate the aforementioned drawbacks of known vaginal rings.

The principle of the vaginal ring according to the invention consists in that one or two rings containing the active treatment or annular sections of synthetic material are arranged on the synthetic support ring. based on silicone elastomer vulcanized by low temperature vulcanization.

The rings containing the active drug preferably have a circular cross-section. However, the cross-section may also have the shape of a circular segment. The dimensions of the support ring and the rings containing the active substance are chosen so that the contact points of the outer and inner edges of the support ring with the active substance-containing ring lie above the axis of the active substance-containing ring, segment in the case of a circular segment. Thus, a favorable fraction of the active ingredient-containing ring in the pocket of the support ring is obtained.

According to the invention, the support ring may have different shapes, which may also differ in their production method.

Giant. 1 shows a cross-section of a support ring of cross-sectional shape, height a with maximum wall thickness b;

Fig. 2 shows a cross-section of a kidney-shaped cross-sectional support ring which is hollow inside;

Fig. 3 shows a cross-section of a hollow profiled ring;

Fig. 4 shows a cross-section of a hollow profiled ring which is open therein;

Fig. 5 shows a section through the support. a ring which has been made in the form of a sandwich;

Fig. 6 shows a cross-section of a support ring with a circular cross-section which is hollow inside; Fig. 7 shows a cross-section of the support ring, which consists of connecting the synthetic mass in the core with another synthetic mass forming the sheathing;

Fig. 8 shows a cross-section of a hollow support ring that is open inwards;

Fig. 9 shows a cross-section of an ellipsoidal cross-sectional support ring;

Fig. 10 shows a cross-section of a hollow support ring with an elpsoid cross-section.

The support ring may consist of any one. a physiologically acceptable synthetic material, provided that it is sufficiently strong and flexible. Synthetic are suitable. masses such as elastopolymers of organopolysiloxanes, such as dimethylated low-temperature vulcanized dimethylpolysiloxane-based elastomer in heat-labile dimethylpolysiloxane elastomers, polyamides, natural and synthetic rubbers, polyesters, polytetrafluoroethylene, or by molding, for shaped bodies.

Another advantageous embodiment consists in vulcanizing on a support ring of low-temperature-cured silicone elastomer a low-temperature-cured silicone-elastomer ring containing active drugs.

The vaginal ring according to the invention consists of the following parts:

The support ring itself has one or two vulcanized layers containing the active drug at the inner and / or outer edge of the support ring.

The drug-containing layers have a circular cross section. The dimensions of the support ring and of the vulcanized rings containing the active substance are chosen such that the cured layers on the outer and inner edges of the support ring do not touch. The active ingredient-containing layers may surround or close the entire support ring, or may also be spun into sections.

The vaginal ring according to the invention have an average size of 0.5 to 20 cm, whereby ^it! size depends on the case of use. In smaller mammals, such as dogs, the ring size is smaller than in larger mammals, such as horses and cows. For female vaginal rings, the outer diameter is about 5 to 10 cm, and for example, for Rhesus monkeys is about 2 to 3 centimeters. The diameter of the cross-section of the ring is 5 to 15 mm, preferably 7 to 10 mm.

The support ring and the rings containing the active substances and / or the vulcanized air layers are produced on the basis of the known cold elastomer vulcanized elastomers. Low temperature vuloamsmg type vulcanized molding compositions based on two-component organopolysiloxanes and components thereof are known, for example, from DAS 1171 641 and 1 900 969, DOS 1 940 124, U.S. Patents 2,823,218, 3,159,601 , 3,159,662 and 3,220,972.

For example, reduced temperature vulcanized silicone rubber compositions comprising 89-91% linear dimethylpolysiloxane containing up to 0.5 mole% of methylvinylsiloxane units and dimethylpolysiloxane molecular weight 500-1000 containing 9-11% SiH are suitable -bonds containing up to 3 SiH bonds and catalyzed by platinum or platinum compounds such as hexachloroplatinic acid (silicone elastomer A, vulcanized at reduced temperature), silicone rubber bicomponent compounds, reduced in temperature, vulcanized at 85-89% dimethylpolysiloxane units with a maximum of 0.5 mole% methylvinylsiloxane units, 5 to 6% dimethylpolysiloxane and SiH bonds, 5 to 10% crosslinking and effect-enhancing dimethylpolysiloxane resins with a maximum of 1.2 mole% methylvinylsiloxane units and are catalysed These include, for example, platinum compounds (silicone elastomer B, vulcanized at reduced temperature), and two-component moldings based on silicone rubber vulcanized at reduced temperature, containing a dimethylpolysToxane copolymer (silicone elastomer C, vulcanized at reduced temperature).

Silicone elastomer C, vulcanized at reduced temperature, used preferably for active medicaments with an unsaturated chemical structure, consists of

I. 20 to 100 parts by weight of organopolysiloxane with a viscosity of 500 to 200,000 cSt (at 25 °) and of the formula:

R i ch _? chsío * I

R

SiO i R

R

Si-CH 2 CH.

i ^x

R prčemž

R represents an alkyl radical (preferably a methyl radical) and / or an aryl radical and is not an integer from 200 to 1600.

II. 0 to 50 parts by weight of a copolymer of organopolysiloxanes consisting of:

a) (R ') 3 SiO ₀ 5 5 units

(b) (R ‘) 2 / vi / SiOo / s - units; and

(c) SiO2 - units, where:

R 'represents monovalent, organic radicals containing no unsaturated groups and at least 50% R' is methyl radicals, the ratio a + b / c being 0.4 to 1.5 (preferably 0.6 to 1.0) and the ratio b / c is 0.02 to 0.5 (preferably 0.05 to 0.15).

III. 5 to 15 parts by weight of an organohydrogen polysiloxane of the formula

R _'a H _b SiO ₄ _ _a _ _b wherein

R 1 represents a monovalent radical having no unsaturated groups and the ratio a: b has a value of 0.5 to 10 (preferably 1.0 to

5) and the sum of the albums is from 1 to 2.5, with at least three carbon atoms present on each molecule bound to different silicon atoms, which molecule contains 50 to 500 mol% unsaturated groups per S ^.; H bonds contained in components I and II and

IV. a catalytic amount of platinum or a platinum compound.

The alkyl and / or aryl radicals contained in component I contain up to 10 carbon atoms.

Examples include methyl, ethyl, propyl, isopropyl, butyl, octyl, xamyl, cyclopentyl, cyclohexyl, phenyl, naphthyl, tolyl, xylyl, benzyl, chlorophenyl, cyanomethyl and 3,3,3-tri- * fluoropropyl residue.

The R @ 1 and R @ 3 moieties contained in components I and II are the same or different and are alkyl radicals having up to 8 carbon atoms, preferably up to 3 carbon atoms. Examples which may be mentioned are methyl, ethyl and n-propyl.

Components I, II and IV form a component of a two-component molding composition based on organopolysiloxane vulcanized at reduced temperature, component III of the cross-linking component,

Component I or a mixture of components I, II and IV or I, II, III and IV may contain metal ions, for example copper (II) ions in an amount of 2.61 to 75 parts by weight of metal ions per part by weight of platinum to retard curing at room temperature.

Although the vulcanization of organopolysiloxane-based molding compositions can be carried out in the presence of a noble metal catalyst even at room temperature, vulcanization at a slightly elevated temperature is particularly preferred. The cure time of the catalysed mixture is 1 to 6 hours at 60 to 120 ° C. For vulcanization, the mixture may be heated briefly above, for example up to 150 ° C for 1 to 10 minutes, but no more than 15 minutes.

The platinum components, components IV, of the molding composition, can be used in forms known per se which catalyze the reaction between hydrogen silicon-binding residues and silicon-binding vinyl residues. These may be metallic platinum per se or platinum on carriers such as silica gel or pulverized coal, or hexachloroplatinic acid and platinum salts such as platinum carbonyldichloride PtCOCh and platindicarbonyldichloride Pt (CO) 2C12.

All of these platinum compounds are useful as catalysts. Pure hexachloroplatinic acid, however, has the drawback that it is relatively poorly soluble in organosilicon compounds containing silane groups. The platinum compounds, which are used as a catalyst in solid form, make crosslinking very slow and difficult to control, just as the reaction itself can be stopped more easily than expected using comparable catalysts in solution. Hexachlorobutyric acid is therefore preferably used as a catalyst dissolved in isopropanol, PtCoCl2 and Pt (CO) 2 Cl2 are used as catalysts dissolved in di. % of organopolysiloxanes containing vinyl groups, 10 to 15 mol% of vinyl groups. At least 0.1 parts by weight of platinum per million parts by weight must be used for components I and II. Since contaminants in the molding compositions may poison such a small amount of catalyst, preferably 10 to 40 ppm platinum is used. Larger amounts of platinum do not affect the reaction.

A particularly preferred embodiment of a vaginal ring according to the invention consists in the fact that * as for the support ring, and the ring of synthetic material, comprising an effective treatment of ^tumors: VA, using the same silicone elastomer cured at reduced temperatures.

A particularly preferred embodiment of the support ring used for. the vaginal ring according to the invention is characterized in that the support ring is of closed-cell foamed silicone rubber. For this purpose, a finely divided composition such as hydrocarbons such as pentane or heptane and halogenated hydrocarbons such as methylene chloride, monofluorochloromethane, trichlorofluoromethane and trichlorotrifluoroethane are added to the mixture to be vulcanized and evaporated during vulcanization.

The vulcanizates obtained from two-component molding compositions based on organopolysiloxanes * are inactive against non-ionic lipophilic active drugs, non-toxic to the living organism, harmless and do not absorb by it.

The active substances contained in the rings containing the active substances are preferably active substances having a hormonal action, such as estrogens and gestagens. For example, you can

3-methoxy-17t-ethynyl-1,3,5 (101estratrien17-ol [Mestranolj,

3-Hydroxy-1,3,5 (10) -estratriene-

-17-on (Ostrou)

17. Eetradiol, estriol and ethylnyradradiol;

4-pregnene-3,20-dione (Progesterone), d-13-ethyl-17α-ethyl-17S-hydroxy-4-gonen-3-one (d-Norgestrel) and its esters,

17-allyl-Kunidide: esterone (Norethisterone) and its esters,

6-chloro-17-hydroxy-1α; 2a-methylenepregna-4,6-dier-3,20-dlonone (Cyproterone) and its esters,

19-norhydroxyprogesterone and its esters,

6-chloro-17-acetoxypregn.a-46 diene-

-3,20-dione (Chlororm-adinone acetate)

15,16a-methylene-17 ₁ d-hydroxy-18-methyl-17α-ethynyl-4-estren-3-one and

15,16H-methylene-17β-hydroxy-18-methyl-17α-ethynyl-4-estren-3-one,

17α-acetoxy-6α-methylprogesterone (Medtroxyprogesterone acetate) a

9,11,10-pregna-4,6-dlen-3,20-dione (Dydrogesterone).

Suitable active drugs are all active drugs if they are non-ionic and lipophilic. Thus, neuroleptics such as butyrophenone derivatives such as Haloperidol or bacteriostats or fungistatics such as Nystatin or Metronidazole are also suitable for incorporation into the silicone elastomer.

The amount of active ingredient incorporated into the silicone elastomer vulcanized at reduced temperature is 10 to 60% and depends in detail on the particular active ingredient or combination of active ingredients. For example, the following total dosage (in mg) may be given:

Cyproterone acetate 200 to 1000 D-NorgesLrel 100 ALIGN! to 500 et‘nylestradOl 20 May to 100 ALIGN! estradiol 20 May to 90 Mestranol 50 to 100 ALIGN! ethinylnortestosterone acetate 150 to 950 estron 10 to 80 estriol 15 Dec to 70 Progesterone 250 to 900 Norethisteron 100 ALIGN! to 600 Cyprcsteron 100 ALIGN! to 900 Norhydroxyprogesterone 250 to 950 Chlormadinone acetate 170 to 850 15,16ia-methylene-17-: hydroxy-18- methyl-17-t-ethynyl-4-estren-3-one : 50 to 750 15,16-Methylene-17α-hydroxy-18- methyl-17α-ethynyl-4-estren-3-one 50 to 750 Dydrogesterone 100 ALIGN! to 550 Metronidazole 300 to 950

Thus, it is readily possible for the outer ring to contain only the gestagen, while the inner ring contains estrogen, and vice versa. Gestagens or estrogens may be administered in combination with, for example, bactericides.

The total amount of active ingredient in the silicone elastomer vulcanized at reduced temperature is estimated to release a constant amount over the day for a desired period of time. These are individually for example:

Cyproterone acetate 300 to 100 ALIGN! ^ g / d D-Norgestrel 30 to 250 Aíg / d, ethinylestradiol 30 to 60 ^ g / d estradiol 20 May to 150 (Ug / d, Mestranolu 20 May to 100 ALIGN! Aíg / d, etinylnortestosteronaa cetate 300 to ; 100 ALIGN! jug / d.

One embodiment of the vaginal ring according to the invention is that it is used for contraception.

At the time of use of the vaginal ring according to the invention, by preventing ovulation, a contraceptive effect is achieved if, for example, it releases 130 to 250 μ% of d-Norgestrel a. 30 to 50 μ $ ethinylestradiol or 800 to 1000 μ & . Vaginal rings which contain an anti-protozoan agent such as Metronidazole and optionally estrogens in the inner or outer rings containing the active ingredients are particularly suitable for the treatment of trichomoniasis. The active drug is formulated in a reduced-temperature vulcanized silicone rubber substrate for the manufacture of a ring containing the active drug. For this purpose, the active ingredient is ground, optionally finely ground or micronized, mixed with a two-component silicone rubber compound vulcanized at a reduced temperature to an air-free suspension, formed into rings and vulcanized by heating, preferably at 40 to 120 Deň: 32 ° C.

The rings containing the active drug have a diameter of 0.5 to 8.0 mm, preferably 1.5 to 5.0 mm for the outer ring, and 0.3 to 0.3 mm for the inner ring. 2.0 mm, preferably 0.4 to 1.6 mm.

The rings containing the active substance are wholly or partially built on the matrix principle. However, the active ingredient-containing rings may also consist of an active ingredient-containing core and an outer shell of any active substance-poor wall thickness, and vice versa, an active drug-containing elastomer coating layer and an active drug-poor core.

Such a drug-poor coating, arranged above the drug-enriched core with the predominantly suspended drug, is obtained, for example, by briefly extracting the drug-containing suspension vulcanizer with a suitable solvent, such as a 1: 1 v / v ethanol / water mixture.

The rings containing the active drugs are inserted into the pocket-shaped recesses of the support ring, optionally with a catalysed two-component compound based on silicone rubber vulcanized at reduced temperature, and the subsequent vulcanization is half-glued into the recesses of the support ring or formed into vulcanized support rings and vulcanized together support ring. The support ring, the outer and / or inner ring containing the active drug, forms a bonded, optionally glued, vaginal ring.

In order to produce a coating containing the active medicaments on the support ring, the active substance is also worked into a substrate of silicone rubber vulcanized at reduced temperature. For this purpose, the active substance is finely ground or optionally micronized. It is sieved with a two-component compound based on silicone rubber vulcanized at reduced temperature to the suspension, using multicolored injection, applied in the form of a layer to the vulcanized support ring and vulcanized by heating. at 40 to 120 ° C.

It may be expedient if the suspension of the synthetic material and the active ingredient is supplemented with an adjuvant such as a surfactant, a foaming agent, a solvent or a resorption inhibitor to impart the desired physical properties to the molded bodies. However, inert excipients such as high d ^; silica, which provides the rings ^{5 with the} desired mechanical properties.

The coatings containing the active medicaments have a layer thickness of 0.1 to 5.0 mm, preferably 0.5 to 3.0 mm, when cured at the outer edge of the support ring, and when cured at the inner edge of the support ring , a layer thickness of 0.1 to 3.0 mm, preferably 0.5 to 2.0 mm.

The coatings containing the active substances are built entirely or partially on the matrix principle.

Since no byproducts are formed when vulcanizing a two-component silicone rubber compound vulcanized at reduced temperature, additional heat treatment of the cured product is unnecessary.

The vaginal ring according to the invention have the advantage that one ^Prior: NNA drug released periodically and constant over a prolonged period of time within the limits of the dosage required for the desired biological effect, such as preventing ovulation. In addition, they have the advantage that the amount of active ingredient which must be incorporated into such a contraceptive can be much smaller than that of known vaginal rings.

Vaginal rings according to the invention based on the forces of the reduced temperature vulcanized elastomer do not break under mechanical stress. When introduced into the body, they cannot be damaged as easily as vaginal springs based on room temperature vulcanized elastomers containing more or less defined mixtures of active fillers with known adverse drug properties ^; added to improve the mechanical properties.

Many useful medicaments can be used successfully with the vaginal ring of the invention which have not been used in known vaginal rings until now with the carrier materials known and used so far.

The vaginal rings manufactured according to the invention can be sterilized in saturated, compressed water vapor at 120 ° C without undesirable changes.

The following examples are intended to explain the invention.

Example 1

The support ring for receiving two active drug-containing rings is made in the form of a tubular ring (cf. FIG. 6) from a copolymer of polyethylene and vinyl acetate (LUPOLEN (g) V 3520 KJ (BASF) by blow molding hollow bodies having the following dimensions: 60 mm outer diameter, 44 mm internal diameter and 3 mm in diameter of the cavity in cross-section of the ring. in this case, the support ring is provided with two circumferential pocket-like depressions which are intended for housing one of the external and ^internal, the ring containing the active drugs. outer ring containing the active The inner ring containing the active drugs has a diameter of 1.0 mm, and after insertion of the rings containing the active substances in the insertion plane, the diameter of the cross-section of the ring is 8.5 mm.

The outer ring containing the drug, 2.0 mm in diameter, was formed from a suspension of 5 parts by weight of d-Norgestrel, 15% by weight. parts by weight of hydrophobic, highly dense silica (AEROSIL R 972 / DEGUSSA); and 8 parts by weight of finely powdered magnesium oxide in 72 parts by weight of a two-component organopolysiloxane molding composition vulcanized at reduced temperature, 1 and V2 min. heating at 120 ° C to vulcanize and vulcanizing at 80 ° C for 3 hours. The two-component molding composition A based on reduced temperature vulcanized organopolysiloxane consists of 75 parts by weight of polyd ^: methylsiloxane having a vinyl group at both ends of the chain, a viscosity of 50,000 cSt at 25 ° C, 25 parts by weight of copolymer composition: 40 mol% SiO ₂ -units, 45 mol% (CH ₃ ) -SiO _{0) 5} -units, 15 mol% Vi (CH ₃ ) ₂ SiO ₂ , 5-units, of 8 parts by weight of the S'H component, consisting of 16.6 mol% (CH3) ₃ SiO _0/5 units, 33.4 mol% _{(CH3) 2} SiO units, 50 mole percent _CH3 HSiO units and 52 ppm of platinum in the form of a 1% solution of Pt (CO) ₂ Cl ₂ , based on the proportion of dimethyl dodoxane having a nyl group at both ends of the chain.

The inner ring containing the active drugs is made from a homogeneous suspension of 3 parts by weight of ethynyl estradiol and 26 parts by weight of hydrophobised, highly disperse silica (AEROSIL ('AR 972 / DEGUSSA)) in 71 parts by weight of a two-component molding composition V based on organopolysiloxane. L ¹ / 2minutovým navulkanizováváním at about 120 ° C and a two hour cure at 105 ° C. the molding two-component composition based on organopolysiloxane ^В: siloxanes vulcanized at a reduced temperature consists of 82.5 parts by weight of polydimethylsiloxane terminated at both chain ends with vinyl group with a viscosity of 1000 cSt at 25 ° C, 15 parts by weight of a copolymer of composition 40 mole% _r SiO units, 45 mol% (CH3) .3SIOq ₅ -jednotek 15 mol-% Vi (CH3) ₂ SiO ₍₎ 5 units, 7.0 parts by weight of a SiH component consisting of 38 moles % SiO ₂ -units, 29 mole% (CH 3) - SiO ₂ -s, 33 mole% (C 3 H 5 O 2 O, · -, - units and 40 ppm platinum as a 2% solution of hexachloroplatinic acid in isopropanol (based on % of polydimethylsiloxane with a nail terminated at both ends).

The active drug-containing rings are inserted into the support ring and are part of the vaginal ring.

Example 2

Dimensional polysiloxane-based molding material (SILASTIC of 4600 / ODW CORNING) is formed into a tubing material with a diameter of 9 mm at 5 mm of a clear width of 1.5 mm in the form of a tubular material of 9 mm diameter at 5 mm of light width by molding, five minutes vulcanizing at 150 ° C. excavation. Sections of this tubular material are formed using catalysed SILASTIC® 4600 into hollow rubber rings (cf. FIG. 6) as support rings and vulcanized for 30 minutes at 130 ° C. The support rings have an outer diameter of 60 mm and an inner diameter of 42 mm, and a recess extending at the outer edge for receiving the drug-containing ring with a diameter of 2 mm. This outer ring, containing D-Norgestrel, is made from the molding composition shown in Example 1 in the same manner as in Example 1 and inserted into the support ring.

Example 3

The D-Norgestrel-containing vaginal ring is produced in a three-step process as a sandwich-shaped support ring vulcanizate with a component of D-Norgestrel-containing rings (cf. FIG. 5). The support ring of this vaginal ring is formed as an outer layer by injection molding with a circumferential notch, made of polyisobutylene with an average molecular weight of about 2,700,000 (OPANOL. B 150 / BASF) - as a two-component B-core silicone rubber core vulcanized temperature and a two-component molding composition based on reduced-temperature cured silicone rubber (as described in Example 1) in admixture with 20 parts by weight of hydrophobic, highly dispersed silica (AEROSIL)

R 972 (DEGUSSA).

The dimensions of the support ring are:. The 62 mm outer diameter, 44 mm inner diameter, the peripheral notch for receiving the outer ring containing D-Norgestrel is 1 mm deep, 3 mm wide.

The rel ring-containing component is formed from the molding composition described in Example 1, p. by forging into the peripheral notch of the support ring and then vulcanizing for 1½ minutes at 115 degrees Celsius as well as subsequent vulcanization for 2 hours at 110 ° C, they are joined to the outer layer of the support ring. This ring component has a circular sectional shape and a radius of curvature of 120 mm at the outer edge.

Example 1 a d 4 *

The vaginal ring, containing D-Norgestrel and ethinylestradiol, sc is produced as a sandwich vulcanizate of kidney cross-section (cf. FIG. 1) by injection-molded multicolored casting. The ring has an outer diameter of 60 mm. The distance a and b is respectively 7.6 and 2.8 millimeters, respectively. To this end, the components containing the D4-C0-R3 and ethinylestradiol are sprayed onto the supporting ring components, one after the other at the outer edge, vulcanized for two minutes at 115 DEG C., and removed from the mold ^; The mold was vulcanized by heating at 89 ° C for two hours.

The support ring component is prepared from a mixture of 23 parts by weight of highly dispersed silica (AEROSIL (§) R 972 / DEGUSSA) and 77 parts by weight of a reduced temperature vulcanized silicone rubber compound described in Example 1.

The ring component containing D-Norgestrel, 2 mm in diameter, rises 0.6 mm from the outer edge of the support ring, forming a circular segment. It is a mixture of 24 parts by weight of highly dispersed silica, 8 parts by weight of micronized silica. D-Norgestrel and 68 parts by weight of a catalytic substrate based on a reduced temperature vulcanized silicone elastomer (SILOPREN '(g) 3008 / BAYER).

The ring component containing 1 mm diameter ethynyl estradiol is lifted 0.4 mm from the outer edge of the support ring, forming a circular segment. Contains in 100 parts by weight 10 parts by weight of micronized ethynyl estradiol and 21 parts by weight of highly dispersed silica in addition to 69 parts by weight of a molding composition based on a reduced temperature vulcanized organopolysiloxane, consisting of 75 parts by weight

16 parts by weight of a polydimethylsiloxane having a vinyl group at both ends of the chain, having a viscosity of 1000 cSt at 25 ° C, 25 parts by weight of a copolymer having the composition: 40 mol% SiO 2 units, 45 mol% (CH ₃ ) ₂ SiO ₁₎ 15 mole percent of VifCl 2 SiO 2 units, 8 parts by weight of a S11 component, consisting of 16.6 mole% (CH 3) ₃ SiO 2, 5-] units, 33.4 mole percent (CH ₃ ) ₂ SiO ₂ units, 0 mole% CH ₃ HSiO units and 10 ppm platinum, based on the total mixture in the form of a 2% solution of hexachloroplatinic acid in isopropanol 1.

Example 5

A vaginal ring containing ethynyl estradiol in addition to ethinylnortestosterone acetate is made as a mechanical support ring made of ethylene / vinyl acetate copolymer (ALATHON (§) 3180) DU

PONT) in the form of a hollow profiled ring with notches extending at the outer edge, with two belt rings based on low temperature vulcanized silicone elastomers containing active drugs and suitable for insertion in the notches (cf. FIG. 3). .

The support ring is formed from hollow profiled sections by welding ends with an outer diameter of 64 mm and an inner diameter of 44 mm, with a bridge and wall thickness of 1.5 mm, one notch each extending 1 mm deep and 3 mm wide and 1 mm at the outer edge. deep and 1 mm wide. The ring component containing ethinylnortestosterone acetate is formed 1 mm thick and 3 mm wide with a clear width of 62 mm from a mixture of 10 parts by weight of micronized ethinylnortestosterone acetate and 22 parts by weight of highly dispersed silica in 68 parts by weight of a molding two-component. 75 parts by weight of polydimethylsiloxane with a chain terminated at both ends with a vinyl group, viscosity 1000 cSt at 25 ° C, 25 parts by weight of a copolymer composition: 40 mol% SiO ₂ - units, 45 mol% (CH ₃ ) ₂ SiO _{0 (} 5- units, 15 mole percent of Vi (CH ₃ ) ₂ SiO ₂ 5'units, 8 parts by weight of SiH component, consisting of 16.6 mole% (CH ₃ ) ₂ SiO ₂ ^units, 33.4 mole% (СНз)? SiO units, 50.0 mol% CH ₃ HSiO units and 30 ppm platinum (based on the total mixture in the form of 1% of Pt (CO) 2 CH in an open-chain dimethylpolysiloxane containing vinyl groups containing 12 mol% dissolved vinyl groups) and 5 parts by weight of divalent copper ions, based on parts by weight of platinum, and then vulcanized at 105 ° C.

The ring component containing ethynyl estradiol is shaped 1 mm thick and 1 mm wide, with a clear width of 58 mm, from the mass described in Example 4 and vulcanized by heating to ° C.

Example 6

The vaginal ring containing 15.16α-methylene-17β-hydroxy-8-methyl-17α-ethynyl-4-esteren-3-one in addition to estriol has the following composition:

A solid rubber rubber ring based on natural rubber with an outer diameter of 36 mm and 6.6 mm in cross-sectional diameter was used as the liner and the injection molding was provided with a sheath of a layer of silicone rubber vulcanized at a reduced temperature of thickness

1.2 mm (cf. FIG. 7). The silicone rubber layer has two 0.5 mm deep cuts at the outer edge of the ring, 1.6 and 3.0 mm wide, respectively. This ring is a support ring for two rings containing active medicaments with a cross-sectional shape of a circular segment which are mechanically connected thereto. The sheathing of the soft rubber ring is carried out with a two-component molding composition A based on the reduced temperature vulcanized organopolysiloxane described in Example 1 and vulcanized at 130 ° C.

A vaginal ring component containing 10 parts by weight of micronized 15.16α-methylene-17β-hydroxy-18-methyl-17α-ethynyl-4-estren-3-one is produced with a chord length of 3.0 mm based on a 20 wt. parts of highly dispersed silica (AEROSIL (§) 200); and 70 parts by weight of the reduced temperature vulcanized silicone rubber two-component mass V described in Example 1.

A vaginal ring component having a cross-section of a circular section and a chord length of 1.6 mm containing estriol is made from a mixture of 12 parts by weight of micronized estriol, 19 parts by weight of highly dispersed silica and 69 parts by weight of the two-component vulcanized silicone rubber. at reduced temperature, formed and cured at 90 ° C for three hours.

Example 7

The vaginal ring, containing D-Norgestrel and ethinylestradiol, is a vulcanizate bonded from the support ring and from components enclosing the support ring in part and containing separately two active drugs (cf. FIG. 7). The core of the support ring is made of rubbery polyurethane as a solid ring with a notch extending at the outer edge, 1.5 mm deep and 3 mm wide and with an outer diameter of 60 mm and a ring diameter of 8 mm. This support ring core is re-soaked in a 20% solution of the catalysed silicone rubber vulcanized at reduced temperature (cf. Example 1) in inethylene chloride and cured for 2 minutes at 125 ° C and cured at 130 ° C for one day. ° C 1.5 mm thick coating.

The notch of this support ring, which has the function of an insert during injection molding, is filled by the two-color injection molding method with the material containing D-Norgestrel described in Example 4 and cured for 1 110 minutes at 110 ° C. Centrally, a D-Norgestrel-containing vaginal ring of Example 1 containing ethinylestradiol, a 1 mm diameter round cord, is sprayed centrally onto the outer edge of the vaginal ring and is vulcanized at 110 ° C for 2 minutes. The prefabricated vaginal ring is vulcanized by heating to 110 ° C for one hour.

Example 8

The D-Norgestrel-containing vaginal ring is made using the support ring described in Example 7 by vulcanizing the D-Norgestrel-containing molding composition described in Example 1 into a notch of the support ring (cf. FIG. 7).

Example 9

The vaginal ring containing D-Norgestrel and ethinylestradiol is made as a mechanical joint of the ellipsoidal cross-sectional support ring (cf. Fig. 9): a = 2 mm, b = 3.5 mm, and two recesses of 0.8 and 1 respectively; 4 mm, running at a distance of 1.5 mm at the outer edge, at a notch width of 1.0 and 2.0 mm, respectively, with an annular cross-sectional ring aligned with these notches and containing the active drug.

The support ring is injection molded from ethylene-vinyl acetate copolymer (ALATHON ® 3185 / DU PONT). The P ^r st ^en ce LNC containing D ^ ^ l ^ r ^ i ^ θ tгel is formed from a material specified in Example 1 and cured at 90 nrnut 110 ° C.

The ring component containing ethinylestradiol is formed from the mass of Example 1 and vulcanized by heating to 105 ° C.

Example 10

A vaginal ring containing 4-pregnen-3.20-dione (Progesterone) is produced as a bonded vulcanizate of the support ring with a notch extending at the outer edge into which the component of the ring containing the progesterone is vulcanized. The ring has an outer diameter of 60 mm, an inner diameter of 42 mm and a clear cross-sectional width of 5 mm, and the notch extending at the outer edge of the ring is 1.5 mm deep and 3 mm wide.

The support ring is formed from a mixture of 20 parts by weight of a highly dispersed silica and 80 parts by weight of a two-component compound B based on the reduced temperature vulcanized silicone rubber composition of Example 1 and cured at 120 ° C. This support ring is used in the second stage of the process as an insertion part, whose molding mass containing Progesterone is sprayed on the circumference of the running notch. This molding composition consists of 15 parts by weight of micronized Progesterone and 20 parts by weight of highly dispersed horseradish oxide in a two-component compound A based on sonicated rubber vulcanized at reduced temperature (composition, see Example 1). After spraying into the hollow ring slots, it is vulcanized by heating to 90 ° C. The drug-containing ring is then cured by heating to 80 degrees Celsius for two hours.

The ring component containing the Progesterone vaginal ring existing as a> compound vulcanizate with a four-step dipping process into an active drug carrier with a drug-poor coating will convert into a drug-rich core. For this purpose, the vaginal ring is left in succession for 10 minutes and 5 minutes in 90%, 5 minutes in 70% and 5 minutes in 50% ethyl alcohol.

Example 11

The vaginal ring, containing 17α-acetoxy-6α-methylprogesterone (Medroxyprogesterone acetate), is made as a mechanical connection of the support ring with a notch extending at the outer edge to accommodate the ring component containing Medroxyprogesterone acetate (cf. Figure 10). a hollow ring with an ellipsoidal cross section has an outer diameter 60 mm, inner diameter 42 mm, wall thickness of 3 mm and is formed from a copolymer ^poly mer et ^y l ^s Nu vin ^yl acetate ^and a Tu (a ^L AT ^HON (§) 3185 / DU PONT) by a method of blowing hollow bodies, with a notch extending at the outer edge that is 1.5 mm deep and 2.5 millimeters wide.

The component containing Medroxyprogesterone acetate is sprayed from a mixture of 20 parts by weight of micronized Medroxyprogesterone acetate, 11 parts by weight of a two-component compound B based on reduced temperature cured silicone rubber (composition cf. Example 1) and cured at 100 ° C.

Example 12

A vaginal ring comprising a 15,163-methylene-17 (S ^{y y} ddox -18-methyl-17a-ethynyl-4-estren-3-one was prepared as a mechanical connection support ring open at the inner edge which is shaped as a hollow profiled ring (cf. Fig. 4) of polyethylene-vinyl acetate copolymer (LUPOLEN V 3520 K / BASF) with a notch4

19 Dec 20 May 2 mm wide and 1 mm deep for receiving a band of a ring containing the active drug. The support ring is made of hollow profiled sections by welding ends with an outer diameter of 62 mm and an inner diameter of 40 mm and has a bridge and wall thickness of 1.5 millimeters. Annular roll containing active drugs is formed from a mixture of 8 parts by weight of 15, 16 ₁ 6 ^{L of} methylene-17 _and 6'-hydroxy-18-methyl-17α-ethynyl-4-estrenone, 19 parts by weight of highly dispersed silica and 73 parts by weight of silicone-based mass В; The rubber vulcanized at a reduced temperature, the composition of which is given in Example 1, and vulcanized by heating to 90 ° C for three hours.

OBJECT OF THE INVENTION

Vaginal ring, characterized in that one or two rings containing the active drug or annular sections of synthetic material based on a low-temperature vulcanization silicone elastomer are arranged on the support ring of synthetic material. 2. The vaginal ring according to item 1, characterized in that, in the case of a circular cross-section, the contact points of the outer and inner edges of the support ring with the active substance-containing ring lie above the axis of the active substance-containing ring or the center line of the circle forming the segment.

Claims (2)

OBJECT OF THE INVENTION Vaginal ring, characterized in that one or two rings containing the active drug or annular sections of synthetic material based on a low-temperature vulcanization silicone elastomer are arranged on the support ring of synthetic material. 2. The vaginal ring according to item 1, characterized in that, in the case of a circular cross-section, the contact points of the outer and inner edges of the support ring with the active substance-containing ring lie above the axis of the active substance-containing ring or the center line of the circle forming the segment. 3 sheets of drawings Severography, n, p., Plant 7, Most