CN1899643B - Pessary or intrauterine medicine release device containing antiestrogenic and anti-pregnant hormone composite preparation and its use - Google Patents

Abstract

The present invention is a kind of pessary or intrauterine medicine releasing device containing one medicine part, and features the medicine part containing anti-estrogen in 40-70 weight portions and anti-progestogen in 30-60 weight portions. The present invention also provides the application of the pessary or the intrauterine medicine releasing device in preparing medicine for treating hysteromyma or endometriosis.

Description

Vaginal ring or intrauterine drug delivery device containing combined anti-estrogens and anti-progestogens and its pharmaceutical use

(1) Technical field

The present invention relates to vaginal rings or intrauterine drug release devices containing anti-estrogens and anti-progestogens compound preparations and their use in pharmacy.

(2) Background technology

At present, there have been many effective exploratory attempts to treat uterine fibroids and endometriosis with drugs, and systemic drugs such as oral or injection are often used. The side effects of the drug make it difficult for the patient to adhere to the drug for a long time, unable to complete the treatment cycle of the drug effect reward, and finally fail, failing to achieve the purpose of treating uterine fibroids.

In the Chinese patent application with the application number 01112712.0 filed by the applicant on April 21, 2001, it initially relates to 1. A vaginal ring for one or at least one drug in Nafoxidine, which provides a continuous, constant, high-quantity zero-order drug release system.

The currently listed LNG-IUD (levonorgestrel intrauterine device) is an intrauterine drug-releasing device produced by Finland's Liras Pharmaceuticals. release layer composition. The applicant proposed a preparation method of the intrauterine drug release device in the patent application 03116814.0 submitted by the applicant.

The technical field urgently needs a compound drug delivery system with strong synergistic effect and clear curative effect. Based on the above-mentioned vaginal ring technology and intrauterine drug delivery device technology, the applicant has developed a drug delivery device containing drugs with synergistic effect.

(3) Contents of the invention

It is an object of the present invention to provide a vaginal ring or intrauterine drug delivery device comprising a synergistic anti-estrogen and anti-progestogen combination formulation.

Another object of the present invention is to provide the application of the above-mentioned vaginal ring or intrauterine drug delivery device in pharmacy.

The first aspect of the present invention provides a vaginal ring, which includes a drug-containing part and a silicone rubber layer coated on the drug-containing part; the drug-containing part contains, based on the total weight of the drug-containing part, 5-70 Active drug by weight, 0.5-20% by weight of physiologically acceptable surfactant and balance of physiologically acceptable dispersant. The thickness of the silicone rubber layer coated on the drug-containing part is 0.01-0.5 mm; it is characterized in that, in the active drug, the anti-estrogen drug is 40- 70 parts by weight, and 30-60 parts by weight of the antiprogestin drug.

Wherein said antiestrogens are selected from raloxifene (Raloxifene), tamoxifene (Tamoxifene), nafoxidine (Nafoxidine) or aromatase inhibitor (Arometase Inhibitor), and described aromatase inhibitor is preferably selected from Anna Anastrozole, Exemestane and Letrzol; and the antiprogestin drug is selected from mifepristone or gestrinone.

A preferred active drug formulation is to mix 60% by weight of mifepristone with 40% by weight of letrozole.

The physiologically acceptable surfactant is preferably selected from Span 20-80, Benzene (Brij) 52-76, OP emulsifier, PEG 400-20000, Pluronic-124 (molecular weight 2090- 2360), Pluronic-188 (molecular weight 7680-9510), sodium lauryl sulfate, sodium tetradecyl sulfate, sodium lauryl sulfate and triethanolamine one or more surfactants mixture.

Described physiologically acceptable dispersant is selected from glycerol, propylene glycol, PEG 400-20000, succinic acid, cholic acid, deoxycholic acid, cetyl alcohol, stearyl alcohol, beta cyclodextrin (molecular weight 1134 ), γ-cyclodextrin (molecular weight 1084-2015) and a mixture of one or more dispersants in silicone rubber. When one of the surfactants is PEGs or Pluronics, the selected dispersant is a substance different from the surfactants.

The silicone rubber can be HTV (high temperature vulcanization or thermal vulcanization, molecular weight 30-1 million), RTV-2 (two-component room temperature vulcanization, molecular weight 0.74-110,000), RTV-1 (one-component room temperature vulcanization, molecular weight 0.74-110,000) or LTV (heat vulcanization, molecular weight 400-20000), American Dow Corning silicone-382 medical grade silicone rubber, American Dow Corning Q7 medical grade silicone rubber series and American Dow Corning implantable grade MDX series, or the corresponding series of medical Silicone Rubber.

The silicone rubber layer coated on the drug-containing part is selected from HTV (high temperature vulcanization or thermal vulcanization, molecular weight 300,000-1 million), RTV-2 (two-component room temperature vulcanization, molecular weight 0.74-110,000), RTV-1 (single Component room temperature vulcanization, molecular weight 0.74-110,000) or LTV (heating vulcanization, molecular weight 400-20000), American Dow Corning silicone-382 medical grade silicone rubber, American Dow Corning Q7 medical grade silicone rubber series and American Dow Corning implantable grade MDX series, Or the corresponding series of medical silicone rubber.

In one embodiment of the present invention, the drug-containing part, preferably the first drug-containing layer part containing an anti-estrogen or an anti-progestogen is located in the center of the vaginal ring, and the center is coated with a second drug-containing layer containing an anti-progestin or an anti-estrogen. The second drug-containing layer is surrounded by a silicone rubber coating.

In another embodiment of the present invention, the center of the vaginal ring includes a hollow portion surrounded by a liner, and the drug-containing portion is located between the liner and the silicone rubber coating. The inner liner can be made of the above-mentioned medical silicone rubber and other medical polymers.

In yet another embodiment of the present invention, the center of the vaginal ring comprises a post of medical grade silicone rubber, said medicated portion, preferably a first medicated layer portion containing an anti-estrogen or an anti-progestin and an anti-progestin containing Or the second drug-containing layer part of the anti-estrogen is coated on the medical rubber column, and then coated with a silicon rubber layer on the second drug-containing layer.

In all embodiments, the silicone rubber layer coated on the drug-containing part has a thickness of 0.02-1 mm.

The second part of the present invention provides an intrauterine drug release device, comprising an intrauterine drug release device (IUD) stent, a first drug-containing layer coated on the stent, and a second drug-containing layer on the first drug-containing layer layer, and a controlled-release layer coated on the second drug-containing layer, the first drug-containing layer and the second drug-containing layer are composed of active drugs independently selected from anti-estrogen drugs and anti-progestogen drugs and medical grade silicone or polymer in a 1-70:99-30 ratio, provided that when the first drug-containing layer contains an anti-estrogen, the second drug-containing layer contains an anti-progestin; or, When the first drug-containing layer contains anti-progestin, the second drug-containing layer then contains anti-estrogen, and it is characterized in that, in the described active drug, by 100 parts by weight of active drug, the anti-estrogenic drug is 40 -70 parts by weight, the antiprogestin drug is 30-60 parts by weight.

The third part of the present invention provides an intrauterine drug release device, including an intrauterine drug release device (IUD) stent, a drug-containing flap layer coated on the stent, and a controlled release layer coated on the drug-containing flap layer, The drug-containing valve layer is formed by mixing active drugs with medical-grade silicone or high molecular polymers in a ratio of 1-70:99-30, and it is characterized in that, in the active drugs, 100% by weight In terms of active drugs, the anti-estrogen drug is 40-70 parts by weight, and the anti-progestin drug is 30-60 parts by weight.

Wherein said antiestrogens are selected from raloxifene (Raloxifene), tamoxifene (Tamoxifene), nafoxidine (Nafoxidine) or aromatase inhibitor (Arometase Inhibitor), and described aromatase inhibitor is preferably selected from Anna Anastrozole, Exemestane and Letrzol; and the antiprogestin drug is selected from mifepristone or gestrinone.

The preferred proportioning scheme of the active drug is that 60% by weight of mifepristone is mixed with 40% by weight of letrozole.

The intrauterine drug delivery device (IUD) bracket is T-shaped, Y-shaped, umbrella-shaped or other non-toxic polyvinyl chloride-lined brackets or silicone rubber brackets with various skeletons similar to the longitudinal arm type.

The content of active drug in each intrauterine drug delivery device is 30mg-200mg, preferably 10-50mg.

The release-controlling membrane is made of silicone or medical polymer, and its thickness is 0.01-0.5mm, preferably 0.05-0.5mm.

Another aspect of the present invention provides the application of the vaginal ring or the intrauterine drug delivery device in the preparation of drugs for treating uterine fibroids or endometriosis.

Description of drawings

Figure 1 is a schematic diagram of the vaginal ring of the present invention.

Figure 2a is a cross-sectional view of a vaginal ring according to one embodiment of the present invention.

Figure 2b is a cross-sectional view of a vaginal ring in another embodiment of the present invention.

Figure 2c is a cross-sectional view of a vaginal ring in yet another embodiment of the present invention.

Figures 3-1, 3-2, and 3-3 are cross-sectional views of the drug-containing layer flap in the intrauterine drug delivery device according to the third aspect of the present invention.

Fig. 4 is a schematic diagram of the drug-containing layer flap in the intrauterine drug delivery device according to the third aspect of the present invention, wherein 1 is the drug-containing flap, and 2 is the mold metal rod.

Fig. 5 is a schematic diagram of the intrauterine drug delivery device of the present invention, wherein 1 is an IUD plastic stent, 2 is a drug-containing layer, and 3 is a controlled release layer.

The present invention will be described below in conjunction with the accompanying drawings.

Fig. 1 is a schematic diagram of the vaginal ring of the present invention. The diameter of the vaginal ring can be 1-10 cm. The vaginal ring is intercepted along the direction a-a, and the cross-sectional diagrams 2a and 2b illustrating the formation of the vaginal ring of the present invention are made.

In Fig. 2a, the shaded part 1 refers to the drug-containing part, and 2 refers to the silicone rubber coating, wherein the thickness of the silicone rubber coating is 0.02-1 mm.

In Fig. 2b, the shaded part 1 refers to the drug-containing part, 2 refers to the silicone rubber coating, and 3 refers to the inner tube. The lining tube is a tube made of medical silicone rubber or other medical polymers, which surrounds the hollow part 4 in the vaginal ring, the diameter of the hollow part 4 can be 2.5-6.5cm, and the thickness of the lining tube is 1-6mm , the total thickness of the first and second drug-containing layers is 0.5-3 mm, and the thickness of the silicone rubber coating is 0.02-1 mm.

In Fig. 2c, the shaded part 1 refers to the drug-containing part, 2 refers to the silicone rubber coating, and the dot part 5 refers to the medical silicone rubber column. The diameter of the medical silicone rubber column is 3-8 cm, and the thickness of the drug-containing layer is 0.5 cm. -3 mm, the silicone rubber coating thickness is 0.02-1 mm.

The preparation process of the vaginal ring of the present invention mainly adopts techniques such as injection vulcanization molding, molding vulcanization molding, extrusion vulcanization molding, and dipping known in the art, and specifically includes the following steps:

A. Prepare the drug-containing part according to the above-mentioned composition of the drug-containing part, put the prepared drug-containing part into a foamed medical silicone rubber tube, put it into a molding mold, and heat-press; or

B. (1) Extrude the medical silicone rubber into a solid column of the required size, that is, the medical rubber column;

(2) Prepare according to the composition of the drug-containing part described herein, knead the preparation and press it into a thin skin;

(3) Coating the thin skin obtained in step (2) on the medical silicone rubber column obtained in (1);

(4) coating a layer of 0.02-1mm medical silicone rubber on the product obtained in (3); or

C. (1) Select a liner tube made of medical silicone rubber or other medical polymer materials with a diameter of 1-6 mm to form a hollow part with a diameter of 2.5-6.5 cm;

(2) Prepare according to the composition of the drug-containing part described herein, knead the preparation and press it into a thin skin;

(3) coating the thin skin obtained in step (2) on the liner pipe with the hollow part obtained in (1);

(4) coating a layer of 0.02-1mm medical silicone rubber on the product obtained in (3); or

D. Add an appropriate amount of silicone rubber to an organic solvent, such as petroleum ether, mix well, then immerse the product obtained in B (3) or C (3) in the dipping solution, take it out after 5 seconds and dry it.

The intrauterine drug release device of the second aspect of the present invention is prepared by the following process:

1. The first drug-containing layer component containing anti-estrogen or anti-progestin and medical-grade silicone or high molecular polymer is directly coated on the T-shaped or r-shaped polyethylene IUD plastic stent with a mold, and then Then superimpose the second drug-containing layer component containing antiprogestin or anti-estrogen different from the active drug in the first drug-containing layer and medical-grade silicone, wherein in the active drug, the active drug is active in 100 parts by weight In terms of drugs, the anti-estrogen drug is 40-70 parts by weight, the anti-progestin drug is 30-60 parts by weight, and the active drug is mixed with medical-grade silicone or high molecular polymer in a ratio of 1-70:99-30 ;

2. Coating silicone rubber or medical polymer material on the second drug-containing layer to obtain a controlled-release layer with a thickness of 0.01-0.5 mm. Alternatively, the intrauterine drug release device of the third aspect of the present invention is prepared by the following steps:

1. Preparation of drug-containing layer valve:

The active drug is mixed with medical-grade silicone or high molecular weight polymer in a ratio of 1-70:99-30, wherein in the active drug, the anti-estrogen is 40 parts by weight based on 100 parts by weight of the active drug -70 parts by weight, 30-60 parts by weight of the antiprogesterone; the mixture is put into a mold for hot pressing and vulcanization to form a drug-containing layer;

2. Attachment of drug-containing flap

Apply a layer of viscous liquid on the inner layer of the drug-containing layer or the longitudinal arm of the stent or generate static electricity by friction, so that the drug-containing layer adheres to the stent to form a seamless cylinder;

3. Coating of controlled release membrane

Swell a cylindrical tube made of silicone or high molecular polymer and insert it into the outer layer of the above-mentioned drug-containing layer, or dissolve silicone or high molecular polymer in a volatile liquid, use a continuous tip, volatilize, and repeat The controlled-release layer is formed by film formation, or a combination of the above two methods is used.

As shown in Figure 3-1 to Figure 3-3, the shape of the mold used in the preparation of the drug-containing layer flap is semicircular or fan-shaped, but it must be ensured that it can be merged into a complete cylindrical shape in the end, preferably The drug-containing layer has 2-4 petals, which can also be pressed into a cylinder through a mold or extruded into a cylinder through an extruder, as shown in Figure 4, and then the cylinder is withdrawn from the mold and inserted into the bracket ; or use a knife to cut the cylindrical drug-containing layer from the vertical end to form several vertical semicircular petals or small semicircular petals, peel off from the mold, and then reattach to the bracket to form a cylindrical drug-containing layer.

Described controlled release layer can preferably be formed like this:

1. Silicone or medical high molecular polymer is made into a cylindrical tube with uniform wall thickness, uniform size, uniform weight and meeting requirements through extrusion or molding process. Then, place the tube in a medical-grade non-polar, volatile liquid that does not affect the quality and performance of the product. After it swells to 2-4 times its original volume, it is inserted into the outer layer of the cylindrical drug-containing layer. . After the liquid volatilizes naturally, a dual controlled-release drug system of reservoir type and rate-controlled release is formed. And at the same time, by virtue of the inward tightening force of the outer controlled-release membrane, the drug-containing valve layer does not fall off and become discrete.

2. A certain amount of silicone or medical polymer is dissolved in a liquid that is volatile and does not affect the quality, process and performance of the drug to make an impregnated release film material, and then the stent covered with the drug-containing valve layer is continuously Impregnation, volatilization, film formation 2-10 times (according to the amount of preset drug release, determine the number of dipping times to form the outer layer controlled release film of the required thickness), and finally combined into a composite reservoir type rate controlled release film Dual controlled release drug system.

3. Combining the first controlled-release membrane method and the second controlled-release membrane method to form a multiple controlled-release drug system that meets the reservoir type and rate-controlled release membrane, so as to achieve different drug release and different metering design requirements.

The liquid that is volatile and does not affect the quality, process and performance of the drug refers to chloroform, ethers or hydrocarbons.

The silicones mentioned include HTV (high temperature vulcanization or heat vulcanization, molecular weight 300-1000,000), RTV-2 (two-component room temperature vulcanization, molecular weight 0.74-110,000) or LTV (heating vulcanization, molecular weight 400-20000), USA Dow Corning SiLastic-382 medical grade silicone rubber, Q7 medical grade silicone rubber series and implant grade MDX series, or other corresponding series of medical silicone rubber.

Described polymer comprises polyvinyl acetate (PVA), ethylene-vinyl acetate copolymer (EVAC), polyacetate acetyl phthalate, methyl cellulose, ethyl cellulose, polyvinyl acetate (PVA), polyacrylic resins, etc.

Detailed ways

Example 1

Weigh 300 mg of mifepristone, 200 mg of letrozole, 0.1 gram of sodium lauryl sulfate, 0.1 gram of Span-20 and 0.7 gram of β-cyclodextrin (molecular weight 1134, produced by Shanghai Reagent Company), mix well Fill it into a silastic-382 medical silicone rubber tube with a wall thickness of 1 mm, put it into a molding mold, and heat press it.

Example 2

Weigh a certain amount of HTV medical rubber (molecular weight 300,000-1,000,000, produced by Shanghai Rubber Products Research Institute) and extrude and vulcanize it into a medical rubber ring with a diameter of 5 cm. Weigh 300 milligrams of mifepristone, 200 milligrams of letrozole, 0.015 grams of Brij52 and 1.2 grams of HTV medical rubber (molecular weight 300,000-1,000,000, produced by Shanghai Rubber Products Research Institute), knead and press into a 1.2-mm-thick first Thin skin, this first thin skin is coated on the above-mentioned medical rubber ring that makes; Take again 200 milligrams of Letrozole, 0.01 gram of Brij52 and 1 gram of HTV medical rubber (molecular weight 30-1,000,000, produced by Shanghai Rubber Products Research Institute) ), after kneading, it is pressed into a second thin skin with a thickness of 1.2 mm, and the second thin skin is coated on the first thin skin, and the obtained article is coated with a 0.02 mm HTV medical silicone rubber thin skin, and molded.

Example 3

Obtain the medical silicone rubber liner tube of RTV-1 (molecular weight 0.74-110,000, Shanghai Rubber Products Research Institute) with a tube diameter of 4 mm by extrusion vulcanization molding, and bend the liner tube to enclose a diameter of 5 cm hollow circle.

Weigh 300 mg of HTV medical rubber (molecular weight 30-1 million, produced by Shanghai Rubber Products Research Institute), 400 mg of mifepristone, 0.3 gram of sodium lauryl sulfate, 0.1 gram of Span-80 and 0.8 gram of PEG 1200, and then Weigh 200 mg of HTV medical rubber (molecular weight 30-1 million, produced by Shanghai Rubber Products Research Institute), 250 mg of letrozole, 0.1 gram of sodium lauryl sulfate, 0.05 gram of Span-80 and 0.3 gram of PEG1200, and mix them respectively After that, they were respectively pressed into the first thin skin and the second thin skin, which were successively coated on the inner liner tube, and then the RTV-1 medical silicone rubber was pressed into a thin skin with a thickness of 0.02 mm, which was coated on the drug thin skin, and hot-pressed and vulcanized to obtain the required products.

Example 4

Weigh 1 gram of LTV (Shanghai Rubber Products Research Institute), add it into 20 ml of petroleum ether, mix well, and obtain an impregnation solution for later use.

Weigh a certain amount of HTV medical rubber (molecular weight 300,000-1,000,000, produced by Shanghai Rubber Products Research Institute) and extrude and vulcanize it into a medical rubber ring with a diameter of 5 cm. Weigh 800 mg of HTV medical rubber (molecular weight 30-1 million, produced by Shanghai Rubber Products Research Institute), 400 mg of mifepristone, then weigh 250 mg of letrozole, 0.15 g of sodium dodecylsulfonate and 0.8 g of PEG 20000, mixed and pressed into a thin skin to cover the obtained medical rubber ring, immerse the obtained ring in the dipping solution obtained above, take it out after 5 seconds and dry it.

Example 5

(1) Weigh 20 grams of medical grade LS-4100 addition-type silicone rubber, 12 grams of mifepristone, and 8 grams of letrozole, mix them evenly on the rubber mixer, put them into a 1/3 semicircular mold, and pressurize Vulcanized into drug-containing layer petals, trimmed, cut length 1.9cm, weight 45-47mg/petal.

(2) Take the polyethylene IUD plastic bracket and soak it in absolute ethanol for two hours, drain it, and set it aside.

(3) Adhere the drug-containing layer valve that meets the requirements with the IUD stent after slight friction, put the outer layer of silicone controlled-release tube into a glass vessel, swell with chloroform to more than double the original volume, and then Insert the outer layer containing the cylindrical drug-containing layer flap, and after it volatilizes naturally, the outer layer returns to the rubber controlled-release tube, which is first tightened inward and covered with the drug-releasing layer composed of multiple drug-containing layer flaps , so as not to make it fall off, discrete, forming a dual controlled release system of composite reservoir type and rate controlled release membrane.

Example 6

(1) After uniformly mixing 3 grams of mifepristone, 7 grams of raloxifene and medical-grade LS-4100 addition-type silicone rubber on a rubber mixer, press it into a cylindrical shape through a mold, pressurize and vulcanize it to form a drug-containing layer, The drug-containing layer has a thickness of 0.75 mm, an inner diameter of 1.5 mm, and an outer diameter of 3 mm, and then the edge is trimmed, and a cylindrical drug-containing layer with a length of 1.9 cm and a weight of 92 mg is cut.

(2) Put the cylindrical drug-containing layer on the longitudinal arm of the IUD stent, then dip in 10% EVAC: chloroform controlled-release dipping membrane solution, volatilize, and form a film twice. After the solvent is completely volatilized naturally, it is combined into a dual controlled drug release system of composite storage type and rate controlled release membrane.

Clinical trial example 1

A 43-year-old female has heavy menstrual flow in the past two years, and the menstrual period is long, accompanied by severe tearing pain. Clinical examination and B-ultrasound examination showed that the size of the uterus is 93×95×96, the volume is enlarged, the shape is full, and the posterior wall of the uterus is muscular. In the layer, there is a quasi-circular and slightly stronger echogenic light group, the largest is about 71×66×59mm, the boundary echo is not clear, the internal echo is not uniform, the color Doppler shows, and the blood flow signal is rich. The endometrium moved forward and was 6.9mm thick, without third lines.

Ultrasound tip: enlarged uterus (adenomyosis with adenomyoma)

The case shows: the patient once took mifepristone 25mg according to the doctor's advice, once a day, and took it continuously for two months. He found hepatic discomfort, poor appetite, and weak expression, so he stopped using the medicine. Afterwards, the B-ultrasound examination showed that the size and volume of the uterus and the fibroids did not shrink.

The patient is replaced with the combined anti-estrogen and anti-progestogen vaginal ring of Example 1. Three months later, the B-ultrasound examination showed that the size of the patient's uterus and fibroids were significantly reduced, the size of the uterus was reduced by 27%, and the size of the fibroids was reduced by 22.6%. Disappeared, no endometrial thickening (6.1mm), no systemic or local discomfort. After continuing to use the anti-estrogen and anti-progestin compound vaginal ring for 3 months, the B-ultrasound examination showed that the patient's uterine volume and fibroids were more significantly reduced, the size of the uterus was reduced by 30%, and the size of the fibroids was reduced by 27.1%. : Amenorrhea for three months (pharmacological), the pain completely disappeared, no thickening of the endometrium (6.5mm), no systemic or local discomfort.

Clinical trial example 2

Change the compound vaginal ring of anti-estrogen and anti-progestin of embodiment 2 to 6 cases of patients who use mifepristone vaginal ring and uterine fibroids without obvious shrinkage. Fibroids all shrunk to varying degrees (10-30%).

Clinical trial example 3

Use the intrauterine drug release device prepared in embodiment 5 or 6 for the 3 patients who used a single mifepristone vaginal ring and uterine fibroids without significant shrinkage. After 3 and a half months, it was shown by B-ultrasound that the uterine muscle Tumors also have different degrees of shrinkage (18-25%).

Therefore, the vaginal ring or intrauterine drug delivery device of the present invention has the following characteristics: drug release is slow, constant, continuous, and long-term, and the drug is released to the target organ in the uterine cavity circulation to achieve the purpose of treatment, so that the more active hormone can Avoid the explosive impact of initial metering and the defects of insufficient dosage afterward, as well as the side effects caused by systemic administration.

Claims (18)

1. A vaginal ring, which comprises a drug-containing part and a silicone rubber layer coated on the drug-containing part; the drug-containing part comprises, in terms of the total weight of the drug-containing part, 5-70% by weight active drug, 0.5-20% by weight of a physiologically acceptable surfactant and the balance of a physiologically acceptable dispersant; the thickness of the silicone rubber layer coated on the drug-containing part is 0.01-0.5 mm; it is characterized in that , in the active drug, based on 100 parts by weight of the active drug, the anti-estrogen drug is 40-70 parts by weight, and the anti-progestin drug is 30-60 parts by weight. 2. The vaginal ring according to claim 1, wherein said anti-estrogen drug is selected from raloxifene, tamoxifen, naphthyridine or aromatase inhibitors; said anti-progestogen drug is selected from mifepristone or gestrinone. 3. The vaginal ring according to claim 2, wherein said aromatase inhibitor is selected from the group consisting of anastazole, esmestane and letrozole. 4. The vaginal ring of claim 3, wherein said active drug consists of 60% by weight of mifepristone and 40% by weight of letrozole. 5. The vaginal ring according to claim 1, wherein said medicated portion is composed of a first medicated layer portion containing an anti-estrogen or an anti-progestogen and a second layer containing an anti-progestogen or an anti-estrogen. Two drug-containing layer parts, the condition is that if the first drug-containing layer part contains anti-progestin drug, then the second drug-containing layer part contains anti-estrogen drug; if the first drug-containing layer part contains anti-estrogen drug The layer part contains anti-estrogens, and the second drug-containing layer part contains anti-progestogens. 6. The vaginal ring according to claim 5, wherein the first drug-containing layer part is located at the center of the vaginal ring, and the second drug-containing layer part covers the central first drug-containing layer part. 7. The vaginal ring according to claim 1, wherein the center of the vaginal ring comprises a hollow part surrounded by an inner liner tube, the drug-containing part is located between the inner liner tube and the silicone rubber layer, and the inner liner tube is made of medical Made of silicone rubber or other medical polymers. 8. The vaginal ring according to claim 5, wherein the center of the vaginal ring comprises a medical silicone rubber column, and the first drug-containing layer is partly coated on the medical rubber column, and the first medical-containing layer The second drug-containing layer part is coated on the drug layer part, and the silicon rubber layer is coated on the second drug-containing layer part. 9. The vaginal ring according to claim 1, wherein the thickness of the silicone rubber layer coated on the drug-containing part is 0.02-0.5 mm. 10. An intrauterine drug delivery device comprising an intrauterine drug release device stent, a first drug-containing layer portion coated on the stent, and a second drug-containing layer portion on the first drug-containing layer portion, and A controlled release layer coated on the second drug-containing layer part, the first drug-containing layer part and the second drug-containing layer part are composed of active drugs independently selected from anti-estrogen drugs and anti-progestogen drugs It is mixed with medical-grade silicone or other polymers at a ratio of 1-70:99-30, provided that when the first drug-containing layer part contains anti-estrogens, the second drug-containing layer layer part then contains anti-progestin drug; or when the first drug-containing layer part contains anti-progestin drug, the second drug-containing layer part then contains anti-estrogen drug, it is characterized in that, in the active Among the medicines, based on 100 parts by weight of the active drug, the amount of the anti-estrogens is 40-70 parts by weight, and that of the anti-progestogens is 30-60 parts by weight. 11. An intrauterine drug release device, comprising an intrauterine drug release device support, a drug-containing valve layer coated on the support, and a controlled release layer coated on the drug-containing valve layer, and the drug-containing valve layer is composed of The active drug is mixed with medical-grade silicone or other polymers at a ratio of 1-70:99-30, and it is characterized in that, in the active drug, the anti- The amount of estrogen medicine is 40-70 parts by weight, and the amount of antiprogestin medicine is 30-60 parts by weight. 12. The intrauterine drug delivery device according to claim 10 or 11, wherein said anti-estrogens are selected from raloxifene, tamoxifen, naphthyridine or aromatase inhibitors; said anti-progestogens are selected from From mifepristone or gestrinone, the aromatase inhibitor is selected from anastazole, esmestane and letrozole. 13. The intrauterine drug delivery device according to claim 10 or 11, wherein said active drug consists of 60% by weight of mifepristone and 40% by weight of letrozole. 14. The intrauterine drug release device according to claim 10 or 11, wherein the intrauterine drug release device bracket is a T-shaped, Y-shaped, umbrella-shaped lined non-toxic polyvinyl chloride stent or silicone rubber stent. 15. The intrauterine drug delivery device according to claim 10 or 11, wherein the active drug content in each intrauterine drug delivery device is 30mg-200mg. 16. The intrauterine drug delivery device according to claim 15, wherein the content of active drug in each intrauterine drug delivery device is 30-50 mg. 17. The intrauterine drug delivery device according to claim 10 or 11, wherein the controlled release layer is made of silicone or other medical polymers, and its thickness is 0.01-0.5mm. 18. The intrauterine drug delivery device according to claim 17, wherein the thickness of the controlled release layer is 0.05-0.5 mm.

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