A method of manufacturing an improved reservoir type pessary

Abstract

This invention discloses an improved reservoir-type vaginal ring. The drug is loaded as a drug-carrying core by mixing it with silicone rubber, and the core is coated with a controlled-release layer made of pure silicone rubber. The drug-carrying core contains a developing agent and a dispersant. The developing agent includes barium sulfate, titanium dioxide, iodotram, iodofol, iopromide, iodophenylhexamol, and iodophenyl ester. The dispersant includes methyl silicone oil, phenyl silicone oil, vinyl silicone oil, hydrogen-containing silicone oil, and glycerin. This invention combines the advantages of existing extrusion and molding methods, effectively controlling the size and regularity of the drug-carrying core of the reservoir-type vaginal ring, ensuring stable and controllable drug content. It can effectively improve the product deformation problems caused by cutting, external force, and hot-pressing vulcanization processes in existing co-extrusion processes.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and specifically to a method for preparing an improved reservoir-type vaginal ring. Background Technology

[0002] A vaginal ring is a flexible, ring-shaped device made of silicone elastomer or thermoplastic plastic that releases medication slowly or at a constant rate into the vagina over a long period, providing systemic or local effects. Vaginal rings are a relatively new long-acting medication with well-studied contraceptive applications, and commercially available products are available. Studies have shown that during treatment, the ethinyl estradiol and estrogenic progesterone carried by the vaginal ring are rapidly absorbed by the vaginal epithelium to maintain stable serum hormone concentrations. Clinical trial data indicate that patients report high satisfaction with vaginal rings, with efficacy and safety comparable to oral contraceptives, and significantly lower levels of systemic side effects. In addition to contraception, vaginal rings can also be used to treat menorrhagia, dysmenorrhea, and polycystic ovary syndrome, providing effective cycle control and symptom relief for patients with these conditions. Recent research suggests that vaginal rings can also be an effective means of delivering antiretroviral drugs for HIV prevention.

[0003] Currently, vaginal ring structures can be mainly divided into three categories: ① Covered metal spring vaginal rings. Their main structure consists of a ring-like body made of elastic matrix material with a fractured surface, covered with a drug-doped matrix coating, and connected at the fracture points by metal springs. This type represents an early design for vaginal rings; ② Matrix-type vaginal rings. These products have a simpler structure, being a uniform ring formed by uniformly mixing the drug with the elastic matrix material. These vaginal rings exhibit a more pronounced drug release during initial use; ③ Reservoir-type vaginal rings. These rings have a double- or multi-layer design: the drug-loaded core is composed of an elastic matrix material mixed with the drug, and a controlled-release layer of drug-free elastic matrix material surrounds the core to control the drug release rate. Building upon the basic two-layer reservoir-type vaginal ring, various other developments have emerged, such as: a) a multi-layer shell-type vaginal ring with three layers: an innermost core of pure elastic matrix material, a middle drug-loaded core composed of a mixture of drug and elastic matrix material, and an outermost controlled-release layer made of pure elastic matrix material; b) a multi-segment reservoir-type vaginal ring, where the drug-loaded core is segmented, with each segment capable of loading different drugs; and c) an insertable reservoir-type vaginal ring, which differs from traditional reservoir-type rings in that the drug-loaded core is not ring-shaped but rather a straight-segment reservoir. Different straight-segment reservoir drug-loaded cores are inserted into the pre-fabricated ring before the controlled-release layer solidifies. Reservoir-type vaginal rings are the optimal choice for flexibly adjusting drug loading and effectively controlling early drug burst release.

[0004] Silicone rubber, with its excellent biocompatibility, tolerance, and stability, has a long history of application in the medical device field, making it an ideal matrix material for vaginal rings. Silicone rubber elastomers are typically cured through addition reactions. Medical-grade silicone rubber elastomers often use platinum complexes for catalytic reactions, resulting in no byproducts and good safety. Two estrogen-containing reservoir-type silicone rubber elastomer vaginal rings have been marketed for treating menopausal symptoms caused by estrogen deficiency. Estring®, developed by Pfizer, uses a double-layer reservoir-type vaginal ring design to load estradiol, providing stable drug release for three consecutive months (7.5 μg / day). Femring®, a multi-segment reservoir-type vaginal ring containing a segmented drug-loaded core, was developed by Warner Chilcott. This product is available in different specifications depending on the length of the drug-loaded core, effectively releasing estradiol acetate for more than three months (50 μg / day or 100 μg / day).

[0005] Taking the production of traditional silicone rubber double-layer reservoir-type vaginal rings as an example, literature and patents indicate that extrusion or injection molding methods are commonly used. If extrusion is used, since the reservoir-type vaginal ring has a double-layer structure, the drug-containing layer and the controlled-release layer of silicone rubber must be co-extruded. The double-layer silicone rubber strips obtained through co-extrusion undergo post-processing such as cutting and ring forming, and are finally heat-cured. The co-extruded double-layer silicone rubber strips have no fixed shape, are prone to deformation at the cut points, and are soft and easily deformed under stress. If deformation occurs, it may lead to substandard quality in the final product. Furthermore, since co-extrusion cannot directly control the size of the extrudate of the inner drug-containing layer, there is a significant risk of substandard drug content in the final product. These two problems increase the difficulty of quality control during the production process. Injection molding typically uses liquid silicone rubber, and the injection molding of double-layer products requires special mold design, also making it impossible to directly control the size of the inner layer.

[0006] Based on literature and patent information, the current solution to this problem is to achieve a certain degree of curing of the extruded silicone rubber rods: the silicone rubber polymer material and crosslinking agent can be cured by allowing the mixture to stand at room temperature for about 7 days. Alternatively, curing can be completed in a shorter time by using high temperatures. Typically, temperatures of about 30°C to 80°C are used for about 6 hours to 5 days. If the temperature is set to 100°C to 150°C, curing is completed in an even shorter time. This method enables the silicone rubber rods to undergo a certain degree of self-curing, producing a certain hardness to resist the deformation of the silicone rubber rods under external forces during subsequent production processes. However, this method is very time-consuming and may cause the rods to sag and deform due to gravity during placement. Summary of the Invention

[0007] In view of this, the present invention improves the traditional co-extrusion process and combines the advantages of extrusion and molding methods to invent a controllable preparation process for silicone rubber drug-containing cores and silicone rubber reservoir-type vaginal rings. This solves the problem of product deformation in the traditional co-extrusion process and the problem of substandard drug content caused by the inability to directly control the size of drug-containing cores. The specific technical solution is as follows: The manufacturing process of the reservoir-type vaginal ring disclosed in this invention combines traditional silicone rubber extrusion and molding methods. The equipment flow chart is shown below. Figure 1 As shown. The preparation process of the present invention can be briefly described as follows: After preparing the materials for the drug-loaded core and the controlled-release layer, the drug-loaded core material is first fed into an extruder, extruded and vulcanized; then, through a specially designed co-extrusion die, the vulcanized drug-loaded core and the controlled-release layer material are co-extruded to obtain an unvulcanized double-layer silicone rubber bar; the unvulcanized double-layer silicone rubber bar is cut to a fixed length using a cutting device, the two ends are joined together to form a ring, and finally placed in a mold for hot-pressing vulcanization to obtain the final product, a storage-type vaginal ring.

[0008] An improved reservoir-type vaginal ring, wherein the drug is loaded as a drug-carrying core by mixing it with silicone rubber, and the core is covered with a controlled-release layer made of pure silicone rubber; the drug-carrying core contains a contrast agent and a dispersant, wherein the contrast agent is one or more of the following: barium sulfate, titanium dioxide, iodotram, iodofol, iopromide, iodobenzyl alcohol, and iodophenyl ester; and the dispersant is one or more of the following: methyl silicone oil, phenyl silicone oil, vinyl silicone oil, hydrogen-containing silicone oil, and glycerin.

[0009] The preparation of the improved reservoir-type vaginal ring includes the following steps: (1) Preparation of drug-loaded core material: Weigh the drug and the developer at a ratio of 1:10 to 10:1, weigh the dispersant and the drug at a ratio of 10:1 to 1:1, mix the weighed materials thoroughly, add the mixed materials to the silicone rubber at a mass ratio of 1:100 to 100:1, mix thoroughly, and the drug-loaded core material is obtained after mixing. (2) Preparation of controlled-release layer material: Silicone rubber is mixed using a rubber mixing machine. After mixing, the controlled-release layer material is obtained. (3) Preparation of drug-loaded core: Cut the drug-loaded core material prepared in (1) into strips 2-8 cm wide and 1-5 cm thick, and extrude them; (4) Preparation of controlled-release layer: Cut the controlled-release layer material in (2) into strips 2-8 cm wide and 1-5 cm thick, co-extrude the drug-carrying core and the controlled-release layer material to achieve the coating of the drug-carrying core by the controlled-release layer; cut the uncured double-layer silicone rubber strips into 8-30 cm, join them into a ring and put them into the mold cavity for hot-press vulcanization molding.

[0010] Further, in (1), the mixing conditions are: using an open rubber mixing mill at a speed of 1 to 100 rpm for 1 to 10 minutes, or using a dual-center mixer at a speed of 1000 to 5000 rpm for 1 to 10 minutes.

[0011] Further, in (2), the mixing conditions are: mixing for 1 to 10 minutes at a speed of 1 to 100 rpm, or mixing for 1 to 10 minutes at a speed of 1000 to 5000 rpm using a dual-center mixer.

[0012] Furthermore, in (3), the co-extrusion die is designed to feed the controlled-release layer material from back to front, and the vulcanized drug-loaded core is conveyed into the co-extrusion die from one side, and finally the double-layer silicone rubber round strip is extruded at the die outlet; the extrusion conditions are: the temperature of the high-temperature setting furnace is set at 100-200℃, the temperature of the vulcanization tunnel furnace is set at 80-180℃, and the conveyor belt speed is 0.1-5rpm, and the drug-loaded core is obtained.

[0013] Furthermore, in (4), the vulcanization parameters of the flat vulcanizing machine are: temperature 50~200℃, vulcanization time 0.5~15min, vacuum degree 0~25kPa, and clamping force 20~50 tons.

[0014] The drug is one or more of estrogen and progestin drugs. The estrogen is one or more of estradiol, estrone, estriol, ethinylestradiol, estradiol valerate, estradiol benzoate, ethinylestradiol methyl ether, ethinylestradiol valerate, conjugated estrogen, hexestrol, and diethylstilbestrol. The progestin drug is one or more of progesterone, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, chlormedrone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone, levonorgestrel, drospirenone, cyproterone acetate, and allylestradiol.

[0015] The silicone rubber used is implantable grade silicone rubber, such as the Liveo series implantable silicone rubber from DuPont, the Silbione series implantable silicone rubber from Elkem, and the MED series implantable silicone rubber from Nusil. The materials used for the drug-loaded core and the controlled-release layer can be the same or different, and one or more of the above-mentioned silicone rubbers can be used.

[0016] Furthermore, two extruders with φ20~φ65 screws are used, with an extruder screw length-to-diameter ratio of 12:1~14:1 and a compression ratio of 2:1~3:1; Furthermore, the extrusion and vulcanization of the drug-loaded silicone rubber rods are carried out first, and then they are co-extruded with the unvulcanized controlled-release silicone rubber layer. After the double-layer silicone rubber rods are extruded, they are not vulcanized in a high-temperature setting furnace or vulcanization tunnel furnace, but are cut in the unvulcanized state using a special cutting tool. After being formed into rings, they are placed in a mold for hot-press vulcanization.

[0017] The technical effects of this invention are as follows: This invention combines the advantages of existing extrusion and molding methods, effectively controlling the size and regularity of the drug-loaded core in reservoir-type vaginal rings, ensuring stable and controllable drug content. It can effectively improve the product deformation problems caused by cutting, external force, and hot-pressing vulcanization processes during the production of existing co-extrusion processes. Figure 2 and Figure 3 ). Attached Figure Description

[0018] Figure 1 This is a process flow diagram of the present invention.

[0019] Figure 2 Comparison images of the appearance of products produced by existing processes and the process of this invention.

[0020] Figure 3 A comparison diagram of cross-sections of products obtained by existing processes and the process of this invention.

[0021] Figure 4 The in vitro release curve of levonorgestrel is shown for the comparative example.

[0022] Figure 5 This is a graph showing the in vitro release curve of levonorgestrel in Example 1.

[0023] Figure 6 This is the in vitro release curve of estradiol in Example 2.

[0024] Figure 7 This is a graph showing the in vitro release curve of progesterone in Example 3.

[0025] Figure 8 This is the in vitro release curve of drospirenone in Example 4. Detailed Implementation

[0026] The present invention will be further described below with reference to the following embodiments and accompanying drawings, but is not limited to the scope of protection of the present invention. Example 1

[0027] Take 50 g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill. Separately, accurately weigh 0.35 g of levonorgestrel, 1 g of barium sulfate, and 1.5 g of dimethicone oil and mix them using a SpeedMixer dual-center mixer. Mix the resulting mixture with the silicone rubber to create a drug-loaded core for later use. Separately, take 200 g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill to create a controlled-release layer. In this embodiment, the operating parameters of the open mixing mill and dual-center mixer are the same as in the comparative embodiment.

[0028] The drug-loaded core material was taken and cut into strips 3 cm wide and 2 cm thick. These strips were fed into an extruder, with the screw speed controlled at 0.3 rpm. The material was then placed in a vulcanizing tunnel furnace for curing and molding. The high-temperature setting furnace temperature was controlled at 130°C, the vulcanizing tunnel furnace temperature at 110°C, and the conveyor belt speed at 2.0 rpm, thus producing the drug-loaded core. A co-extrusion die was installed on the extruder, and the drug-loaded core was placed into the die. Finally, a cutting device was installed at the rear end of the co-extrusion die, and the extrusion of the double-layer silicone rubber strip began. The controlled-release layer material was cut into strips 6 cm wide and 2 cm thick and fed into the extruder, with the screw speed controlled at 0.85 rpm. A cutting device was used to cut the double-layer silicone rubber strips to a length of 15 cm, producing a double-layer silicone rubber strip intermediate. The cut intermediate was placed in a flat vulcanizing mold for hot-pressing vulcanization molding. After vulcanization, a levonorgestrel reservoir-type vaginal ring sample was obtained. The vulcanization parameters set in this embodiment were the same as those in the comparative embodiment. The release rate of the sample in this embodiment and the sample in the comparative embodiment were tested using the same method. Example 2

[0029] Take 50g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill. Separately, accurately weigh 0.16g of estradiol, 1g of barium sulfate, and 1.5g of dimethicone oil and mix them using a SpeedMixer dual-center mixer. Mix the resulting mixture with the silicone rubber to form the drug delivery core, ready for use. Separately, take 200g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill to form the controlled-release layer. In this embodiment, the operating parameters of the open mixing mill and dual-center mixer are the same as in the comparative embodiment.

[0030] The drug-loaded core material was taken and cut into strips 3 cm wide and 2 cm thick. These strips were fed into an extruder, with the screw speed controlled at 0.3 rpm. The material was then placed in a vulcanizing tunnel oven for curing and molding. The high-temperature setting oven temperature was controlled at 130℃, the vulcanizing tunnel oven temperature at 100℃, and the conveyor belt speed at 2.0 rpm, thus producing the drug-loaded core. A co-extrusion die was installed on the extruder, and the drug-loaded core was placed into the die. Finally, a cutting device was installed at the rear end of the co-extrusion die, and the extrusion of the double-layer silicone rubber strip began. The controlled-release layer material was cut into strips 6 cm wide and 2 cm thick and fed into the extruder, with the screw speed controlled at 0.85 rpm. A cutting device was used to cut the double-layer silicone rubber strips to a length of 15 cm, producing a double-layer silicone rubber strip intermediate. The cut intermediate was placed in a flat vulcanizing mold for hot-pressing and vulcanization molding. After vulcanization, the estradiol reservoir-type vaginal ring sample was obtained. The vulcanization parameters are: vulcanization temperature 115℃, vulcanization time 5 min, and clamping force 35 tons. Example 3

[0031] Take 50g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill. Separately, accurately weigh 0.35g of progesterone, 1g of barium sulfate, and 2.2g of dimethicone oil and mix them using a SpeedMixer dual-center mixer. Mix the resulting mixture with the silicone rubber to form the drug-loaded core, ready for use. Separately, take 200g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill to form the controlled-release layer. In this embodiment, the operating parameters of the open mixing mill and dual-center mixer are the same as in the comparative embodiment.

[0032] The drug-loaded core material was taken and cut into strips 3 cm wide and 2 cm thick. These strips were fed into an extruder, with the screw speed controlled at 0.3 rpm. The material was then placed in a vulcanizing tunnel oven for curing and molding. The high-temperature setting oven temperature was controlled at 130℃, the vulcanizing tunnel oven temperature at 100℃, and the conveyor belt speed at 2.0 rpm, thus producing the drug-loaded core. A co-extrusion die was installed on the extruder, and the drug-loaded core was placed into the die. Finally, a cutting device was installed at the rear end of the co-extrusion die, and the extrusion of the double-layer silicone rubber strip began. The controlled-release layer material was cut into strips 6 cm wide and 2 cm thick and fed into the extruder, with the screw speed controlled at 0.85 rpm. A cutting device was used to cut the double-layer silicone rubber strips to a length of 15 cm, producing a double-layer silicone rubber strip intermediate. The cut intermediate was placed in a flat vulcanizing mold for hot-pressing and vulcanization molding. After vulcanization, the estradiol reservoir-type vaginal ring sample was obtained. The vulcanization parameters are: vulcanization temperature 115℃, vulcanization time 5 min, and clamping force 35 tons. Example 4

[0033] Take 50g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill. Separately, accurately weigh 0.35g of drospirenone, 1g of barium sulfate, and 2.0g of dimethicone oil and mix them using a SpeedMixer dual-center mixer. Mix the resulting mixture with the silicone rubber to form the drug-loaded core, ready for use. Separately, take 200g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill to form the controlled-release layer. In this embodiment, the operating parameters of the open mixing mill and dual-center mixer are the same as in the comparative embodiment.

[0034] The drug-loaded core material was taken and cut into strips 3 cm wide and 2 cm thick. These strips were fed into an extruder, with the screw speed controlled at 0.3 rpm. The material was then placed in a vulcanizing tunnel oven for curing and molding. The high-temperature setting oven temperature was controlled at 130℃, the vulcanizing tunnel oven temperature at 100℃, and the conveyor belt speed at 2.0 rpm, thus producing the drug-loaded core. A co-extrusion die was installed on the extruder, and the drug-loaded core was placed into the die. Finally, a cutting device was installed at the rear end of the co-extrusion die, and the extrusion of the double-layer silicone rubber strip began. The controlled-release layer material was cut into strips 6 cm wide and 2 cm thick and fed into the extruder, with the screw speed controlled at 0.85 rpm. A cutting device was used to cut the double-layer silicone rubber strips to a length of 15 cm, producing a double-layer silicone rubber strip intermediate. The cut intermediate was placed in a flat vulcanizing mold for hot-pressing and vulcanization molding. After vulcanization, the estradiol reservoir-type vaginal ring sample was obtained. The vulcanization parameters are: vulcanization temperature 115℃, vulcanization time 5 min, and clamping force 35 tons. Comparative Examples

[0035] Take 50 g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill. The parameters of the open mixing mill are as follows: rotation speed 15 rpm, roller surface temperature 20℃, and mixing time 10 min. Separately, accurately weigh 0.35 g of levonorgestrel, 1 g of barium sulfate, and 1.5 g of dimethicone oil and mix them using a SpeedMixer dual-center mixer. The parameters of the dual-center mixer are as follows: rotation speed 2000 rpm, mixing time 3 min, and vacuum degree 10 kPa. The mixed material is then combined with the silicone rubber to form a drug-loaded core for later use. Mixing is also performed using an open mixing mill with the following parameters: rotation speed 15 rpm, roller surface temperature 20℃, and mixing time 10 min. Separately, take 200 g each of implantable solid silicone rubber Q7-4735A and B components and mix them using an open mixing mill to form a controlled-release layer. The mixing parameters of the open mixing mill are as follows: rotation speed 15 rpm, roller surface temperature 20℃, and mixing time 10 min.

[0036] The silicone rubber for the drug-loaded core and the silicone rubber for the controlled-release layer were fed into a conventionally designed co-extrusion production line, with both the drug-loaded core and the controlled-release layer produced using extruders. The extruder parameters were set as follows: speeds of 0.3 rpm and 0.85 rpm for the two extruders, respectively. After co-extrusion, the material was cut using a cutting device to a length of 15 cm. The cut intermediate was then placed in a flat vulcanizing mold for hot-pressing and vulcanization. The vulcanization parameters were: vulcanization temperature 125℃, vulcanization time 3 min, and clamping force 35 tons. Upon completion of vulcanization, a levonorgestrel reservoir-type vaginal ring sample prepared using the conventional process was obtained.

[0037] In vitro release rate test of reservoir-type vaginal rings The release rate of levonorgestrel was determined using a 500 ml amber glass bottle as the dissolution vessel and 200 ml of an aqueous solution containing 1% 2-hydroxypropyl-β-cyclodextrin as the dissolution medium. The bottle was screwed shut and placed in a constant-temperature rotary shaker at 37°C and 100 rpm. The dissolution medium was collected every 24 hours as the test solution for the corresponding day, and the assay was performed continuously for 14 days. An appropriate amount of levonorgestrel reference standard was accurately weighed, dissolved in methanol, and quantitatively diluted to a solution containing approximately 320 μg per ml. 5 ml of this solution was accurately measured and placed in a 100 ml volumetric flask, diluted to the mark with methanol-water (50:50), and shaken well. Another 5 ml of this solution was accurately measured and placed in a 100 ml volumetric flask, diluted to the mark with the dissolution medium, and shaken well to obtain the reference solution. The levonorgestrel content was determined using high-performance liquid chromatography (HPLC).

[0038] The chromatographic conditions for levonorgestrel detection are as follows: octadecylsilane-bonded silica gel is used as the packing material (Waters Spherisorb ODS2 125×3.0 mm, 3 μm column is recommended), acetonitrile-water (50:50) is used as the mobile phase, the detection wavelength is 200 nm, the column temperature is 38℃, the flow rate is 0.8 ml / min, and the injection volume is 50 μl.

[0039] For the release assay of estradiol, a 500 ml amber glass bottle was used as the dissolution container, and 200 ml of 0.9% physiological saline was used as the dissolution medium. The bottle was screwed on tightly and placed in a constant-temperature rotary shaker at 37°C and a shaking frequency of 150 rpm. The dissolution medium was collected every 24 hours as the test solution for the corresponding day, and the assay was performed continuously for 14 days. An appropriate amount of estradiol reference standard was accurately weighed, dissolved in anhydrous ethanol, and quantitatively diluted to a solution containing approximately 200 μg per ml. 5 ml of this solution was accurately measured and placed in a 100 ml volumetric flask, diluted to the mark with acetonitrile-water (25:75), and shaken well. Another 5 ml of this solution was accurately measured and placed in a 100 ml volumetric flask, diluted to the mark with the dissolution medium, and shaken well. This was used as the reference solution. The estradiol content was detected using high-performance liquid chromatography (HPLC).

[0040] The chromatographic conditions for estradiol detection are as follows: octadecylsilane-bonded silica gel is used as the packing material (Waters Spherisorb ODS2 125×3.0 mm, 3 μm column is recommended), acetonitrile-water (25:75) is used as the mobile phase, the detection wavelength is 205 nm, the column temperature is 35℃, the flow rate is 1.0 ml / min, and the injection volume is 80 μl.

[0041] The method for detecting progesterone release is the same as that for estradiol, and the chromatographic conditions are in accordance with the 2020 edition of the Chinese Pharmacopoeia.

[0042] The release rate of drospirenone was detected using the same method as that of estradiol, with the following chromatographic conditions: octadecylsilane-bonded silica gel as the packing material (Waters Spherisorb ODS2 125×3.0 mm, 3 μm column is recommended), acetonitrile-water (40:60) as the mobile phase, detection wavelength of 275 nm, column temperature of 30 °C, flow rate of 1.0 ml / min, and injection volume of 100 μl.

[0043] result: A comparison of the appearance of the vaginal ring of Embodiment 1 and the vaginal ring of the comparative embodiment. Figure 2 and Figure 3 As shown. The drug-loaded core of the sample in Example 1 is regular, uniform, and controllable, with almost no deformation (Note: Figure 2 The sample made in this way has a slightly shorter inner core length, making it easier to compare and observe the flatness of the seam. Normal samples can achieve perfect ring formation of the drug-loaded core. In contrast, the sample in the comparative example experiences radial deformation of the drug-loaded core due to the radial force exerted on the product during the molding process (resulting in an elliptical cross-section). Because the drug-loaded core is in a viscous flow state, partial deformation at the interface may occur during the cutting process, and irregular deformation may also occur during the molding process. Figure 2 (Left side of the left image).

[0044] The hardness of the levonorgestrel vaginal ring in the comparative embodiment of the present invention is 39.5 HA, and the in vitro release curve is as follows. Figure 4 As shown, the sample can achieve slow release of levonorgestrel during the 14-day observation period, with a release rate in the range of 12–30 μg / day.

[0045] The levonorgestrel vaginal ring of Example 1 of this invention has a hardness of 39.8 HA, and its in vitro release curve is as follows. Figure 5 As shown, the sample also achieved stable controlled release of levonorgestrel during the 14-day observation period, and the early release level was more stable than that of the comparative example sample, with the release rate controllable within the range of 18~30 μg / day.

[0046] The estradiol vaginal ring of Example 2 of this invention has a hardness of 39.5 HA, and its in vitro release curve is shown below. Figure 6 As shown, the sample can achieve stable release of estradiol for 14 days, with the release rate controllable within the range of 5~10 μg / day.

[0047] The hardness of the progesterone vaginal ring in Example 3 of this invention is 39.2 HA, and the in vitro release curve is as follows. Figure 7 As shown, the sample can achieve stable release of progesterone for 14 days, with the release rate controllable within the range of 12~20 μg / day.

[0048] The hardness of the drospirenone vaginal ring in Example 4 of this invention is 39.8 HA, and the in vitro release curve is as follows. Figure 8 As shown, the sample can achieve stable release of drospirenone for 14 days, with the release rate controllable within the range of 16~25 μg / day.

[0049] Of course, it should be understood that the above description is merely for illustrating the application of the principles of the present invention. Those skilled in the art can devise various modifications and alternatives without departing from the spirit and scope of the invention, and the appended claims are intended to encompass these modifications and alternatives. Thus, although the features and details of the invention have been described above in conjunction with what are currently considered to be the most practical and preferred embodiments, it will be apparent to those skilled in the art that many modifications can be made without departing from the principles and concepts set forth herein, including but not limited to changes in size, material, shape, form, operational function and mode of operation, components, and uses.

Claims

1. An improved reservoir-type vaginal ring, characterized in that, The drug is loaded as a drug-carrying core by mixing it with silicone rubber, and its exterior is covered with a controlled-release layer made of pure silicone rubber. The drug-carrying core contains a developer and a dispersant. The developer is one or more of the following: barium sulfate, titanium dioxide, iodotram, iodofol, iopromide, iodobenzyl alcohol, and iodophenyl ester. The dispersant is one or more of the following: methyl silicone oil, phenyl silicone oil, vinyl silicone oil, hydrogen-containing silicone oil, and glycerin.

2. The preparation of an improved reservoir-type vaginal ring as described in claim 1, characterized in that, Includes the following steps: Materials for preparing drug-loaded cores: Weigh the drug and developer at a ratio of 1:10 to 10:1, weigh the dispersant and drug at a ratio of 10:1 to 1:1, mix the weighed materials thoroughly, add the mixed materials to silicone rubber at a mass ratio of 1:100 to 100:1, mix thoroughly, and the drug-loaded core material is obtained after mixing. (2) Preparation of controlled-release layer material: Silicone rubber is mixed using a rubber mixing machine. After mixing, the controlled-release layer material is obtained. (3) Preparation of drug-loaded core: Cut the drug-loaded core material prepared in (1) into strips 2-8 cm wide and 1-5 cm thick, and extrude them; (4) Preparation of controlled-release layer: Cut the controlled-release layer material in (2) into strips 2-8 cm wide and 1-5 cm thick, co-extrude the drug-carrying core and the controlled-release layer material to achieve the coating of the drug-carrying core by the controlled-release layer; cut the uncured double-layer silicone rubber strips into 8-30 cm, join them into a ring and put them into the mold cavity for hot-press vulcanization molding.

3. The method for preparing a reservoir-type vaginal ring according to claim 2, characterized in that, The mixing conditions in (1) are: use an open rubber mixing mill to mix for 1 to 10 minutes at a speed of 1 to 100 rpm, or use a dual-center mixer to mix for 1 to 10 minutes at a speed of 1000 to 5000 rpm.

4. The method for preparing the reservoir-type vaginal ring according to claim 2, characterized in that, The mixing conditions in (2) are: mixing for 1 to 10 minutes at a speed of 1 to 100 rpm, or mixing for 1 to 10 minutes at a speed of 1000 to 5000 rpm using a dual-center mixer.

5. The method for preparing a reservoir-type vaginal ring according to claim 2, characterized in that, In (3), the co-extrusion die is designed to feed the controlled-release layer material from back to front, and the vulcanized drug-loaded core is conveyed from one side into the co-extrusion die, and finally the double-layer silicone rubber round strip is extruded at the die outlet; the extrusion conditions are: the temperature of the high-temperature shaping furnace is set at 100-200℃, the temperature of the vulcanization tunnel furnace is set at 80-180℃, and the conveyor belt speed is 0.1-5rpm, and the drug-loaded core is obtained.

6. The method for preparing a reservoir-type vaginal ring according to claim 2, characterized in that, In (4), the vulcanization parameters of the flat vulcanizing machine are: temperature 50~200℃, vulcanization time 0.5~15min, vacuum degree 0~25kPa, and clamping force 20~50 tons.

7. The method for preparing a reservoir-type vaginal ring according to claim 1, characterized in that, The drug is one or more of estrogen and progestin drugs. The estrogen is one or more of estradiol, estrone, estriol, ethinylestradiol, estradiol valerate, estradiol benzoate, ethinylestradiol methyl ether, ethinylestradiol valerate, conjugated estrogen, hexestrol, and diethylstilbestrol. The progestin drug is one or more of progesterone, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, chlormedrone acetate, hydroxyprogesterone caproate, norethindrone, norethindrone, levonorgestrel, drospirenone, cyproterone acetate, and allylestradiol.

8. The method for preparing a reservoir-type vaginal ring according to claim 1, characterized in that, The silicone rubber used is implantable silicone rubber, such as the Liveo series implantable silicone rubber from DuPont, the Silbione series implantable silicone rubber from Elkem, and the MED series implantable silicone rubber from Nusil. The materials used for the drug-loaded core and the controlled-release layer can be the same or different, and one or more of the above-mentioned silicone rubbers can be used.

9. The method for preparing a reservoir-type vaginal ring according to claim 2, characterized in that, The extruder screw used in step (3) has a diameter of φ20~φ35, a length-to-diameter ratio of 12:1~14:1, and a compression ratio of 2:1~3:

1. The extruder screw used in step (4) has a diameter of φ35~φ65, a length-to-diameter ratio of 12:1~14:1, and a compression ratio of 2:1~3:

1.

10. The method for preparing a reservoir-type vaginal ring according to claim 2, characterized in that, The drug-loaded silicone rubber rods are extruded and vulcanized first, and then co-extruded with the unvulcanized controlled-release silicone rubber layer. After the double-layer silicone rubber rods are extruded, they are not vulcanized in a high-temperature setting furnace or vulcanization tunnel furnace. Instead, they are cut in the unvulcanized state using a special cutting tool, formed into rings, and then placed in a mold for hot-press vulcanization.

Images