Silicone rubber pipe sleeve as well as preparation method and application thereof

Abstract

The invention relates to a medical silicone rubber pipe sleeve which is prepared from the following raw materials: 600-900 parts of a pipe sleeve rubber base material, 0-4 parts of a platinum complex and 0-10 parts of refined hydrogen-containing silicone oil. The pipe sleeve rubber base material is prepared from methyl vinyl silicone rubber (the vinyl content is 0.16-0.21% by mole, and the molecular weight is 500,000-600,000), white carbon black and vinyl silicone oil (the vinyl content is 0.08-0.12% by weight, and the viscosity is 1-60,000 mPa.S), and the pipe sleeve rubber base material is cut and received after being mixed and re-mixed for many times until the pipe sleeve rubber base material is transparent. The preparation method comprises the following steps: firstly, mixing, re-mixing the pipe sleeve rubber base material, and cooling after heat treatment; and adding a platinum complex and refined hydrogen-containing silicone oil, mixing, re-mixing, cooling, and sealing and storing. Methyl vinyl silicone rubber, white carbon black and vinyl silicone oil are adopted as raw materials, the component proportion and characteristics are accurately regulated and controlled, a stable three-dimensional network structure is constructed, the performance of a pipe sleeve rubber base material is improved, specific refined hydrogen-containing silicone oil and a platinum complex are selected, the dosage is strictly controlled, a cross-linked structure is accurately regulated and controlled, and it is ensured that the interior is uniform and stable; the initial release effect of the medicine is optimized.

Description

Technical Field

[0001] The present application relates to the technical field of medical materials, and in particular to a silicone rubber tube sleeve and a preparation method and application thereof. Background Art

[0002] Subcutaneous implants are a new type of targeted drug delivery dosage form that combines drug controlled release technology and biomedical material science, providing a new solution for sustained-release preparations.

[0003] The drugs in subcutaneous implants are usually encapsulated in a special carrier. Through subcutaneous implantation, the polymer carrier containing the drug (such as silicone rubber, polymer, etc.) is placed in the body. The release rate and duration of the drug are controlled by the carrier, so that the drug is released into the blood at a constant rate, thereby achieving the purpose of treatment.

[0004] In the field of contraception, after the implant is implanted subcutaneously, the drug begins to be slowly released into the surrounding tissues through the small pores of the carrier or the osmotic mechanism. These drug molecules are then absorbed into the blood circulation through local capillaries, thereby exerting a contraceptive effect. Due to the stability and continuity of drug release, subcutaneous implants can provide contraceptive effects for up to several years, which greatly reduces the inconvenience of frequently changing contraceptive methods or taking medication regularly. In addition, this method of administration can avoid the first-pass effect, thereby improving the bioavailability and contraceptive effect of the drug.

[0005] However, for levonorgestrel subcutaneous implants, although the levonorgestrel as the active ingredient is effectively encapsulated in the silicone rubber carrier, there are still some problems in practical application. In particular, the drug release amount is often not stable enough. In the early stage of release, the drug release amount may be too large, which may cause fluctuations in drug concentration and produce strong side effects on the human body, such as menstrual disorders, irregular vaginal bleeding, amenorrhea, etc., and may even have a series of complex effects on the contraceptive effect. Summary of the invention

[0006] In order to solve the problem of unstable drug release of levonorgestrel subcutaneous implant in practical application, especially the fluctuation of drug concentration caused by excessive drug release in the initial stage of release, the present application hereby provides a silicone rubber tube sleeve and its preparation method and application.

[0007] In the first aspect, the present application provides a method for preparing and applying a silicone rubber tube sleeve using the following technical solutions: A silicone rubber tube sleeve, the raw materials used for preparation are measured by weight and include the following components: 600-900 parts of pipe sleeve rubber base material, 0-4 parts of platinum complex, 0-10 parts of refined hydrogen-containing silicone oil; The pipe sleeve rubber base material is prepared by the following method: methyl vinyl silicone rubber, white carbon black, and vinyl silicone oil are added to a plastic refiner in sequence and uniformly mixed, and then the mixed materials are peeled off from the plastic refiner, cooled and then put into the plastic refiner for mixing, and the above operation is repeated until the mixed material is transparent, and then cut into sheets and collected to obtain the pipe sleeve rubber base material; the raw materials used for the preparation of the pipe sleeve rubber base material are calculated by weight, including: 400-600 parts of methyl vinyl silicone rubber, 250-450 parts of white carbon black, 15-30 parts of vinyl silicone oil; The vinyl content in the methyl vinyl silicone rubber is 0.16-0.21% by molar ratio and the molecular weight is 500,000-600,000; the vinyl silicone oil is a vinyl-terminated polydimethylsiloxane with a vinyl weight percentage content of 0.08-0.12% and a viscosity of 10,000-60,000 mPa·S.

[0008] By adopting the above technical scheme: the preparation of the silicone rubber tube sleeve in the levonorgestrel subcutaneous implant is improved, and the problem of unstable drug release is effectively solved, especially the situation of excessive drug release in the early stage of release is reduced, thereby reducing the side effects of drug concentration fluctuations on the human body and improving the stability and reliability of the contraceptive effect.

[0009] Analyzing the reasons, it may be: The vinyl molar ratio of methyl vinyl silicone rubber is precisely controlled at 0.16-0.21%. This range of vinyl content helps silicone rubber form a more stable three-dimensional network structure during the cross-linking process, thereby improving the physical strength, elasticity and chemical stability of the tube sleeve, which helps to reduce drug leakage during the release process and ensure that the drug is released at a more constant rate; The molecular weight of methyl vinyl silicone rubber is controlled within the range of 500,000-600,000. Silicone rubber in this molecular weight range has good processing performance and formability, while maintaining good elastic recovery ability, which helps to obtain a uniform and dense tube structure during the preparation process and reduce the sudden release of drugs at the initial stage of release. At the same time, as a reinforcing filler, silica can significantly improve the tensile strength and tear strength of silicone rubber, while improving its wear resistance and weather resistance, which helps to extend the service life of the silicone rubber tube and ensure the stable release of drugs over a long period of time. Vinyl silicone oil can also undergo cross-linking reaction with methyl vinyl silicone rubber to further improve the stability and durability of the tube.

[0010] In addition, by stripping the material from the plasticizer and re-mixing it several times until the material becomes transparent, the uniform mixing of the components can be ensured, thereby improving the quality and performance of the tube sleeve. The mixed material is cut into sheets and then collected for subsequent processing and molding. It also helps to maintain the uniformity and consistency of the tube sleeve, which is important for the stable release of the drug.

[0011] Preferably, the vinyl content of the methyl vinyl silicone rubber is 0.18% by molar ratio and the molecular weight is 500,000-600,000; the vinyl silicone oil is a vinyl-terminated polydimethylsiloxane with a vinyl weight percentage content of 0.10% and a viscosity of 10,000-60,000 mPa·s.

[0012] By adopting the above technical solution: the quality and performance of the silicone rubber tube can be significantly improved, and the stable release of the drug can be achieved. Preferably, the raw materials used in the preparation of the silicone rubber tube sleeve are composed of the following components in parts by weight: 800-850 copies of pipe sleeve rubber base material 2-3 parts of platinum complex; The platinum complex is platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane or platinum-cyclovinylmethylsiloxane complex.

[0013] By adopting the above technical solution: selecting a specific platinum complex and accurately controlling its dosage, accurate control of the cross-linking structure of the silicone rubber tube can be achieved, the cross-linking structure is optimized, and the drug is slowly and controllably released in the body, thereby maintaining a constant drug concentration and reducing fluctuations. This control helps to regulate the release rate and cycle of the drug, thereby achieving a more stable sustained-release effect.

[0014] Preferably, the raw materials used in the preparation of the silicone rubber tube sleeve are composed of the following components in parts by weight: 600-800 copies of pipe sleeve rubber base material 5-8 parts of refined hydrogen-containing silicone oil; The refined hydrogen-containing silicone oil is trimethyl or dimethyl hydrogen or hydroxyl terminated polymethyl hydrogen siloxane, the hydrogen content is 1.4-1.8% by weight, and the viscosity is 20-40cst.

[0015] By adopting the above technical solution: the specific chemical structure and hydrogen content of the refined hydrogen-containing silicone oil are made to react more quickly and completely with the active groups in the rubber base material, thereby improving the vulcanization efficiency, and the raw material ratio is precisely controlled to ensure the uniformity and stability of the internal structure of the tube sleeve, thereby providing reliable guarantee for the controlled release function. In a second aspect, the present application provides a method for preparing a silicone rubber sleeve, which adopts the following technical solution: A method for preparing a silicone rubber tube sleeve comprises the following preparation steps: S1: placing the raw materials for preparing the pipe sleeve rubber base material in a plastic purifier according to the feeding amount, mixing them, and kneading them at 80-110° C., then peeling the mixed material from the plastic purifier, and then putting it into the plastic purifier for re-kneading at 60-80° C., repeating the above operation 15-20 times, and finally peeling the material and cutting it into sheets, and performing heat treatment at the same time, and then cooling it to room temperature to obtain the pipe sleeve rubber base material for standby use; S2: The sleeve rubber base material, the platinum complex and the refined hydrogen-containing silicone oil are placed in a plastic refiner for mixing and kneading. Then, the mixed materials are peeled off from the plastic refiner and placed in the plastic refiner for re-kneading. The above operation is repeated 15-20 times. After cooling, the mixture is sealed and stored at 2-8°C to obtain the product.

[0016] By adopting the above technical solution: high-quality silicone rubber tube sleeves can be prepared, which have the advantage of precise cross-linking reaction control, which helps to improve the uniformity of the product.

[0017] Preferably, the heat treatment conditions in step S1 are vacuum degree ≥ 0.09 MPa, 150-160° C., and heating treatment for 2-3 h.

[0018] By adopting the above technical solution: heat treatment under the condition of vacuum degree ≥ 0.09Mpa, the content of impurities such as moisture, low-boiling volatiles and unreacted monomers in the material can be significantly reduced. The removal of these impurities helps to improve the purity and stability of the silicone rubber sleeve. At the same time, the temperature of 150-160°C helps to promote the regular arrangement of silicone rubber molecular chains and the formation of cross-linked structures, and promotes the regular arrangement of molecular chains; And the 2-3 hours of heating treatment can further eliminate the stress inside the silicone rubber material and improve the uniformity and stability of the material.

[0019] Preferably, the mixing condition in step S2 is 60-70°C, and the re-milling condition is 40-60°C.

[0020] By adopting the above technical solution: controlling the temperature of mixing and re-refining, it is possible to reduce excessive cross-linking reaction during mixing and re-refining. Excessive cross-linking can cause the material to harden and become brittle, thereby reducing its processing performance and physical properties.

[0021] In a third aspect, the present application provides an application of a silicone rubber tube sleeve, which adopts the following technical solution: The silicone rubber tube sleeve is used in the preparation of levonorgestrel subcutaneous implants as a carrier and a sustained-release medium for the active ingredient levonorgestrel.

[0022] By adopting the above technical solution: the silicone rubber tube sheath, as a material with good biocompatibility and stable chemical properties, can be used as a carrier of the active ingredient of the levonorgestrel drug. It can not only effectively wrap, fix and carry the drug, but also maintain the stability and activity of the drug for a long time. Relying on the precise sustained-release effect, the silicone rubber tube sheath in the present application can reduce the sudden release and concentration fluctuation of levonorgestrel in the body, thereby reducing the possible side effects and adverse reactions.

[0023] In summary, the present application uses methyl vinyl silicone rubber, white carbon black and vinyl silicone oil as raw materials, and successfully constructs a more stable three-dimensional network structure by precisely controlling the proportions and properties of these components (such as vinyl content, molecular weight and viscosity, etc.), significantly improving the physical properties of the rubber base material of the tube sleeve, and carefully selecting refined hydrogen-containing silicone oil with a specific chemical structure and hydrogen content, as well as a specific platinum complex, and strictly controlling their usage, thereby achieving precise control of the cross-linking structure of the silicone rubber tube sleeve, ensuring the uniformity and high stability of the internal structure of the tube sleeve, and thus optimizing the slow and controlled release effect of the drug; During the preparation process, we took the steps of stripping the material from the plasticizer and remixing it several times until the material reached a transparent state. This measure ensured that all components were evenly mixed, thereby greatly improving the overall quality and performance of the sleeve. In addition, we heat-treated the material under the condition of a vacuum degree of not less than 0.09Mpa, effectively removing impurities and significantly improving the purity and stability of the silicone rubber sleeve. At the same time, the appropriate heat treatment temperature and time also promoted the neat arrangement of the silicone rubber molecular chains and the perfect formation of the cross-linked structure, further enhancing the uniformity and stability of the material; This application also makes full use of the excellent biocompatibility and chemical stability of the silicone rubber tube, and uses it as an ideal carrier for the active ingredient of the levonorgestrel drug, achieving effective packaging, firm fixation and convenient carrying of the drug. This design not only optimizes the sustained-release effect of the drug, reduces drug leakage, improves the uniformity of the drug, but also significantly reduces the sudden release and concentration fluctuation of levonorgestrel in the body, thereby effectively reducing possible side effects and adverse reactions. DETAILED DESCRIPTION

[0024] The present application is further described below in conjunction with the embodiments. The raw materials used in the present application are all common commercially available materials except for the following special instructions.

[0025] Preparation Example 1-8 A pipe sleeve rubber base material, various raw materials and corresponding amounts (g) / (ml) are shown in the following table.

[0026] Table 1: Raw materials and amounts used in the preparation of the sleeve rubber base material The preparation method of the above-mentioned pipe sleeve rubber base material comprises the following steps: Weigh methyl vinyl silicone rubber according to the amount and place it in a double-drum plastic refiner, adjust the roller spacing to <5mm, turn on the equipment and mix it at 80℃, then weigh white carbon black according to the amount, add it to the double-drum plastic refiner and mix it evenly with the methyl vinyl silicone rubber, then take vinyl silicone oil according to the amount and add it to the double-drum plastic refiner, continue to mix evenly, peel the mixed material from the roller, put it back into the double-drum plastic refiner for re-refining, repeat the above operation 15 times until the mixed material becomes transparent, then cut it into sheets, put it into an oven, and heat it at 160℃ for 2h with a vacuum degree of ≥0.09MPa. After the treatment is completed, cool it to room temperature, seal it and store it for use.

[0027] The vinyl content in the methyl vinyl silicone rubber is 0.18% by molar ratio and the molecular weight is 500,000-600,000; the vinyl silicone oil is a vinyl-terminated polydimethylsiloxane with a vinyl weight percentage of 0.10% and a viscosity of 40,000 mPa·S.

[0028] Preparation Examples 9-10 A pipe sleeve rubber base material, the raw material dosage and preparation method thereof are the same as those in Preparation Example 1, the only difference being that the usage specifications of the methyl vinyl silicone rubber are different, as shown in the table below for details.

[0029] Table 2: Comparison of the usage of methyl vinyl silicone rubber Preparation Examples 11-14 A pipe sleeve rubber base material, the raw material dosage and preparation method thereof are the same as those in Preparation Example 1, the only difference being that the specification of the vinyl silicone oil used is different, as shown in the table below for details.

[0030] Table 3: Comparison table of vinyl silicone oil usage In vitro release test In the process of preparing the levonorgestrel implant, the silicone rubber tube sleeve prepared in the example was used as a drug release carrier. This carrier was placed under a UV lamp for uniform irradiation before use, and the irradiation time was controlled between 2 and 4 hours to ensure that its surface was fully disinfected and pretreated; then, we used a sealing glue to strictly seal one end of the silicone rubber tube sleeve to prepare for subsequent filling work; Next, 75 mg of levonorgestrel API was taken and crushed to 2.69 μm. The crushed drug was evenly filled into the pre-treated silicone rubber tube sleeve. After the filling was completed, the other end of the tube sleeve was sealed again with sealing glue. After curing, a levonorgestrel skin implant with a specification of 43 mm × 2.5 mm was obtained. In order to evaluate the long-term release stability and performance of the prepared intradermal implants, 5 batches of levonorgestrel intradermal implants prepared from different batches were selected for in vitro release tests. Physiological saline was used as the in vitro release medium to simulate the environment in the human body. The speed of the shaker was set to 85r / min to ensure that the drug could be stably released under simulated physiological conditions. Through long-term in vitro release experiments, we observed and recorded its daily release and calculated the average drug release amount, where D0-D1 was the first day, and the average daily drug release was calculated every 10 days thereafter: D2-D11 was from the 2nd day to the 11th day, D12-D21 was from the 12th day to the 21st day, and so on.

[0031] Examples 1-5 A silicone rubber tube sleeve, various raw materials and corresponding amounts (g) / (ml) are shown in the following table.

[0032] Table 4: Raw materials and dosage for preparing silicone rubber sleeve The platinum complex is platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane; The above-mentioned silicone rubber tube sleeve is prepared by the following preparation method: The platinum complex and the tube sleeve rubber base material prepared in Preparation Example 8 were placed in a double-drum plasticizer according to the predetermined feeding amount and mixed, and kneaded at 60°C for 2.5 hours. Then, the kneaded material was peeled off from the drum, rolled into a cylindrical shape, and placed in the double-drum plasticizer again for re-kneading at 45°C for 0.5 hours. The above operation was repeated 15 times. After cooling, it was sealed and stored at 5°C to obtain the silicone rubber tube sleeve.

[0033] Example 6 A silicone rubber tube sleeve, the raw material dosage and preparation method thereof are the same as those in Example 1, the only difference being that the platinum complex is a platinum-cyclovinylmethylsiloxane complex.

[0034] Embodiment 7-19 A silicone rubber tube sleeve, the raw material dosage and preparation method thereof are the same as those in Example 1, the only difference being that the tube sleeve rubber base material used comes from a different source, as shown in the table below for details.

[0035] Table 5: Corresponding table of sources of rubber base materials for pipe sleeves in various embodiments Group Source of rubber base material for pipe sleeve Example 7 Prepared from Preparation Example 1 Example 8 Prepared from Preparation Example 2 Example 9 Prepared from Preparation Example 3 Example 10 Prepared by Preparation Example 4 Embodiment 11 Prepared from Preparation Example 5 Example 12 Prepared from Preparation Example 6 Embodiment 13 Prepared from Preparation Example 7 Embodiment 14 Prepared from Preparation Example 9 Embodiment 15 Prepared from Preparation Example 10 Example 16 Prepared from Preparation Example 11 Embodiment 17 Prepared from Preparation Example 12 Embodiment 18 Prepared from Preparation Example 13 Embodiment 19 Prepared from Preparation Example 14 The silicone rubber tube sleeves prepared in Examples 1-19 were subjected to in vitro release tests according to the aforementioned test method, and the test results are as follows.

[0036] Table 6: In vitro drug release test results of Examples 1-19 According to the above experimental data, it can be found that the silicone rubber tube sleeve prepared by Examples 1-6, when used as a drug release carrier for levonorgestrel, has a moderate drug release in the initial release period (D0-D11), and no high concentration appears at the standard drug release of about 34 mg, and also maintains a high stability in the later release period (D52-D61), with the drug release being moderate in the initial period, stable in the middle period, and slowly decreasing in the later period; In Examples 7-13, the drug release amount showed a state of slowly increasing in the early stage, slightly fluctuating in the middle stage, and gradually decreasing in the late stage, and the drug release state was slightly inferior to that of Example 1; In Examples 14-19, the drug release amount increased rapidly in the early stage, decreased rapidly in the middle stage, and gradually decreased in the late stage, and the drug release performance was poor, which means that in the early stage of medication, the drug concentration may be too high and exceed the threshold; Since the vinyl content of the methyl vinyl silicone rubber in Examples 14-15 is different, the crosslinking density and elastic modulus of the rubber base may change, and this change may affect the diffusion rate and release pattern of the drug, causing the drug release amount to increase rapidly in the early stage and decrease rapidly in the middle stage; As for Examples 16-19, due to the different vinyl content or viscosity of the vinyl silicone oil, the crosslinking degree of the rubber base and the compatibility of the drug molecules may be affected, and the change in viscosity may affect the diffusion path and rate of the drug. These factors work together to cause the drug release to show a faster upward trend in the early stage and then rapidly decrease; Therefore, Example 1 can be used as a preferred example among Examples 1-19.

[0037] Examples 20-24 A silicone rubber tube sleeve, various raw materials and corresponding amounts (g) / (ml) are shown in the following table.

[0038] Table 7: Raw materials and dosage for preparing silicone rubber sleeve The refined hydrogen-containing silicone oil is trimethyl-terminated polymethyl hydrogen siloxane, with a hydrogen content of 1.4% by weight and a viscosity of 20 cst; The above-mentioned silicone rubber tube sleeve is prepared by the following preparation method: According to the predetermined feeding amount, the refined hydrogen-containing silicone oil and the tube sleeve rubber base material prepared in Preparation Example 8 are placed in a double-drum plastic refiner for mixing, and kneading is carried out at 60°C for 2.5 hours. Then, the kneaded material is peeled off from the drum, rolled into a cylindrical shape, and placed in the double-drum plastic refiner again for re-kneading at 45°C for 0.5 hours. The above operation is repeated 15 times. After cooling, it is sealed and stored at 5°C to obtain the silicone rubber tube sleeve.

[0039] Embodiment 25 A silicone rubber tube sleeve, the raw material dosage and preparation method of which are the same as those of Example 24, the only difference being that the refined hydrogen-containing silicone oil is dimethyl hydrogen-terminated polymethyl hydrogen siloxane, the hydrogen content is 1.4% by weight, and the viscosity is 20 cst.

[0040] Embodiment 26 A silicone rubber tube sleeve, the raw material dosage and preparation method of which are the same as those of Example 24, the only difference being that the refined hydrogen-containing silicone oil is hydroxyl-terminated polymethyl hydrogen siloxane, the hydrogen content is 1.4% by weight, and the viscosity is 20 cst.

[0041] Embodiment 27 A silicone rubber tube sleeve, the raw material dosage and preparation method of which are the same as those of Example 24, the only difference being that the refined hydrogen-containing silicone oil is trimethyl-terminated polymethyl hydrogen siloxane, the hydrogen content is 1.6% by weight, and the viscosity is 20 cst.

[0042] Embodiment 28 A silicone rubber tube sleeve, the raw material dosage and preparation method of which are the same as those of Example 24, the only difference being that the refined hydrogen-containing silicone oil is trimethyl-terminated polymethyl hydrogen siloxane, the hydrogen content is 1.8% by weight, and the viscosity is 20 cst.

[0043] Embodiment 29 A silicone rubber tube sleeve, the raw material dosage and preparation method of which are the same as those of Example 24, the only difference being that the refined hydrogen-containing silicone oil is trimethyl-terminated polymethyl hydrogen siloxane, the hydrogen content is 1.8% by weight, and the viscosity is 30 cst.

[0044] Embodiment 30 A silicone rubber tube sleeve, the raw material dosage and preparation method of which are the same as those of Example 24, the only difference being that the refined hydrogen-containing silicone oil is trimethyl-terminated polymethyl hydrogen siloxane, the hydrogen content is 1.8% by weight, and the viscosity is 40 cst.

[0045] Examples 31-43 A silicone rubber tube sleeve, the raw material dosage and preparation method thereof are the same as those in Example 16, the only difference being that the tube sleeve rubber base material used comes from a different source, as shown in the table below for details.

[0046] Table 8: Corresponding table of sources of rubber base materials for pipe sleeves in various embodiments Group Source of rubber base material for pipe sleeve Embodiment 31 Prepared from Preparation Example 1 Embodiment 32 Prepared from Preparation Example 2 Embodiment 33 Prepared from Preparation Example 3 Embodiment 34 Prepared by Preparation Example 4 Embodiment 35 Prepared from Preparation Example 5 Embodiment 36 Prepared from Preparation Example 6 Embodiment 37 Prepared from Preparation Example 7 Embodiment 38 Prepared from Preparation Example 9 Embodiment 39 Prepared from Preparation Example 10 Embodiment 40 Prepared from Preparation Example 11 Embodiment 41 Prepared from Preparation Example 12 Embodiment 42 Prepared from Preparation Example 13 Embodiment 43 Prepared from Preparation Example 14 Embodiment 44 A silicone rubber tube sleeve, various raw materials and corresponding amounts (g) / (ml) are shown in the following table.

[0047] Table 9: Raw materials and dosage for preparing silicone rubber sleeve The above-mentioned silicone rubber tube sleeve is prepared by the following preparation method: The platinum complex, refined hydrogen-containing silicone oil and the tube sleeve rubber base material prepared in Preparation Example 8 were placed in a double-drum plasticizer according to the predetermined feeding amount and mixed, and kneaded at 60°C for 2.5 hours. Then, the kneaded material was peeled off from the drum, rolled into a cylindrical shape, and placed in the double-drum plasticizer again for re-kneading at 45°C for 0.5 hours. The above operation was repeated 15 times. After cooling, it was sealed and stored at 5°C to obtain the silicone rubber tube sleeve.

[0048] The silicone rubber tube sleeves prepared in Examples 20-44 were subjected to in vitro release tests according to the aforementioned test method, and the test results are as follows.

[0049] Table 10: In vitro drug release test results of Examples 20-44 Based on the test data, we can draw the following conclusions: In Examples 20 to 24, the prepared silicone rubber tube sleeve as a sustained-release carrier of levonorgestrel has excellent performance. In the early release period (D0-D11), the drug release amount is stably maintained within the range of about 34 mg, and there is no excessive peak concentration. In the late release period (D52-D61), the drug release amount is also stable, showing an ideal release pattern: initial gentle release, mid-term stable and continuous, and late slow reduction. This is mainly attributed to the proper selection of the type and amount of refined hydrogen-containing silicone oil, which forms a stable cross-linked structure, thereby promoting the gentle release of the drug. The hydrogen content, viscosity and end-capping group of the refined hydrogen-containing silicone oil have a positive effect on the diffusion rate and release pattern of the drug; In contrast, in Examples 27 to 37, when the silicone rubber tube was used as a drug release carrier, the drug release characteristics showed certain fluctuations. In the early stage of release, the drug release amount gradually and slowly increased; in the middle stage, there was a small fluctuation; in the later stage, the drug release amount began to gradually decrease, which may be related to the increase in hydrogen content or the change in viscosity. These factors may have accelerated the release of the drug or changed its release curve, resulting in a slightly inferior drug release state compared to Example 24. In Examples 38 to 43, the variation trend of the drug release amount is more significant: it increases rapidly in the early stage, decreases sharply in the middle stage, and decreases slowly in the late stage. Such drug release performance may not meet the requirements of safety or efficacy, because the drug concentration may increase abnormally in the early stage of medication, exceeding the required threshold value, which may be related to the source and property differences of the rubber base material of the tube sleeve, resulting in changes in the drug diffusion path and rate; In Example 44, the situation is more complicated. The drug release amount reaches a relatively high level (45.39 μg) in the early stage and continues to rise sharply in the middle stage. Then, the drug release amount begins to decline, but it still maintains a relatively high level (32.84 μg) in the later stage of drug release. This may be due to the additional addition of platinum complex as a catalyst, which causes the cross-linking reaction to be too rapid and violent, thereby accelerating the release of the drug. In addition, the interaction between the platinum complex and the levonorgestrel drug molecules may also affect the release pattern of the drug.

[0050] The above are all modifications without creative contribution or solutions that obviously constitute technical inspiration that can be made to the present embodiment as needed by technical personnel in this field after reading this specification, but they should be protected by patent law as long as they are within the scope of the claims of this application.

Claims

1. A silicone rubber tube sleeve, characterized in that: The raw materials used for the preparation are measured by weight and include the following components: 600-900 parts of pipe sleeve rubber base material, 0-4 parts of platinum complex, 0-10 parts of refined hydrogen-containing silicone oil; The pipe sleeve rubber base material is prepared by the following method: methyl vinyl silicone rubber, white carbon black and vinyl silicone oil are added into a plastic refiner in sequence and uniformly mixed, then the mixed materials are peeled off from the plastic refiner, and then put into the plastic refiner again for mixing after cooling, and the above operation is repeated until the mixed materials are transparent, and then cut into sheets and collected to obtain the obtained material; The raw materials used for preparing the sleeve rubber base material include, by weight: Methyl vinyl silicone rubber 400-600 parts 250-450 parts of white carbon black 15-30 parts of vinyl silicone oil; The vinyl content in the methyl vinyl silicone rubber is 0.16-0.21% by molar ratio, and the molecular weight is 500,000-600,000; the vinyl silicone oil is a vinyl-terminated polydimethylsiloxane with a vinyl weight percentage content of 0.08-0.12% and a viscosity of 10,000-60,000 mPa·S.

2. The silicone rubber sleeve according to claim 1, characterized in that: The vinyl content of the methyl vinyl silicone rubber is 0.18% by molar ratio and the molecular weight is 500,000-600,000; the vinyl silicone oil is a vinyl-terminated polydimethylsiloxane with a vinyl weight percentage content of 0.10% and a viscosity of 10,000-60,000 mPa·s.

3. The silicone rubber sleeve according to claim 1, characterized in that: The raw materials used for preparing the silicone rubber tube sleeve are composed of the following components in parts by weight: 800-850 copies of pipe sleeve rubber base material 2-3 parts of platinum complex; The platinum complex is platinum (0)-1,3-diethene-1,1,3,3-tetramethyldisiloxane or platinum-cyclovinylmethylsiloxane complex.

4. The silicone rubber sleeve according to claim 1, characterized in that: The raw materials used for preparing the silicone rubber tube sleeve are composed of the following components in parts by weight: 600-800 copies of pipe sleeve rubber base material 5-8 parts of refined hydrogen-containing silicone oil; The refined hydrogen-containing silicone oil is trimethyl or dimethyl hydrogen or hydroxyl terminated polymethyl hydrogen siloxane, the hydrogen content is 1.4-1.8% by weight, and the viscosity is 20-40cst.

5. The method for preparing the silicone rubber sleeve according to any one of claims 1 to 4, characterized in that: The method comprises the following preparation steps: S1: placing the raw materials for preparing the pipe sleeve rubber base material in a plastic purifier according to the feeding amount, mixing them, and kneading them at 80-110° C., then peeling the mixed material from the plastic purifier, and then putting it into the plastic purifier for re-kneading at 60-80° C., repeating the above operation 15-20 times, and finally peeling the material and cutting it into sheets, and performing heat treatment at the same time, and then cooling it to room temperature to obtain the pipe sleeve rubber base material for standby use; S2: The sleeve rubber base material, the platinum complex and the refined hydrogen-containing silicone oil are placed in a plastic refiner for mixing and kneading. Then, the mixed materials are peeled off from the plastic refiner and placed in the plastic refiner for re-kneading. The above operation is repeated 15-20 times. After cooling, the mixture is sealed and stored at 2-8°C to obtain the product.

6. The method for preparing the silicone rubber sleeve according to claim 5, characterized in that: The heat treatment conditions in step S1 are vacuum degree ≥ 0.09Mpa, 150-160°C, and heating treatment for 2-3h.

7. The method for preparing the silicone rubber sleeve according to claim 5, characterized in that: The mixing condition in step S2 is 60-70°C, and the re-milling condition is 40-60°C.

8. Use of the silicone rubber tube sleeve according to any one of claims 1 to 4 in the preparation of a levonorgestrel subcutaneous implant, characterized in that: As a carrier and controlled-release medium for the active pharmaceutical ingredient levonorgestrel.

Images