Silicone material, silicone tube, implant, pharmaceutical composition, and method for measuring drug release amount

Abstract

The present invention discloses a silicone material, a silicone tube, an implant, a pharmaceutical composition, and a method for measuring a drug release amount. In parts by weight, the raw material composition of the silicone material includes 100 parts of R-vinyl silicone rubber, 20-80 parts of a reinforcing agent, 0.3-3.0 parts of hydrogen-containing silicone oil, and ≧0.000002 parts of a catalyst, preferably 0.000002-0.00005 parts, the vinyl content in the R-vinyl silicone rubber is 0.10-0.50 mol%, the Si-H group content in the hydrogen-containing silicone oil is 0.18-1.6 mol%, the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl in the R-vinyl silicone rubber is (0.5-4):1, and optionally further includes an inhibitor. The silicone tube produced by the silicone material of the present invention has excellent mechanical properties and good biocompatibility, and the drug release curve after the implant produced by the silicone tube is loaded with an active drug is stable.

Description

[Technical field]

[0001] This application claims priority to Chinese patent application No. 202210273495X, filed on March 18, 2022. This application cites the above-mentioned Chinese patent application in full.

[0002] This application claims priority to Chinese patent application No. 2022102727087, filed on March 18, 2022. This application cites the above Chinese patent application in full.

[0003] This application claims priority to Chinese patent application No. 2022102727072, filed on March 18, 2022. This application cites the above-mentioned Chinese patent application in full.

[0004] This application claims priority to Chinese patent application No. 2022102791223, filed on March 18, 2022. This application cites the above Chinese patent application in full.

[0005] This application claims priority to Chinese patent application No. 2023102715686, filed on March 20, 2023. This application cites the above-mentioned Chinese patent application in full.

[0006] This application claims priority to Chinese patent application No. 2023102715690, filed on March 20, 2023. This application cites the above-mentioned Chinese patent application in full.

[0007] This application claims priority to Chinese patent application No. 2023102737238, filed on March 20, 2023. This application cites the above-mentioned Chinese patent application in full.

[0008] This application claims priority to Chinese patent application No. 2023102715718, filed on March 20, 2023. This application cites the above-mentioned Chinese patent application in full.

[0009] [Technical field] The present invention relates to a silicone material, a silicone tube, an implant, a pharmaceutical composition, and a method for measuring the amount of drug released. [Background technology]

[0010] Modern common contraceptive methods include non-hormonal contraceptives (male / female condoms, male / female sterilization, etc.) and hormonal contraceptives (various oral contraceptives, subdermal implants, progestin intrauterine devices, contraceptive injections, etc.). Among them, hormonal contraceptives have consistently shown reliable contraceptive efficacy.

[0011] Since the concept of "sustained-release preparations" was proposed, sustained-release preparations for contraception have made great progress, and they effectively avoid the disadvantages of surgical contraception and the reduced compliance with oral contraceptives. Sustained-release preparations that provide long-term contraception, particularly subdermal contraceptive implants, are expected to be used in a wide range of applications in the field of contraception.

[0012] Levonorgestrel (LNG), also known as Norlevo, is listed in the pharmacopoeias of China, the United States, the United Kingdom, Japan, and other countries. Currently, there are many single-agent and combined contraceptives with levonorgestrel as the main drug on the international and Chinese markets, and it is the earliest and most widely used over-the-counter drug in clinical use.

[0013] Gestodene is a third-generation contraceptive that provides contraceptive efficacy at low clinical doses without estrogenic activity, has both good antiestrogenic activity and slight androgenic activity, tends to be 100% bioavailable, and is currently the only progesterone that does not require metabolism to function.

[0014] Subdermal implants mainly contain active drugs in a carrier and are implanted subcutaneously. The implant controls the release of the drug through the carrier, and the drug is absorbed into the blood circulation through the local capillaries, achieving stable release for several years and achieving long-term contraceptive effect. This formulation can avoid the first-pass effect in the gastrointestinal tract, thereby greatly improving the bioavailability of the drug. Subdermal implants are not suitable for IUD implantation, but are suitable for people who want long-term contraception. After implantation, if a woman wants to become pregnant, she can remove the implant to restore her ability to become pregnant.

[0015] Silicone materials are one of the most biocompatible synthetic materials today, and medical textbooks in the 1960s recognized silicone as an important implant material, and its practical use has been reported very extensively. The American company Dow Corning has provided numerous literature reports demonstrating that silicone gel breast implants are safe for the human body, and research into organic silicone materials has led to their increasingly widespread use in the medical field. Some researchers have carried out many animal experiments, and no side effects have been observed when silicone materials are implanted in animals for three years, gradually proving their safety when implanted in the human body.

[0016] At present, additive silicone rubber is mainly used in the manufacture of medical products, especially silicone rubber products that are implanted in the human body for a long time, and additive silicone rubber is mainly used in various situations such as contact with blood and implantation in the body. Existing silicone rubber is generally manufactured through a simple extrusion process, such as the manufacturing process disclosed in Chinese Patent CN1727409A. Silicone rubber tubes manufactured by this additive method have poor mechanical properties and are difficult to meet the requirements for clinical use. Summary of the Invention

[0017] The technical problem to be solved by the present invention is to provide a silicone material and a manufacturing method thereof, a silicone tube, and an implant containing the same, in order to overcome the drawback that the mechanical properties of the silicone rubber tube manufactured by the additive method in the prior art are poor and it is difficult to meet the requirements for clinical use. The silicone tube manufactured by the silicone material of the present invention has excellent mechanical properties and good biocompatibility, the drug release curve of the implant manufactured by the silicone tube is stable, and when the loaded drug is a contraceptive drug (e.g., gestodene, levonorgestrel, estradiol), the manufactured implant can provide a significant contraceptive effect in rats.

[0018] Silicone Material The present invention comprises, in parts by weight: R-vinyl silicone rubber: 100 parts; Reinforcing agent: 20-80 parts; Hydrogen-containing silicone oil: 0.3 to 3.0 parts; Catalyst: ≧0.000002 parts, preferably 0.000002-0.00005 parts; Including, however, R in the R-vinyl silicone rubber is a substituted or unsubstituted C1 to C5 linear or branched alkane, a substituted or unsubstituted C6 to C 20 It is an aromatic hydrocarbon, The vinyl content in the R-vinyl silicone rubber is 0.10 to 0.50 mol %, The hydrogen-containing silicone oil has a Si-H group content of 0.18 to 1.6 mol %, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-4):1; Optionally, further comprising an inhibitor, the inhibitor being capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil; A silicone material raw material composition is provided.

[0019] In the present invention, R in the R-vinyl silicone rubber may be a substituted or unsubstituted C1 to C5 linear alkane, for example, methyl.

[0020] When the R is methyl, the R-vinyl silicone rubber is a methylvinyl silicone rubber.

[0021] Here, the methylvinyl silicone rubber may be a typical methylvinyl silicone rubber in the art, for example, a methylvinyl silicone rubber having a relative molecular weight of 100,000 to 800,000 g / mol.

[0022] In the present invention, the vinyl content in the R-vinyl silicone rubber is preferably 0.10 to 0.23 mol %, for example, 0.17 mol % or 0.23 mol %, and more preferably 0.17 to 0.23 mol %.

[0023] In the present invention, the reinforcing agent may be a reinforcing agent that can improve the hardness of the R-vinyl silicone rubber that is common in the art, such as one or more of white carbon black, diatomaceous earth, quartz powder, fine silica powder, calcium carbonate, aluminum hydroxide, magnesium oxide, white titanium powder, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate, and calcium carbonate, for example, white carbon black.

[0024] Here, the white carbon black can be a common white carbon black in the art, such as gaseous white carbon black, precipitated white carbon black, gel white carbon black or surface-treated white carbon black, preferably gaseous white carbon black. The gaseous white carbon black can be gaseous white carbon black purchased from Dalian Shengsen Nano Silicon Carbon Materials Co., Ltd.

[0025] Here, the calcium carbonate may be any calcium carbonate common in the art, for example precipitated calcium carbonate.

[0026] In the present invention, the amount of the reinforcing agent used is preferably 30 to 80 parts, for example, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, or 60 parts.

[0027] In the present invention, the hydrogen-containing silicone oil can be any hydrogen-containing silicone oil commonly used in the art, such as hydrogen-containing silicone oil purchased from Guangdong Silicon Ye New Material Technology Co., Ltd.

[0028] In the present invention, the amount of the hydrogen-containing silicone oil used is preferably 0.4 to 2.8 parts, for example, 0.42 parts, 0.67 parts, 0.84 parts, 1.01 parts, 1.26 parts, 1.36 parts, 1.51 parts, 1.68 parts, or 2.52 parts.

[0029] In the present invention, the content of Si-H groups in the hydrogen-containing silicone oil is preferably 0.36 to 1.6 mol %, for example, 0.36 mol %, 0.5 mol %, 0.75 mol %, 1.0 mol %, or 1.6 mol %.

[0030] In the present invention, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is preferably (0.8 to 4.0):1, for example, (0.8 to 3.0):1 or (0.8 to 2.0):1, and also, for example, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1 or 3.0:1, and preferably (1.2 to 1.8):1 or (1.2 to 1.5):1.

[0031] In the present invention, the inhibitor may be an inhibitor that can inhibit the addition reaction of R-vinyl silicone rubber (e.g., methyl vinyl silicone rubber) and hydrogen-containing silicone oil at room temperature, which is commonly used in the art, such as an alkynol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol, or 2-methyl-3-butyn-2-ol.

[0032] In the present invention, the amount of the inhibitor used is preferably 0.03 to 2.0 parts, for example, 0.3 to 1.0 part, and for example, 0.3 parts, 0.5 parts, 0.7 parts, or 0.9 parts.

[0033] In the present invention, the catalyst may be a catalyst that can catalyze the addition reaction between methylvinylsilicone rubber and hydrogen-containing silicone oil that is common in the art, such as a rhodium catalyst, a palladium catalyst, or a platinum catalyst, and preferably a platinum catalyst.

[0034] Here, the platinum concentration in the platinum catalyst may be 3000 ppm, where 3000 ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million.

[0035] In the present invention, the amount of the catalyst used is preferably 0.000005 to 0.00005 parts, for example, 0.000005 parts, 0.00001 parts, 0.00002 parts, or 0.00003 parts.

[0036] In the present invention, the vulcanization principle of the two-liquid addition type silicone rubber: The two-liquid addition type room temperature vulcanization silicone rubber, for example, uses vinyl dimethicone as the base polymer and hydrogen-containing silicone oil as the crosslinking agent, and under the catalytic action of a catalyst (e.g., platinum catalyst), a hydrosilylation reaction occurs between the vinyl group and the hydrogen group to form a crosslinked network structure, which can control the drug release.

[0037] Since the intermolecular force of polyorganosilane is very small, when raw rubber is vulcanized by itself, it has poor mechanical properties and is not useful. In order to improve its mechanical properties, it is generally reinforced with a filler, and white carbon black is the most commonly used reinforcing filler, which can greatly increase the hardness of silicone materials. Among them, silazane-treated gas-phase white carbon black has a hydrophobic surface, so it is easy to disperse in silicone materials and has a better reinforcing effect.

[0038] Raw rubber can be reacted at room temperature after being mixed with fillers, crosslinking agents, and catalysts, but the kneading and processing of rubber requires a certain time, and if the reactants harden prematurely during the operation, the desired shape and properties cannot be obtained. This is especially true for addition-type silicone rubber. Therefore, the catalytic reaction is generally almost ineffective before vulcanization (mixing at room temperature), and is required to react rapidly once the vulcanization temperature is reached. The method of inhibiting the reaction is usually to add an inhibitor. The inhibitor can form a complex of a certain form with the platinum catalyst, and an effective inhibitor is left in the rubber for a long time and will only be vulcanized when it is heated to the specified vulcanization temperature. Commonly used are alkynol-based compounds, nitrogen-containing compounds, organic peroxides, etc., which have good compatibility.

[0039] In a preferred embodiment of the present invention, the silicone material raw material composition comprises, in parts by weight: Methylvinylsilicone rubber: 100 parts; Reinforcing agent: 20-80 parts; Hydrogenated silicone oil: 0.3 to 3.0 parts; Catalyst: 0.000002~0.00005 parts; Inhibitor: 0.03-2.0 parts; Includes. however, The vinyl content in the methyl vinyl silicone rubber is 0.10 to 0.50 mol %, The hydrogen-containing silicone oil has a Si-H group content of 0.18 to 1.6 mol %, The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinyl silicone rubber is (0.5-4:1).

[0040] In a preferred embodiment of the present invention, the silicone material raw material composition comprises, in parts by weight: Methylvinylsilicone rubber: 100 parts; Reinforcing agent: 30-60 parts; Hydrogenated silicone oil: 0.4-2.8 parts; Catalyst: 0.000002~0.00005 parts; Inhibitor: 0.3-1.0 parts; Includes. however, The vinyl content in the methyl vinyl silicone rubber is 0.17 to 0.23 mol %, The hydrogen-containing silicone oil has a Si-H group content of 0.18 to 1.6 mol %, The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinyl silicone rubber is (0.8-2:1).

[0041] In a preferred embodiment of the present invention, the silicone material raw material composition comprises, in parts by weight: Methylvinylsilicone rubber: 100 parts; Reinforcing agent: 30-45 parts; Hydrogenated silicone oil: 0.42-2.52 parts; Catalyst: 0.000002~0.00005 parts; Inhibitor: 0.3-0.9 parts; Includes. however, The vinyl content in the methyl vinyl silicone rubber is 0.17 to 0.23 mol %, The hydrogen-containing silicone oil has a Si-H group content of 0.5 to 1.0 mol %, The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinylsilicone rubber is (1.2-1.8:1).

[0042] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 1]

[0043] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 2]

[0044] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 3]

[0045] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 4]

[0046] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 5]

[0047] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 6]

[0048] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 7]

[0049] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 8]

[0050] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 9]

[0051] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 10]

[0052] In some preferred embodiments of the present invention, the silicone material source composition, in parts by weight, is any one of the following numbers: [Table 11]

[0053] The present invention further provides a method for producing a silicone material, comprising the step of shaping a mixture of a raw composition of the silicone material by a catalytic addition process. (1) In the raw material composition of the silicone material, R-vinyl silicone rubber: 100 parts; Reinforcing agent: 20-80 parts; Hydrogenated silicone oil: 0.3 to 3.0 parts; Catalyst: ≧0.000002 parts, preferably 0.000002-0.00005 parts; Includes. however, R in the R-vinyl silicone rubber is a substituted or unsubstituted C1 to C5 linear or branched alkane, a substituted or unsubstituted C6 to C 20 It is an aromatic hydrocarbon, The vinyl content in the R-vinyl silicone rubber is 0.10 to 0.50 mol %, The hydrogen-containing silicone oil has a Si-H group content of 0.18 to 1.6 mol %, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-4):1; Optionally, further comprising an inhibitor, said inhibitor being capable of inhibiting the addition reaction between said R-vinyl silicone rubber and said hydrogen-containing silicone oil; (2) The catalyst addition process includes a first heat treatment and a second heat treatment in sequence, the temperature of the first heat treatment is 250 to 360°C, and the temperature of the second heat treatment is 120 to 300°C, for example, 120 to 280°C.

[0054] In some preferred embodiments of the present invention, the components and the contents thereof in the raw material composition of the silicone material are as described above.

[0055] In the present invention, the catalyst addition process may be an extrusion process.

[0056] In the present invention, the temperature of the first heat treatment may be 250 to 330°C, for example, 270°C, 280°C, 300°C, or 330°C.

[0057] In the present invention, the time of the first heat treatment is related to the processing length of the catalyst addition process, for example, the extrusion length of the extrusion process, and for example, when the processing length of the first heat treatment is 0.8 m, the time of the first heat treatment may be about 5 seconds.

[0058] In the present invention, the temperature of the second heat treatment may be 150 to 300°C, for example, 150 to 280°C, for example, 150°C, 180°C, 210°C, 260°C, or 280°C.

[0059] In the present invention, the time of the second heat treatment is related to the processing length of the catalyst addition process, for example, the extrusion length of the extrusion process, and for example, when the extrusion length of the second heat treatment is 2.5 m, the time of the second heat treatment may be about 2 minutes.

[0060] In the present invention, after the second heat treatment, a third heat treatment can be further carried out.

[0061] Here, the temperature of the third heat treatment may be 100 to 280°C, for example, 180°C.

[0062] Here, the time period of the third heat treatment is preferably 0 to 72 hours, for example, 0 hour, 24 hours, 48 ​​hours or 72 hours.

[0063] In the present invention, the temperature of the first heat treatment is preferably 270°C, and the temperature of the second heat treatment is preferably 180°C.

[0064] In the present invention, the catalyst addition process can be extrusion molding in a tubular die. When extruding in a tubular die, the silicone material is in a tubular shape.

[0065] In the present invention, the mixture of raw material compositions of the silicone material can be prepared by the following method: Method 1: When the raw material composition of the silicone material does not contain an inhibitor, the method for producing the mixture includes: Step S1 of uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A; Step S2 of obtaining mixture B by mixing mixture A with the hydrogen-containing silicone oil in the presence of the catalyst. Including, Method 2: When the raw material composition of the silicone material further contains an inhibitor, the method for producing the silicone material includes: Step S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A; Step S2: Dividing the mixture A into components A1 and A2, mixing the component A1 and the catalyst to obtain component B1, and mixing the component A2 with the hydrogen-containing silicone oil and the inhibitor to obtain component B2; Step S3 of mixing the component B1 and the component B2 to obtain a mixture B Includes.

[0066] In the above-mentioned methods 1 and 2, the reinforcing agent can be pretreated by a method commonly used in the art, for example, by drying the reinforcing agent at 100 to 210°C (e.g., 180 to 210°C, or e.g., 200°C) for 1 to 24 hours (e.g., 24 hours) before use.

[0067] In the above methods 1 and 2, the R-vinyl silicone rubber can be pretreated by a method commonly used in the art, such as drying the rubber at 30 to 60°C (e.g., 40°C) for 1 to 24 hours (e.g., 24 hours) before use.

[0068] Here, in the method 1 and the method 2, the mixing in S1 is The method includes the steps of enveloping the R-vinyl silicone rubber with the reinforcing agent, thinly extruding the rubber in an open mill, and compressing the rubber into tablets.

[0069] In the above methods 1 and 2, the mixture A may be allowed to stand in a desiccator at room temperature for 24 to 72 hours.

[0070] Here, in the method 1 and the method 2, the mixing in S1 is The method includes a step of kneading the R-vinyl silicone rubber and the reinforcing agent in a kneader at 30°C for 30 minutes, removing the mixture, placing it on an open mill in a triangular pattern with a roll spacing of 1 to 10 mm (e.g., 1 mm), milling it five times, winding up the film into a roll, and leaving it for a further 24 hours to obtain mixture A.

[0071] Here, in the method 1, before carrying out the catalyst addition process, the mixture B can be subjected to post-treatment such as milling 4 to 6 times in an open mill using triangular milling, and then uniformly slicing and taking out.

[0072] Here, in the method 2, the mixing of the component B1 and the component B2 includes the steps of putting the component B1 and the component B2 in an open mill in a ratio of 1:1, milling the components 4 to 6 times in a triangular manner, and uniformly slicing and taking out the components.

[0073] The present invention further provides a method for producing a silicone material, comprising the steps of: Method 1: When the raw material composition of the silicone material does not contain an inhibitor, the method for producing the silicone material includes: Step S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A; Step S2 of obtaining mixture B by mixing mixture A and hydrogen-containing silicone oil in the presence of the catalyst, and adding the catalyst. Including, Method 2: When the raw material composition of the silicone material further contains an inhibitor, the method for producing the silicone material includes: Step S1 of uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A; Step S2: Dividing the mixture A into components A1 and A2, mixing the component A1 and the catalyst to obtain component B1, and mixing the component A2 with the hydrogen-containing silicone oil and the inhibitor to obtain component B2; Step S3 of mixing the component B1 and the component B2 to obtain a mixture B and carrying out catalyst addition Includes.

[0074] In some preferred embodiments of the present invention, the components and the contents thereof in the raw material composition of the silicone material are as described above.

[0075] In some preferred embodiments of the present invention, the conditions of Method 1 and Method 2 are as described above.

[0076] The present invention further provides a silicone material produced by the above method.

[0077] When the catalyst addition process is performed by extrusion in a tubular die, the silicone material is in a tubular shape.

[0078] The present invention further provides a silicone tube produced by a method of extruding the silicone material into a tubular shape.

[0079] Alternatively, in the method for producing the silicone material, the catalyst addition process is carried out in a tubular mold to obtain the silicone tube.

[0080] The present invention further provides the use of said silicone material or said silicone tubing as a release rate controlling medium in a sustained release formulation.

[0081] Pharmaceutical Compositions In the prior art, subcutaneous implants are generally produced by directly filling the drug substance into the silicone tube. However, due to the small particle size of the drug substance after grinding and easy to generate static electricity, the drug substance powder is highly scattered during the filling process, and a large amount of drug substance powder adheres to the outer surface of the silicone tube, which not only causes drug substance waste, but also affects the health of staff, and is prone to sudden drug release, which may affect the safety of users. At the same time, spontaneous aggregation of drug substance also affects the drug release stability of the implant.

[0082] Furthermore, if the structure (e.g., wall thickness, length or diameter), composition (ingredients and content) and manufacturing method (process parameters) of the silicone tube remain unchanged, the prior art subdermal implants cannot adjust the drug release amount.

[0083] Therefore, there is an urgent need to provide a pharmaceutical composition and a manufacturing method thereof that can effectively solve the above problems. The pharmaceutical composition can prevent scattering of the raw drug powder during the filling process, reduce the static electricity of the raw drug powder, facilitate the filling of the drug, and also prevent the natural aggregation of the drug. Furthermore, the subcutaneous implant made from the pharmaceutical composition has high drug release stability, and at the same time, by adjusting the pH value by adding different types of insoluble acids and bases, subcutaneous implants with different daily release amounts can be obtained, and the drug release stability is high.

[0084] In order to overcome the drawbacks of the prior art, in which the drug core (drug substance) powder of the subdermal implant scatters, and adheres in large amounts to the outer wall of the implant tube due to strong static electricity of the drug substance powder, and the unstable release of the drug due to natural agglomeration of the drug makes it difficult to accurately fill a small amount of drug, and further the poor release stability of the manufactured implant, a pharmaceutical composition, a manufacturing method and use thereof, and an implant containing the same are provided. The pharmaceutical composition of the present invention is less likely to generate static electricity, is easy to fill, can effectively prevent powder scattering and natural agglomeration, has a high utilization rate of the drug substance, and improves the drug release stability of the subdermal implant manufactured from the pharmaceutical composition.

[0085] The present invention provides a pharmaceutical composition comprising an active pharmaceutical ingredient and a poorly soluble auxiliary material, including a silicone material.

[0086] In the present invention, the density of the poorly soluble auxiliary material may be 1 to 10,000 g / L, for example, 1,000 g / L.

[0087] The poorly soluble auxiliary material may have a particle size of 1 to 200 μm.

[0088] The pore size of the silicon material may be less than 1 μm, for example, 0 nm, 5 nm, 10 nm, 18 nm, 50 nm or 100 nm. Those skilled in the art can understand that when the pore size of the silicon material is 0 nm, the silicon material is a non-porous silicon material.

[0089] In said silicon material, the silica content may be more than 50%, preferably 80%, 90%, 95%, 99% or 99.8%.

[0090] In the present invention, the refractory auxiliary material may include one or more of white carbon black, AL-1FP mesoporous silicon, XDP3050 mesoporous silicon, and XDP3150 mesoporous silicon.

[0091] Here, the white carbon black is preferably gas phase white carbon black, precipitated white carbon black, gel white carbon black, or white carbon black obtained by surface treatment.

[0092] Preferably, the refractory auxiliary material is one or more of white carbon black, AL-1FP mesoporous silicon, XDP3050 mesoporous silicon and XDP3150 mesoporous silicon.

[0093] More preferably, the refractory auxiliary material is one or more of white carbon black, AL-1FP mesoporous silicon and XDP3050 mesoporous silicon.

[0094] In the present invention, the poorly soluble auxiliary material may further include a poorly soluble weak acid and / or a poorly soluble weak base.

[0095] Here, the sparingly soluble weak acid preferably includes one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, and more preferably includes boric acid and / or fumaric acid.

[0096] Here, the poorly soluble weak base preferably includes one or more of magnesium hydroxide, aluminum hydroxide, zinc hydroxide, ferrous hydroxide, and magnesium oxide, and more preferably includes one or more of magnesium hydroxide, aluminum hydroxide, and zinc hydroxide.

[0097] In the present invention, the poorly soluble auxiliary material may be one of the following a to z: a, white carbon black; b, white carbon black and magnesium hydroxide; c, white carbon black and aluminum hydroxide; d, white carbon black and zinc hydroxide; e, white carbon black and fumaric acid; f, white carbon black and boric acid; g, AL-1FP mesoporous silicon; h, AL-1FP mesoporous silicon and XDP3050 mesoporous silicon; i, AL-1FP mesoporous silicon and XDP3150 mesoporous silicon; j, AL-1FP mesoporous silicon and magnesium hydroxide; k, AL-1FP mesoporous silicon and aluminum hydroxide; l, AL-1FP mesoporous silicon and zinc hydroxide; m, AL-1FP mesoporous silicon and fumaric acid; n, AL-1FP mesoporous silicon and boric acid; o, XDP3050 mesoporous silicon; p, XDP3050 mesoporous silicon and magnesium hydroxide; q, XDP3050 mesoporous silicon and aluminum hydroxide; r, XDP3050 mesoporous silicon and zinc hydroxide; s, XDP3050 mesoporous silicon and fumaric acid; t, XDP3050 mesoporous silicon and boric acid; u, XDP3150 mesoporous silicon; v, XDP3150 mesoporous silicon and magnesium hydroxide; w, XDP3150 mesoporous silicon and aluminum hydroxide; x, XDP3150 mesoporous silicon and zinc hydroxide; y, XDP3150 mesoporous silicon and fumaric acid; z, XDP3150 mesoporous silicon and boric acid.

[0098] In the present invention, the poorly soluble auxiliary material may be one or more of white carbon black and molybdic acid, silicic acid, tungstic acid and germanic acid, such as white carbon black and molybdic acid, white carbon black and silicic acid, white carbon black and tungstic acid, or white carbon black and germanic acid.

[0099] Alternatively, the sparingly soluble auxiliary material may further be white carbon black and ferrous hydroxide and / or magnesium oxide, for example, white carbon black and ferrous hydroxide, or white carbon black and magnesium oxide.

[0100] Alternatively, the refractory auxiliary material may further be one or more of AL-1FP mesoporous silicon and molybdic acid, silicic acid, tungstic acid and germanic acid, such as AL-1FP mesoporous silicon and molybdic acid, AL-1FP mesoporous silicon and silicic acid, AL-1FP mesoporous silicon and tungstic acid, or AL-1FP mesoporous silicon and germanic acid.

[0101] Alternatively, the refractory auxiliary material may further be AL-1FP mesoporous silicon and ferrous hydroxide and / or magnesium oxide, for example AL-1FP mesoporous silicon and ferrous hydroxide, or AL-1FP mesoporous silicon and magnesium oxide.

[0102] Alternatively, the refractory auxiliary material may further be XDP3050 mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid, such as XDP3050 mesoporous silicon and molybdic acid, XDP3050 mesoporous silicon and silicic acid, XDP3050 mesoporous silicon and tungstic acid, or XDP3050 mesoporous silicon and germanic acid.

[0103] Alternatively, the refractory auxiliary material may further be XDP3050 mesoporous silicon and ferrous hydroxide and / or magnesium oxide, for example XDP3050 mesoporous silicon and ferrous hydroxide, or XDP3050 mesoporous silicon and magnesium oxide.

[0104] Alternatively, the refractory auxiliary material may further be XDP3150 mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid, such as XDP3150 mesoporous silicon and molybdic acid, XDP3150 mesoporous silicon and silicic acid, XDP3150 mesoporous silicon and tungstic acid, or XDP3150 mesoporous silicon and germanic acid.

[0105] Alternatively, the refractory auxiliary material may further be XDP3150 mesoporous silicon and ferrous hydroxide and / or magnesium oxide, for example XDP3150 mesoporous silicon and ferrous hydroxide, or XDP3150 mesoporous silicon and magnesium oxide.

[0106] In the present invention, the content of the drug substance may be 10% to 99.9%, for example, 50% to 99.5%, or for example, 95%, where the percentage is the mass percentage of the drug substance in the pharmaceutical composition.

[0107] The content of the poorly soluble auxiliary material may be 0.1% to 90%, for example, 0.1% to 50%, or for example, 0.5% to 5%, the percentage being the mass percentage of the poorly soluble auxiliary material in the pharmaceutical composition.

[0108] In the present invention, when the poorly soluble auxiliary materials are two or three of white carbon black, AL-1FP mesoporous silicon, and XDP3050 mesoporous silicon, the mass ratio thereof may be any ratio.For example, when the poorly soluble auxiliary materials are two of white carbon black, AL-1FP mesoporous silicon, and XDP3050 mesoporous silicon, the mass ratio thereof is (0.001-1000):1.

[0109] Furthermore, for example, when the poorly soluble auxiliary material is XDP3150 mesoporous silicon and fumaric acid, the mass ratio thereof is (0.01 to 100):1, and preferably 9:1, 1.5:1, or 0.43:1.

[0110] Furthermore, for example, when the poorly soluble auxiliary material is gas-phase white carbon black and boric acid, the mass ratio thereof may be (0.01 to 100):1, and is preferably 9:1, 1.5:1, or 0.43:1.

[0111] Furthermore, for example, when the poorly soluble auxiliary material is XDP3050 mesoporous silicon and magnesium hydroxide, the mass percentage thereof may be (0.01 to 100):1, and preferably is 9:1, 1.5:1, or 0.43:1.

[0112] Furthermore, for example, when the poorly soluble auxiliary material is AL-1FP mesoporous silicon and zinc hydroxide, the mass percentage thereof may be (0.01 to 100):1, and is preferably 9:1, 1.5:1, or 0.43:1.

[0113] In the present invention, the drug substance may be a small molecule drug with a solubility of less than 100 mg / mL.

[0114] In the present invention, the molecular weight of the drug substance may be less than 1000 Da.

[0115] In the present invention, the active pharmaceutical ingredient in the drug substance may include an active pharmaceutical ingredient acting on the reproductive system, or an active pharmaceutical ingredient acting on the urinary system, or an active pharmaceutical ingredient acting on chronic diseases related to metabolism and nutrition, or an active pharmaceutical ingredient used in the treatment of chronic diseases related to connective tissue and rheumatism, or an active pharmaceutical ingredient used in the treatment of hyperlipidemia, tumor treatment, neuropsychiatric disease treatment, chronic dental disease (tooth decay, periodontal disease), simple obesity treatment, chronic lower back pain treatment, or leukemia treatment, or an active pharmaceutical ingredient acting on the circulatory system, or an active pharmaceutical ingredient acting on the respiratory system, or an active pharmaceutical ingredient acting on the digestive system, or an active pharmaceutical ingredient acting on the blood system, or an active pharmaceutical ingredient acting on the endocrine system.

[0116] Here, the pharmaceutical active ingredient acting on the reproductive system may include pharmaceutical active ingredients used in contraception or steroidal estrogens.

[0117] The active pharmaceutical ingredient used in said contraception may be any conventional in the art, preferably levonorgestrel, gestodene or gestrinone.

[0118] The steroidal estrogen is preferably estradiol.

[0119] Here, the pharmaceutical active ingredient acting on the urinary system preferably includes a pharmaceutical active ingredient used in the treatment of chronic nephritis, chronic renal failure, or chronic prostatitis.

[0120] The active pharmaceutical ingredient used in the treatment of chronic prostatitis is preferably a nonsteroidal anti-inflammatory drug, more preferably ibuprofen. In general, the medicines used in the treatment of chronic prostatitis include antibiotics (e.g., fluoroquinolones (e.g., norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (e.g., erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracycline), alpha receptor blockers (e.g., doxazosin, terazosin, etc.), nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib, etc.), analgesics (e.g., acetaminophen, etc.), opioids (e.g., bumorphine, fentanyl, nalbuphine, pentazocine, etc.), anti-neuropathic analgesics (e.g., serotonin, duloxetine, venlafaxine), anti-epileptic drugs (e.g., pregabalin, etc.), M receptor blockers (e.g., solifenacin, tolterodine, etc.).

[0121] The medicines used for the treatment of chronic nephritis may generally be angiotensin converting enzyme inhibitors (e.g., benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (e.g., irbesartan, valsartan, losartan, etc.), calcium channel blockers (e.g., amlodipine, felodipine, nifedipine, etc.), β-receptor blockers (e.g., atenolol, bisoprolol, carvedalol, propranolol, etc.), diuretics (e.g., furosemide, spironolactone, hydrochlorothiazide, befluthiazide, bumetanide, etc.), immunosuppressants (e.g., prednisone, inova, methylprednisolone, cyclophosphamide, dexamethasone, etc.), statin lipid lowering drugs (e.g., fluvastatin, simvastatin, pravastatin, etc.).

[0122] The medicines used in the treatment of chronic renal failure may generally be angiotensin converting enzyme inhibitors (e.g., benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (e.g., irbesartan, valsartan, losartan, etc.), diuretics (e.g., furosemide, spironolactone, hydrochlorothiazide, befluthiazide, bumetanide, etc.), iron preparations (ferrous fumarate, etc.), complex amino acids, α-keto acids, and recombinant human erythropoietin.

[0123] Here, the active pharmaceutical ingredient acting on chronic diseases related to metabolism and nutrition preferably includes active pharmaceutical ingredients for anti-diabetes, nutritional deficiency, gout suppression, or osteoporosis treatment.

[0124] The active pharmaceutical ingredient used for suppressing gout is preferably a gout attack suppressant, such as colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, 4-aminosalicylic acid, saspirin, benorilate, more preferably ibuprofen. In general, the gout suppressant may also be a uricosuric agent (such as benzbromarone, probenecid, etc.), a uric acid synthesis blocker (such as allopurinol).

[0125] The antidiabetic drug may generally be an anti-type 1 diabetes drug (e.g., insulin), an anti-type 2 diabetes drug. The anti-type 2 diabetes drug may be a sulfonylurea (e.g., glimepiride, gliquidone), a glinide drug (e.g., repaglinide, nateglinide), a metformin drug (e.g., metformin), an α-glucosidase inhibitor (e.g., acarbose, voglibose), a DPP-4 inhibitor (e.g., sitagliptin), a GLP-1 receptor agonist (e.g., liraglutide, exenatide) or an SGLT-2 inhibitor (e.g., dapagliflozin, empagliflozin).

[0126] Medication used to treat said nutritional deficiencies may generally be drugs targeted at gastrointestinal disorders (eg omeprazole, mosapride), nutritional supplements (eg vitamin E).

[0127] The osteoporosis treatment drug may generally be a bisphosphonate drug (e.g., alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonate, disodium clodronate, sodium zoledronate, sodium risedronate), a calcitonin drug (e.g., salmon calcitonin), an estrogen drug (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), a selective estrogen receptor modulator (SERMs) drug (e.g., raloxifene, benthiophene), a RANKL inhibitor, a parathyroid hormone drug, a glutamine monofluorophosphate drug, a strontium salt drug (e.g., strontium ranelate), an activated vitamin D and its analogs (e.g., calcitriol, α-calciferol), or a vitamin K (e.g., menatetrenone).

[0128] Here, the active pharmaceutical ingredient used for the treatment of chronic diseases involving connective tissue and rheumatism preferably includes treatment of rheumatoid arthritis, treatment of systemic lupus erythematosus, treatment of ankylosing spondylitis, treatment of Sjogren's syndrome, treatment of vasculitis, treatment of idiopathic inflammatory myopathy, treatment of systemic sclerosis, or treatment of osteoarthritis.

[0129] The active pharmaceutical ingredient used in the treatment of rheumatoid arthritis is preferably a nonsteroidal anti-inflammatory drug, such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, nabumetone, more preferably meloxicam or ibuprofen. In general, the drug used in the treatment of rheumatoid arthritis may be a glucocorticoid drug (e.g., hydrocortisone, dexamethasone, prednisone), a slow-acting antirheumatic drug (e.g., methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide).

[0130] The active pharmaceutical ingredient used in the treatment of osteoarthritis is preferably an analgesic, such as ibuprofen, voltaren, meloxicam, celecoxib, loxoprofen sodium, nimesulide, more preferably ibuprofen or meloxicam.Generally, the drug used in the treatment of osteoarthritis may be a cartilage-nutritional drug, an opioid drug (e.g., oxycodone, Tramcontin).

[0131] The drugs used to treat systemic lupus erythematosus may generally be nonsteroidal anti-inflammatory drugs (e.g., naproxen, fenbid), antimalarials, glucocorticoids (e.g., prednisone acetate, methylprednisolone), immunosuppressants (e.g., methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), or biological agents (e.g., rituximab, belimumab).

[0132] The drugs used to treat ankylosing spondylitis may generally be non-steroidal drugs (e.g., diclofenac sodium, etoricoxib, celecoxib, nabumetone, oricoxib), disease-modifying antirheumatic drugs (e.g., sulfasalazine, methotrexate, hydroxychloroquine), glucocorticoid drugs (e.g., prednisone, prednisolone, dexamethasone), and biological TNF-α antagonists (e.g., etanercept).

[0133] The drugs used to treat Sjogren's syndrome may generally be systemic therapeutic agents (e.g., levamisole, transfer factor coenzyme Q10, thymosin), glucocorticoid drugs (e.g., prednisone), or immunosuppressants (e.g., hydroxychloroquine, azathioprine, iguratimod).

[0134] Drugs used to treat said vasculitis may generally be glucocorticoid drugs (eg, prednisone, methylprednisolone, dexamethasone), immunosuppressants (eg, cyclophosphamide, cyclosporine, azathioprine).

[0135] The drugs used to treat said idiopathic inflammatory myopathies may generally be glucocorticoid drugs (e.g., dexamethasone, prednisone, hydrocortisone, methylprednisone), immunosuppressants (e.g., cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolate mofetil).

[0136] The drugs used to treat systemic sclerosis may generally be antifibrotic drugs (e.g., colchicine), vasoactive drugs (e.g., nifedipine), and other commonly used drugs (e.g., naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, tocilizumab).

[0137] Here, the active pharmaceutical ingredient used in the treatment of the neuropsychiatric disorder may generally be a drug used in the treatment of schizophrenia, antidepressant treatment, opioid abuse treatment or anxiety treatment, preferably a drug used in the treatment of schizophrenia, more preferably a phenothiazine (e.g., chlorpromazine), a thioxanthene (e.g., chlorprothixol), a butyrophenone (e.g., haloperidol), a dibenzodiazepine (e.g., olanzapine, clozapine), a benzisoxazole (e.g., risperidone, paliperidone), a benzisothiazole (e.g., ziprasidone), a dibenzothiazepine (e.g., quetiapine), a quinolone (e.g., aripiprazole), and more preferably a benzisoxazole (e.g., paliperidone).

[0138] The antidepressant may generally be a tricyclic antidepressant (e.g., imipramine, clomipramine, amitriptyline), a monoamine oxidase inhibitor (e.g., moclobemide), a selective serotonin reuptake inhibitor (e.g., sertraline), a serotonin and norepinephrine reuptake inhibitor (e.g., venlafaxine), a serotonin blockade and reuptake inhibitor (e.g., trazodone), a norepinephrine and dopamine reuptake inhibitor (e.g., bupropion), a norepinephrine inhibitor (e.g., reboxetine), an alpha-2 adrenergic receptor blocker (e.g., mirtazapine).

[0139] The drugs used to treat opioid abuse may generally be buprenorphine or methadone.

[0140] Medications used in the treatment of said anxiety disorders may generally be benzodiazepines (eg, diazepam), 5-HT1A receptor partial agonists (eg, buspirone), beta-adrenergic receptor blockers (eg, propranolol), valproate.

[0141] Here, the drugs used to treat hyperlipidemia may generally be statin drugs (e.g., simvastatin, atorvastatin, pravastatin), fibrate drugs (e.g., fenofibrate, bezafibrate, gemfibrozil), or niacin drugs (e.g., niacin).

[0142] Here, the antitumor drug generally includes anti-breast cancer drugs (e.g., azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, megestrol, cetuximab, or leuprolide), anti-prostate cancer drugs (e.g., degarelix, leuprolide, histrelin, flunitratonium, estramustine, cyproterone), anti-ovarian cancer drugs (e.g., carboplatin, topotecan, methotrexate), anti-rectal cancer drugs (e.g., panitumumab), anti-colon cancer drugs (e.g., bevacizumab, oxaliplatin), anti-liver cancer drugs (e.g., sorafenib), anti-lung cancer drugs (e.g., erlotinib, gefitinib, docetabine), anti-kidney cancer drugs (e.g., erlotinib, gefitinib, docetabine), anti-renal ... The therapeutic agent may be a drug (e.g., pazopanib, everolimus, temsirolimus), an anti-gastric cancer drug (e.g., fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), an anti-pancreatic cancer drug (e.g., nimotuzumab), an anti-esophageal cancer drug (e.g., docetaxel, paclitaxel, cisplatin, gemcitabine, tedio, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), an anti-skin cancer drug (e.g., fluorouracil), an anti-lymphoma drug (e.g., vincristine, bexarotene, dacarbazine, etoposide), an anti-myeloma drug (e.g., bortezomib), an anti-cervical cancer drug (e.g., bleomycin) or an anti-bladder cancer drug (e.g., epirubicin, BCG).

[0143] Here, drugs used to treat chronic dental diseases (e.g., tooth decay, periodontal disease) are generally divided into nitroimidazole drugs (e.g., metronidazole, tinidazole, ornidazole), penicillin drugs, and other commonly used drugs (minocycline, chlorhexidine acetate).

[0144] Here, the drugs used to treat simple obesity may generally be sibutramine, fenfluramine hydrochloride.

[0145] Here, the active pharmaceutical ingredient used for treating the chronic lower back pain is preferably a non-steroidal analgesic, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen, or voltaren, and more preferably ibuprofen or meloxicam.

[0146] The drugs used to treat said leukemia are generally drugs that inhibit nucleic acid biosynthesis (e.g., cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect the DNA structure and function of cancer cells (e.g., busulfan, mitomycin, chlorambucil, L-phenylalanine mustard, cyclophosphamide), drugs that inhibit the transcription process and suppress RNA synthesis (e.g., daunorubicin, adriamycin, doxorubicin, aclarubicin), drugs that suppress protein synthesis and function (e.g., vindesine, vincristine, L-aspartylase, homoharringtonine), and other commonly used drugs (e.g., interferon, fludarabine, arsenic trioxide, etoposide, carmustine).

[0147] Here, the medicament active ingredient acting on the circulatory system preferably includes a medicament active ingredient used in the treatment of chronic heart failure, coronary heart disease, congenital heart disease, chronic infective endocarditis, or chronic pericarditis.

[0148] The active pharmaceutical ingredients used in the treatment of coronary heart disease generally include drugs that improve the symptoms of angina pectoris (e.g., puerarin, isosorbide mononitrate), antiplatelet aggregation drugs (e.g., aspirin, clopidogrel bisulfate, ticagrelor), lipid-lowering plaque stabilizing drugs (e.g., atorvastatin, rosuvastatin, pravastatin), drugs that inhibit sympathetic nerve activity (e.g., metoprolol, bisoprolol fumarate), drugs that improve myocardial remodeling (e.g., angiotensin-converting enzyme inhibitors and The active pharmaceutical ingredient used in the treatment of chronic heart failure may be a cardiac inotropic agent (e.g., digitalis, digoxin, sidilan), a vasodilator (e.g., sodium nitroprusside, nitroglycerin, an invertase inhibitor (e.g., enalapril, lenopril, etc.), or a diuretic (e.g., furosemide, hydrochlorothiazide, spironolactone).

[0149] The active pharmaceutical ingredients used in the treatment of said congenital heart disease may generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide or coenzyme Q10.

[0150] The active pharmaceutical ingredient used in the treatment of said chronic infective endocarditis may generally be an antibiotic (eg, vancomycin, cephalosporins, penicillins, aminoglycosides).

[0151] The active pharmaceutical ingredient used in the treatment of said chronic pericarditis may generally be digitalis.

[0152] Here, the pharmaceutical active ingredient acting on the respiratory system may include pharmaceutical active ingredients generally used in the treatment of chronic obstructive pulmonary emphysema, the treatment of asthma, the treatment of chronic pulmonary heart disease, the treatment of chronic respiratory failure, the treatment of silicosis or the treatment of pulmonary fibrosis.

[0153] The active pharmaceutical ingredients used in the treatment of chronic obstructive pulmonary emphysema may generally be bronchodilators (including β-receptor agonists and anticholinergics), inhaled hormones (e.g., budesonide, fluticasone), theophylline antiasthmatics (e.g., theophylline), expectorants (e.g., carbocisteine, fodosine), and glucocorticoids and antibiotics (e.g., penicillins, glycosides, and cephalosporins) may be appropriately used according to the needs of the disease.

[0154] The active pharmaceutical ingredients used in the treatment of asthma may generally be commonly used inhalants (e.g., beclomethasone, budesonide, fluticasone, mometasone), beta2 agonists (e.g., albuterol), sustained release theophylline, leukotriene modifiers (used for co-administration), anticholinergics (e.g., isopropylscopolamine), antihistamines (e.g., astemizole, ketotifen).

[0155] The active pharmaceutical ingredients used in the treatment of said chronic pulmonary heart disease may generally be antibiotics (e.g., amoxicillin, ceftizoxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (e.g., selective β2 receptor agonists, theophylline drugs), non-specific inflammation of the airways (e.g., prednisone), inhalants (e.g., vicodone), respiratory stimulants (e.g., lobeline, doxapram, Duxil, etc.).

[0156] The active pharmaceutical ingredients used in the treatment of said chronic respiratory failure may generally be bronchospasm relievers and expectorants (eg, albuterol, acetylcysteine, etc.).

[0157] The pharmaceutical active ingredients used in the treatment of said silicosis may generally be Siping, acetylcysteine, aluminum preparations, polyvinylpyridine-N-oxide, and Danshen.

[0158] The active pharmaceutical ingredients used in the treatment of said pulmonary fibrosis may generally be pirfenidone, nintedanib, glucocorticoids (e.g., methylprednisolone, prednisone), immunosuppressants (e.g., azathioprine, methotrexate, etc.), colchicine, interferon, ACEI or statins, etc.

[0159] Here, the pharmaceutical active ingredient acting on the digestive system may include pharmaceutical active ingredients generally used in the treatment of chronic gastritis, peptic ulcer, intestinal tuberculosis, chronic enteritis, chronic diarrhea, chronic hepatitis, liver cirrhosis, chronic pancreatitis, and chronic cholecystitis.

[0160] The active pharmaceutical ingredients used in the treatment of said chronic gastritis may generally be painkillers (atropine, propantheline bromide, etc. may be used), PPI proton pump inhibitors (e.g. lansoprazole, omeprazole, etc.) may be used for increasing gastric acidity, H2 receptor blockers (e.g. cimetidine, ranitidine, aluminum amine hydroxide, etc.) may be used for mild symptoms, digestive aids (pancreatin may be added), bile reflux (metoclopramide and domperidone, cholestyramine may be used, sucralfate may bind with bile acid).

[0161] The active pharmaceutical ingredients used in the treatment of said peptic ulcers may generally be levofloxacin, tinidazole, omeprazole.

[0162] The active pharmaceutical ingredient used in the treatment of intestinal tuberculosis may generally be rifampicin.

[0163] The active pharmaceutical ingredients used in the treatment of said chronic enteritis may generally be anti-inflammatory analgesics, probiotics, antispasmodic analgesics (eg atropine, propantheline bromide).

[0164] The active pharmaceutical ingredients used in the treatment of said chronic diarrhea may generally be antidiarrheal drugs (e.g., montmorillonite powder, diphenoxylate, loperamide), intestinal microbial preparations (e.g., lactobacilli, bifidobacteria), spasmolytics (e.g., pinaverium bromide).

[0165] The active pharmaceutical ingredients used in the treatment of said chronic hepatitis may generally be hepatoprotectants (e.g., silymarin-based preparations, Schisandra chinensis-based preparations, etc.), antifibrotic drugs (e.g., oral herbal preparations), antiviral drugs (e.g., conventional interferon and polyethylene glycolated interferon), oral nucleoside antiviral drugs (e.g., lamivudine, adefovir dipivoxil, telbivudine, entecavir), and immunosuppressants (azathioprine).

[0166] The active pharmaceutical ingredient used in the treatment of liver cirrhosis may generally be a drug for treating hepatitis B (e.g., a nucleoside analogue), a drug for treating autoimmune hepatitis (e.g., a glucocorticoid), an anti-inflammatory drug, a hepatoprotective drug, an anti-liver fibrosis drug (e.g., reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, etc.), a drug for treating spontaneous bacterial peritonitis (e.g., an antibiotic), or a drug for treating portal hypertension (e.g., carvedilol).

[0167] The active pharmaceutical ingredients used in the treatment of chronic pancreatitis may generally be analgesics (eg, buprenorphine and fentanyl), pancreatic enzyme therapeutics (eg, pancreatin).

[0168] The active pharmaceutical ingredients used in the treatment of chronic cholecystitis may generally be antibacterial and anti-inflammatory drugs (e.g., levofloxacin, ciprofloxacin, amoxicillin), antispasmodic analgesics, and choleretic drugs (e.g., ursodeoxycholic acid).

[0169] Here, the pharmaceutical active ingredient acting on the blood system may include pharmaceutical active ingredients generally used in the treatment of chronic anemia, chronic myeloid leukemia, and chronic lymphocytic leukemia.

[0170] The drugs used in the treatment of chronic anemia may generally be trace elements (e.g., folic acid, vitamin b12, etc.), bone marrow stimulants (e.g., strychnine nitrate, securinine, hyoscyamine, etc.), cobamamide, glucocorticoids (meprednisone, methylprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (e.g., ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, ferrous sucrose, low molecular weight dextran iron, ferrous carboxymaltose, ferrous isomaltose, ferrous glucuronate, nano-iron oxide, sorbitol, etc.), and erythropoiesis promoters (recombinant human erythropoietin alpha, darbepoetin alpha, etc.).

[0171] The drugs used to treat said chronic lymphocytic leukemia may generally be tyrosine kinase inhibitors (eg, imatinib, nilotinib, bosutinib, ponatinib, etc.), homoharringtonine.

[0172] Drugs used in the treatment of chronic lymphocytic leukemia may generally be chemotherapy-based (e.g., nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted (e.g., idelalisib, venetoclax, ibrutinib, imatinib, dasatinib, etc.), monoclonal antibodies (e.g., ofatumumab, rituximab, atlizumab, alemtuzumab, etc.).

[0173] Here, the pharmaceutical active ingredient acting on the endocrine system may include pharmaceutical active ingredients generally used for the treatment of chronic lymphocytic thyroiditis, hyperthyroidism, and hypothyroidism.

[0174] The drugs used to treat chronic lymphocytic thyroiditis may generally be thyroxines (e.g., levothyroxine, thyroxine), glucocorticoids (e.g., meprednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0175] The drugs used to treat hyperthyroidism may generally be thiouracils (e.g., propylthiouracil, methylthiouracil, etc.), imidazoles (e.g., methimazole, carbimazole, etc.), iodine and iodides (e.g., Lugol's solution, etc.), radioactive iodine (e.g., iodine-131, etc.), beta-receptor blockers (e.g., metoprolol, atenolol, bisoprolol, carvedilol, propranolol, etc.).

[0176] The drug used to treat hypothyroidism may generally be a thyroxine-based drug (eg, levothyroxine, levothyroxine sodium, thyroxine, etc.).

[0177] Preferably, the drug substance is a levonorgestrel drug substance, a gestodene drug substance, an ibuprofen drug substance, a paliperidone drug substance, a meloxicam drug substance, or a puerarin drug substance.

[0178] In the present invention, when the drug substance is Gestodene drug substance, the Gestodene drug substance is generally in a powder form. The particle size of the Gestodene drug substance is preferably 1 to 180 μm, more preferably 2.81 μm.

[0179] The levonorgestrel drug substance may be D(-)-17α-ethynyl-17β-hydroxy-18-methylestradiol-4-en-3-one as is common in the art. Here, the levonorgestrel drug substance is generally in powder form. The particle size of the levonorgestrel drug substance is preferably 1-180 μm, for example, 2.12 μm.

[0180] When the drug substance is ibuprofen drug substance, the ibuprofen drug substance is in a powder form. The particle size of the ibuprofen drug substance is preferably 1 to 200 μm, for example, 80 μm.

[0181] When the drug substance is a paliperidone drug substance, the paliperidone drug substance is in a powder form. The particle size of the paliperidone drug substance is preferably 1 to 200 μm, for example, 1 μm, 10 μm, 50 μm, 80 μm, 120 μm, 150 μm, or 180 μm.

[0182] When the drug substance is a meloxicam drug substance, the meloxicam drug substance is in a powder form. The particle size of the meloxicam drug substance is preferably 1 to 200 μm, for example, 1 μm, 10 μm, 50 μm, 80 μm, 120 μm, 150 μm, or 180 μm.

[0183] When the drug substance is a puerarin drug substance, the puerarin drug substance is in a powder form. The particle size of the puerarin drug substance is preferably 1 to 200 μm, for example, 1 μm, 10 μm, 50 μm, 80 μm, 120 μm, 150 μm, or 180 μm.

[0184] In the present invention, the pharmaceutical composition is generally in powder form.

[0185] The present invention further provides a method for preparing said pharmaceutical composition, comprising the step of mixing said drug substance with said poorly soluble auxiliary material.

[0186] Here, the mixing methods and conditions may be those conventional in the art.

[0187] The present invention further provides the use of said pharmaceutical composition in the manufacture of an implant.

[0188] Here, the pharmaceutical composition is the drug core of the implant.

[0189] The diameter of the drug core is preferably 1.5 to 4.0 mm, for example, 1.6 mm or 2.0 mm.

[0190] The length of the drug core is preferably 1.0 to 4.0 cm, for example, 1.5 cm, 2.2 cm, or 3.9 cm.

[0191] Implants The present invention further provides an implant comprising a drug core containing an active pharmaceutical ingredient and the silicone tube described above.

[0192] Here, the active pharmaceutical ingredient may be a small molecule drug with relatively low solubility, for example, a drug active ingredient with a drug solubility of ≦100 mg / mL (using water as a solvent) and a drug molecular weight of less than 1000 Da, such as one or more of levonorgestrel, gestodene, gestrinone, estradiol, ibuprofen, paliperidone, meloxicam, and puerarin.

[0193] The pharmaceutical active ingredient may be a pharmaceutical active ingredient having a solubility of ≦60 mg / mL (using water as the solvent) and a drug molecular weight of less than 1000 Da, such as levonorgestrel, gestodene, gestrinone, estradiol, ibuprofen, paliperidone, meloxicam or puerarin.

[0194] The pharmaceutical active ingredient may be a pharmaceutical active ingredient having a solubility of ≦50 mg / mL (using water as the solvent) and a drug molecular weight of less than 1000 Da, such as levonorgestrel, gestodene, gestrinone, estradiol, paliperidone, meloxicam or puerarin.

[0195] The pharmaceutical active ingredient may be a pharmaceutical active ingredient with a solubility of ≦10 mg / mL (using water as the solvent) and a drug molecular weight of less than 1000 Da, such as levonorgestrel, gestodene, gestrinone, estradiol, meloxicam or puerarin.

[0196] The pharmaceutical active ingredient may be a pharmaceutical active ingredient with a solubility of ≦5 mg / mL (using water as the solvent) and a drug molecular weight of less than 1000 Da, such as meloxicam or puerarin.

[0197] In the present invention, the drug core may be a powdered drug core.

[0198] Here, in the powdered drug core, the particle size of the active pharmaceutical ingredient may be 2 to 180 μm.

[0199] When the drug core is a powdered drug core, the implant can be prepared according to the following method.

[0200] The silicone tubing is cut into segments, filled with the powdered drug cores, and both ends are sealed with silicone to obtain the implant.

[0201] In the present invention, the drug core may be a pharmaceutical composition as described above.

[0202] In the present invention, the outer diameter of the silicone tube is preferably 2.0 to 5.0 mm, for example, 2.4 mm or 2.6 mm.

[0203] In the present invention, the length of the silicone tube is preferably 1.5 to 4.5 cm, for example, 1.9 cm or 4.4 cm.

[0204] In the present invention, the wall thickness of the silicone tube is preferably 0.2 to 0.5 mm, for example, 0.2 mm, 0.3 mm, 0.4 mm, or 0.5 mm.

[0205] In the present invention, the drug release area of ​​the silicone tube is preferably 0.4 to 15.0 cm 2 For example, 0.69 cm 2 , 1.38cm 2 , 2.07cm 2 , 2.76cm 2 or 3.45 cm 2 It is.

[0206] In the present invention, the diameter of the drug core is preferably 1.5 to 4.0 mm, for example, 1.6 mm or 2.0 mm.

[0207] In the present invention, the length of the drug core is preferably 1.0 to 5.0 cm, for example, 1.0 to 4.0 cm, also for example, 1.5 cm or 3.9 cm, also for example, 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm.

[0208] In some preferred embodiments of the present invention, the specifications of the implant are as shown in the table below, and the active drug ingredient in the drug core is preferably levonorgestrel. [Table 12]

[0209] In some preferred embodiments of the present invention, the specifications of the implant are as shown in the table below, and the active drug ingredient in the drug core is preferably Gestodene: [Table 13]

[0210] In some preferred embodiments of the present invention, the specifications of the implant are as shown in the table below, and the active drug ingredient in the drug core is preferably estradiol: [Table 14]

[0211] The method for producing the implant of the present invention is to extrude the silicone material into a tube or cut the silicone tube into segments, then fill them with drugs, seal both ends with adhesive, and then package and sterilize to produce the implant of the present invention.

[0212] The present invention further provides an implant comprising the pharmaceutical composition and a silicone tube.

[0213] The method of producing the implant may comprise filling the silicone tube with the pharmaceutical composition.

[0214] In the present invention, the silicone tube may be any of those conventional in the art. Preferably, the raw material composition of the silicone tube is as described above.

[0215] Method for measuring the amount of drug released from implants In order to overcome the drawback of the prior art that it is difficult to accurately evaluate the drug release amount of an implant based on the physical parameters of the implant, an implant and a method for measuring the drug release amount thereof are provided. The implant of the present invention can realize a stable release of a drug, and the release amount can be precisely controlled, and an implant with a required drug release amount can be obtained by changing the lateral area of ​​the drug-containing portion.

[0216] The present invention further provides an implant comprising a drug core and a silicone tube.

[0217] The drug core contains an active pharmaceutical ingredient and has a particle size D 50 is 180 μm or less, The raw material composition of the silicone tube comprises, in parts by weight: R-vinyl silicone rubber: 100 parts; Hydrogenated silicone oil: 0.3 to 3.0 parts; Reinforcing agent: 20-80 parts; Catalyst: ≧0.000002 parts, preferably 2×10 -6 -5×10 -5 Department; Includes. however, R in the R-vinyl silicone rubber is a substituted or unsubstituted C1 to C5 linear or branched alkane, a substituted or unsubstituted C6 to C 20 It is an aromatic hydrocarbon, The vinyl content in the R-vinyl silicone rubber is 0.05 to 0.50 mol %, The hydrogen-containing silicone oil has a Si-H group content of 0.18 to 1.6 mol %, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-4.0):1; The method for producing the silicone tube includes a step of extruding a raw material mixture for the silicone tube.

[0218] In the present invention, the medicament active ingredient is as described above.

[0219] Preferably, the active pharmaceutical ingredient is levonorgestrel, gestodene, ibuprofen, paliperidone, meloxicam, puerarin or estradiol.

[0220] In the present invention, the drug core may be a powdered drug core.

[0221] In the present invention, the particle size D of the medicament active ingredient 50 is preferably 1 to 180 μm, for example, 2.12 μm, 2.81 μm, 43.24 μm, 80.3 μm, or 100 μm. 50 is generally obtained by grinding.

[0222] In the present invention, the mass of the active pharmaceutical ingredient in the drug core (ie, drug loading) can be any conventional in the art.

[0223] When the medicament active ingredient is gestodene, the amount of the drug carried is preferably 10 to 100 mg, for example, 12.5 mg, 22.8 mg, 29.6 mg, 42 mg, 60 mg, or 84 mg.

[0224] When the active pharmaceutical ingredient is levonorgestrel, the drug loading amount is preferably 15 to 300 mg, for example, 15 mg, 36 mg, 72 mg, 75 mg, 100 mg, 150 mg, 180 mg, 216 mg, or 252 mg.

[0225] When the pharmaceutical active ingredient is estradiol, the amount of the drug carried is preferably 10 to 300 mg, for example, 75 mg or 100 mg.

[0226] When the active pharmaceutical ingredient is ibuprofen, the drug loading amount is 10 to 2000 mg, for example, 40 mg or 100 mg.

[0227] When the active pharmaceutical ingredient is meloxicam, the drug loading amount is 10 to 2000 mg, for example, 40 mg or 100 mg.

[0228] When the active pharmaceutical ingredient is paliperidone, the drug loading amount is 10 to 2000 mg, for example, 40 mg or 100 mg.

[0229] When the pharmaceutical active ingredient is puerarin, the amount of the drug carried is 10 to 2000 mg, for example, 40 mg or 100 mg.

[0230] In the present invention, the drug core preferably further comprises auxiliary materials, which include silicone materials and poorly soluble pH adjusting agents.

[0231] Wherein, the silicon material is, for example, white carbon black and / or mesoporous silicon. The white carbon black is, for example, vapor-phase white carbon black. The mesoporous silicon is, for example, one or more of mesoporous silicon AL-1FP, mesoporous silicon XDP3050 and XDP3150.

[0232] Here, the pore size of the silicon material may be less than 1 μm, such as 0 nm, 5 nm, 10 nm, 18 nm, 50 nm or 100 nm. Those skilled in the art can understand that when the pore size of the silicon material is 0 nm, the silicon material is a non-porous silicon material.

[0233] In said silicon material, the silica content may be more than 50%, preferably 80%, 90%, 95%, 99% or 99.8%.

[0234] Here, the pH adjuster includes a poorly soluble weak acid and / or a poorly soluble weak base.

[0235] Here, the sparingly soluble weak acid preferably includes one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, and more preferably includes boric acid and / or fumaric acid.

[0236] Here, the poorly soluble weak base preferably includes one or more of magnesium hydroxide, aluminum hydroxide, zinc hydroxide, ferrous hydroxide, and magnesium oxide, and more preferably includes one or more of magnesium hydroxide, aluminum hydroxide, and zinc hydroxide.

[0237] Here, the mass ratio of the auxiliary materials to the active pharmaceutical ingredients is preferably 1:1.

[0238] In the present invention, the raw material composition of the silicone tube may be the same as the raw material composition of the silicone material.

[0239] In the present invention, the extrusion molding step may be the same as the molding step in the method for producing the silicone material.

[0240] In the present invention, the implant preferably further includes a blast removal treatment, and the blast removal treatment is generally for removing drug powder attached to the surface of the silicone tube of the implant. Since the surface of the levonorgestrel or gestodene implant that has not been blast removed will have powder electrostatically adsorbed to the silicone tube, it will cause a very obvious burst release effect in the release of the implant, making its initial release amount closer to the steady-state release amount, and reducing the risk caused by the sudden release of the drug after the implant is embedded in the body, it is necessary to carry out the blast removal treatment in advance.

[0241] Here, the blast removal treatment may be a common one in the art, for example, comprising mixing the implant with absolute ethanol, ultrasonicating for 1 minute, repeating this for 3 times, then adding 100 mL of distilled water and leaving overnight, and discarding the exudate the next day.

[0242] In the present invention, the wall thickness of the silicone tube may be that which is conventional in the art, and is preferably 0.1 to 0.5 mm, for example, 0.3 mm or 0.4 mm.

[0243] In the present invention, the inner diameter of the silicone tube may be a common one in the art, and is preferably 1 to 5 mm, for example, 1.4 mm, 1.6 mm, 1.8 mm, or 2.0 mm.

[0244] In the present invention, the outer diameter of the silicone tube may be a common one in the art, and is preferably 1 to 6 mm, for example, 2.6 mm.

[0245] In the present invention, if the daily drug release amount needs to be changed after the implant is manufactured, the side area of ​​the drug core can be adjusted, and the side area of ​​the drug core and the drug release amount are directly proportional. For example, if the daily drug release amount needs to be increased, the side area of ​​the drug core is increased. When the drug core is cylindrical and the diameter of the drug core is fixed, the length of the drug core can be 0.5 to 25 cm, for example, 0.8 cm, 1.4 cm, 2.2 cm, 2.7 cm, 3.3 cm, 4.3 cm, 9 cm, 15 cm, 18 cm, or 21 cm, and when the length of the drug core is fixed, the diameter of the drug core can be 0.5 to 10 mm, for example, 0.5 mm, 0.8 mm, 1.4 mm, 1.6 mm, 2.0 mm, 2.7 mm, 3.3 mm, 4.3 mm, 6.8 mm, 9.0 mm, or 10.0 mm. Alternatively, the lateral area of ​​the drug core can be adjusted by simultaneously adjusting the length and diameter of the drug core, which in turn can adjust the amount of drug released.

[0246] The present invention further provides a method for measuring the drug release amount of the implant, comprising a step of simulating to obtain a mathematical model equation: y=kx+b with different lateral areas and daily drug release amounts of drug cores having the implant.

[0247] y is the daily drug release amount in μg / d, and x is the lateral area of ​​the drug core in cm 2 where x=πDL, D: diameter of the drug core, and L: length of the drug core.

[0248] In the present invention, those skilled in the art will know that the daily drug release amount may have the meaning commonly understood in the art, and generally refers to simulating the daily drug release amount in the body in vitro.

[0249] From the above mathematical model formula, the lateral area of ​​drug release is related only to the diameter D and length L of the drug core; when the length of a fixed drug core is constant, the lateral area of ​​the drug core, i.e., the drug release area, can be adjusted by adjusting the diameter of the drug core; when the diameter of the drug core is fixed, the lateral area of ​​the drug core can be adjusted by adjusting the length of the drug core; further, the lateral area of ​​the drug core can be adjusted by simultaneously adjusting the length and diameter of the drug core.

[0250] In the present invention, when the medicament active ingredient is gestodene, preferably, k has a value of 4 to 16, and b has a value of (-4) to 4. Preferably, R 2 >0.99, where the k value is, for example, 6.257, 7.520, 8.7363, 8.8140, 9.057, 10.229 or 11.591.

[0251] Here, the b value is preferably 0 to 1, for example, 0.0802, 0.1767, 0.498, 0.561, 0.587, 0.708, or 0.802.

[0252] Here, the R 2is, for example, 0.9947, 0.998, 0.9982, 0.9987, 0.9998 or 0.9999.

[0253] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is Gestodene, the mathematical model formula is y=11.591x+0.561, R 2 =0.9947.

[0254] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is Gestodene, the mathematical model formula is y=6.257x+0.498, R 2 =0.998.

[0255] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is Gestodene, the mathematical model formula is y=7.520x+0.587, R 2 =0.9987.

[0256] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is Gestodene, the mathematical model formula is y=10.229x+0.802, R 2 =0.9982.

[0257] In a specific embodiment of the present invention, when the drug core is Gestodene, the mathematical model formula is y=9.057x+0.708, R 2 =0.9987.

[0258] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is Gestodene, the mathematical model formula is y=8.7363x+0.0802, R 2 =0.9999.

[0259] In a specific embodiment of the present invention, when the drug core is Gestodene, the mathematical model formula is y=8.8140x+0.1767, R 2 =0.9998.

[0260] In the present invention, when the active pharmaceutical ingredient is levonorgestrel, k preferably has a value of 1 to 10, b has a value of (-6) to 6, and preferably R 2 >0.99.

[0261] Here, the k value is, for example, 3.412, 4.2459, 5.0172, 5.6294, 5.6865, 5.8036, 6.4689, 6.4978 or 6.6085.

[0262] Here, the b value is preferably -2-1, for example -1.7641, -1.919, -0.2767, -0.2482, -0.9893, -0.3064, 0.3281, 0.3967 or 0.5.

[0263] Here, the R 2 is, for example, 0.9951, 0.997, 0.9973, 0.9957, 0.9978, 0.998 or 0.9979.

[0264] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=4.2459x+0.3967, R 2 =0.9957.

[0265] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=6.4978x-1.9190, R 2 =0.9979.

[0266] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=6.4689x-0.2767, R 2 =0.9973.

[0267] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=5.8036x-0.2482, R 2 =0.9973.

[0268] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=3.4120x-0.9893, R 2 =0.9978.

[0269] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=6.6085x+0.3064, R 2 =0.997.

[0270] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=5.0172x+0.3281, R 2 =0.998.

[0271] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=5.6865x-1.7641, R 2 =0.9951.

[0272] In a specific embodiment of the present invention, when the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is y=5.6294x+0.5000, R 2 =0.9970.

[0273] In the present invention, according to the mathematical model formula established above, the drug release amount of the implant with different drug core lateral areas can be quantitatively manufactured and measured.

[0274] In the present invention, it is well known to those skilled in the art that the k and b values ​​in the above mathematical model formula are calculated based on at least three sets of data of implants with different lateral areas of the drug core and daily drug release amounts.

[0275] In the present invention, to obtain the drug release amount of the implant to be detected, it is generally known to those skilled in the art that the y value obtained by the mathematical model is substituted with the lateral area of ​​the drug core of the implant to be detected. According to the mathematical model formula, it can be seen that the daily drug release amount of the implant can be changed by changing the lateral area of ​​the drug core. Combined with the definition of the lateral area of ​​the drug core, when the length and diameter of the drug core are determined, the lateral area of ​​the drug core is also determined, so that the required daily drug release amount can be obtained by changing the length and diameter of the drug core, or by simultaneously changing the length and diameter of the drug core.

[0276] In the present invention, the daily release amount has the meaning generally understood in the art, and generally refers to the daily drug release amount when the drug release medium is water or an aqueous solvent.Research has shown that the drug release amount of the implant into water or an aqueous solvent is consistent with the drug release amount in the body.

[0277] In the present invention, the vinyl content in the R-vinyl silicone rubber refers to the molar ratio, and the vinyl molar ratio refers to the number of moles of vinyl per 100 moles of the R-vinyl silicone rubber.

[0278] In the present invention, the hydrogen content in the hydrogen-containing silicone oil refers to a molar ratio, and the molar ratio of the hydrogen content refers to the number of moles of hydrogen per 100 moles of the hydrogen-containing silicone oil.

[0279] In the present invention, PHR is the number of parts by mass of each corresponding specific component per 100 parts by mass of R-vinyl silicone rubber (for example, methyl vinyl silicone rubber).

[0280] In the present invention, the room temperature refers to 25°C ± 5°C.

[0281] In the present invention, the terms "first", "second", "third", etc. are used to describe each heat treatment, but these heat treatments should not be limited by such terms. These terms are used only to distinguish one heat treatment from another.

[0282] As long as it does not violate the common knowledge of the technical field, the above-mentioned preferable conditions can be arbitrarily combined to obtain each preferable embodiment of the present invention.

[0283] The reagents and materials used in the present invention are commercially available.

[0284] The positive advances of the present invention are as follows:

[0285] (1) The silicone tube produced from the silicone material of the present invention has excellent mechanical properties and good biocompatibility, and the drug release curve after an active drug is loaded into an implant produced from the silicone tube is stable. When the loaded drug is a contraceptive drug (e.g., gestodene, levonorgestrel), the produced implant can provide a significant contraceptive effect in rats.

[0286] (2) The positive effects of the present invention are: the pharmaceutical composition of the present invention is less likely to generate static electricity, is easy to fill, can effectively prevent powder scattering and natural aggregation of powder, can adjust the filling amount and drug release amount, has a high utilization rate of the active ingredient, and the implant made from the pharmaceutical composition has high drug release stability.

[0287] (3) In the present invention, by specially selecting the particle size of the active pharmaceutical ingredient in the drug core and the manufacturing process of the silicone tube, the implant manufactured can accurately control the daily drug release amount of the active pharmaceutical ingredient, and the release is stable. At the same time, there is a linear positive correlation between the release side area of ​​the drug core in the implant of the present invention and the daily drug release amount of the drug, so that the required implants with different daily drug release amounts can be obtained by changing the side area of ​​the drug core in the implant. [Brief description of the drawings]

[0288] [Figure 1] 1 is a flowchart of a manufacturing process for a silicone tube. [Diagram 2] 1 is a flow chart of a silicone tube extrusion process. [Diagram 3] Photograph of the GEST contraceptive implant. [Figure 4] The relationship between the daily drug release amount and release time in vitro for Gestodene implants ZJ001, ZJ002, and ZJ003. [Diagram 5] This shows the relationship between the daily drug release amount and release time in vitro for Gestodene implants ZJ001, ZJ002, and ZJ003 (based on Figure 4, this is a daily drug release amount diagram after simplifying the data with 5 days as one cycle). [Figure 6] Pathological images of muscle tissue after Gestodene implantation, where A, C, and E are pathological images (HE, ×2) 3, 10, and 30 days after implantation, respectively, and B, D, and F are pathological images (HE, ×20) 3, 10, and 30 days after implantation, respectively. [Figure 7] Vaginal smears of a rat's estrous cycle, where panel A is proestrus, panel B is estrus, panel C is metestrus, and panel D is between the two estrus phases. [Figure 8] 13 shows images of vaginal plugs in rats, where FIG. 1 shows rat number 1 in the GEST implant experiment I administration group, which has a normal estrous cycle and a vaginal smear, showing a milky white vaginal plug observed at the vaginal opening when vaginal secretions were collected 13 days after implantation, and FIG. 14 shows rat number 4 in the GEST implant experiment I administration group, which has a normal estrous cycle and a vaginal plug observed at the vaginal opening when vaginal secretions were collected 20 days after implantation. [Figure 9] It is an overcured silicone tube manufactured at a front curing tunnel temperature of 360℃. [Figure 10]Tissue section (A, HE, ×2) on day 3 after levonorgestrel implant in SD rats; partial view of tissue section (B, HE, ×20) on day 3 after implant in SD rats; tissue section (C, HE, ×2) on day 10 after implant in SD rats; and partial view of tissue section (D, HE, ×20) on day 10 after implant in SD rats. [Figure 11] 1 shows the release curves of the daily dose of LNG implants in the blast-removed and untreated groups. [Figure 12] 1 shows the release curves of the cumulative dose of LNG implants in the blast removal group and the untreated group. [Figure 13] It is a linear relationship between 1 / T and ln(K). [Figure 14] These are the results of LH measurement in rats administered levonorgestrel I. [Figure 15] The relationship between the drug surface area of ​​the silicone tube and the amount of estradiol released. [Figure 16] 13 is a graph showing the relationship between the ex vivo daily drug release amount and release time of the implant in Example 22. [Figure 17] 1 shows the relationship curves between different release times and daily drug release amounts of Gestodene implants in the control experiment of Example 27 and raw rubber with 0.23% vinyl content. [Figure 18] 1 is a relationship curve of daily drug release amount with different release times of Gestodene implants in Example 27 and the control experiment with a molar ratio of 1.5:1. [Figure 19] 1 is a relationship curve of different release time and daily drug release amount of Gestodene implants in Example 27 and the control experiment with wall thickness of 0.5 mm. [Figure 20] 1 is a relationship curve of different release times and daily drug release amounts of Gestodene implants in Example 27 and the control experiment in which the drug particle size is 80.3 μm. [Figure 21] 1 is a relationship curve of different release times and daily drug release amounts of Gestodene implants in Example 27 and the control experiment with a drug loading of 29.6 mg. [Figure 22]1 is a relationship curve of the different release time and daily drug release amount of levonorgestrel implant in the control experiment of Example 28 and raw rubber with 0.23% vinyl content. [Diagram 23] 1 shows the relationship curves of different release times and daily drug release amounts of levonorgestrel implants in Example 28 and control experiments with molar ratios of 1.2:1 and 1.5:1. [Figure 24] FIG. 27 is the relationship curve of different release time and daily drug release amount of levonorgestrel implants with different white carbon black contents in Example 28. [Diagram 25] 1 is a relationship curve of the cumulative release amount of the active pharmaceutical ingredient with different release times of the levonorgestrel implant of Example 28 and the implant with a particle size of 43.24 μm. [Figure 26] 13 is a relationship curve of different release time and daily drug release amount of the levonorgestrel implants of Example 28 and its different wall thicknesses. [Figure 27] 2 is a relationship curve showing different release times and daily drug release amounts of the levonorgestrel implants of Example 28 and its different drug loadings. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0289] The present invention will be further described below in the form of examples, but the present invention is not limited to the scope of the examples. In the following examples, the experimental methods for which no specific conditions are described are selected according to the usual methods and conditions or product instructions.

[0290] In the following examples and comparative examples: The vinyl content in the methylvinylsilicone rubber refers to the molar ratio, and the vinyl molar ratio refers to the number of moles of vinyl per 100 moles of the methylvinylsilicone rubber. The hydrogen content in the hydrogen-containing silicone oil refers to a molar ratio, and the molar ratio of the hydrogen content refers to the number of moles of hydrogen per 100 moles of the hydrogen-containing silicone oil.

[0291] I. Gestodene long-acting contraceptive implant

[0292] 1. Method for determining the content and ex vivo release of Gestodene contraceptive implant

[0293] (1) Chromatography conditions Chromatography column: Diamonsil® C18 column (250 mm × 4.60 mm, 5 μm); Mobile phase: methanol-water (80:20, v / v); Column temperature: 30°C; Detection wavelength: 239nm; Flow rate: 1mL min -1 ; Injection volume: 20μL.

[0294] (2) In vitro release experiment method The filled implant was placed in an ethanol solution and sonicated in an ultrasonic device for 30 min. After sonication, the implant was blown dry and placed in a stoppered Erlenmeyer flask containing the release solvent. The stoppered Erlenmeyer flask was placed in a shaker at a temperature of 37 °C and a shaking speed of 100 r min -1 After 24 hours, it was removed and blow-dried.

[0295] Both ends of the blow-dried Gestodene implant were glued to the bottom and wall of a stoppered Erlenmeyer flask, respectively, using silicone rubber adhesive, and the silicone tube part filled with Gestodene drug substance powder was suspended in the stoppered Erlenmeyer flask so as not to touch the wall (it was ensured that the contact area between the drug-containing part and the release solvent was stable during the shaking process). After gluing, the mixture was left for 24 hours until the adhesive was completely cured. After curing, the required amount of release medium was accurately poured into the stoppered Erlenmeyer flask and placed in a shaker, and the temperature was set to 37°C and the shaking speed to 100 r·min. -1 Every 24 hours, samples were taken, the solvent was replaced, and the samples were kept for testing.

[0296] 2. Manufacturing of two-liquid additive silicone tubes

[0297] 1. Equipment and Reagents

[0298] 1.1 Equipment [Table 15]

[0299] 1.2 Reagents [Table 16]

[0300] 2 Measurement method

[0301] 2.1 Optimization of the manufacturing process of silicone tubing

[0302] 2.1.1 Formulation [Table 17] Note: PHR is the number of parts by mass of the corresponding component per 100 parts by mass of the polymer compound (methyl vinyl silicone rubber). ppm refers to parts per million and represents the concentration of platinum in the platinum catalyst, 3000ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million, and PHR represents the proportion of platinum catalyst in the silicone tube formulation. For example, in the above formulation, 0.000002-0.00005 parts of platinum catalyst are added to 100 parts of methyl vinyl silicone rubber, and the platinum concentration in the platinum catalyst is 3000 parts per million.

[0303] 2.1.2 Manufacturing process (1) Pretreatment of raw rubber: Raw rubber (methyl vinyl silicone rubber) and gas-phase white carbon black were placed in a kneader in a prescribed ratio so that the gas-phase white carbon black would be completely wrapped in the raw rubber, and the raw rubber wrapped around the white carbon black was thinly extruded in an open mill. After the raw rubber and the white carbon black were completely mixed, the mixture was pressed into tablets, removed, completely wrapped in plastic wrap, sealed in a Ziploc bag, and stored in a desiccator at room temperature for 24 to 72 hours before use.

[0304] (2) Preparation of matrix component: The reserved raw rubber to which white carbon black was added was divided into two equal parts based on mass, and separated into component A and component B. The prescribed amounts of hydrogen-containing silicone oil, which is a crosslinking agent, and methylbutynol, which is an inhibitor, were added to component A, and the mixture was thoroughly mixed and milled in an open mill, after which it was stored in a desiccator at room temperature for 24 to 72 hours for use.

[0305] (3) Preparation of catalyst component: A prescribed amount of platinum catalyst was added to component B, and the mixture was thoroughly mixed and milled in an open mill, and then stored in a desiccator at room temperature for 24 to 72 hours for use.

[0306] (4) Components A and B, which had been held for the same period, were mixed and milling continued using an open mill, after which the flakes were held for 12 hours.

[0307] (5) The reserved rubber was sliced ​​into thin slices and stored for future use.

[0308] The flowchart of steps (1) to (5) above may be seen in FIG.

[0309] After the two-liquid silicone rubber material is produced, it is extruded into tablets to produce silicone tubes. In the extrusion process, the silicone rubber material is extruded through a screw and then extruded through a mold to produce a silicone tube. Due to the high temperature in the front vulcanization tunnel, the extruded silicone tube is rapidly vulcanized and initially molded. Then, it enters the rear vulcanization tunnel to continue vulcanization and nearly complete the addition reaction of the silicone tube. Finally, the silicone tube is placed in an oven at a predetermined temperature to carry out oven vulcanization and ensure that the addition reaction of the silicone tube is completed.

[0310] During the extrusion process, the front vulcanization tunnel, rear vulcanization tunnel, and oven provided vulcanization conditions for the addition reaction of raw rubber and hydrogen-containing silicone oil, resulting in the cured silicone material. The extrusion speed, mold, and pulling speed of the rear vulcanization tunnel (extrusion speed was 3.5 r min -1 and the tensile speed in the rear vulcanization tunnel was 0.1 m s -1 The outer diameter of the mold core is 2.50 mm, and the inner diameter of the mouth mold is 3.90 mm. The outer diameter and wall thickness of the produced silicone tube are adjusted to produce silicone tubes with different specifications, and the extrusion process is as shown in Figure 2.

[0311] 2.1.3 Silicone tube performance test The tensile strength Ts is the maximum tensile force that the silicone tube can withstand during the fracture process and indicates the maximum resistance of the sample to external damage. The breaking elongation Eb is the deformation state when the impression sample breaks, and represents the allowable deformation range before the sample breaks. Tear strength T refers to the strength at which the silicone tube is torn, and indicates the resistance of the sample to tearing. Hardness H is the ability of the silicone tube to withstand external extrusion.

[0312] 2.1.3.1 Tensile stress-strain performance test The tensile stress-strain properties were measured according to the GB / T 828-2009 method. The prepared silicone tube specimen was symmetrically placed in the upper and lower grippers of the servo system tensile machine so that the tensile force was evenly distributed on the cross section, the clamp distance was set to 50 mm, the elongation sampling device was prepared, and the tensile machine was started so that the tensile speed of the specimen was 200 mm / min. The maximum tensile stress during the tensile process, the length of the specimen when pulled to break, and the force required to tear the specimen were recorded. The breaking elongation, tensile strength, and tear strength of the specimen were calculated according to the following formulas.

[0313] Elongation at break (%)E b =100(L b -L0) / L0 L b -gauge length when the specimen breaks, mm; L0 - initial gauge length of the specimen, mm.

[0314] Tensile strength (Mpa) Ts=Fm / Wt Fm - maximum recorded force, W - width of the narrow part of the cutter, mm, t - thickness of the length part of the test specimen.

[0315] Tear strength (KN / m) T=F / t F - maximum force at which the specimen breaks, t - thickness of specimen (mm).

[0316] 2.1.3.2 Strength test The hardness test of the product was measured according to GB / T 531.1-2008. After the manufactured matrix component polymer and catalyst component polymer were thoroughly mixed, they were cured and molded at room temperature, manufactured into a test piece with a thickness of 6 mm, and cut into a square test piece of 24 x 24 mm. The test piece was placed on a solid surface, and the hardness tester was held, and the pressure foot was smoothly pressed against the test piece, so that the pressure foot was completely in contact with the test piece, and the data was read within 1 second, and the measurement was performed three times at different positions, and the average value was taken.

[0317] The preferred physical and mechanical performance indicators of silicone tubing products are as shown in the table below. [Table 18]

[0318] 2.1.4 Optimization of the manufacturing process of silicone tubing This test has a set prescription, and the breaking elongation, tensile strength, tear strength and hardness are used as mechanical indicators. The front vulcanization tunnel temperature (primary vulcanization temperature) of the extrusion process, the rear vulcanization tunnel temperature (secondary vulcanization temperature) and the oven vulcanization time (tertiary vulcanization time) were measured.

[0319] 2.1.4.1 Consideration of front vulcanization tunnel temperature (primary vulcanization temperature) After the silicone is extruded by single screw, the inhibitor in the silicone tube is decomposed into gas by high temperature in a high-temperature oven, and then the catalyst starts to act, the catalytic addition reaction is carried out, and the silicone tube is quickly fixed and molded. The oven temperature has a great impact on the appearance and mechanical index of the extruded silicone tube, if the temperature is too low, the vulcanization is insufficient, the outer wall of the tube is not molded, and subsequent pulling is difficult, if the temperature is too high, the silicone tube is easily over-vulcanized, and the mechanical index is reduced. The outer diameter of the silicone tube is rapidly contracted by the high-temperature oven, and returns to normal after leaving the high-temperature oven, but this change may affect the outer diameter and wall thickness of the silicone tube.

[0320] In this test, the temperature of the front vulcanization tunnel was set at 270℃, 300℃, 330℃, and 360℃, respectively, and the breaking elongation, tensile strength, tear strength, and hardness were used as mechanical indicators to study the temperature of the high-temperature oven (in the consideration of the front vulcanization tunnel temperature, the extrusion time of the front vulcanization tunnel is about 5 seconds and short, the rear vulcanization tunnel temperature is 180℃, the reaction time is about 2 minutes and short, the oven vulcanization temperature is 180℃, and the time is 48 hours, and the other process conditions are the same as the 2.1.2 manufacturing process of this part, and the formulation is also the same as the 2.1.1 formulation of this part). The outer diameter and wall thickness of the manufactured silicone tube were measured to consider whether the temperature change in the front vulcanization tunnel affects the size of the silicone tube.

[0321] [Table 19]

[0322] 2.1.4.2 Consideration of rear cure tunnel temperature (second cure temperature) After the silicone tube is extruded, it is quickly vulcanized through the front vulcanization tunnel, and after the initial hardening and molding, it needs to be further hardened at a certain temperature and time and vulcanized at a low temperature through the rear vulcanization tunnel of 2.5m, so that the silicone tube is basically molded.

[0323] In this test, the temperature of the rear vulcanization tunnel was set at 120℃, 150℃, 180℃, and 210℃, and the breaking elongation, tensile strength, tear strength, and hardness were used as mechanical indicators to study the rear vulcanization tunnel temperature (in the consideration of the rear vulcanization tunnel temperature, the front vulcanization tunnel temperature was 270℃, the extrusion time of the front vulcanization tunnel was about 5 seconds, and the reaction time of the rear vulcanization tunnel was about 2 minutes, and the oven vulcanization temperature was 180℃, and the time was 48 hours, and the other process conditions were the same as the 2.1.2 manufacturing process of this part, and the formulation was also the same as the 2.1.1 formulation of this part). The outer diameter and wall thickness of the produced silicone tube were measured to consider whether the temperature change in the rear vulcanization tunnel affects the size of the silicone tube.

[0324] [Table 20]

[0325] 2.1.4.3 Consideration of oven curing time (tertiary curing time) In order to completely vulcanize the silicone tube, the silicone tube was oven vulcanized (tertiary vulcanization). If the tertiary vulcanization time is insufficient, the silicone tube will not be completely vulcanized, and if the vulcanization time is too long, the silicone tube will be easily over-vulcanized. The tertiary vulcanization times set in this test were 0 hours, 24 hours, 48 ​​hours, and 72 hours, and the oven vulcanization time was measured using the breaking elongation rate, tensile strength, tear strength, and hardness as mechanical indicators. (In considering the oven vulcanization time, the front vulcanization tunnel temperature was 270°C, the time was about 5 seconds, the rear vulcanization tunnel temperature was 180°C, the time was about 20 seconds, the oven vulcanization temperature was 180°C, and the other process conditions were the same as the 2.1.2 manufacturing process of this part, and the recipe was also the same as the 2.1.1 recipe of this part.)

[0326] [Table 21]

[0327] 2.1.5 Consideration of catalyst usage amount In this test, the amounts of raw rubber, hydrogen-containing silicone oil, inhibitor, and reinforcing agent used remained unchanged at 100 PHR, 1.01 PHR, 0.7 PHR, and 30 PHR, respectively. The amount of catalyst was changed to 0.000005 PHR, 0.00001 PHR, 0.00002 PHR, and 0.00003 PHR, respectively, and mechanical properties such as breaking elongation, tensile strength, tear strength, and hardness of the silicone tube with different catalyst amounts were measured.

[0328] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0329] [Table 22]

[0330] 2.1.6 Considerations regarding the dosage of inhibitors Under the catalysis of platinum, the addition reaction between raw rubber and hydrogen-containing silicone oil can be carried out at room temperature, and the addition reaction can be carried out rapidly, resulting in rapid hardening of the silicone material. In order to prevent the silicone rubber from hardening in the extruder cavity during the extrusion process, an inhibitor, methylbutynol, can be added to the silicone rubber to prevent the reaction from taking place at room temperature.

[0331] In this test, the amounts of raw rubber, hydrogen-containing silicone oil, catalyst, and reinforcing agent used were fixed at 100 PHR, 1 PHR, 0.00001 PHR, and 30 PHR, respectively. The amount of inhibitor used was changed to 0.3 PHR, 0.5 PHR, 0.7 PHR, and 0.9 PHR, respectively, and the mechanical properties such as breaking elongation, tensile strength, tear strength, and hardness of the silicone tube with different amounts of inhibitor used were measured.

[0332] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0333] [Table 23]

[0334] 2.1.7 Consideration of vinyl content in raw rubber According to the principle of the addition reaction between methylvinyl rubber and hydrogen-containing silicone oil, it is found that the vinyl content of the rubber has a great impact on the crosslinking degree of the silicone tube. Under the catalytic action of platinum catalyst, the rubber is added with hydrogen-containing silicone oil, and vinyl polysiloxane is the crosslinking bond in the formed network structure, and its molecular chain length determines the crosslinking density after crosslinking and curing.

[0335] In this test, the molecular weight of vinyl polysiloxane, the amount of hydrogen-containing silicone oil, catalyst, inhibitor, and gas-phase white carbon black used were fixed at 100 PHR, 1 PHR, 0.00001 PHR, 0.7 PHR, and 30 PHR, respectively, and did not change. The vinyl content of vinyl polysiloxane was changed to 0.05%, 0.07%, 0.17%, and 0.23%, respectively, and the mechanical properties such as breaking elongation, tensile strength, tear strength, and hardness of silicone tubes with different vinyl contents were measured.

[0336] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0337] [Table 24]

[0338] 2.1.8 Consideration of the amount of gas phase white carbon black used Since the hardness of raw rubber is too low to be suitable for molding or processing, vapor phase white carbon black is added to the raw rubber to strengthen the hardness of the produced silicone tube and improve the hardness of the raw rubber.

[0339] In this test, the amounts of 0.17% vinyl content raw rubber, hydrogen-containing silicone oil, catalyst, and inhibitor were fixed at 100 PHR, 1 PHR, 0.00001 PHR, and 0.7 PHR, respectively, and did not change. The amount of gaseous white carbon black added was changed to 20, 30, 40, 45, 50, and 60 PHR, respectively, and the mechanical properties such as breaking elongation, tensile strength, tear strength, and hardness of the silicone tube with different amounts of gaseous white carbon black added were measured.

[0340] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0341] [Table 25]

[0342] 2.1.9 Considerations of hydrogen-containing silicone oil The hydrogen-containing silicone oil acts as a crosslinking agent and crosslinks with raw rubber. The amount of silicone oil added can be calculated according to the following formula:

number

[0343] 2.1.9.1 Consideration of hydrogen content in hydrogen-containing silicone oil In this test, the amounts of raw rubber with 0.17% vinyl content, catalyst, inhibitor, and gas-phase white carbon black used were fixed at 100 PHR, 0.00001 PHR, 0.7 PHR, and 40 PHR, respectively, and did not change. The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinyl silicone rubber was 1.2:1. Silicone tubes were manufactured using hydrogen-containing silicone oils with hydrogen contents of 0.18%, 0.36%, 0.5%, 0.75%, 1.0%, and 1.6%, respectively, and the mechanical properties such as breaking elongation, tensile strength, tear strength, and hardness of the silicone tubes with different hydrogen contents were measured.

[0344] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0345] [Table 26]

[0346] 2.1.9.2 Consideration of the amount of hydrogen-containing silicone oil used In this test, the amount of raw rubber with 0.17% vinyl content, catalyst, inhibitor and reinforcing agent used was fixed at 100 PHR, 0.00001 PHR, 0.7 PHR and 40 PHR, respectively, and did not change. A hydrogen-containing silicone oil with a hydrogen content of 0.75% was selected, and the molar ratio of Si-H group in the hydrogen-containing silicone oil to vinyl in the methylvinyl silicone rubber was set to 1:1, 1.2:1, 1.5:1 and 1.8:1, respectively, to carry out the experiment, and the mechanical properties such as breaking elongation, tensile strength, tear strength and hardness of the silicone tube with different amounts of hydrogen-containing silicone oil used were measured.

[0347] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0348] [Table 27]

[0349] 3. Results and Discussion

[0350] 3.1 Optimization of the manufacturing process of silicone tubing

[0351] 3.1.1 Front vulcanization tunnel temperature considerations Using the above recipe, the extrusion speed was set at 3.5 r min -1 , tensile speed is 0.1 m s -1 The temperature of the front vulcanization tunnel was changed to 270℃, 300℃, 330℃, and 360℃, and three different molds were used to manufacture the silicone tubes. The outer diameter and wall thickness of the silicone tubes were measured, and the results are as follows:

[0352] The effect of the front cure tunnel temperature on the outside diameter of the silicone tubing is shown in the table below. [Table 28] Note: Mold size (mold core diameter / mold mouth inner diameter): 3 # Mold(2.01 / 3.50);4 # Mold (2.50 / 3.90);5 # Mold (3.02 / 4.32).

[0353] The mechanical properties of the silicone tubes produced by varying the temperature of the front vulcanization tunnel were tested, and the results are shown in the table below. [Table 29]

[0354] The measurement results of the outer diameter and wall thickness of the silicone tube showed that the outer diameter and wall thickness of the silicone tubes produced in different molds changed little even as the front vulcanization tunnel temperature increased, the temperature of the front vulcanization tunnel had no effect on the final outer diameter and wall thickness of the silicone tube, and the effect of the front vulcanization tunnel temperature on the size of the silicone tube when the silicone tube was subsequently produced could be eliminated.

[0355] The mechanical results showed that with the increase of the pre-vulcanization temperature, the elongation at break, tensile strength, and tear strength of the silicone tube decreased continuously, and the hardness increased continuously. Here, the mechanical indexes of the silicone tubes produced at 270°C and 300°C all met the requirements, and the silicone tube produced at 270°C was better overall. The experiment found that the higher the temperature of the pre-vulcanization tunnel, the more likely the silicone tube produced to have bubbles. Considering everything, the temperature of the pre-vulcanization tunnel was preferably 270°C.

[0356] After the silicone is extruded from the extruder, it first passes through the front vulcanization tunnel to rapidly increase the temperature, decomposing the inhibitor into gas, and the catalyst plays a catalytic role, which allows the crosslinking reaction to proceed rapidly, and the outer wall of the silicone tube is rapidly hardened and molded. If the temperature of the front vulcanization tunnel is too low, the crosslinking reaction is slow and incomplete, the silicone tube cannot be hardened quickly, and the silicone is easily stretched and deformed, making it impossible to carry out the extrusion process. If the temperature of the front vulcanization tunnel is too high, the silicone tube is easily partially over-vulcanized, which makes the silicone tube too hard and brittle, greatly reducing the mechanical properties and losing its value.

[0357] 3.1.2 Rear vulcanization tunnel temperature considerations Using the above recipe, the extrusion speed was fixed at 3.5 r / min, the pulling speed was fixed at 0.1 m / s, and the rear vulcanization tunnel temperature was changed to 120, 150, 180, and 210°C. Three different molds were used to manufacture silicone tubes, and the outer diameter and wall thickness of the silicone tubes were measured. The results are as follows:

[0358] The effect of rear cure tunnel temperature on the outside diameter of the silicone tubing is shown in the table below. [Table 30] Note: Mold size (mold core diameter / mold mouth inner diameter): 3 # Mold(2.01 / 3.50);4 # Mold (2.50 / 3.90);5 # Mold (3.02 / 4.32).

[0359] The mechanical properties of silicone tubes manufactured at different temperatures in the rear curing tunnel were tested and the results are shown in the table below. [Table 31]

[0360] The measurement results of the outer diameter and wall thickness of the silicone tube showed that the outer diameter and wall thickness of the silicone tube produced in different molds changed little even as the temperature of the rear vulcanization tunnel increased, and it can be concluded that the temperature of the rear vulcanization tunnel does not affect the final outer diameter and wall thickness of the silicone tube. From this, it can be determined that the temperature change during the manufacturing process does not affect the molded size of the silicone tube.

[0361] The mechanical results showed that with the increase in the temperature of the rear vulcanization tunnel, the breaking elongation, tensile strength, tear strength and hardness of the silicone tube all increased. When the rear temperature reached 180°C, its mechanical indexes were close to 210°C. This showed that the mechanical performance requirements could be met if the rear vulcanization tunnel temperature was 180°C. In addition, a belt conveyor was installed in the rear vulcanization tunnel, and it was not preferable to set the temperature too high, so the temperature of the rear vulcanization tunnel was preferably 180°C.

[0362] The main purpose of the rear vulcanization tunnel is to provide conditions for the subsequent addition reaction of silicone and to allow the vulcanization reaction to proceed further. Therefore, if the rear vulcanization tunnel temperature is too high, it is easy to cause over-vulcanization, but with an appropriate temperature, the crosslinking reaction can be sufficient and the mechanical index can be improved.

[0363] 3.1.3 Measurement of oven curing time The oven curing time was set at 180° C. The oven curing was carried out for 0, 24, 48, and 72 hours, respectively, and the mechanical indexes were measured. [Table 32]

[0364] The results showed that after oven curing, the elongation at break of the silicone tube decreased but still met the required values, the tensile strength and tear strength both increased and then decreased, and the hardness gradually increased. The tensile strength and tear strength of the silicone tube cured in the oven for 48 hours were optimal, and the elongation at break and hardness both met the standards. The final oven curing conditions were preferably 180°C for 48 hours.

[0365] The mechanical properties of the oven-vulcanized silicone tube are improved compared with those of the unvulcanized silicone tube, which indicates that the crosslinking reaction is insufficient immediately after the silicone tube is extruded from the rear vulcanization tunnel. After the silicone tube comes out of the rear vulcanization tunnel of the extruder, it is basically cured, but the crosslinking reaction inside it is insufficient, so in order to ensure the complete vulcanization reaction of the silicone tube, it is necessary to carry out oven vulcanization on the silicone tube, and oven vulcanization is the final step to ensure the complete vulcanization of the silicone tube. However, if the oven vulcanization time continues to increase, the silicone tube will be over-vulcanized, the toughness of the silicone tube will decrease, and the brittleness will increase. Therefore, the oven vulcanization time must be appropriate, not too short, not too long.

[0366] 3.1.4 Measurement of catalyst usage The amount of catalyst used was changed to 0.000005, 0.00001, 0.00002, and 0.00003 PHR to produce silicone tubes, and the mechanical indexes are as follows: [Table 33]

[0367] From the above results, it was found that when the amount of catalyst added increases from 0.000005 PHR to 0.00001 PHR, the kinetic indices all increase, but when the amount of catalyst used increases continuously, the kinetic indices do not show a significant difference. Therefore, the amount of catalyst used is preferably 0.00001 PHR.

[0368] If the amount of catalyst added is too small, the catalyst will be unevenly distributed in the rubber material, and the crosslinking reaction will not occur in some rubber materials with insufficient catalyst, resulting in poor mechanical properties of the silicone tube produced. If the catalyst is added in excess, the mechanical index will not change significantly, and the excess catalyst cannot improve the mechanical properties of the silicone tube. In addition, the platinum catalyst is a precious metal, so it is necessary to use it without waste.

[0369] 3.1.5 Consideration of inhibitor dosage The formulation composition, amount used, and process were fixed, and the amount of inhibitor used was changed to 0.3 PHR, 0.5 PHR, 0.7 PHR, and 0.9 PHR to manufacture silicone tubes, and the mechanical indexes are as follows: [Table 34]

[0370] The results show that when the amount of inhibitor used increases, the elongation at break, tensile strength, and tear strength all increase and then decrease, and when the amount of inhibitor added is 0.7 PHR, the elongation at break, tensile strength, and tear strength are the best. Therefore, the amount of inhibitor added is preferably 0.7 PHR.

[0371] If the amount of inhibitor is too small, some vulcanization reaction may occur at room temperature, and after the silicone tube is vulcanized again, over-vulcanization may occur, which may reduce the mechanical index. Therefore, when the amount of inhibitor added is increased, the breaking elongation, tensile strength, and tear strength of the silicone tube all increased. When the amount of inhibitor was increased to 0.9 PHR, its mechanical index became equal to that of the silicone tube with 0.7 PHR added, indicating that the inhibitor added amount of 0.7 PHR exerted the best inhibitory effect, and when it was increased to 0.9 PHR, the inhibitor was excessive.

[0372] 3.1.6 Consideration of vinyl content in raw rubber Silicone tubes were manufactured by fixing the formulation, amount used, and process, and changing the vinyl content of the raw rubber to 0.05%, 0.07%, 0.17%, and 0.23%, and the mechanical index results are as follows. [Table 35]

[0373] The results showed that with increasing vinyl content of raw rubber, the breaking elongation, tensile strength and tear strength of the extruded silicone tube increased and then decreased, and an extreme value appeared when the vinyl content of the raw rubber was 0.17%, and the hardness increased with increasing vinyl content. The vinyl content of the raw rubber is preferably 0.17%.

[0374] The vinyl content of 0.05% and 0.07% is too low, and the crosslink density is too low. With the increase of vinyl content, the crosslink density continues to increase, and the mechanical index is also better. When the vinyl content is increased to 0.23%, the crosslink density is high, and the hardness of the silicone tube is high, but the breaking elongation is decreased, so the breaking elongation rate is poor, and therefore the tensile strength and tear strength are low. The silicone tube made with too high vinyl content has high hardness, but at the same time it is brittle and easy to break. Although the hardness of the silicone tube with 0.23% vinyl content meets the requirements, its breaking elongation rate, tensile strength and tear strength are all inferior to the silicone tube with 0.17% vinyl content.

[0375] 3.1.7 Consideration of the amount of gas phase white carbon black used The silicone tube was manufactured by changing the amount of gaseous white carbon black to 20 PHR, 30 PHR, 40 PHR, 45 PHR, and 50 PHR while keeping the formulation, dosage, and process constant. When the amount of white carbon black was 20 PHR (Example 7-1), the silicone tube was too soft, so this amount was excluded. The remaining mechanical index results are as follows: [Table 36]

[0376] The results show that with the increase in the amount of gaseous white carbon black added, the hardness of the extruded silicone tube increases significantly, while the tensile strength and tear strength do not change significantly, and the breaking elongation tends to decrease, but all are within the acceptable range. According to the requirements, the hardness of the silicone tube needs to be 50-70, and the amount of gaseous white carbon black added is preferably 40PHR.

[0377] When the amount of gaseous white carbon black added is insufficient, the hardness of the silicone tube is too low, resulting in poor moldability during extrusion molding and rough surface. The more gaseous white carbon black added, the stronger the hardness of the silicone tube and the stronger the resistance of the silicone tube to external extrusion. The purpose of adding gaseous white carbon black is to strengthen the hardness of the silicone material, so when other mechanical indicators are relatively good, the hardness data is mainly referred to. When the amount of gaseous white carbon black used is 40PHR, the hardness reaches the standard, and at the same time, the breaking elongation, tensile strength and tear strength are good. When the amount of gaseous white carbon black added is too much, the hardness of the silicone material is too large, so the extruder power is insufficient during extrusion, the discharge speed is unstable, and the hardness is too high, so the extrusion die is easy to move, resulting in uneven wall thickness of the extruded silicone tube.

[0378] 3.1.8 Considerations of hydrogen-containing silicone oil

[0379] 3.1.8.1 Consideration of hydrogen content in hydrogen-containing silicone oil The formula, amount used, and process are fixed, the vinyl molar ratio of the Si-H group of the hydrogen-containing silicone oil to the base polymer is fixed at 1.2, and the hydrogen content of the hydrogen-containing silicone oil is changed to 0.18%, 0.36%, 0.5%, 0.75%, 1%, and 1.6% to manufacture silicone tubes, and the mechanical index results are as follows: [Table 37]

[0380] The results show that hydrogen-containing silicone oil causes great changes in the mechanical properties of silicone tube.With the increase of hydrogen content of hydrogen-containing silicone oil, the hardness of the silicone tube produced keeps increasing, and the breaking elongation, tensile strength and tear strength increase and then decrease, and when the hydrogen content of hydrogen-containing silicone oil is 0.75%, the peak value appears, and finally, the hydrogen content of hydrogen-containing silicone oil is preferably 0.75%.

[0381] After the molar ratio of Si-H group in hydrogen-containing silicone oil and vinyl in methylvinyl silicone rubber is fixed, the mass of hydrogen-containing silicone oil with low hydrogen content is increased, because hydrogen-containing silicone oil is transparent oily substance, the more the amount is increased, the higher the viscosity is, and the strength of the silicone tube produced is relatively low.With the increase of hydrogen content in hydrogen-containing silicone oil, the amount of hydrogen-containing silicone oil is decreased, and as Si-H group becomes denser, local crosslinking reaction occurs rapidly, crosslinking density continues to increase, when silicone rubber is stretched, the flexibility of crosslinking bond is small, regular arrangement cannot be efficiently achieved, and only a part of crosslinking bond jointly supports external force, so that the elasticity of silicone tube is reduced, and its tensile strength and tear strength are both reduced.

[0382] 3.1.8.2 Consideration of the amount of hydrogen-containing silicone oil used The formula, amount used, and process are fixed, the hydrogen content of the hydrogen-containing silicone oil is fixed at 0.75%, and the molar ratio of Si-H group to vinyl of base polymer is changed to 1:1, 1.2:1, 1.5:1, and 1.8:1 to manufacture silicone tubes, and the mechanical index results are as follows: [Table 38]

[0383] From the results, it can be seen that when the hydrogen content of hydrogen-containing silicone oil is fixed, with the increase in the amount of hydrogen-containing silicone oil added, its hardness, breaking elongation, tensile strength and tear strength tend to increase and then decrease, and peak values ​​appear when the molar ratio is 1.2:1. The molar ratio of Si-H group in hydrogen-containing silicone oil to vinyl in methylvinyl silicone rubber is preferably 1.2:1.

[0384] When the amount of hydrogen-containing silicone oil is increased, the addition reaction is more fully carried out, the crosslinking points are increased, and the tensile strength is increased.However, when the amount of hydrogen-containing silicone oil is too much, the crosslinking density is too high, the toughness is reduced, and the silicone tube produced is hard and brittle.When the molar ratio of addition is increased to 1.8:1, the amount of hydrogen-containing silicone oil becomes excessive, and the excess hydrogen-containing silicone oil inhibits the execution of some crosslinking reactions, and the crosslinking degree is reduced, and the mechanical indexes are all reduced.

[0385] 3.2 Optimal silicone tubing manufacturing The formulation is as shown in the table below. [Table 39]

[0386] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0387] The composition of the drug core is: The drug core is 42 mg of micronized Gestodene bulk powder having a particle size of 2.81 μm.

[0388] The mechanical index of the silicone tube is as shown in the table below. [Table 40] Note: Eb-elongation at break; Ts-tensile strength; T-tear strength; H-hardness.

[0389] The breaking elongation and hardness of the three batches of silicone tubing produced in parallel according to the optimized formulation and process met the standards, and the tensile strength and tear strength were both significantly improved compared with the standards. The mechanical properties of the three batches of silicone tubing were similar, indicating good reproducibility of the formulation and process.

[0390] 3. Manufacturing and in vitro release study of Gestodene implant Silicone tubes were used as implant carriers because they can stably control drug release over a long period of time. After considering the process of silicone tubes based on mechanical indicators, it is necessary to consider the controlled drug release of silicone tubes.

[0391] 1. Equipment and Reagents

[0392] 1.1 Equipment TS-100B Type Thermostatic Shaker Shanghai Jiecheng Experimental Instrument Co., Ltd. High-Performance Liquid Chromatograph Shimadzu Corporation KQ-250DE CNC ultrasonic cleaner Kun Shan Ultrasonic Instruments Co., Ltd. AG245 Microelectronic Balance Type Electronic Analytical Balance Mettler Toledo, Switzerland

[0393] 1.2 Reagents Gestodene (purity 98%, batch number: 20190327) Hebei Mokai Technology Development Co., Ltd. KN-300N Silicone Adhesive Kanglibang Polymer New Materials Co., Ltd.

[0394] 2. Experimental Method

[0395] 2.1 Manufacturing of Gestodene Implants Silicone tubes were prepared according to the formulations and processes of each of the following examples, and the silicone tubes were used as drug release carriers to control drug release. A self-made silicone tube was taken, disinfected by soaking in 75% ethanol for 30 minutes, then dried, and one end of the silicone tube was sealed with silicone adhesive for use. Drug (42 mg of Gestodene raw drug powder with a micronized particle size of 2.81 μm) was filled into a drug-filling funnel, and the other end was sealed with silicone adhesive and cured for 24 hours to prepare a Gestodene implant (wherein the silicone tube wall thickness of the Gestodene implant is 0.3 mm, and the drug release area is 94.2 mm 2 (which is

[0396] 2.2 Selection of release solvent The implants produced need to be implanted in the subcutaneous tissue of the human upper arm, which has a pH close to neutral, so the release solvent can be selected from water or saline. The raw materials of Gestodene before and after grinding were made supersaturated with water and saline, placed in a shaker and shaken for 72 hours, then removed, centrifuged, and the supernatant was filtered. The equilibrium solubility of Gestodene drug substance in water and saline before and after grinding was measured using high performance liquid chromatography, and the appropriate release solvent was selected based on the results.

[0397] 2.3 Measurement of external emissions and influencing factors

[0398] 2.3.1 Measurement of silicone tubes cured in an oven In the silicone tube manufacturing experiment, the mechanical index of the silicone tube that is oven vulcanized for 48 hours is better, and it can be judged that the silicone tube that is oven vulcanized is fully vulcanized.In order to further determine whether the silicone tube that is oven vulcanized affects the results of drug in vitro release, use the silicone tube that is unvulcanized and oven vulcanized (corresponding to the silicone tube in the above-mentioned Example 3-1 and Example 3-3) to fill the implants with the same specifications, the same drug-containing part length, and the same drug loading amount, and carry out the in vitro release experiment, and consider the effect of oven vulcanization on the in vitro data of drug.

[0399] 2.3.2 Measurements of silicone tubing manufactured with different vinyl contents In addition to the amount of hydrogen-containing silicone oil added, the vinyl content of the raw rubber also has a significant effect on the degree of crosslinking of the silicone tube. To measure the effect of vinyl content on the in vivo release of the drug, silicone tubes were made with raw rubber with vinyl contents of 0.17% and 0.23%, and the effect of silicone tubes made with different vinyl contents on the in vitro release of gestodene was examined.

[0400] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0401] [Table 41]

[0402] 2.3.3 Consideration of silicone tubes manufactured with different molar ratios of Si-H groups in hydrogen-containing silicone oil and vinyl in methylvinylsilicone rubber The implant was placed in the release solvent, which entered the silicone tube through the holes, and after dissolving the drug, the drug was released by utilizing the concentration difference.The silicone tubes were made with 0.17% vinyl content raw rubber and 0.75% hydrogen content hydrogen-containing silicone oil in a molar ratio of 1:1.2 and 1:1.5, respectively, and other factors were the same.The effect of the amount of hydrogen-containing silicone oil added on the daily drug release of the implant was examined.

[0403] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, the time is 48 hours, and the other process conditions are the same as in 2.1.2 manufacturing process in "2.2 Manufacturing of liquid-type additive silicone tube".

[0404] [Table 42]

[0405] 3. Results and Discussion

[0406] 3.1 Manufacturing of Gestodene Contraceptive Implant When manufacturing the implant, special attention should be paid to the static electricity of the drug substance to prevent the drug substance powder from adhering to the outer wall of the silicone tube, and when sealing the implant, attention should be paid to ensure that the irregular shape of the adhesive does not affect the drug release area of ​​the drug-containing part. Finally, implants with different specifications are manufactured with good appearance, uniform sealing part, and uniform drug loading in the drug-containing part, and the GEST (Gestodene) contraceptive implant is as shown in Figure 3.

[0407] 3.2 Selection of in vitro release solvent The equilibrium solubility results of GEST in different solvents are as follows: [Table 43]

[0408] The results showed that the solubilities of the two particle sizes of Gestodene drug substance in water were both greater than those in saline, and the solubility of the unmilled drug substance was greater than that after milling, and finally, water was selected as the release medium for the in vitro release experiments.

[0409] Theoretically, the smaller the particle size of the drug substance, the larger the contact area with the solvent and the greater the solubility, but experimental data showed that the solubility of the ground drug substance was reduced. During the experiment, it was observed that after grinding, the drug substance had a relatively large static charge and was prone to aggregation, and the contact area with the solvent may be smaller due to the large particle size of the raw material, so the dissolution was reduced.

[0410] 3.3 Consideration of factors influencing external release

[0411] 3.3.1 Considerations of oven-cured silicone tubes The effect of the oven curing process on in vitro emissions is shown in the table below. [Table 44]

[0412] See the table below for the effect of the oven curing process on daily in vitro release. [Table 45]

[0413] The results show that the daily average drug release of the implant filled with the silicone tube vulcanized in the oven is lower than that of the implant filled with the silicone tube not vulcanized in the oven, but the difference is small, and the release of the implant made with the silicone tube vulcanized in the oven is more stable than the in vitro release of the silicone tube without vulcanization.In addition, the mechanical index of the silicone tube vulcanized in the oven is better, so considering the release data and mechanical index, it is more preferable to fill the silicone tube vulcanized in the oven at a temperature of 180°C for 48 hours.

[0414] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0415] 3.3.2 Consideration of silicone tubing manufactured with different vinyl contents See the table below for the effect of vinyl content on in vitro release. [Table 46]

[0416] See the table below for the effect of vinyl content on daily ex vivo emissions. [Table 47]

[0417] The results showed that the silicone tubes made from rubber with different vinyl contents (0.17% and 0.23%) had a significant effect on the average in vitro drug release of the implants, the initial burst of the rubber with 0.23% vinyl content was greater than that of 0.17%, and the in vitro release of the silicone tube made from rubber with 0.17% vinyl content was more stable. At the same time, the mechanical indexes of the silicone tube with 0.17% vinyl content were better. 3.3.3 Consideration of different amounts of hydrogen-containing silicone oil used for silicone tubing

[0418] For the effect of the amount of hydrogen-containing silicone oil used on ex vivo release, see the table below. [Table 48] NOTE: The molar ratio refers to the molar ratio of Si-H groups in the hydrogen-containing silicone oil and vinyl in the methylvinyl silicone rubber.

[0419] Please refer to the table below for the effect of the amount of hydrogen-containing silicone oil used on daily ex vivo release. [Table 49]

[0420] The results showed that the daily drug release of the contraceptive implant filled in the silicone tube made with the formula of 0.17% vinyl content raw rubber and 0.75% hydrogen content hydrogen-containing silicone oil, the molar ratio of vinyl in methylvinylsilicone rubber to Si-H group in hydrogen-containing silicone oil is 1:1.2, is slightly less than that of the contraceptive implant filled in the silicone tube made with the formula of 1:1.5 vinyl in methylvinylsilicone rubber to Si-H group in hydrogen-containing silicone oil, but the drug release curve is relatively stable. Since the implant must first achieve stable release, it was found that the molar ratio of vinyl in methylvinylsilicone rubber to Si-H group in hydrogen-containing silicone oil is 1:1.2, which is suitable for controlled drug release.

[0421] 3.4 Long-term in vitro release experiment of Gestodene implant Three batches of Gestodene contraceptive implants (where the silicone tube wall thickness of Gestodene implants is 0.3 mm and the drug release area is 94.2 mm 2 The drug substance of gestodene was crushed to a particle size of 2 to 4 μm (e.g., 2.81 μm), and 42 mg of crushed gestodene drug substance was filled in a filling funnel) for ZJ001, ZJ002, and ZJ003, respectively, at a temperature of 37 °C and 100 r·min -1 A long-term in vitro release experiment was carried out under the condition of shaker speed of 1000 to determine whether the formulation can achieve long-term release stability and long-term controlled release effect. The results are as follows: [Table 50]

[0422] The long-term release data for ZJ001, ZJ002 and ZJ003 implants are shown in the table below. [Table 51-1] [Table 51-2]

[0423] Based on the 80-day drug release data in the table, the relationship diagram between the daily drug release amount and release time of three batches of Gestodene subdermal contraceptive implants with the same specifications was drawn, as shown in Figure 4.

[0424] As can be basically seen from Figure 4, the three batches of preparations with the same specifications do not have significant differences in the drug release fluctuation range when observing the curves, and the overall trend is consistent. All of them fluctuate greatly in the early stage, but gradually stabilize in the later stage, and the daily in vitro drug release of the final preparation is almost stable within the drug release range of 17-20 μg. After reviewing the literature, it was found that the release of 10-20 μg of gestodene per day can have a contraceptive effect on the human body. The drug release of these three batches of preparations was almost stable from 11-80 days to 17-20 μg, meeting the expectations of the experiment.

[0425] The above data was summarized and simplified into a 5-day cycle to observe the long-term drug release status of the three batches of preparations. The relationship between the amount of drug released at each time of implantation and the release time. [Table 52]

[0426] According to the data in the table above and the curve changes in Figure 5, we can see that:

[0427] (1) The drug release of the implant is unstable and has large fluctuations during the first 10 days. During this stage, some of the residual drug may gradually dissolve on the surface of the silicone tube, which leads to unstable drug release and large drug release in the early stage.

[0428] (2) The subsequent release of the implant was more stable. Overall, the initial release of the implant showed a decreasing trend and then showed a relatively stable state after small fluctuations. The drug release was maintained at 17 μg-20 μg. The drug release met the requirements. The results showed that Gestodene contraceptive implant could achieve controlled release for at least 3 months.

[0429] (3) The average drug release amounts of the three batches of implants were 19.70, 19.15, and 18.84 μg, respectively. The RSD values ​​were 2.26%. The results indicated that the reproducibility of the three batches of formulations was good, and the long-term in vitro release data were basically consistent.

[0430] 4. Experiments on Gestodene contraceptive implants in rats The silicone tube produced meets the mechanical index, can stably control the drug release, and has good biocompatibility in the body, and does not irritate the tissues in the body. In this section, the silicone tube extract is mainly injected into rats to study the irritation of the silicone tube to the rat's skin, and the silicone tube is implanted in rats for a long period of time, and tissue slices are taken from the surrounding tissue to measure the tissue irritation of the silicone tube. By implanting different specifications of contraceptive implants in rats, the change trend of the rat's weight before and after implantation is observed to study whether the contraceptive implant affects the normal growth of rats, the change of the estrous cycle of rats is observed by vaginal smear after implantation, and whether the rat develops a vaginal plug, and the luteinizing hormone (LH) level in the rat's body after implantation of the contraceptive implant is detected to study the contraceptive effect.

[0431] 1. Equipment and Reagents

[0432] 1.1 Equipment XS105 Electronic Analytical Balance Mettler-Toledo Instrument Co., Ltd. SMD200-2 Electronic Analytical Balance Ohaus International Trade Co., Ltd. TG16MW Tabletop High Speed ​​Centrifuge Hunan Herexi Instrument and Equipment Co., Ltd. KQ-250DE CNC ultrasonic cleaner Kunshan Ultrasonic Instrument Co., Ltd. Rat LH Kit Shanghai Tongwei Biotechnology Co., Ltd. Electron Microscope Shenzhen Zhongwei Kechuang Technology Co., Ltd. Autoclave Shanghai Shenan Medical Instrument Factory

[0433] 1.2 Reagents Gestodene (purity 98%, batch number: 20190327) Hebei Mokai Technology Development Co., Ltd. Crystal Violet Tianjin Damao Chemical Reagent Factory Physiological saline Shandong Yuwang Chemical Reagent Co., Ltd. 4% paraformaldehyde solution Shanghai Yantuo Biotechnology Co., Ltd.

[0434] 1.3 Experimental animals Twelve healthy male SD rats weighing 180–200 g and 57 healthy female SD rats weighing 180–200 g were purchased from Benxi Changsheng Biotechnology Co., Ltd., permit number: SCXK(Liao)2020-0001.

[0435] 2. Experimental Method

[0436] 2.1 Local irritation experiment of silicone tubes in rats The prepared silicone tubes (silicone tubes in formulations ZJ001, ZJ002, and ZJ003) were cut into small pieces, immersed in 10 mL of pyrogen-free sterilized purified water, and heated and extracted at 70°C for 24 hours, after which the extracts were sterilized by high pressure for use. Six experimental rats were selected and randomly divided into two groups, one experimental group and the other saline control group, and the hair on the backs of the rats was removed and prepared. In the experimental group, 0.2 mL of the extract was injected intradermally on one side of the dorsal spine, and in the control group, 0.2 mL of saline was injected intradermally on one side of the dorsal spine. The skin reaction at the injection site was observed at 24 hours, 48 ​​hours, and 72 hours.

[0437] 2.2 Histopathological examination of rats after silicone tube implantation The prepared silicone tube was sealed and allowed to completely harden before being sterilized for use. Experimental rats were selected and randomly divided into three groups, with three rats in each group. Sterilized homemade silicone tubes were implanted into the back of each rat, and the rats were euthanized 3, 10, and 30 days after implantation, respectively, and 2 cm of tissue around the implanted silicone tube was removed, and the skin tissue was fixed with 4% paraformaldehyde and stored for tissue section observation. The presence or absence of inflammatory reactions such as redness and swelling in the surrounding tissue was observed, and tissue section experiments were performed to observe whether there were any abnormal lesions in the subcutaneous tissue and muscle at the site where the silicone tube was implanted.

[0438] 2.3 Efficacy study of Gestodene contraceptive implant in rats With the optimal formulation and process, silicone tubes with an outer diameter of 2.38 mm and a wall thickness of 0.3 mm (corresponding to the silicone tubes and drug cores of the above-mentioned formulations ZJ001, ZJ002, and ZJ003) were manufactured, and five specifications of Gestodene implants (including the length of the drug-containing part / drug loading amount) were prepared for use, with the specifications being: (1) 0.2 cm / 2.3 mg, (2) 0.5 cm / 5.4 mg, (3) 1 cm / 10.5 mg, (4) 2 cm / 20.7 mg, and (5) 4 cm / 41.1 mg.

[0439] Forty-two female rats were selected and detected by vaginal smears whether they had normal estrous cycles. Forty-two female SD rats weighing approximately 180-200 g were randomly divided into I, II, III, IV, and V experimental dosage groups (corresponding to the following implant specifications: [1] 0.2 cm / 2.3 mg, [2] 0.5 cm / 5.4 mg, [3] 1 cm / 10.5 mg, [4] 2 cm / 20.7 mg, and [5] 4 cm / 41.1 mg), one blank group (group K), and one levonorgestrel silicone rod positive control group (group Y) (levonorgestrel silicone rod I, purchased from Liaoning Ludan Pharmaceutical Co., Ltd.).

[0440] An appropriate amount of anesthetic was injected into the abdominal cavity of the rat, and after the rat was anesthetized, the hair on the back of the neck was removed, then disinfected with 2% iodine tincture, and a small opening of about 0.5 cm was cut with surgical scissors in the local skin of the back side of the rat, and the needle was inserted subcutaneously to the mark of the needle with a dedicated implant needle, and the sterilized implant was placed into the implant needle, and then the implant needle was inserted into the skin until the implant could be fully inserted, and then the implant needle was pulled out, and the implant was left under the skin, and the incision was sutured, and the wound was disinfected with 2% iodine tincture. 24 hours after implantation in the rats, they were kept in the same cage as male rats with a female-female ratio of 3:1.

[0441] 2.3.1 Observation of rat condition The rats' weights were measured and recorded before the implantation surgery, and 30 days after implantation of the Gestodene contraceptive implants, the rats' weights were measured again to observe whether they grew normally after the implants were implanted in their bodies, and the rats' mental state, activity, urination, and defecation were observed daily.

[0442] 2.3.2 Observation of the rat estrous cycle through vaginal smear experiments The estrous cycle of rats averages 4-5 days and is generally divided into four phases: proestrus, estrus, metestrus, and diestrus. Proestrus and estrus can be fertilized by mating and ovulation, metestrus is a period of degeneration and destruction of the reproductive tract, and diestrus is a period of relatively quiescence and slow growth. The vaginal smear method was usually used to determine the course of the estrous cycle in rats. When the contraceptive implant exerts its contraceptive effect, the rat should be free of estrus.

[0443] Vaginal smear method: The rat was taken out, the animal was held in place with the palm of the hand, a thin cotton swab moistened with saline was gently inserted about 0.5 cm into the vagina of the female rat, and then slowly rotated to take it out, and the vaginal contents on the swab were evenly applied to a glass slide, the slides were numbered and naturally dried, and then stained with crystal violet. After air drying, the vaginal smear was observed under an electron microscope to determine the estrous cycle of the rats. The rats that underwent implantation surgery were subjected to vaginal smear experiments three days after implantation, and vaginal secretions were collected before 9 a.m. every day. The changes in the estrous cycle of the experimental rats were observed by vaginal smears.

[0444] 2.3.3 Determining mating pregnancy status of rats by observing vaginal plugs When the implant has a contraceptive effect, female rats do not mate with male rats because they do not have a estrus period, so the contraceptive effect can be judged by observing whether the rats have a vaginal plug after matching the cages. After mating, semen remains in the vaginal opening of the rat to form a vaginal plug, and the vaginal plug is generally milky white, and some have a slight yellowish tinge. Since rats generally mate at night, in order to more accurately observe the mating status of rats, the collection of vaginal secretions and the observation of the vaginal plug should be completed by 9:00 a.m. The rats that underwent the implant operation were observed to see whether they had a vaginal plug before undergoing the vaginal smear experiment three days after implantation.

[0445] 2.3.4 Measurement of LH levels in rats by enzyme immunoassay Pregnodene mainly acts on the hypothalamus and pituitary gland, significantly reducing the levels of FSH (follicle-stimulating hormone) and LH (luteinizing hormone) in the body, causing the ovaries not to ovulate, and has a significant anti-estrogenic effect, which can thicken the cervical mucus and inhibit the penetration of sperm. It exhibits strong progesterone activity on the changes in the endometrium, which leads to the thinning of the endometrium, the lower columnar degree of endometrial epithelial cells, and the reduced secretory function, which is unfavorable for the implantation of pregnant eggs. After the rats were implanted with the contraceptive implant, their LH levels were significantly reduced compared with the blank control group, proving that the contraceptive implant achieved the contraceptive effect.

[0446] After the implantation surgery, the female rats were cage-matched and vaginal secretions were collected daily, followed by blood collection from the orbit. Blood was collected in EP tubes moistened with anticoagulant and then centrifuged (5000 r min) for approximately 10 min. -1 The supernatant was carefully collected and stored in a refrigerator at -80°C. The LH levels in the rats were detected by enzyme immunoassay to determine the efficacy of the drug.

[0447] 3 Experimental results and discussion

[0448] 3.1 Tissue irritation experiment of silicone tubes in rats In the experimental group, 0.2 mL of the extract was injected intradermally on one side of the dorsal spine of the rats, and in the control group, 0.2 mL of saline was injected intradermally on one side of the dorsal spine of the rats. The skin reactions at the injection sites were observed 24 hours, 48 ​​hours, and 72 hours later. Each injection site was dissected, but no reactions such as redness, swelling, or necrosis were found, and the results were negative.

[0449] 3.2 Histopathological examination of rats after silicone tube implantation On days 3, 10, and 30 after implantation, muscle tissues were collected from the implantation site and their pathological images (HE, ×2 or HE, ×20) were observed, as specifically shown in FIG.

[0450] The results showed that 3 days after the implantation of the silicone tube (see Figures 6, A and B), an acute inflammatory reaction occurred, the epidermal layer was slightly thickened, the dermal layer was rich in collagen fibers, a large cystic cavity structure was formed in the local subcutaneous tissue, and there was connective tissue proliferation with abundant lymphocyte infiltration around it. On the 10th day after the implantation (see Figures 6, C and D), the acute inflammatory reaction gradually disappeared, the epidermal layer was slightly thickened, the dermal layer was rich in collagen fibers, a large cystic cavity structure was formed in the local subcutaneous tissue, and there was connective tissue proliferation with diffuse lymphocyte infiltration around it. 30 days after the implantation (see Figures 6, E and F), the structure of the epidermal layer was intact, the structure of squamous epithelial cells was normal and tightly arranged, the dermal layer was rich in collagen fibers, a large cystic cavity structure was formed in the local subcutaneous tissue, and there was mild connective tissue proliferation with diffuse lymphocyte and macrophage infiltration around it.

[0451] All of the implanted areas had large cystic cavities, which indicated that implanting the implant would cause a certain amount of damage to the subcutaneous tissue. Mild connective tissue proliferation occurred around the cystic cavities, i.e., at the junction between the silicone tube and the tissue, and a membrane gradually formed. When the silicone tube was dissected on the third day after implantation, it was observed that the silicone tube was prone to prolapse, and when dissected on the 10th day after implantation, a membrane formed around the silicone tube, making it difficult to move, indicating that as the implantation time progresses, a membrane forms around the silicone tube, making it difficult for the silicone tube to come off in the body. Furthermore, the inflammatory reaction was at its maximum on the third day after implantation, and the inflammation gradually decreased as the implantation time progressed, indicating that the inflammatory reaction caused by the implantation of the silicone tube can gradually recover.

[0452] 3.3 Efficacy study of Gestodene contraceptive implant in rats

[0453] 3.3.1 Changes in rat body weight before and after implantation After the implantation surgery, the rats were observed for their feeding and activity. Their urination and defecation were normal, and they showed no mental depression.

[0454] The body weights of the rats before and after implantation are shown in the table below. [Table 53]

[0455] Observing the data on the weight changes of the rats over a one-month period, it was found that the implantation surgery and silicone tube had no effect on the rats' growth, and the weight change trends of the rats in the experimental group were almost the same as those in the blank group. Overall, it was found that the Gestodene implant had no effect on the growth of the rats.

[0456] 3.3.2 Observation of the rat estrous cycle using vaginal smears For the rats in the blank control group, vaginal secretions of female rats were collected at fixed times every 24 hours, and the estrous cycle was observed by crystal violet staining smears, and compared with the rats in the experimental group. After continuous collection for one month, it was found that the rats basically went into estrus about once every 7 days, and the vaginal smears of the rat estrous cycle are shown in Figure 7. When the vaginal smears of the rats implanted with the commercially available levonorgestrel implant were observed, no rats went into estrus, and all of them had a contraceptive effect.

[0457] The experimental group was divided into five dosage groups. According to the observation of vaginal smears for one month, the rats in the four dosage groups of Experiment II, III, IV, and V began to have a large amount of mucus in the vaginal secretions 4 days after implantation, and there were a large amount of white blood cells in the vaginal smears, but no keratinocytes, indicating that the rats did not have a normal estrous cycle. However, the rats in No. 1 and No. 4 in Experiment I group still had a complete estrous cycle change, and contraception failed in these two rats, indicating that the dosage may have a low contraceptive effect on rats and a low contraceptive rate.

[0458] 3.3.3 Determining mating pregnancy status of rats by observing vaginal plugs Observation of vaginal plugs showed that rat number 1 in the experimental I dosage group had a normal estrous cycle in the vaginal smear, and when vaginal secretions were collected on the 13th day after implantation, a milky white vaginal plug was observed at the vaginal opening, as shown in Figure 8A, and rat number 4 was found to have a vaginal plug on the 20th day after implantation, as shown in Figure 8B. This result showed that two female rats, number 1 and number 4 in the experimental I dosage group, mated with male rats, and both rats went into estrus, indicating that the contraception had failed. No vaginal plugs were found in any of the rats in the remaining dosage groups and the commercially available positive group, proving that they did not mate with male rats, proving that the contraceptive effect was present.

[0459] 3.3.4 Measurement of LH concentration in rat plasma by enzyme immunoassay Enzyme immunoassay was used to detect the LH levels in the rats. The results of the LH levels in the rats in six rats in each group 28 days after implantation of the Gestodene contraceptive implant are as follows:

[0460] The LH levels in the rats are shown in the table below. [Table 54] Note: * indicates P<0.01 compared with the blank group.

[0461] The results showed that the LH level data of the positive control group and each experimental dosage group had significant differences compared with the blank group (P<0.01). The above table is the average value obtained from the six rats in each experimental group. In addition, the results of vaginal smear and vaginal plug showed that two rats in the experimental I dosage group failed to prevent pregnancy, so the LH level data of the six rats in the experimental I dosage group are listed individually, and the results are as follows:

[0462] The LH levels for each rat in the Experiment I dose groups are shown in the table below. [Table 55] Note: * indicates P<0.01 compared with the blank group.

[0463] The results showed that the LH levels of two rats, number 1 and 4, in the dosage group of Experiment I were not significantly different from the blank group, but were significantly different from the remaining four rats and the blank group (P<0.01).

[0464] Observation of the LH level data in rats shows that compared with the blank group, the II, III, IV, V experimental dosage groups and the positive control group all significantly reduced the LH level in rats, and the higher the dosage, the lower the LH level, which shows that the hormone inhibition effect is better. Observation of the LH level data in rats of numbers 1 and 4 in experimental dosage group I shows that their LH levels are higher and more variable than those of other numbers, which shows that the drug release of the implants implanted in these two rats is unstable and does not achieve the effect of contraception. The length of the drug-containing part of the implant in experimental dosage group I is only 0.2 cm, so the operation during the manufacture of the implant is not easy, and the drug filling is unstable, so that two rats in this dosage group failed to achieve contraception, and the remaining four rats all achieved the effect of contraception.

[0465] 4 Summary of the main story

[0466] (1) A local irritation experiment on rats using silicone tube exudate confirmed that the silicone tube is safe and non-irritating to the local skin of rats. A silicone tube implantation experiment confirmed that the manufactured silicone tube was non-irritating to rat tissues, had high tissue compatibility, and did not cause inflammation or irritation to the surrounding rat tissues after implantation.

[0467] (2) Through implantation experiments, it was proved that the rats grew normally after implantation based on the weight changes of the rats before and after implantation, the estrous cycle of the rats was observed based on the stained smear of vaginal secretions, the pregnancy and mating status of the rats was observed based on the vaginal plug, and the contraceptive effect of Gestodene implant was measured through three experiments on the changes in the LH level in the rats' bodies after implantation. The results showed that the effective dosage group showed good contraceptive effect, no estrous rats were observed in the vaginal smear, and no vaginal plug was observed, and the LH level was significantly lower than that of the normal group.

[0468] (3) Efficacy experiments using rats showed that the contraceptive effect of Gestodene implants with a drug-containing area of ​​0.2 cm and a drug load of 2.3 mg was low, with a contraceptive rate of less than 70%. When the drug-containing area was 0.5 cm or more and the drug load was 5.4 mg or more, the implants showed good contraceptive effects.

[0469] II, levonorgestrel long-acting implant

[0470] 1. Method for determining the content and ex vivo release of levonorgestrel contraceptive implant

[0471] (1) Chromatography conditions Chromatography column: Diamonsil® C 18 column (4.6 mm × 250 mm, 5 μm); Mobile phase: methanol:water (80:20, v / v); Column temperature: 30°C; Detection wavelength: 240nm; Flow rate: 1.0mL min -1 ; Injection volume: 20μL.

[0472] (2) Method for measuring the amount of external release The release experiment used horizontal shaking method, a set of 6 implants was fixed to the wall of a 125mL stoppered Erlenmeyer flask with adhesive, and there should be an appropriate distance between each implant (to prevent the implants from floating on the liquid surface during release, which would cause inaccurate release results). 100mL of distilled water was accurately measured and poured into the Erlenmeyer flask, and the Erlenmeyer flask was placed in a thermostatic air shaker at 37℃ and shaken at an amplitude of 100 times / min, and the same volume of solvent was replaced every 24 hours. The sample was filtered through a 0.22μm microporous membrane and detected according to the chromatographic conditions in this part (1), and the injection volume was 20μL.

[0473] 2. Manufacturing and evaluation of addition type silicone rubber tubes Methylvinylsilicone rubber and hydrogen-containing silicone oil undergo a silicon hydrogen addition reaction in the presence of a platinum catalyst, and at the same time, an appropriate reinforcing agent is added to produce an addition-type silicone rubber product. This product has excellent physiological inertness, is non-toxic, odorless, has good biocompatibility, is resistant to biological aging, has good breathability, causes no side effects when implanted in the body, and changes in its physical properties are minimal even when implanted in the body for long periods of time, making it suitable for use in a variety of situations, including contact with blood and implantation in the body.

[0474] This part is made by adding a reinforcing agent (silicone) to linear polymer methylvinyl silicone rubber, which has vinyl groups at the terminal groups, and then undergoing an addition reaction under the catalytic action of a platinum catalyst, which crosslinks the material into a mesh-like polymer elastomer. This is then extruded into a tubular shape using an extruder and further vulcanized in an oven to obtain an addition-type silicone tube.

[0475] 1. Equipment and materials The equipment, reagents and materials are the same as those in "I. Gestodene long-acting contraceptive implant; II. Manufacture of two-liquid addition type silicone tube".

[0476] 2. Manufacturing and measurement of addition type silicone rubber tubes

[0477] 2.1 Manufacturing of addition-type silicone rubber tubes using high-temperature vulcanization method The manufacturing process is the same as that of the silicone tube in "I. Gestodene long-acting contraceptive implant; II. Manufacturing of two-liquid addition type silicone tube".

[0478] 2.2 Measurement of the physical and mechanical properties of addition type silicone rubber tubes It is the same as 2.1.3 Performance test of silicone tube in "I. Gestodene long-acting contraceptive implant; II. Manufacture of two-liquid addition type silicone tube".

[0479] 3. Methods and Results

[0480] 3.1 Considerations for silicone tube formulation

[0481] 3.1.1 Consideration of polydimethylsiloxane vinyl content To investigate the effect of different vinyl content rubber (polydimethylsiloxane) on the physical and mechanical performance of silicone tubing, an extrusion curing experiment of silicone tubing was carried out as shown in the table below. [Table 56] PHR: The number of parts by mass of the component per 100 parts by mass of the polymer compound.

[0482] The vinyl at the end of methylvinyl silicone rubber undergoes an addition reaction with the active hydrogen atoms of hydrogen-containing silicone oil, crosslinking it into a polymer elastomer. As such, the vinyl acts as an active group and is the crosslinking point that forms a polymer network. The vinyl content affects the physical and mechanical performance of medical silicone rubber tubing.

[0483] As shown in the mechanical properties in the table below, the hardness of the silicone tube increases with increasing vinyl content, but the properties of the silicone tube such as breaking elongation, tensile strength, and tear strength show a mountain-shaped change in which they initially increase and then decrease. When the vinyl content is 0.05%, the crosslinking points formed by the addition reaction are few, the tear strength and tensile strength of the silicone tube are both small, and the mechanical properties are too low to be used later. When the vinyl content is 0.23%, the crosslinking points formed by the reaction are too many, the elongation at break of the silicone tube decreases, and the tensile strength and tear strength also decrease slightly. This is because the crosslinking density is too high, the crosslinking points formed are too many, the crosslinks are short, and the rigidity increases. At this time, the hardness of the silicone tube increases, the elongation at break decreases significantly, the internal crosslinks cannot be arranged regularly and effectively, the inefficient crosslinking network increases, and the number of crosslinks that can withstand external forces decreases, resulting in a decrease in the mechanical properties of the silicone tube such as tensile strength and tear strength. When the vinyl content of the raw rubber is 0.17%, the internal crosslinks are distributed regularly and reasonably, and the physical and mechanical properties of the silicone tube are all excellent, so the preferred methyl vinyl silicone rubber is methyl vinyl silicone rubber with a vinyl content of 0.17%. [Table 57]

[0484] 3.1.2 Screening of White Carbon Black Ratio Compared with other silicone raw rubbers, the main chain of methylvinyl silicone raw rubber is a single-chain structure, the length of the Si-O bond on the molecular chain is longer than the CO and C-C σ bonds, and it does not contain isolated double bonds and does not contain other large groups or polar groups, so its molecular chain has strong flexibility, and its mechanical properties are inferior in macro performance. In order to improve the mechanical properties of methylvinyl silicone rubber, it is generally filled with different fillers according to its different uses, and white carbon black is the inorganic filler most compatible with silicone rubber because its main component and chemical bond are similar to those of silicone rubber, and it is a reinforcing agent that is often used in silicone rubber products.

[0485] An experiment was carried out using the formulation shown in the table below to examine the effect of the amount of white carbon black used on the mechanical properties of the silicone tube. [Table 58] PHR: The number of parts by mass of the component per 100 parts by mass of the polymer compound.

[0486] The effect of the amount of white carbon black used on the physical and mechanical properties of silicone tubing is as shown in the table below. When the amount of white carbon black used is within the range of 30PHR~40PHR, as the amount of white carbon black used increases, the hardness of the silicone tubing gradually increases, the deformation of the extruded tubing decreases, the wall thickness of the tubing becomes more uniform, and other physical and mechanical properties such as the tensile strength, tear strength, and elongation at break of the tubing are all excellent. However, when the amount of white carbon black used increases to 40PHR, the hardness of the rubber material increases, the extrusion power of the extruder is slightly insufficient, the extrusion speed fluctuates greatly, and the shape of the extruded tubing becomes uneven.

[0487] White carbon black can improve the mechanical properties of vulcanized rubber because its surface hydroxyl can interact with polymers, and the spatial network structure formed between white carbon black and polymers allows the molecular chains to slide and absorb the shock of external forces due to the large amount of physical adsorption when silicone rubber is deformed by external forces, and acts as a buffer against friction or hysteresis deformation caused by external forces, while at the same time making the stress distribution uniform. Therefore, by adding an appropriate amount of white carbon black, the mechanical properties of silicone rubber can be improved without excessively reducing the tensile elasticity of silicone rubber. Therefore, the silicone tube is manufactured by adding white carbon black in an amount of preferably 35% by mass of raw rubber. [Table 59]

[0488] 3.1.3 Consideration of the amount of hydrogen-containing silicone oil used Using raw rubber with a vinyl content of 0.17% and hydrogen-containing silicone oil with a hydrogen content of 0.75%, the amount of the corresponding hydrogen-containing silicone oil was calculated according to the vinyl content, and the calculation formula was as follows:

number

[0489] [Table 60] Note: PHR: Parts by mass of the component per 100 parts by mass of the polymer compound. In the above table, the vinyl mole percentage of the raw rubber is 0.17%, and the hydrogen mole percentage of the hydrogen-containing silicone oil is 0.75%.

[0490] The experimental results show the mechanical properties in the table below. As the amount of hydrogen-containing silicone oil used increases, the physical and mechanical properties of the silicone tube show a mountain-shaped change. This is also related to the density of crosslinking points in the silicone tube. Based on the reaction mechanism, the hydrogen and vinyl in the hydrogen-containing silicone oil are involved in the reaction at a molar ratio of 1:1. When the A value is less than 1, the amount of active hydrogen involved in the addition reaction is insufficient, and the crosslinking points formed by the addition reaction are few. With the increase in the A value, the tensile strength, tear strength and hardness of the silicone tube gradually increase, and reach a peak value when the A value is 1.2. That is, when the hydrogen molar ratio of vinyl to hydrogen-containing silicone oil is 1:1.2, the physical and mechanical properties of the silicone tube are the best. When the amount of hydrogen-containing silicone oil is slightly excessive, the addition reaction occurs sufficiently and the mechanical properties of the extruded tube reach the optimal state. However, when the amount of hydrogen-containing silicone oil used continues to increase, the crosslinking density of the silicone tube becomes large, the crosslinking points become disordered, and the physical and mechanical properties of the silicone tube begin to deteriorate. Therefore, the amount of hydrogen-containing silicone oil used is calculated when adding, and the A value is preferably 1.2.

[0491] [Table 61]

[0492] 3.2 Consideration of the manufacturing process of silicone tubes

[0493] 3.2.1 Vulcanization temperature and time considerations [Table 62]

[0494] After the silicone rubber is extruded from the extruder, it passes through a short front vulcanization tunnel (0.8m) through a conveyor belt to be vulcanized at high temperature, and then passes through a long rear vulcanization tunnel (2.5m) through a conveyor belt to be vulcanized, which is the first vulcanization stage, and its main purpose is to mold the silicone tube. The purpose of high-temperature vulcanization in the short drying tunnel is to quickly mold the silicone tube and reduce the deformation of the silicone tube during the subsequent conveyor belt vulcanization, and the temperature when the silicone tube passes through the short drying tunnel should not be too high, otherwise over-vulcanization will occur (Figure 9) (the front vulcanization tunnel temperature corresponding to the over-vulcanization state in Figure 9 is 360°C), which will destroy the internal polymer of the silicone tube, cause the silicone tube to crack under tension, and cause a sharp decline in various physical and mechanical properties. Since the vulcanization reaction needs to continue in order to mold the silicone tube, the vulcanization temperature in the rear vulcanization tunnel should not be too low. However, if the temperature in the rear vulcanization tunnel exceeds 200°C, it will affect the life of the conveyor belt. Therefore, the temperature when the silicone tube passes through the rear vulcanization tunnel by the conveyor belt is 180°C, which is good for molding the silicone tube, with little deformation and no over-vulcanization.

[0495] After the first stage of heating and molding, the reaction time was short, so the crosslinking of the silicone tube was insufficient and the crosslinking density was insufficient. Therefore, secondary vulcanization was carried out in an oven at 180°C to further promote the crosslinking reaction. After 0 hours, 12 hours, 24 hours, 48 ​​hours and 72 hours, samples were taken to measure their physical and mechanical properties, and various changes in physical and mechanical properties of the silicone tube after oven vulcanization were observed.

[0496] [Table 63]

[0497] The change in the physical and mechanical properties of the silicone tube and the secondary vulcanization time are shown in the table below. When the secondary vulcanization time is 0-48 hours, the internal crosslinking reaction of the silicone tube continues, the crosslinking points increase, the breaking elongation of the silicone tube decreases, and the tensile strength and tear strength are significantly higher than those of the primary vulcanization silicone tube. When the secondary vulcanization time is 48-72 hours, the internal crosslinking reaction of the silicone tube is basically completed, and the tear strength, tensile strength, etc. of the silicone tube increase slightly, but as the vulcanization time increases, the silicone tube begins to be over-vulcanized, and the internal crosslinking bonds and chain segments begin to undergo thermal decomposition reactions, and the tensile strength, tear strength, etc. of the silicone tube begin to decrease. After a comprehensive comparison of the physical and mechanical properties of the silicone tube after secondary vulcanization, it was found that the secondary vulcanization conditions are preferably 180°C and 48 hours.

[0498] [Table 64]

[0499] 4. Biological performance test of additive silicone tubes Implants that are placed in the body must be safe, reliable, and non-toxic in terms of biological properties to ensure the safety of implantation. This material was subjected to the following biological tests in accordance with GBT16175-2008-Experimental Methods for Biological Evaluation of Medical Silicone Materials to determine whether it has good biocompatibility and meets the requirements for implantation in the body.

[0500] 4.1 Acute toxicity tests The prepared clean silicone tube (corresponding to the silicone tube of Example 14-4 above) was cut to a length of 5 cm, immersed in 100 mL of double distilled water, and extracted by heating at 70°C for 24 hours, and then sterilized in an autoclave at 121°C for 30 minutes for further use.

[0501] Ten healthy SD rats weighing approximately 200g were randomly divided into an experimental group and a control group, one group was injected with the above extract at a dose of 5mL / kg into the tail vein, the other group was injected with the same dose of saline into the tail vein, and the condition of the rats was observed within 24 hours, 48 ​​hours, and 72 hours. As a result, no side effects or deaths were observed.

[0502] 4.2 Hemolysis experiment A hemolysis test was performed according to General Rule 1148 of the 2020 edition of the Chinese Pharmacopoeia. 1 mL of blood was collected from a healthy rabbit, placed in an Erlenmeyer flask containing glass beads, and shaken for 10 minutes to remove fibrinogen to obtain defibrated blood. Approximately 10 volumes of 0.9% sodium chloride solution were added and shaken uniformly, then centrifuged at 1000 rpm for 15 minutes, the supernatant was removed, and the precipitated red blood cells were further washed three times with 0.9% sodium chloride solution according to the above method until the supernatant no longer appeared red. The obtained red blood cells were made into a 2% suspension using 0.9% sodium chloride solution for use.

[0503] Five clean glass test tubes were taken, tubes numbered 1 and 2 were test tubes, tube numbered 3 was negative control tube, tube numbered 4 was positive control tube, and tube numbered 5 was test control tube. As shown in the table below, 2% red blood cell suspension, 0.9% sodium chloride solution, purified water, and the extract from "4.1 Acute Toxicity Test" were added in sequence, mixed uniformly, and then immediately placed in a thermostatic shaker at 37℃±0.5℃ for incubation. After 3 hours, the hemolysis and coagulation reactions were observed.

[0504] The hemolysis test is as shown in the table below. [Table 65]

[0505] The experimental results showed that there was no significant difference between tubes 1, 2, 3 and 5 with the naked eye, the supernatant was clear, and the positive control tube 4 showed hemolysis, indicating that the hemolysis test of the material was negative.

[0506] 4.3 Stimulation testing Ten healthy SD rats weighing approximately 200 g were selected and randomly divided into an experimental group and a control group, and the hair on both sides of the rats' dorsal spine (an area of ​​approximately 3 × 3 cm) was removed 4 hours before the start of the test.

[0507] An appropriate amount of the extract obtained in "4.1 Acute Toxicity Test" was dropped onto a 2.5 x 2.5 cm absorbent gauze, and the soaked gauze was placed on the depilated area of ​​the rat and fixed with tape. For the control group, saline gauze was applied and fixed in place in the same manner as above. When the gauze was removed and observed after 4 hours, no skin reaction was observed.

[0508] Ten healthy SD rats weighing 200g were selected and randomly divided into an experimental group and a saline control group. In the experimental group, the extract was injected into the skin on one side of the rat's back at 5 points, each at 0.2mL, and the same amount of saline was injected into the other side of the back. In the saline control group, the rats were injected with an equal amount of saline on both sides of their backs according to the above procedure. After the injection, the condition of each injection site was observed within 24, 48, and 72 hours. No redness, swelling, necrosis, or other phenomena were observed, and the irritation test result of this substance was negative.

[0509] 4.4 Short-term burial experiment A large number of clean silicone tubes (corresponding to the silicone tube of Example 14-4 above) with an outer diameter of 2.4 mm, an inner diameter of 1.6 mm, and a length of 35 mm were prepared, and both ends were sealed with adhesive, and then washed with distilled water and sterilized at 121°C for 30 minutes. After sterilization was completed, the silicone tubes were dried for use. 12 healthy SD rats weighing about 200 g were selected, and after the rats were anesthetized, the sterilized silicone tubes were implanted into the rat's dorsal skin with an implantation needle, and the wounds were sutured. The rats were then raised normally, and on the 3rd and 10th days after implantation, 5 SD rats were randomly selected and euthanized, and the tissues around the silicone tubes were taken out to prepare tissue sections for histological observation.

[0510] During the implantation period of the silicone tube, the rats had a normal diet, daily life, and normal weight gain. No abnormal lesions were observed with the naked eye in the subcutaneous and muscle tissues of the implantation site. The experimental results of the tissue sections are shown in Figure 10. Figure 10 (A) is a whole image of the tissue section 3 days after implantation, in which mild epidermal thickening was observed, and Figure 10 (B) is a partial image of the tissue section 3 days after implantation, in which proliferation of connective tissue was observed around the implantation site (arrow at the left end), accompanied by scattered lymphocyte infiltration (arrow in the center), and multinucleated giant cells (arrow at the rightmost end). According to the grading criteria for inflammatory cell reaction, the degree of tissue inflammatory cell reaction 3 days after implantation was grade III. Figure 10 (C) shows the overall view of the tissue section 10 days after implantation, where mild epidermal thickening was still observed, and Figure 10 (D) shows a partial view of the tissue section 10 days after implantation, where proliferation of connective tissue was observed around the area (arrow at the far right) accompanied by diffuse lymphocytes (arrow at the far left). According to the grading criteria for inflammatory cell reactions, the degree of tissue inflammatory cell reaction 10 days after implantation was grade II. During the period when the silicone tube was implanted, the rats had a normal diet, daily life, and normal weight gain. No abnormal lesions were observed with the naked eye in the subcutaneous and muscle tissues of the implanted area.

[0511] As the implantation time increased, the degree of inflammatory reaction at the implantation site of the rats gradually decreased, and the results of the tissue sections showed that the degree of inflammatory cell reaction at the implantation site of the rats was less than grade IV at one week, and less than grade II at four weeks, which met the index requirements of the tissue reaction degree in the implantation experiment part of "GBT16175-2008-Experimental Method for Biological Evaluation of Medical Silicone Materials", and the implantation experiment result of the silicone tube material was pass.

[0512] The grading criteria for the inflammatory cell response are shown in the table below. [Table 66]

[0513] The biocompatibility of the silicone tube was evaluated through acute toxicity tests, hemolysis tests, irritation tests, implantation tests, etc., and the silicone tube was found to have good biocompatibility, laying the foundation for the subsequent production of implants.

[0514] III. Preparation and Evaluation of Levonorgestrel Long-Acting Implants Silicone rubber has excellent breathability and biological inactivity, and long-acting contraceptive implants using silicone rubber as a carrier can slowly and continuously release the contained drug, maintain long-term contraceptive efficacy, and avoid the first-pass effect of the liver.

[0515] In this section, we mainly carried out the preparation and in vitro release experiments of levonorgestrel long-acting implants, measured the factors affecting the in vitro release of levonorgestrel implants, compared the homemade formulation with the commercially available implants through long-term release experiments, and measured the conditions for accelerated experiments.

[0516] 1. Equipment and medicine

[0517] 1.1 Equipment [Table 67]

[0518] 1.2 Medicines and Reagents [Table 68]

[0519] 2. Preparation of long-acting levonorgestrel implant and in vitro release test

[0520] 2.1 Manufacturing of Levonorgestrel Long-Acting Implants

[0521] 2.1.1 Silicone rubber tube treatment Additive silicone tubes (outer diameter 2.4 mm, inner diameter 1.6 mm) that met the requirements in terms of appearance and performance were cut to the same length of 35 mm, placed in a 100 mL beaker, an appropriate amount of detergent was added, and ultrasonically treated in distilled water for 30 minutes. The tubes were then rinsed three times with distilled water and further washed with 75% ethanol before being air-dried for use.

[0522] [Table 69]

[0523] The specific process is as follows: the front vulcanization tunnel is 270°C, the vulcanization time is about 5 seconds, the rear vulcanization tunnel is 180°C, the vulcanization time is about 2 minutes, the oven vulcanization temperature is 180°C, and the time is 48 hours. The other process conditions are the same as the manufacturing process 2.1.2 in "II. Manufacturing of two-liquid additive type silicone tube".

[0524] Drug core formulation: micronized levonorgestrel powder with a particle size of 2.12 μm.

[0525] 2.1.2 Implant Manufacturing One end of the silicone tube was folded, and 36 mg of LNG (levonorgestrel) powder was accurately filled into the tube through a tool at the other end (the length of the drug core is 30 mm), then both ends of the silicone tube were sealed using glue, and the silicone tube was kneaded and vibrated after the glue was cured to ensure uniform distribution of the drug in the silicone tube. After that, the powder attached to the surface of the silicone tube was washed off, and the above steps were repeated six times to obtain one set of levonorgestrel implants (the wall thickness of the levonorgestrel implant used here is (2.4~1.6) / 2=0.4 mm, and the drug release area was calculated based on S=πd×L (where d is the inner diameter of the silicone tube, and L is the length of the drug-containing part).

[0526] 2.2 In vitro release experiment of long-acting levonorgestrel implant The experimental method for the in vitro release rate of the levonorgestrel long-acting implant was carried out according to Part 1, “Method for measuring in vitro release rate”.

[0527] The degree of in vitro release of the implant is an important indicator for quality control, determines the contraceptive efficacy and is the basis for subsequent clinical use.

[0528] 3 Experimental methods and results

[0529] 3.1 Research into factors affecting the degree of ex vivo release of levonorgestrel implants

[0530] 3.1.1 Effect of silicone tube manufacturing recipe on the degree of implant release from the body Silicone tube is the functional membrane of the implant, and methylvinyl rubber with vinyl end groups and hydrogen-containing silicone oil are cross-linked by the action of additives, and since drugs need to diffuse to the outside through the silicone tube, the properties of the silicone tube itself also affect drug release. Implants with the same specifications manufactured with clean silicone tubes that met the physical and mechanical requirements were selected, and after blast removal treatment, they were placed in a shaker to carry out the release experiment, and samples were sampled continuously for 35 days to consider the effect of the silicone tube manufacturing formula on the degree of implant release from the body.

[0531] 3.1.1.1 Effect of vinyl content on the degree of ex vivo release from implants Silicone tubes were extruded using raw rubber with vinyl contents of 0.17% and 0.23%, and implants were manufactured according to "2.1 Manufacturing of Levonorgestrel Long-Acting Implants" in this section, and in vitro release experiments were performed. [Table 70]

[0532] The daily release amounts of the silicone tubes corresponding to Examples 16-1 and 16-2 are as shown in the table below. [Table 71]

[0533] The experimental results are shown in the table above, and both groups of implants can be released stably. The daily release of the implant made of raw rubber with vinyl content of 0.23% was less than that of the implant made of raw rubber with vinyl content of 0.17%.

[0534] When the implant is released, the drug small molecules move outward through the wall of the silicone tube, and the drug dissolved in the membrane diffuses to the interface between the membrane and the release solvent, and finally disperses and dissolves in the receptor. The density of crosslinking points in the silicone tube affects the relaxation process of the polymer chain segments, and controls the diffusion behavior of the drug through the crosslinking network; that is, the size of the polymer crosslinking network in the silicone tube, the higher the crosslinking density, the more crosslinking points there are, which leads to a "molecular sieve effect" on the diffusion of the drug, and the shorter the length of the molecular chain, the less mobile the chain segment is, and the lower the ability of the drug to pass through the gap between the chains, the lower the solubility of the drug in the membrane and the slower the release rate of the drug.

[0535] 3.1.1.2 Effect of the amount of hydrogen-containing silicone oil used on the degree of implant release from the body The silicone tubes manufactured with different amounts of hydrogen-containing silicone oil (A value of adding hydrogen-containing silicone oil is 1, 1.2, 1.5 respectively) were subjected to in vitro release degree experiments. The formulations are shown in the table below. [Table 72]

[0536] The daily release amounts of the silicone tubes corresponding to Examples 17-1, 17-2, and 17-3 are as shown in the table below. [Table 73]

[0537] The amount of hydrogen-containing silicone oil used had little effect on the release rate of LNG, and when the A value was 1.5, the release rate of the implant was slightly smaller than when the A values ​​were 1 and 1.2. This was mainly caused by the difference in the diffusion rate of the drug in the silicone tube due to the difference in the crosslinking degree in the silicone tube. 3.1.1.3 Effect of the amount of white carbon black used on the degree of ex vivo release from the implant

[0538] Release measurements were carried out on silicone tubing loaded with different amounts of white carbon black, the formulations being as shown in the table below. [Table 74]

[0539] The daily release amounts of the silicone tubes corresponding to Examples 18-1, 18-2, and 18-3 are as shown in the table below. [Table 75]

[0540] The amount of white carbon black used had a small effect on the release of the implants, with an increase in the amount of white carbon black used resulting in a slight decrease in the release of the implants.

[0541] In conclusion, the manufacturing formula of the silicone tube has a certain effect on the release of the implant, and the main reason is the effect of the difference in the solubility of the drug small molecule in the silicone tube due to the difference in the crosslinking degree in the silicone tube. However, the drug is released stably in all of these silicone tubes with different formulas, and there is no significant difference in the diffusion rate of the drug in the silicone tube, that is, the diffusion rate is not too slow to release the drug, and the drug release rate is not too fast to cause bursts, so it is preferable to use the silicone tube with the best mechanical properties (formulation: 100 PHR of raw rubber with a vinyl content of 0.17%, 35 PHR of white carbon black, A value of hydrogen-containing silicone oil = 1.2, 10 PHR of catalyst). -5 PHR, inhibitor 0.7PHR) was selected to prepare the implant and better meet the long-term and stable release of the implant in the body.

[0542] 3.1.2 Effect of blast removal on the degree of implant release from the body According to "2.1 Preparation of Levonorgestrel Long-acting Implant" in this section, two groups of levonorgestrel implants were prepared. One group was placed in a shaker without any treatment to carry out the in vitro release experiment, and the other group was added with 50mL of anhydrous ethanol in a stoppered Erlenmeyer flask, and then ultrasonicated for 1 minute, which was repeated three times, and then added with 100mL of distilled water and left overnight. The next day, the leaching solution was discarded, and the implant was placed in a shaker to carry out the in vitro release experiment. Samples were taken at fixed points every day for 12 consecutive days to observe the in vitro release status of the implant. The experimental results are shown in the following table and Figures 11 and 12.

[0543] As shown in Figures 11 and 12, the daily drug release of the implants that had not been previously blast-removed was higher during the first 12 days, and the daily release was unstable, showing a very significant downward trend. The relative burst release of the implants (Day 1 release / Mean release) was expressed by comparing the release of the implants on the first day with the average drug release of the previous day. Experiments showed that the relative burst release of the blast-removed implants was close to 1, which indicated that the daily release of the blast-removed levonorgestrel implants was very gradual from the initial release. The cumulative drug release (Q C ) and drug release time (t) linearly (R 2 = 0.996), the drug release rate conformed to zero-order drug release kinetics, and there was no significant variation in the daily drug release curve.

[0544] The surface of the levonorgestrel implant that was not blasted has powder electrostatically adsorbed to the silicone tube, which causes a very obvious burst release effect on the release of the implant, so that its initial release amount can be closer to the steady-state release amount, shorten the observation time of the in vitro release, and reduce the risk caused by the sudden release of the drug after the implant is embedded in the body, so it is necessary to carry out corresponding processing. After the blasted removal treatment, the initial release amount of the implant reached a steady state.

[0545] The release data for the LNG implant is shown in the table below. [Table 76] Note:Q C : Cumulative drug release

[0546] 3.2 Comparison of levonorgestrel implants with commercially available preparations The commercial levonorgestrel silicone rod I contains 6 medicinal silicone rods, each silicone rod contains 36 mg of LNG powder, the total drug loading is 216 mg, the outer diameter of the silicone tube is 2.4 mm, the wall thickness of the tube is 0.4 mm, and the length of the drug core is 30 mm. After observing the influencing factors of the above in vitro release experiment, 2.4 mm × 1.6 mm × 35 mm × 6 silicone tubes were selected to prepare 6 levonorgestrel implants with a drug core length of 30 mm and a drug loading of 216 mg. The commercial formulation (levonorgestrel silicone rod (I), purchased from Liaoning Ludan Pharmaceutical Co., Ltd.) and the levonorgestrel implant were both subjected to blast removal treatment and then subjected to a 100-day in vitro release experiment.

[0547] During the 100-day release period, the daily drug release curves of the implants were as shown in the table below. The daily drug release amounts of the homemade formulation (silicone tube corresponding to Example 18-2) and the commercially available formulation were both very stable, with no significant burst release or release decay.

[0548] The in vitro emission data for LNG homemade and commercially available formulations are shown in the table below. [Table 77] Note:Q C : Cumulative drug release

[0549] As shown in the table below, the in vitro release rate of the homemade formulation was not significantly different from that of the commercial formulation. During the in vitro release experiment, the RSD value of the daily drug release rate of the homemade formulation was 7.19%, and the RSD value of the daily drug release rate of the commercial formulation was 6.70%, which indicated that the drug release stability of the two groups of formulations was relatively similar, and the release behavior was consistent with zero-order release. [Table 78-1] [Table 78-2] [Table 78-3]

[0550] 4. In vitro acceleration experiment Levonorgestrel implants need to maintain effective drug concentrations in the body for several years, so rapid release or unexpected changes in release of the formulation in the body may cause serious side effects. For long-acting implants, screening of formulations by real-time drug release requires a long cycle, which is inconvenient. Therefore, finding a suitable drug release acceleration method plays a very important role in the optimization and quality control of formulations. Although increasing temperature is widely used in in vitro accelerated experiments of formulations, accelerated tests need to more accurately predict the real-time release of reactions, so it is also necessary to determine whether there is a correlation between accelerated drug release and normal drug release.

[0551] 4.1 Experimental Method The implant was manufactured with a clean silicone tube (corresponding to the formulation of Example 18-2, the front vulcanization tunnel was 270 ° C, the vulcanization time was about 5 seconds, the rear vulcanization tunnel was 180 ° C, the vulcanization time was about 2 minutes, the oven vulcanization temperature was 180 ° C, the time was 48 hours, the formulation of the drug core: levonorgestrel powder with a micronized particle size of 2.12 μm) with an outer diameter of 2.4 mm, an inner diameter of 1.6 mm, and a length of 35 mm (the length of the silicone tube is 35 mm, the length of the pure drug core is 30 mm, and the extra 5 mm is the length of the adhesive at both ends). With reference to the drug release situation at 37 ° C, the release of LNG under the conditions of 45 ° C and 55 ° C was measured. With reference to the normal release conditions, 100 mL of water was used as the solvent, and release samples were taken every 1 to 3 hours and replaced with new solvent, and three sets of experiments were performed in parallel at each temperature.

[0552] 4.2 Experimental results The release data of LNG implants released outside the body at different temperatures is shown in the table below. [Table 79] Note:Q C :Cumulative drug release.

[0553] The release rate of LNG increases with temperature and is related to the Arrhenius equation, which is:

number

number

[0554] In the formula, K is calculated from the drug release amount at different temperatures, and a straight line is drawn between ln(K) and 1 / T, with a slope of -Ea / 2.303R. Based on the straight line drawn by applying the Arrhenius equation at multiple temperatures set in the temperature acceleration experiment, the predicted drug release rate at 37°C was read and compared with the drug release rate obtained from the actual 37°C drug release experiment. It was determined whether the drug release rate in this temperature increase acceleration experiment could predict the actual drug release rate. Therefore, ln(K)=-18841.7+64.507(R 2 =0.999), and the linear relationship between ln(K) and 1 / T is shown in FIG. 13. The predicted drug release rate K at 37° C. calculated by this formula is 37℃ = 51.94 μg was close to the actual drug release amount when the implant was at 37°C, and the accelerated experimental drug release was in good correlation with the normal drug release.

[0555] From the data in the above table, it can be seen that the drug release rate of LNG at 45°C is about 4.5 times that of 37°C, and the drug release rate of LNG at 55°C is about 28 times that of 37°C. That is, the release amount in 24 hours at 37°C is close to the release amount in 5.2 hours at 45°C, and the release amount in 24 hours at 37°C is close to the release amount in 51 minutes at 55°C, which greatly saves the time of in vitro release experiments; by increasing the release temperature, the in vitro release amount of LNG can be increased, and the experimental time of in vitro drug release experiments can be shortened.

[0556] 4. Pharmacokinetic study of levonorgestrel long-acting implant This section mainly carried out a pharmacokinetic study of levonorgestrel implants in rats. Subcutaneous implants with different specifications were implanted into rats, and the changes in the estrous cycle of SD rats after implantation were observed by vaginal smears, the LH (luteinizing hormone) levels in the rats were measured by enzyme immunoassay, and the mating behavior of the rats was monitored to study the contraceptive effect of subcutaneous levonorgestrel implants.

[0557] 1. Equipment and Reagents

[0558] 1.1 Equipment [Table 80]

[0559] 1.2 Reagents [Table 81]

[0560] 1.3 Experimental animals SD rats (license number: SCXK(Liao)2020-0001) Liaoning Changsheng Biotechnology Co., Ltd.

[0561] 2. Experimental Method

[0562] 2.1 Method of administration Using 2.4mm x 1.6mm silicone tubes, five specifications of levonorgestrel implants (formulation corresponding to Example 18-2, anterior vulcanization tunnel is 270°C, vulcanization time is about 5 seconds, posterior vulcanization tunnel is 180°C, vulcanization time is about 20 seconds, oven vulcanization temperature is 180°C, time is 48 hours, drug core formulation: levonorgestrel powder with micronized particle size of 2.12 μm) (drug core length / drug loading) were manufactured for use, and the five specifications were respectively: I (3mm / 3.6mg), II (10mm / 12mg), III (15mm / 18mg), IV (20mm / 24mg), V (30mm / 36mg).

[0563] The specific formulation is as shown in the table below. [Table 82]

[0564] 14 healthy SD male rats weighing about 200g were randomly divided into 7 groups for use, and 42 healthy female SD rats weighing about 200g were randomly divided into 7 dose groups, namely, a blank tube group (negative control group), a positive control group, and 5 dose groups, the positive control group used levonorgestrel licone rod I (purchased from Liaoning Ludan Pharmaceutical Co., Ltd.) with a drug core length of 30mm, and the blank tube also used a silicone tube with an outer diameter of 2.40mm and a wall thickness of 0.5mm, cut into 15mm segments, and glued at both ends for use. All formulations and silicone tubes need to be sterilized by autoclaving (121℃, 30min) before use.

[0565] The implantation method for the treatment group was the same as that in "2.3 Experiment on the efficacy of Gestodene contraceptive implant in rats" in "I. Gestodene long-acting contraceptive implant; IV. Experiment on Gestodene contraceptive implant in rats". 24 hours after implantation, the blank group and the drug-treated group were both placed in a cage with males and females, and each cage contained 6 female rats and 2 male rats.

[0566] 2.2 Observation of the rat vulva and preparation of vaginal smears To monitor the estrus, mating and pregnancy of the rats, the characteristics of the vulva were observed and recorded at 9:00 am every day for 30 consecutive days after dosing, vaginal smears were prepared from the rats, and the characteristics of the exfoliated vaginal epithelial cells were observed and recorded.

[0567] 2.2.1 Preparation method for rat vaginal smears Weigh out 0.1g of crystal violet powder and dissolve it in 100mL of distilled water to prepare 0.1% gentian violet solution for use, prepare a clean anti-stripping slide and label it for use, and soak a cotton swab in sterile saline for use. Remove the female rat from the cage, place it on the cage cover, grab the rat's tail with one hand and slowly lift it up to expose the rat's vaginal opening, use a cotton swab to gently wipe the rat's vaginal opening to clean up the urine, insert the previously prepared moistened cotton swab into the rat's vagina about 0.5cm, gently rotate it 1-2 times, and evenly apply the cotton swab to the anti-stripping slide to prepare a smear. After drying the anti-exfoliation slide coated with rat vaginal exfoliated cells, 50μL of absolute ethanol was added dropwise to fix it for 10 minutes, 50μL of gentian violet solution was added dropwise to the anti-exfoliation slide and left for 1 minute, the anti-exfoliation slide was immersed in distilled water for 1 minute, then rinsed with distilled water for 10 seconds, and the anti-exfoliation slide was allowed to dry naturally. After the anti-exfoliation slide was dried naturally, it was sealed with neutral rubber and the rat vaginal smear was observed under an electron microscope.

[0568] 2.2.2 Observation of the estrous cycle in rats using vaginal smears The method for determining the estrous cycle of rats is as shown in the table below. [Table 83]

[0569] 2.3 Measurement of LH concentration in rat plasma by enzyme immunoassay

[0570] 2.3.1 Collection of Blood Samples From the third day after administration, for 28 consecutive days, 100 μL of blood was collected from the orbit at 9:30 a.m. every day, placed in an EP tube pretreated with heparin sodium, mixed uniformly, and then centrifuged for 10 min at a rotation speed of 5000 r·min -1 The supernatant was transferred to an EP tube and stored at -80°C for testing.

[0571] 2.3.2 Measurement of LH concentration in rat plasma by enzyme immunoassay After the levonorgestrel implant was implanted in the rats, the pharmacodynamic behavioral properties of the levonorgestrel implant in the rats were measured by observing the LH level in the rats' plasma. Serum samples were collected and the content of LH (luteinizing hormone) in the rats' serum was detected using the enzyme immunoassay kit, strictly following the instructions of the kit.

[0572] A standard curve was created from the concentrations of the standards and the OD values, and the LH concentrations in the serum samples were calculated from the standard curve.

[0573] 2.3.3 Statistical processing Data were analyzed using SPSS21.0 analysis software, and experimental results were expressed as mean ± standard deviation (mean ± SD). One-way ANOVA was used to evaluate the overall variance differences between the means of multiple groups, and LSD was used for multiple comparisons when data variances were homogeneous, and Dunnett T3 was used for multiple comparisons when variances were unequal. Unpaired t-tests were used for comparisons between two groups. P < 0.05 was considered to indicate a significant difference.

[0574] 3. Results and Discussion

[0575] 3.1 Monitoring results of estrus and mating status of rats By observing the daily vulva condition and vaginal smear of the rats in each group, it was determined whether the rats were in heat and mated. During the experimental period, the rats had normal meals and rest, and showed normal weight gain. In the experiment, in the blank group after cage matching, a white gelatinous vaginal plug was detected in the vagina of the female rats. The vaginal plug is formed by the mixture of the male rat's semen, the female rat's vaginal secretion and the vaginal epithelial cells hardening immediately after exposure to air, which is an important sign that mating was successful. In addition, it could be observed that the vaginal smear of each female rat in the blank tube group showed a complete estrous cycle, the progesterone level in the body of the rats in the blank tube group was normal, and the rats showed normal estrus and mating behavior.

[0576] In the treatment groups, after implanting the formulations in the rats in the four dose groups II, III, IV, and V and the positive control group, during the one-month test, the rats' vulvas were examined and found to have tightly closed vaginal openings, dry vulvas, no secretions, no redness or swelling, and no vaginal plugs. When the vaginal smears were observed, the presence of a large number of white blood cells, a typical characteristic of diestrus, was confirmed, indicating that the rats were in diestrus and had no normal estrus. However, in the I treatment group, the female rats numbered 2 and 4 were found to have complete estrous cycles by vulvar examination and vaginal smear examination, indicating that the implantation of the levonorgestrel implants at the doses in the two rats had no contraceptive effect.

[0577] 3.2 Changes in LH levels in rats The experimental results are shown in the table below. After the levonorgestrel implant was implanted in the rats, the LH levels in the rats' bodies were significantly reduced, that is, the LH levels of the rats in the positive control group and different dosage groups were significantly different compared with the blank tube group (P<0.05). The experiment found that the LH levels in the rats' bodies were affected by the dosage of LNG, and the higher the dosage of LNG, the lower the LH levels in the rats' bodies.

[0578] In the estrus cycle of rats, the secretion of LH is regulated by GnRH (gonadotropin releasing hormone), and LH showed an obvious peak in the proestrus period of rats. In the treatment group and the positive control group, levonorgestrel mainly acts on the hypothalamus and pituitary gland, so that it inhibits the release of GnRH through a negative feedback mechanism, reduces the secretion of LH, and the peak of LH level is significantly reduced or disappeared, the process of growth and maturation of follicular follicles is affected, the ovaries are not ovulated, and the contraceptive effect is realized. This is consistent with the observation results of vaginal smears, and after the implant exerted its effect in the rats, the rats maintained the estrus state, and the LH peak present in the proestrus period was inhibited by negative feedback control, the rats did not ovulate, and the male and female rats did not mate, so the pregnancy of the rats was prevented. However, the LH level in the blank tube group was not inhibited, the LH peak before estrus still existed, and the rats could still normally estrus, mate, and become pregnant. [Table 84] Note: * indicates P<0.05 compared with the blank group.

[0579] In addition, the dose of the V group was consistent with that of the positive control group, and the experiment showed that the LH levels in the rats of the two groups were also similar (V group LH = 36.61 ± 2.43 IU L -1 , positive control group LH = 39.91 ± 4.75 IU L -1 ) and comparing the LH levels in the rats of the two groups, no significant difference was found (P>0.05), indicating that the implant produced in this study has the same effect as the commercially available formulation Levonorgestrel Silicone Rod I.

[0580] In addition, in the vaginal smear examination of the rats in the I dosage group, it was found that two rats had estrus, and the measurement results of LH of the rats in this group are shown in Figure 14. In the experiment, it was found that the LH levels in the bodies of two rats, No. 2 and No. 4, were close to the LH levels of the rats in the blank group, but the LH levels of the remaining rats were significantly different from the LH levels of the rats in the blank group (P<0.05). Combined with the results of the vaginal smear examination, it was shown that the levonorgestrel implants in these two rats had no medicinal effect. The reason for this is that the length of the drug core of the implant (3mm / 3.6mg) is too short, so during production, the drug powder of the partial implant may penetrate into the adhesive, making it difficult to release the drug, resulting in insufficient drug release, and no contraceptive effect was obtained after implantation in the rats.

[0581] 4 Summary of this chapter

[0582] (1) The experiment was carried out to determine whether the rats had estrus or mating behavior by observing the vulva and vaginal smears of rats in different groups, and to study whether the levonorgestrel implant had medicinal effects in rats by measuring the LH levels in the rats in different groups. The experiment found that the LH levels in the rats in groups I, II, III, IV, V and the positive control group were significantly lower than those in the blank group (P<0.05), the LH levels in the rats decreased with increasing dosage of the implant, and the rats in groups II, III, IV, V and the positive control group did not have estrus or mating behavior after the levonorgestrel implant was implanted in their bodies.

[0583] (2) In the experiment, it was found that the LH levels in the rats that received implants of the same dosage as the positive control group were also close to those in the positive control group, with no significant difference (P>0.05), indicating that the implants produced in this study have the same effect as the commercially available levonorgestrel silicone rod formulation.

[0584] (3) During the experimental period, the rats exhibited normal daily activities, eating, drinking, and weight gain, and the implants had no adverse effects on the rats.

[0585] III. Long-acting estradiol implant

[0586] 1. Method for determining the content and ex vivo release of estradiol in long-acting implants

[0587] (1) Measurement method of content Take one estradiol implant, cut open the silicone tube, cut the drug core into several small fragments, put it into a 100mL measuring flask, add 10mL of methanol to infiltrate, leave it for 3 hours to swell, dilute to the mark with absolute ethanol, shake evenly and filter, accurately measure 0.2mL of additional filtrate, put it into a 50mL measuring flask, dilute to the mark with mobile phase, shake evenly, inject 20μL of sample into HPLC, calculate the drug content based on the standard curve. The chromatographic conditions are as follows: Chromatography column: Diamonsil® C18 column (250 mm x 4 mm, 5 μm) Mobile phase: acetonitrile-water (55:45, v / v) Column temperature: 25℃ Detection wavelength: 202 nm Flow rate: 0.8mL min -1 Injection volume: 20μL

[0588] (2) Method for measuring the degree of release The release rate was measured by the horizontal shaking method. One estradiol implant was taken and fixed in a 100 mL stoppered Erlenmeyer flask with adhesive, and arranged so that the implants were intertwined. 100 mL of distilled water was accurately measured as the release solvent, and the stoppered Erlenmeyer flask was placed in a thermostatic shaker with an amplitude of 100 r min -1The temperature was 37°C, and it was ensured that the implant was always under the liquid surface. Samples were taken every 24 hours and replaced with the same volume of release medium. The sample solution was filtered through a 0.22 μm microporous membrane and then injected according to the content measurement method in (1), and the drug release amount was calculated based on the standard curve.

[0589] 2. Research on the manufacture and in vitro release of estradiol reservoir-type implants

[0590] 1. Equipment and Reagents

[0591] 1.1 Equipment It is similar to the device in "I. Gestodene long-acting contraceptive implant; 3. Manufacturing and in vitro release study of Gestodene implant."

[0592] 1.2 Materials [Table 85]

[0593] The remaining materials are the same as those in "I. Gestodene Long-Acting Contraceptive Implant; III. Preparation and In Vitro Release Study of Gestodene Implant."

[0594] 2. Experimental Method

[0595] 2.1 Fabrication of estradiol reservoir-type implants The composition and manufacturing method of the silicone tube are as follows. [Table 86]

[0596] Using extrusion molding technology, various types of additive controlled release silicone tubes were manufactured, and mechanical properties such as breaking elongation, tensile strength, and tear strength were used as evaluation indexes to measure the silicone tube formulation and process factors. The final silicone tube formulation was determined to be: 100 PHR of methyl vinyl silicone rubber, 0.17 mol% vinyl content of vinyl polysiloxane, 30 PHR of gas-phase white carbon black, 1.01 PHR of hydrogen-containing silicone oil, 1.2:1 molar ratio of Si-H group in hydrogen-containing silicone oil to vinyl in methyl vinyl silicone rubber, 0.75 mol% hydrogen content of hydrogen-containing silicone oil, 0.7 PHR of 2-methyl-3-butyne-2-ol, 0.00001 PHR of platinum catalyst (3000 ppm), and the process conditions were: vulcanization temperature of the front vulcanization tunnel was 300°C (vulcanization time was about 5 seconds), vulcanization temperature of the rear vulcanization tunnel was 280°C (vulcanization time was about 2 minutes), and the oven temperature was 180°C (time was 48 hours). Silicone tubes were manufactured with wall thicknesses of 0.2 / 0.4 / 0.6 mm.

[0597] The tube is sealed with adhesive and cured for 24 hours, after which the drug is filled into the filling funnel. After filling is complete, the other end is also sealed with KN-300N adhesive and cured for 24 hours. After curing is complete, check for drug leakage. After confirming that there is no leakage, wash with absolute ethanol for 30 seconds repeatedly to complete the manufacturing process. The particle size of estradiol D 50 The diameter is 9.5 μm, the wall thickness is 0.2 mm, the outer diameter is 2.2-2.3 mm, and the emission area is 2.7±0.5 cm 2 Thus, a reservoir-type estradiol implant was obtained.

[0598] 2.2 Release conditions Pure water was selected as the release solvent, and a thermostatic shaker at 37°C was used as the release device.

[0599] 2.3 Measurement of external emissions and influencing factors

[0600] 2.3.1 Vulcanization temperature During the manufacturing process of the silicone tube, the mechanical index of the silicone tube manufactured under the vulcanization conditions of 300℃ in the front vulcanization tunnel and 280℃ in the rear vulcanization tunnel was better, and the silicone tube was more completely vulcanized. Based on this, without changing other conditions, silicone tubes with different vulcanization temperatures were manufactured into implants, and in vitro release experiments were carried out to discuss the effect of vulcanization temperature on the drug release behavior in vitro.

[0601] [Table 87]

[0602] 2.3.2 Silicone Tube Wall Thickness The effect of the wall thickness of the silicone tube on the in vitro drug release behavior was examined. Implants with the same length and outer diameter were manufactured using silicone tubes with wall thicknesses of 0.2 mm, 0.4 mm, and 0.6 mm obtained above, and the in vitro release data was measured.

[0603] [Table 88]

[0604] 2.3.3 Drug release area The silicone implant controls drug release through a cylindrical silicone tube, and the drug release area can be expressed by the following formula: S = πd × L In the formula: d is the inner diameter of the silicone tubing, and L is the length of the drug-containing portion.

[0605] As can be seen from the formula, the drug release area can be changed by changing the length of the drug-containing part and the inner diameter of the silicone tube. Considering that it is easier and more convenient to change the length of the drug-containing part, in this experiment, the outer diameter of the silicone tube is fixed at 2.4 mm, the wall thickness is fixed at 0.2 mm, and the estradiol implants with drug-containing part lengths of 1, 2, 3, 4, and 5 cm are densely packed for external release, and the change in the amount of drug released in vitro with the length of the drug-containing part is considered.

[0606] [Table 89]

[0607] 2.4 Long-term in vitro release experiment of estradiol reservoir-type implant After determining the wall thickness and formulation of the silicone tube in the implant, the vulcanization temperature, the drug loading amount, and the drug release area, three batches of the optimal formulation were manufactured, and their long-term stable release performances were considered, and the trend of the daily release amount was observed.

[0608] The preparation and formulation of the silicone tube were the same as those in 2.1, and the other preparation conditions were: the front vulcanization tunnel was 300°C (vulcanization time was about 5 seconds), the rear vulcanization tunnel was 280°C (vulcanization time was about 2 minutes), and the oven temperature was 180°C (vulcanization time was 48 hours). The wall thickness of the produced silicone tube was 0.2 mm. 50 was 9.5 μm.

[0609] 3. Results and Discussion

[0610] 3.1 Fabrication of estradiol reservoir-type implants Reservoir-type implants with different specifications were manufactured, which had good appearance, uniform sealing areas, and drug-containing areas that were uniformly filled with drugs.

[0611] 3.2 Measurement of influencing factors of external emissions

[0612] 3.2.1 Vulcanization conditions [Table 90-1] [Table 90-2]

[0613] The results showed that changing the vulcanization temperature of the silicone tube did not significantly affect the average daily release of the implant, with only slight variations observed. Therefore, a silicone tube with better mechanical properties was selected for the manufacture of the implant, i.e., a silicone tube manufactured under vulcanization conditions of 300°C for the front vulcanization tunnel and 280°C for the rear vulcanization tunnel was selected.

[0614] 3.3.2 Silicone Tube Wall Thickness [Table 91-1] [Table 91-2]

[0615] The results showed that by controlling factors such as outer diameter and release area invariably, the in vitro release amount of estradiol reservoir-type implants made from silicone tubes with three different wall thicknesses gradually decreased with increasing wall thickness. In order to ensure the drug release amount, the wall thickness needs to be as thin as possible, but in the actual work process, the silicone tube with a wall thickness of 0.2 mm is already at its limit, and if the wall thickness is further reduced, it is difficult to ensure smooth extrusion molding of the silicone tube, so the wall thickness of the silicone tube was finally determined to be 0.2 mm.

[0616] 3.3.3 Consideration of drug release area of ​​silicone tube The effect of the length of the drug core in the silicone tubing on in vitro release is shown in the table below. [Table 92]

[0617] The results showed that the daily drug release of the estradiol reservoir implants increased with increasing release area. To further determine the relationship between the release area of ​​the implants and the drug release amount, data analysis was performed on the drug release amount and release area of ​​the five groups of formulations, with the results shown in Figure 15.

[0618] From the fitting equation and the image, it can be seen that there is a linear relationship between the drug release amount and the release area, and with the increase of the release area, the drug release amount also increases. Based on this relationship, the drug release amount can be adjusted by fixing the outer diameter and wall thickness of the silicone tube and adjusting the release area. In actual use, due to the large individual differences between patients, estradiol reservoir-type implants of different specifications can be manufactured to meet different needs, so as to realize personalized administration, reduce side effects, and obtain the maximum therapeutic effect.

[0619] 3.4 Long-term in vitro release experiment of estradiol implant Under the same conditions as the final formulation (2.4 estradiol reservoir-type implants as described above in this section), three batches of reservoir-type implants were manufactured and long-term in vitro release experiments were carried out at a temperature of 37°C and a shaker speed of 100 rpm, and the results are shown in the table below. [Table 93-1] [Table 93-2] [Table 93-3] [Table 93-4]

[0620] The results showed that the daily release of the three batches of implants fluctuated in the early stage, but gradually stabilized in the later stage, and the average daily ex vivo release was stable within the range of 10-15 μg, and this trend was similar between batches, indicating good reproducibility. According to the literature, the commonly used replacement dose for estradiol replacement therapy is 20-40 μg per day, and the implantation of two implants achieved the desired therapeutic effect, which was consistent with the expectations of the experiment.

[0621] IV. Pharmaceutical Compositions

[0622] Example 22 Preparation of pharmaceutical composition: The ingredients in the table below were mixed to obtain a pharmaceutical composition (powdered drug core), where the particle size of the Gestodene drug substance was 2.81 μm.

[0623] [Table 94]

[0624] Silicone tubing manufacturing: Step S1: Methylvinylsilicone rubber is wrapped with a reinforcing agent, thinly extruded by an open mill, tableted, and mixed uniformly to obtain mixture A, and mixture A is stored in a desiccator at room temperature for 24 to 72 hours; Step S2: Divide mixture A into components A1 and A2, mix component A1 with a catalyst to obtain component B1, and mix component A2 with hydrogen-containing silicone oil and an inhibitor to obtain component B2; Step S3: Mix component B1 with component B2 to obtain mixture B; Step S4: Mixture B is extruded into a tube, and then catalyst is added. It was produced by

[0625] Here, the catalyst addition involves subjecting mixture B to a first heat treatment (temperature is 270°C, time is about 5 seconds), a second heat treatment (temperature is 180°C, time is about 2 minutes), and a third heat treatment (temperature is 180°C, time is 24 hours) in sequence.

[0626] The raw material composition of the silicone tube in Examples 22-1, 22-1, and 22-3 includes the components in the table below, where the relative molecular weight of the methylvinyl silicone rubber is 100000-800000g / mol, the vinyl content in the methylvinyl silicone rubber is 0.17mol%, the Si-H group content in the hydrogen-containing silicone oil is 0.75mol%, and the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl in the methylvinyl silicone rubber is 1.2:1.

[0627] [Table 95]

[0628] Preparation of implant: Take the silicone tube prepared above, soak in 75% ethanol for 30 minutes to disinfect, then dry, and seal one end of the silicone tube with silicone adhesive for use. Fill with a filling funnel to prepare pharmaceutical composition, and fill the powder-type drug core of the implant with a filling length of 2.0 cm, and seal the other end with silicone, and harden for 24 hours to prepare gestodene implant. Here, the outer diameter of the silicone tube is 2.6 mm, and the wall thickness is 0.3 mm.

[0629] During the filling process, no powder scattering and no spontaneous agglomeration of the powder of the pharmaceutical composition was observed.

[0630] Comparative Example 1 The drug core of the implant of Comparative Example 1 was made of Gestodene raw material, and the rest was the same as in Example 22.

[0631] During the filling process, it was observed that Gestodene powder scattered, a large amount of the powder adhered to the outer surface of the silicone tube, and the powder naturally aggregated.

[0632] Effect Example 1: Method for measuring implant release from the body

[0633] 1. Chromatography Conditions Chromatography column: Diamonsil® C18 column (250 mm × 4.60 mm, 5 μm); Mobile phase: methanol-water (80:20:v / v); Column temperature: 30°C; Detection wavelength: 239nm; Flow rate: 1mL min -1 ; Injection volume: 20μL.

[0634] 2. Place the filled implant into the ethanol solution, put it into the ultrasonic device and sonicate for 30 minutes. After sonication, blow dry the implant and place it into a stoppered Erlenmeyer flask with the release solvent added. Place the stoppered Erlenmeyer flask into a shaker, set the temperature to 37℃ and the shaking speed to 100r·min -1 After 24 hours, it was removed and blow-dried.

[0635] Both ends of the blow-dried Gestodene implant were attached to the bottom and wall of a stoppered Erlenmeyer flask, respectively, using silicone rubber sealant, and the silicone tube part filled with Gestodene drug substance powder was suspended in the stoppered Erlenmeyer flask so as not to touch the wall (during the shaking process, it was confirmed that the contact area between the drug-containing part and the release solvent was stable). After bonding, it was left for 24 hours until the adhesive was completely cured. After curing, the required amount of release solvent was accurately poured into the stoppered Erlenmeyer flask and placed in a shaker, and the temperature was set to 37°C and the shaking speed to 100 r·min -1 Samples were taken every 24 hours, the medium was changed, and the samples were stored for testing.

[0636] The measurement results are shown in the table below. The relationship between the in vitro daily drug release amount and the release time of the implants in Examples 22-1, 22-2, 22-3 and Comparative Example 1 is shown in FIG.

[0637] [Table 96]

[0638] From the above table, it can be seen that after adding poorly soluble auxiliary materials to the pharmaceutical composition, the static electricity of the raw powder during drug loading is effectively improved, especially AL-1FP mesoporous silicon and XDP3050 mesoporous silicon have significantly improved loading efficiency. From the in vitro release data, it was found that the RSD value of in vitro release was significantly lower than that of Comparative Example 1, which does not add poorly soluble additives to the drug core, and the lower the RSD value, the smaller the difference with the daily release amount, and the smaller the overall release fluctuation, which ensures stable drug release. Therefore, the addition of poorly soluble additives significantly improved the test stability of the implant, among which, when the poorly soluble additive was AL-1FP mesoporous silicon, it showed the highest drug release stability, and the fluctuation range of the daily drug release amount was very small. Based on the observation of the release data, it was found that the auxiliary material significantly increased the daily drug release amount and showed excellent stability.

[0639] Effect Example 2: Implant Intrabody Pharmacodynamics Study The above implants of Example 22-1, Example 22-2, Example 22-3 and Comparative Example 1 were implanted into rats, and the changes in the estrous cycle of SD rats after implantation were observed using vaginal smear samples, LH (luteinizing hormone) levels in the rats' bodies were measured using enzyme immunoassay, and the mating behavior of the rats was monitored to study the contraceptive effect of subcutaneous implantation.

[0640] 1. Equipment and Reagents 1.1 Equipment XS105 Electronic Analytical Balance Mettler-Toledo Instrument Co., Ltd. SMD200-2 Electronic Analytical Balance Ohaus International Trade Co., Ltd. TG16MW Tabletop High Speed ​​Centrifuge Hunan Herexi Instrument and Equipment Co., Ltd. KQ-250DE CNC ultrasonic cleaner Kunshan Ultrasonic Instrument Co., Ltd. Rat LH Kit Shanghai Tongwei Biotechnology Co., Ltd. Electron Microscope Shenzhen Zhongwei Kechuang Technology Co., Ltd. Autoclave Shanghai Shenan Medical Instrument Factory 1.2 Reagents Gestodene (purity 98%, batch number: 20190327) Hebei Mokai Technology Development Co., Ltd. Crystal Violet Tianjin Damao Chemical Reagent Factory Physiological saline Shandong Yuwang Chemical Reagent Co., Ltd. 4% paraformaldehyde solution Shanghai Yantuo Biological Technology Co., Ltd.

[0641] 1.3 Experimental animals Twenty-six healthy male SD rats weighing 180–200 g and 93 healthy female SD rats weighing 180–200 g were purchased from Benxi Changsheng Biotechnology Co., Ltd., permit number: SCXK(Liao)2020-0001.

[0642] 2. Experimental Method

[0643] 2.1 Local stimulation experiment of blank silicone tube in rat body Silicone tubes were prepared according to the methods of Example 22-1, Example 22-2, and Example 22-3 above, but no drug powder was filled in them, and they were used as blank silicone tubes (specifications: outer diameter: 2.6 mm, wall thickness: 0.3 mm). The blank silicone tubes were cut into small pieces, immersed in 10 mL of pyrogen-free sterile purified water, and extracted by heating at 70°C for 24 hours, and then the extract was sterilized by high pressure for use. Six experimental rats were selected and randomly divided into two groups, one as the experimental group and the other as the saline control group, and the hair on the backs of the rats was removed and prepared. In the experimental group, 0.2 mL of the extract was injected intradermally on one side of the dorsal spine of the rats, and in the control group, 0.2 mL of saline was injected intradermally on one side of the dorsal spine of the rats. The skin reaction at the injection site was observed at 24 hours, 48 ​​hours, and 72 hours.

[0644] 2.2 Histopathological examination of rats after implantation of blank silicone tubes The blank silicone tubes produced were sealed, and the adhesive was allowed to completely harden before being autoclaved for use. Nine experimental rats were selected and randomly divided into three groups, with three rats in each group. Sterilized homemade silicone tubes were implanted into the back of each rat, and the rats were euthanized 3, 10, and 30 days after implantation, respectively, and 2 cm of tissue around the implanted silicone tube was removed, and the skin tissue was fixed in 4% paraformaldehyde and stored for tissue section observation. The presence or absence of inflammatory reactions such as redness and swelling in the surrounding tissue was observed, and tissue section experiments were performed to observe whether there were any abnormal lesions in the subcutaneous and muscle areas where the silicone tubes were implanted.

[0645] 2.3 Efficacy study of Gestodene contraceptive implant in rats According to the above-mentioned recipe and process (corresponding to the silicone tube and drug core of Example 22-1, Example 22-2, Example 22-3 and Comparative Example 1), silicone tube with outer diameter of 2.60 mm and wall thickness of 0.3 mm was manufactured, and Gestodene implant with the following specifications was manufactured, which was divided into experimental groups I, II, III and IV, and each group was further divided into low dosage group, medium dosage group and high dosage group, as shown in the table below.

[0646] [Table 97]

[0647] Experimental group I: low dose group 1cm / 10.36mg, medium dose group 2.2cm / 22.8mg, high dose group 4cm / 41.45mg (length of drug-containing portion / drug loading amount). Experimental groups II, III, and IV (same specifications, but adding different types of auxiliary materials): low-dose group 1 cm / 5.18 mg / 5.18 mg, medium-dose group 2.2 cm / 11.4 mg / 11.4 mg, high-dose group 4 cm / 20.725 mg / 20.725 mg (length of drug-containing part / drug-carrying amount / additive amount).

[0648] Experimental medium dose group I, experimental medium dose group II, experimental medium dose group III, and experimental medium dose group IV correspond to Comparative Example 1 and Examples 22-1, 22-2, and 22-3, respectively. In each experimental group, compared with the medium dose group, the low dose group has a shorter length of the drug-containing portion, a smaller amount of drug loaded and additives, and all other properties are similar (e.g., the composition of the drug core and the manufacturing method, etc.), and compared with the medium dose group, the high dose group has a longer length of the drug-containing portion, a larger amount of drug loaded and additives, and all other properties are similar (e.g., the composition of the drug core and the manufacturing method, etc.).

[0649] 78 female rats were selected and vaginal smears were performed to confirm whether they had normal estrous cycles. 78 female SD rats weighing approximately 180-200g were randomly divided into blank group, and experimental groups I, II, III, and IV. Within experimental groups I, II, III, and IV, three dosage groups were further set up: low, medium, and high (Experiment I medium dosage group, Experiment II medium dosage group, Experiment III medium dosage group, and Experiment IV medium dosage group correspond to Comparative Example 1, Example 22-1, Example 22-2, and Example 22-3, respectively), and each group consisted of 6 female rats and 2 male rats.

[0650] An appropriate amount of anesthetic was injected into the abdominal cavity of a female rat, and after the rat was anesthetized, the hair on the back of the neck was removed, then disinfected with 2% iodine tincture, a small opening of about 0.5 cm was cut with surgical scissors in the local skin of the dorsal lateral side of the rat, and a needle dedicated for implants was inserted subcutaneously to the marked line of the needle, and the sterilized implant was placed into the needle, and then the needle with the implant was inserted was inserted into the skin until the implant could be fully inserted, and then the needle was pulled out, and the implant was left under the skin, the incision was sutured, and the wound was disinfected with 2% iodine tincture. 24 hours after implantation into the female rats, they were kept in the same cage as the male rats with a 3:1 female to male ratio.

[0651] 2.3.1 Observation of rat condition This is the same as "2.3.1 Observation of rat condition" in "I. Gestodene long-acting contraceptive implant; 4. Experiments on Gestodene contraceptive implant in rats."

[0652] 2.3.2 Observation of the rat estrous cycle through vaginal smear experiments This is the same as "2.3.2 Observation of rat estrous cycle through vaginal smear experiments" in "I. Gestodene long-acting contraceptive implant; 4. Experiments on Gestodene contraceptive implant in rats."

[0653] 2.3.3 Determining mating pregnancy status of rats by observing vaginal plugs This is the same as "2.3.3 Determination of mating pregnancy status of rats by observation of vaginal plug" in "I. Gestodene long-acting contraceptive implant; 4. Experiments on Gestodene contraceptive implant in rats."

[0654] 2.3.4 Measurement of LH levels in rats by enzyme immunoassay This is the same as "2.3.4 Measurement of luteinizing hormone (LH) levels in rats by enzyme immunoassay" in "I. Gestodene long-acting contraceptive implant; 4. Experiments with Gestodene contraceptive implant in rats."

[0655] 3 Experimental results and discussion

[0656] 3.1 Tissue stimulation experiment with silicone tube in rats In the experimental group, 0.2 mL of the extract was injected intradermally on one side of the dorsal spine of the rats, and in the control group, 0.2 mL of saline was injected intradermally on one side of the dorsal spine of the rats. The skin reactions at the injection sites were observed 24 hours, 48 ​​hours, and 72 hours later. Each injection site was dissected, but no reactions such as redness, swelling, or necrosis were found, and the results were negative.

[0657] 3.2 Histopathological examination of rats after silicone tube implantation Muscle tissues were collected from the implantation site 3, 10, and 30 days after implantation, and pathological images (HE, ×2 or HE, ×20) were observed.

[0658] The results showed that 3 days after the implantation of the blank silicone tube, an acute inflammatory reaction occurred, the epidermal layer was slightly thickened, the dermal layer was rich in collagen fibers, a large cystic cavity structure was formed in the local subcutaneous tissue, and there was connective tissue proliferation with abundant lymphocyte infiltration around it. On the 10th day after implantation, the acute inflammatory reaction gradually disappeared, the epidermal layer was slightly thickened, the dermal layer was rich in collagen fibers, a large cystic cavity structure was formed in the local subcutaneous tissue, and there was connective tissue proliferation with diffuse lymphocyte infiltration around it. 30 days after implantation, the structure of the epidermal layer was intact, the structure of squamous epithelial cells was normal and tightly arranged, the dermal layer was rich in collagen fibers, a large cystic cavity structure was formed in the local subcutaneous tissue, and there was mild connective tissue proliferation with diffuse lymphocyte and macrophage infiltration around it.

[0659] Since there was a large cystic cavity in each of the implanted areas, it was shown that implanting the silicone tube would cause a certain amount of damage to the subcutaneous tissue, and mild connective tissue proliferation occurred around the cystic cavity, i.e., at the junction between the silicone tube and the tissue, and gradually formed a membrane. When the silicone tube was dissected on the third day after implantation, it was observed that the silicone tube was prone to escape, and when it was dissected on the 10th day after implantation, a membrane was formed around the silicone tube, making it difficult to move, indicating that with a longer implantation time, a membrane is formed around the silicone tube, making it difficult for the silicone tube to come off in the body. Furthermore, the inflammatory reaction was at its maximum on the third day after implantation, and the inflammation gradually decreased with the increase in implantation time, indicating that the inflammatory reaction caused by the implantation of the silicone tube can be gradually recovered.

[0660] 3.3 Efficacy study of Gestodene contraceptive implant in rats

[0661] 3.3.1 Changes in rat body weight before and after implantation After the implantation surgery, the rats were observed for their feeding and activity. Their urination and defecation were normal, and they showed no mental depression.

[0662] The body weights of the rats before and after implantation are shown in the table below. [Table 98]

[0663] Observation of the rats' weight change data over a one-month period showed that the implantation surgery and silicone tube had no effect on the rats' growth, and the weight change trend of the rats in the experimental group was almost the same as that of the blank group. Overall, it was found that Gestodene implants had no effect on the rats' growth.

[0664] 3.3.2 Observation of the rat estrous cycle using vaginal smears For the rats in the blank control group, the vaginal secretions of the female rats were collected at regular intervals for 24 hours every day, and crystal violet stained smears were performed to observe the estrous cycle, and compared with the rats in experimental groups I, II, III, and IV. After continuous collection for one month, it was found that the rats basically went into estrus about once every seven days.

[0665] Observation of vaginal smears for one month showed that rats in the low, medium and high dose groups in Experiment I, II, III and IV began to have a large amount of mucus in their vaginal secretions 4 days after implantation, and vaginal smears contained a large amount of leukocytes, but no keratinocytes, indicating that the rats did not have a normal estrous cycle.

[0666] 3.3.3 Determining mating pregnancy status of rats by observing vaginal plugs When vaginal plugs were observed, none were found in the low, medium and high dose groups in Experiment I, II, III and IV, proving that the rats did not mate with male rats, proving that the rats have a contraceptive effect.

[0667] 3.3.4 Measurement of LH concentration in rat plasma by enzyme immunoassay Enzyme immunoassay was used to detect the LH levels in the rats. The results of the LH levels in the rats in six rats in each group 28 days after implantation of the Gestodene contraceptive implant are as follows:

[0668] The LH levels in the rats are shown in the table below. [Table 99]

[0669] The results are shown in Figure 3. Compared to the blank group, the low, medium and high dose groups in Experiment I, II, III and IV all showed a significant decrease in the LH levels in the rats' bodies. The higher the dose, the lower the LH levels and the higher the hormone-blocking effect. Here, Experiment III, which added the poorly soluble auxiliary material AL-1FP mesoporous silicon, showed the best in vitro drug release stability, and the daily drug release amount was significantly improved by adding the auxiliary material. The internal data also showed that the lower the LH level, the better the hormone-blocking effect. Compared to the silicone tube filled with only Gestodene raw powder, the in vitro drug release was significantly improved after adding the poorly soluble auxiliary material, indicating that the internal drug efficacy was improved.

[0670] V, 4 types of membrane-controlled long-acting implants

[0671] 1. Manufacturing of membrane-controlled long-acting implants The membrane-controlled implant is composed of an addition-type silicone tube and a powder-type drug core. The silicone tube is manufactured by adding a reinforcing agent to methylvinyl silicone raw rubber, and then adding a rubber compound manufactured using hydrogen-containing silicone oil, inhibitors, and catalysts as compounding agents, and then vulcanizing it at high temperature through an extrusion process. The drug core is manufactured by directly mixing the drug powder and auxiliary materials. Finally, the uniformly mixed drug powder is filled into the silicone tube, and the silicone tube filled with the drug and auxiliary material powder is sealed with adhesive to manufacture a membrane-controlled long-acting implant.

[0672] (1) The composition of the addition type silicone tube is as follows: The basic composition of silicone tube is base polymer, reinforcing agent, crosslinking agent, catalyst, and inhibitor. Methylvinylpolysiloxane is selected as the base polymer, the vinyl content is 0.18%-0.23%, the reinforcing agent is gas-phase white carbon black, the amount of addition is 30-50 PHR, the crosslinking agent is hydrogen-containing silicone oil, the amount of addition is 0.3-2.0 PHR, the concentration of platinum catalyst is 3000 ppm, the amount of addition is 0.000002-0.5 PHR, and the inhibitor is 2-methyl-3-butyn-2-ol, the amount of addition is 0.03-2.0 PHR.

[0673] The specific composition is as follows: [Table 100]

[0674] (2) The manufacturing process for addition type silicone tubing is as follows:

[0675] (i) Drying pretreatment of rubber materials: The reinforcing agent, gas-phase white carbon black, was placed in a 130°C oven and dried for 12 to 24 hours for use, and the methyl vinyl silicone raw rubber was dried at 40°C for 12 to 24 hours for use.

[0676] (ii) Preparation of rubber compound: Put the prescribed amount of gaseous white carbon black and methyl vinyl silicone raw rubber into a kneader, and after the gaseous white carbon black and raw rubber are uniformly mixed, take them out to obtain a rubber compound, put them into an open mill and extrude them thinly, and the rubber material is further uniformly mixed by the shearing action of two rollers of the open mill, and then the rubber material is taken out from the open mill in the form of a sheet, wrap the rubber material with a cling film, seal it in a ziplock bag, and store it in a desiccator for 12 to 24 hours for use.

[0677] (iii) Preparation of components A and B: Each rubber compound was divided into two components, A and B. The prescribed amount of hydrogen-containing silicone oil and inhibitor was added to component A, which was then mixed uniformly in an open mill and then thinly extruded several times to be taken out in the form of a sheet. The prescribed amount of platinum catalyst was added to component B, which was then mixed uniformly in an open mill and then thinly extruded several times to be taken out in the form of a sheet. The prepared components A and B were each wrapped in plastic wrap, sealed in a ziplock bag, and stored in a desiccator for 12 to 24 hours before use.

[0678] (iv) Mixing of A and B components: The stored A and B components were placed in an open mill in a 1:1 ratio, milled 4 to 6 times in a triangular manner to ensure uniform mixing of A and B components, and then taken out in the form of a sheet on the open mill and cut into strips.

[0679] (v) Extrusion of silicone tube: A suitable size mold was installed, the screw speed of the extruder was set, the cut silicone strips were fed into the extruder, and the rubber material was continuously extruded from the opening of the mold driven by the rotation of the screw to form a silicone tube.

[0680] (vi) Primary vulcanization process: The silicone tube extruded from the mold opening first passes through the front vulcanization tunnel (vertical hot air vulcanization channel) to carry out rapid high-temperature vulcanization (the temperature is 300°C and the vulcanization time is about 5 seconds), which is called the primary vulcanization process, so that the silicone tube rapidly changes from a sticky soft state to an elastic state and is preformed.

[0681] (vii) Secondary vulcanization: After the primary vulcanization, the tube is further vulcanized in the rear vulcanization tunnel (horizontal hot air vulcanization channel) to carry out the secondary vulcanization (temperature is 280°C, vulcanization time is about 2 minutes), so that the vulcanization reaction of the silicone tube is sufficient and optimal crosslinking is achieved. The completed silicone tube is then continuously transported by the belt conveyor of the rear vulcanization tunnel and oven vulcanized at 180°C for 48 hours, after which a silicone tube with a wall thickness of 0.2 mm is obtained.

[0682] Silicone tube treatment: Additive silicone tubes (outer diameter 2.4 mm, inner diameter 1.6 mm) that met both the appearance and performance standards were cut to the same length of 44 mm, placed in a 100 mL beaker, added with an appropriate amount of distilled water, and ultrasonically treated for 30 minutes. Then, rinsed with distilled water three times, washed with 75% ethanol, and air-dried for use.

[0683] Manufacture of the implant: one end of the silicone tube was sealed and dried, and the other end of the silicone tube was filled with 80 mg of pharmaceutical composition powder using a tool and sealed with adhesive. After the adhesive hardened, the silicone tube was kneaded and vibrated to ensure uniform distribution of the drug in the silicone tube. Finally, the powder on the outside of the silicone tube was washed clean.

[0684] During the filling process, the pharmaceutical composition was observed to be free of powder scattering and spontaneous agglomeration of powder.

[0685] (3) The formulation of the powdered drug core is as shown in the table below. [Table 101] Note: The content ratios of the drug substance, the content of poorly soluble auxiliary materials, and the content of poorly soluble pH regulators in the above table refer to the mass ratios in the drug core. The total mass of the drug core is 80 mg, and the particle size D of ibuprofen is 50 is 80 μm, and the particle size of paliperidone D 50 is 10 μm, and the particle size of meloxicam D 50 is 80 μm, and the particle size of puerarin D 50 is 80 μm.

[0686] Preparation of pharmaceutical composition: The ingredients in the above table were mixed to obtain a pharmaceutical composition (powdered drug core).

[0687] Preparation of pharmaceutical composition: The ingredients in Table 8 were mixed to obtain a pharmaceutical composition (powder drug core).

[0688] Here, the particle size of the ibuprofen drug substance is 80 μm, the molecular weight is 206.28, it is insoluble in water, the solubility is 60 μg / mL, it is acidic, the LogP value is 3.72, and the pKa is 4.45.

[0689] The particle size of the meloxicam drug substance is 80 μm, the molecular weight is 351.4, it is insoluble in water, the solubility is 3.4 μg / mL, it is acidic, the LogP value is 3.35, and the pKa is 4.

[0690] The particle size of the paliperidone drug substance is 10 μm, the molecular weight is 426, it is insoluble in water, the solubility is 50 μg / mL, it is alkaline, the LogP value is 3.02, and the pKa is 7.72.

[0691] The particle size of the puerarin drug substance is 80 μm, the molecular weight is 432, it is poorly soluble in water, the solubility is 4 mg / mL, it is alkaline, the LogP value is -0.67, and the pKa is 6.45.

[0692] [Table 102-1] [Table 102-2]

[0693] (4) Treatment of silicone tubes: Additive silicone tubes (outer diameter 2.4 mm, inner diameter 1.6 mm) that met both the appearance and performance standards were cut to the same length of 44 mm, placed in a 100 mL beaker, added with an appropriate amount of distilled water, and ultrasonically treated for 30 minutes. After that, the tubes were rinsed three times with distilled water and further washed with 75% ethanol, and then air-dried for use.

[0694] (5) Preparation of implant: One end of the silicone tube was sealed and dried, and the other end of the silicone tube was filled with 80 mg of pharmaceutical composition powder using a tool and sealed with adhesive. After the adhesive hardened, the silicone tube was kneaded and vibrated to uniformly mix the drug auxiliary materials into the silicone tube. Finally, the powder on the outside of the silicone tube was washed cleanly.

[0695] 2. Method for determining the content and ex vivo release of membrane-controlled long-acting implants

[0696] (1) Ibuprofen

[0697] Chromatography conditions Chromatography column: Agilent® C18 column (4.6 mm × 150 mm, 5 μm); Mobile phase: methanol: 1% sodium acetate buffer (70:30, v / v); Column temperature: 35°C; Detection wavelength: 273nm; Flow rate: 1.0mL min -1 ; Injection volume: 20μL.

[0698] How to measure the degree of release The release experiment was carried out using the horizontal shaking method. One implant was taken and both ends of the implant were fixed to the bottom and wall of a 20 mL vial using silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After bonding, the vial was left for 12 hours until the silicone adhesive was completely cured. 15 mL of distilled water was accurately measured as the release solvent and poured into an Erlenmeyer flask. The Erlenmeyer flask was placed in a thermostatic air shaker and shaken at a temperature of 37°C and 100 r·min -1 The same volume of the solvent was replaced every 24 hours. The release solution was filtered through a 0.22 μm microporous membrane and detected according to the above chromatographic conditions, and the injection volume was 20 μL.

[0699] (2) Paliperidone

[0700] Chromatography conditions Chromatography column: Agilent® C8 column (4.6 × 100 mm, 2.7 μm); Mobile phase: methanol:acetonitrile:water (5:25:70, v / v) (adjusted to pH 3 with phosphoric acid and triethylamine); Column temperature: 35°C; Detection wavelength: 270nm; Flow rate: 0.8mL min -1 ; Injection volume: 20μL.

[0701] How to measure the degree of release The release experiment was carried out using the horizontal shaking method. One implant was taken and both ends of the implant were fixed to the bottom and wall of a 100 mL stoppered Erlenmeyer flask using silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After bonding, the silicone adhesive was left for 12 hours until it was completely cured. 100 mL of distilled water was accurately measured as the release solvent and poured into the Erlenmeyer flask. The Erlenmeyer flask was then placed in a thermostatic air shaker and shaken at 100 r·min at a temperature of 37°C. -1 The same volume of the solvent was replaced every 24 hours. The release solution was filtered through a 0.22 μm microporous membrane and detected according to the above chromatographic conditions, and the injection volume was 20 μL.

[0702] (3) Meloxicam

[0703] Chromatography conditions Chromatography column: Agilent® C18 column (4.6 mm × 150 mm, 5 μm); Mobile phase: methanol: 0.5% aqueous phosphoric acid (70:30, v / v); Column temperature: room temperature; Detection wavelength: 270nm; Flow rate: 1.0mL min -1 ; Injection volume: 20μL.

[0704] How to measure the degree of release The release experiment was carried out using the horizontal shaking method. One implant was taken and both ends of the implant were fixed to the bottom and wall of a 20 mL vial using silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After bonding, the vial was left for 12 hours until the silicone adhesive was completely cured. 15 mL of distilled water was accurately measured as the release solvent and poured into an Erlenmeyer flask. The Erlenmeyer flask was placed in a thermostatic air shaker and shaken at a temperature of 37°C and 100 r·min -1 The medium was replaced with the same volume every 24 hours. The release was filtered through a 0.22 μm microporous membrane and detected according to the above chromatographic conditions, with an injection volume of 20 μL.

[0705] (4) Puerarin

[0706] Chromatography conditions Chromatography column: Diamonsil® C 18 column (4.6 mm × 250 mm, 5 μm); Mobile phase: methanol:water (70:30, v / v); Column temperature: 35°C; Detection wavelength: 250nm; Flow rate: 1.0mL min -1 ; Injection volume: 20μL.

[0707] How to measure the degree of release The release experiment was carried out using the horizontal shaking method. One implant was taken and both ends of the implant were fixed to the bottom and wall of a 20 mL vial using silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After bonding, the vial was left for 12 hours until the silicone adhesive was completely cured. 15 mL of distilled water was accurately measured as the release solvent and poured into an Erlenmeyer flask. The Erlenmeyer flask was placed in a thermostatic air shaker and shaken at a temperature of 37°C and 100 r·min -1 The same volume of the solvent was replaced every 24 hours. The release solution was filtered through a 0.22 μm microporous membrane and detected according to the above chromatographic conditions, and the injection volume was 20 μL.

[0708] 3. In vitro release results of membrane-controlled long-acting implants

[0709] (1) Ibuprofen [Table 103-1] [Table 103-2]

[0710] As can be seen from the above table, after adding poorly soluble auxiliary materials to the pharmaceutical composition, the static electricity of the raw powder during drug loading is effectively improved, especially when the poorly soluble auxiliary material is XDP3150 mesoporous silicon, the loading efficiency is significantly improved; after adding the poorly soluble acidic auxiliary material fumaric acid, the release amount of the implants is greatly adjusted, and at the same time, the drug release stability is significantly improved.

[0711] (2) Meloxicam [Table 104-1] [Table 104-2]

[0712] As can be seen from the above table, after adding poorly soluble auxiliary materials to the pharmaceutical composition, the static electricity of the raw powder during drug loading can be effectively improved, especially when the poorly soluble auxiliary material is gaseous white carbon black, the loading efficiency is significantly improved; after adding the poorly soluble acidic auxiliary material boric acid, the release amount of the implants is greatly adjusted, and at the same time, the drug release stability is significantly improved.

[0713] (3) Paliperidone [Table 105-1] [Table 105-2]

[0714] As can be seen from the above table, after adding poorly soluble auxiliary materials to the pharmaceutical composition, the static electricity of the raw powder during drug loading can be effectively improved, especially when the poorly soluble auxiliary material is XDP3050 mesoporous silicon, the loading efficiency is significantly improved; after adding the poorly soluble alkaline auxiliary material magnesium hydroxide, the release amount of the implants is greatly adjusted, and at the same time, the drug release stability is significantly improved.

[0715] (4) Puerarin [Table 106-1] [Table 106-2]

[0716] From the above table, it can be seen that after adding poorly soluble auxiliary materials to the pharmaceutical composition, the static electricity of the raw powder during drug loading is effectively improved, and the loading efficiency is significantly improved; after adding the poorly soluble alkaline auxiliary material zinc hydroxide, the release amount of the implants is greatly adjusted, and at the same time, the drug release stability is significantly improved.

[0717] VI Implant

[0718] Example 27 (Gestodene Implant) The Gestodene implant comprises a drug core and a silicone tube, and the drug active ingredient in the drug core has a particle size of D after grinding. 50 The diameter of the gestodene is 2.81 μm, the length of the filling (i.e., the length of the drug core) is 2.2 cm, and the drug loading is 22.8 mg. The prepared silicone tube was disinfected by soaking in 75% ethanol for 30 minutes and then dried, and one end of the silicone tube was sealed with silicone adhesive for use. Gestodene was filled in a filling funnel, and the other end was sealed with silicone and cured for 24 hours to prepare a gestodene implant.

[0719] The composition of the raw material mixture for the silicone tube is the same as that of ZJ001 in "I. Gestodene long-acting contraceptive implant" "3. Production and in vitro release study of Gestodene implant 3.4 Long-term in vitro release experiment of Gestodene implant".

[0720] Preparation of silicone tube: The above silicone tube raw material mixture was extruded and oven vulcanized. The extrusion was heat-treated at 270°C and 180°C, respectively, and the extrusion speed was controlled at 3.5r / min. The extrusion was carried out by a single-screw extruder, and the oven vulcanization was carried out at 180°C for 48 hours. The inner diameter of the produced silicone tube was 2.0mm, the outer diameter was 2.6mm, and the wall thickness was 0.3mm.

[0721] Example 28 (Levonorgestrel Implant) The levonorgestrel implant includes a drug core and a silicone tube, and the active pharmaceutical ingredient in the drug core has a particle size of D 50 The drug core is 2.12μm levonorgestrel (abbreviated as LNG). The silicone tube (outer diameter 2.4mm, inner diameter 1.6mm) was cut into the same length of 35mm, placed in a 100mL beaker, added with an appropriate amount of detergent, sonicated with distilled water for 30 minutes, then rinsed with distilled water three times, further washed with 75% ethanol, and then air-dried for use. One end of the silicone tube was folded, and the other end was precisely filled with 36mg of LNG powder through a tool into the tube (the length of the drug core is 30mm), then both ends of the silicone tube were sealed using glue, and the silicone tube was kneaded and vibrated after the glue was cured to ensure uniform distribution of the drug in the silicone tube. After that, the powder attached to the surface of the silicone tube was washed off, and the above steps were repeated six times to obtain one set of levonorgestrel implants.

[0722] Based on Example 27, the composition (parts by weight) of the raw material mixture for the silicone tube is adjusted as follows, and the rest is the same as in Example 27: White carbon black: 35 parts;

[0723] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinylsilicone rubber is 1.5:1.

[0724] The preparation of the silicone tube was the same as in Example 27.

[0725] Effect Example 3

[0726] 1. Establishment of a method for measuring in vitro release of gestodene implants The chromatography conditions and the in vitro release test method are the same as those in "I. Gestodene long-acting contraceptive implant; 1. Measurement of Gestodene contraceptive implant content and measurement method of in vitro release".

[0727] The in vitro release method of gestodene used the horizontal shaking method. One of the manufactured implants was taken and fixed to the wall of a 50 mL stoppered Erlenmeyer flask with adhesive to prevent the implant from floating on the liquid surface during release, resulting in inaccurate release results. 50 mL of distilled water was accurately measured and poured into the Erlenmeyer flask, and the Erlenmeyer flask was placed in a thermostatic air shaker at 37°C and shaken at an amplitude of 100 times per minute. The same volume of solvent was replaced every 24 hours. The sample was filtered through a 0.22 μm microporous membrane and detected by injection into liquid chromatography.

[0728] 2. In vitro release study of Gestodene implants In vitro release experiments were carried out for implants with different silicone tube wall thicknesses, drug core lateral areas, and drug particle sizes, and a long-acting contraceptive implant capable of achieving a daily drug release of 10-30 μg was manufactured based on the in vitro release results. The manufactured implants were implanted in the subcutaneous tissue of the human upper arm, which has a pH close to neutral, so the release solvent could be selected from water or saline. The Gestodene raw material before and after crushing was made supersaturated with water and saline, placed in a shaker for 72 hours, then removed, centrifuged, and the supernatant was filtered. The apparent solubility of Gestodene drug substance before and after crushing in water and saline was measured using high performance liquid chromatography, and the appropriate release solvent was selected based on the results. Water was selected as the release solvent for the in vitro release experiment. In the experiment to measure the amount of in vitro release described below, before carrying out the in vitro release experiment, the implant in Example 27 was subjected to a blast removal treatment in advance, that is, 50 mL of anhydrous ethanol was added to an Erlenmeyer flask containing the implant in Example 27, and then ultrasonic treatment was carried out for 1 minute, which was repeated three times, and then 100 mL of distilled water was added and left overnight, and the leaching solution was discarded the next day and placed in a shaker to carry out the in vitro release.

[0729] The following in vitro drug release data were obtained by producing three batches in parallel, and the long-term stable release and reproducibility of the implants were measured at the same time.

[0730] The equipment used is as follows: TS-100B Type Thermostatic Shaker Shanghai Jiecheng Experimental Instrument Co., Ltd. High-Performance Liquid Chromatograph Shimadzu Corporation KQ-250DE CNC ultrasonic cleaner Kun Shan Ultrasonic Instruments Co., Ltd. AG245 Microelectronic Balance Type Electronic Analytical Balance Mettler Toledo, Switzerland

[0731] (1) Silicone tubes made from raw rubber with different vinyl contents Silicone tubes were made with different vinyl content of raw rubber, and other procedures were the same as in Example 27, and the effect of silicone tubes made with different vinyl content on the ex vivo release of gestodene was measured. The test results are shown in the table below.

[0732] [Table 107]

[0733] As can be seen from the above table, the silicone tube with vinyl content of 0.1% has too low vinyl content and too low release, while the silicone tube with vinyl content of 0.4% and 0.5% has too high vinyl content and too high release, and the RSD values ​​of their in vitro release are all much higher than the vinyl contents of 0.17% and 0.23%, and the higher the RSD value, the larger the daily release fluctuation and the larger the overall release fluctuation, which indicates that stable drug release cannot be achieved.Therefore, by comparison, when the vinyl content is 0.17% and 0.23%, not only can the release requirement be met, but also the appropriate RSD value can be achieved, so that stable drug release can be guaranteed.

[0734] As can be seen from FIG. 17, the silicone tubes made from raw rubber with vinyl contents of 0.17% and 0.23% had a significant effect on the average in vitro drug release of the implants, with the initial burst of the raw rubber with a vinyl content of 0.23% being greater than that of 0.17%, and the silicone tube made from raw rubber with a vinyl content of 0.17% exhibiting a more stable in vitro release.

[0735] The linear relationship between the drug release amount and the drug core side area of ​​the implant manufactured using No. 2 (vinyl content is 0.23%) in the "silicone tube manufactured with raw rubber of different vinyl content" is as shown in the table below. [Table 108]

[0736] The results showed that the daily drug release of Gestodene contraceptive implants increased with increasing drug core side area.To determine the relationship between drug core side area and daily drug release in vitro, data analysis was performed on the drug release and drug core side area of ​​the six groups of formulations.

[0737] The relationship between the drug core side area and the amount of drug released from the implant is y = 11.591x + 0.561, R 2 =0.9947, and the approximation equation shows that there is a linear relationship between the drug release amount and the drug core side area, and the drug release amount increases with the increase in the drug core side area. Based on this relationship, the drug release amount can be adjusted by fixing the inner diameter, outer diameter and wall thickness of the silicone tube and adjusting the length of the drug core. In the actual use of the implant, there are large individual differences and body weights vary greatly, so that gestodene implants with different specifications can be manufactured to realize individual administration, which can ensure the contraceptive effect while greatly reducing side effects.

[0738] (2) Silicone tubes manufactured using different amounts of hydrogen-containing silicone oil Silicone tube is manufactured using different molar ratios of Si-H group in hydrogen-containing silicone oil and vinyl in R-vinyl silicone rubber, other procedures are the same as in Example 27, and the effect of the amount of hydrogen-containing silicone oil added on the daily release of the implant is considered.The test results are shown in the following table. [Table 109]

[0739] As can be seen from the above table, when the molar ratio of silicone tube is 0.3:1, the release amount is too low, but when the molar ratio is 3:1, the release amount is too high, and the RSD values ​​of their in vitro release are all much higher than 1.2:1 and 1.5:1, and the higher the RSD value, the larger the fluctuation of daily release amount and the larger the fluctuation of overall release, which indicates that stable drug release cannot be achieved.Therefore, by comparison, when the molar ratio is 1.2:1 and 1.5:1, not only can the release amount requirement be met, but also the appropriate RSD value can be achieved, so that stable drug release can be guaranteed.

[0740] Combined with Figure 18, it can be seen that the daily drug release of the contraceptive implant filled with a silicone tube manufactured with a hydrogen-containing silicone oil molar ratio of 1.2:1 is slightly higher than that of the contraceptive implant filled with a silicone tube manufactured with a hydrogen-containing silicone oil molar ratio of 1.5:1, and there is no significant difference in the stability of the drug release curves.

[0741] The linear relationship between the drug release amount and the length of the drug-containing portion of the implant manufactured using No. 2 in "Silicone tubes manufactured with different amounts of hydrogen-containing silicone oil" (the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is 1.5:1) is shown in the table below. [Table 110]

[0742] The results showed that the daily drug release of Gestodene contraceptive implants increased with increasing drug core length when the drug core diameter was fixed.The daily drug release of Gestodene contraceptive implants increased with increasing drug core diameter when the drug core length was fixed.Data analysis was performed on the drug release and release side area of ​​different formulations to determine the relationship between the release side area and the amount of drug released in vitro.

[0743] The relationship between the drug core area of ​​the implant and the daily drug release amount satisfies the following formula: y = 6.257x + 0.498, R 2 =0.9982, from the approximation equation, it can be seen that there is a linear relationship between the daily drug release amount and the release side area, and the drug release amount increases with the increase in the release side area. Based on this relationship, the drug release amount was adjusted by fixing the outer diameter and wall thickness of the silicone tube and adjusting the length of the drug core, or by fixing the length of the drug core and adjusting the outer diameter and wall thickness of the silicone tube. In the actual use of the implant, there are large individual differences and large differences in body weight, so Gestodene implants with different specifications can be manufactured to realize individual administration, which can ensure the contraceptive effect while greatly reducing side effects.

[0744] (3) Silicone tubes with different wall thicknesses The implant with the wall thickness of silicone tube of 0.5mm was manufactured, and other procedures were the same as those in Example 27, and in vitro release data was measured to measure the effect of the wall thickness of the self-made silicone tube on the in vitro release of the implant.The test results are shown in the table below. [Table 111]

[0745] As can be seen from the combination with Figure 19, when the outer diameter and the length of the drug-containing part are controlled at a predetermined value, the in vitro release data of the Gestodene contraceptive implants filled in the silicone tubes with two different wall thicknesses are almost similar, and it can be concluded that the wall thickness of the silicone tube from 0.3mm to 0.5mm has little effect on the in vitro release rate of the drug. In the actual drug filling process, the silicone tube with a wall thickness of 0.5mm has a too small inner diameter, making it very difficult to fill the drug, while the silicone tube with a wall thickness of 0.3mm has a relatively large inner diameter, making it much easier to fill the drug. After comprehensive consideration, the wall thickness of the silicone tube was finally selected to be 0.3mm.

[0746] The linear relationship between the drug release amount and the length of the drug-containing portion of the implants manufactured using the "silicone tubes of different wall thicknesses" number 2 (wall thickness 0.5 mm) is shown in the table below. [Table 112]

[0747] From the data in the above table, the linear relationship between the drug core area of ​​the implant and the daily release amount is y=7.520x+0.587, R 2 =0.9987.

[0748] (4) Gestodene of different particle sizes in the drug core Gestodene with different packing particle size of 80.3 μm was prepared, and other procedures were the same as in Example 27. The test results are shown in the table below. [Table 113]

[0749] As can be seen in combination with Figure 20, the daily average drug release of the implant loaded with Gestodene API after grinding was lower than that of the non-ground one with the same specifications, which was cross-verified with the solubility measurement results. After grinding, the particle size of the API decreased, but it aggregated into small clusters due to electrostatic adsorption, which in turn reduced the contact area with the release solvent, thereby reducing the in vitro release. Observing the drug release curves of the in vitro release of the two implants, it was found that the implant loaded with the drug substance that had not been subjected to air jet milling showed a large fluctuation in the in vitro drug release amount around 23 days, while the drug release curve of the implant loaded with the drug substance after milling was stable from 10 to 20 days and did not show a large fluctuation around 20 days. Based on this result, it can be concluded that when the drug substance is milled by air jet milling and then loaded into the implant to perform in vitro release, it shows a more stable release curve, so by selecting the drug processed by milling to manufacture the implant, better stability can be achieved.

[0750] The relationship between the drug release amount and the length of the drug-containing portion of the implants manufactured using Gestodene number 2 (particle size: 80.3 μm) of "Different particle sizes in the drug core" is shown in the table below. [Table 114]

[0751] The results showed that when the length of the drug core was fixed, the daily drug release of Gestodene contraceptive implants increased with increasing diameter of the drug core.When the diameter of the drug core was fixed, the daily drug release of Gestodene contraceptive implants increased with increasing length of the drug core.

[0752] To determine the relationship between the drug release side area of ​​the implant and the amount of drug released in the body, data analysis was performed on the drug release amount and drug core side area of ​​different formulations. The relationship between the drug core side area of ​​the implant and the daily drug release amount was y=10.229x0.802, R 2 = 0.9982, and the approximation equation shows that there is a linear relationship between the drug release amount and the release side area, and the drug release amount increases as the release side area increases.

[0753] Based on this relationship, the drug release amount was adjusted by fixing the outer diameter and wall thickness of the silicone tube and adjusting the length of the drug core, or by fixing the length of the drug core and adjusting the inner and outer diameters of the silicone tube.In the actual use of the implant, there are large individual differences and large differences in body weight, so that Gestodene implants with different specifications can be manufactured to realize individual administration, and side effects can be greatly reduced while ensuring the contraceptive effect.

[0754] (5) Silicone tubes with different drug loadings Implants with a drug loading of 29.6 mg were prepared, and the other procedures were the same as in Example 27. The test results are shown in the table below. [Table 115]

[0755] As can be seen in combination with Figure 21, when the wall thickness and filling length of the same silicone tube were controlled, the daily in vitro drug release of implants with different drug loadings was basically the same, indicating that with the same drug core side area, the drug loading amount had basically no effect on the in vitro release of the implant.

[0756] When the loading length is 2.2 cm and the drug loading amount is 22.8 mg, the loading effect is relatively good; however, when 29.6 mg is loaded, loading becomes more difficult and the silicone tube partially swells, and the average drug release amount is slightly higher than that of the formulation with a drug loading amount of 22.8 mg. However, this is not directly related to the drug loading amount, but is thought to be due to the loading part of the silicone tube swelling, the tube wall stretching, and the drug core side area increasing slightly, resulting in a slight increase in the release amount.

[0757] The linear relationship between the length of the drug-containing portion and implant number 2 (drug loading: 29.6 mg) in the "silicone tube with different drug loadings" is as shown in the table below. [Table 116]

[0758] From the data in the above table, a linear relationship between the drug core area of ​​the implant and the daily release amount was found, y=9.057x0.708, R 2 =0.9987. 3. Establishment of a mathematical model between the area of ​​the drug core of the implant and the daily drug release amount

[0759] Based on the above consideration of the drug release amount of Gestodene implant, it is found that vulcanization, different vinyl content, different dosage of hydrogen-containing silicone oil, particle size of Gestodene may affect the stability of drug release in vitro, and also affect whether a stable positive linear correlation can be established between the drug core side area and the drug release amount, and the drug release amount of the implant can be obtained based on the drug core side area of ​​the implant.As a result of multi-factor consideration, the drug release amount of Gestodene implant with different drug core side area prepared in Example 27 was measured, and a positive linear correlation was established between the two.

[0760] Since the implant controls drug release through a cylindrical silicone tube, the drug release lateral area of ​​the drug can be expressed by the formula S = πd × L, where d - the inner diameter of the silicone tube and L - the length of the drug-containing portion.

[0761] As can be seen from the formula, when the inner diameter of the silicone tube (0.5-10.0 mm) is fixed, the lateral area of ​​the drug core can be changed by changing the length of the drug core. When the length of the silicone tube (0.8-21 cm) is fixed, the lateral area of ​​the drug core can be changed by changing the diameter of the drug core. In this test, a silicone tube with a fixed diameter is selected, and the length of the drug core is 0.8cm, 1.4cm, 2.2cm, 2.7cm, 3.3cm, 4.3cm, 9cm, 15cm, 18cm and 21cm, respectively, is filled with Gestodene implants for extracorporeal release, and other conditions are the same as in Example 27, and the change pattern of the amount of extracorporeal drug release according to the side area of ​​the drug core is considered. In this test, a silicone tube with a fixed length is selected, and the wall thickness is 0.3mm, and the silicone tube with the inner diameter is 0.5mm, 0.8mm, 1.4mm, 1.6mm, 2.0mm, 2.7mm, 3.3mm, 4.3mm, 6.8mm, 9.0mm or 10.0mm is prepared, and Gestodene powder is filled in each of them to prepare Gestodene implants for extracorporeal release, and other conditions are the same as in Example 27, and the change pattern of the amount of extracorporeal drug release according to the side area of ​​the drug core is considered. The test results are shown in the table below.

[0762] [Table 117] [Table 118]

[0763] When the diameter of the drug core is fixed, the daily drug release of Gestodene contraceptive implant increases with the increase in the length of the drug core. Based on the data of different drug core lateral areas and daily drug release obtained above, a mathematical model equation between the two was established. Established mathematical model: y=8.7363x+0.0802, R 2 =0.9999.

[0764] When the length of the drug core is fixed, the daily drug release of Gestodene contraceptive implant increases with the increase of the diameter of the drug core. Based on the data of different drug core lateral areas and daily drug release obtained above, a mathematical model equation between the two was established. Established mathematical model: y=8.8140x+0.1767, R 2 =0.9998.

[0765] From the approximation equation and the image, it can be seen that there is a linear relationship between the daily drug release amount and the drug core side area of ​​the implant, and the drug release amount increases with the increase of the drug core side area of ​​the implant. Based on this relationship, the drug release amount can be adjusted by fixing the outer diameter and wall thickness of the silicone tube and adjusting the length of the drug core. In addition, the drug release amount can be adjusted by fixing the length of the implant and adjusting the inner and outer diameters of the silicone tube, and the drug release amount can also be adjusted by simultaneously adjusting the inner and outer diameters of the silicone tube and the length of the drug core. In the actual use of the implant, there are large individual differences and large differences in body weight, so Gestodene implants with different specifications can be manufactured to realize individual administration, which can ensure the contraceptive effect while greatly reducing side effects.

[0766] Effect Example 4

[0767] 1. Establishment of a method for measuring the in vitro release of levonorgestrel implants The release experiment used horizontal shaking method, and a set of six implants was fixed to the wall of a 125mL stoppered Erlenmeyer flask with adhesive, and an appropriate distance was maintained between each implant (to prevent the implants from floating on the liquid surface during release, which would cause inaccurate release results). 100mL of distilled water was accurately measured and poured into the Erlenmeyer flask, and the Erlenmeyer flask was placed in a thermostatic air shaker at 37℃ and shaken at an amplitude of 100 times / min, and the same volume of solvent was replaced every 24h. The sample was filtered through a 0.22μm microporous membrane and detected according to the following chromatographic conditions, and the injection volume was 20μL.

[0768] Chromatography column: Diamonsil® C 18 column (4.6 mm × 250 mm, 5 μm); Mobile phase: methanol:water (80:20, v / v); Column temperature: 30°C; Detection wavelength: 240nm; Flow rate: 1.0mL min -1 ; Injection volume: 20μL.

[0769] 2. Effect of the manufacturing formula of silicone tube on the ex vivo release of levonorgestrel implant Implants of the same specifications manufactured with clean silicone tubes that met the physical and mechanical requirements were selected, and after blasting treatment, they were placed in a shaker to carry out the release experiment. Samples were collected for 35 consecutive days to examine the effect of the silicone tube manufacturing formula on the degree of implant release from the body.

[0770] (1) Effect of vinyl content on implant release rate A silicone tube was extruded using raw rubber with a vinyl content of 0.23%, and then made into an implant, and the rest was the same as in Example 28, and the effect of silicone tubes made with different vinyl contents on the in vitro release of levonorgestrel was examined. The test results are shown in the table below. [Table 119]

[0771] As can be seen in combination with Figure 22, both groups of implants could release stably, and the daily drug release of the implant made of raw rubber with a vinyl content of 0.23% was less than that of the implant made of raw rubber with a vinyl content of 0.17%. The relationship between the drug release amount and the length of the drug-containing part of the implant made of 0.23% raw rubber was more linear.

[0772] The linear relationship between the drug release amount and the drug core side area of ​​the implant manufactured using No. 2 (vinyl content is 0.23%) in "Effect of vinyl content on implant ex vivo release rate" is as shown in the table below. [Table 120]

[0773] The results showed that when the length of the drug core was fixed, the daily drug release of the levonorgestrel contraceptive implant increased with an increase in the diameter of the drug core.When the diameter of the drug core was fixed, the daily drug release of the levonorgestrel contraceptive implant increased with an increase in the length of the drug core.

[0774] In order to determine the relationship between the drug core side area of ​​the implant and the daily drug release amount in vitro, data analysis was performed on the drug release amount and drug core side area of ​​different formulations, and the relationship between the drug core side area of ​​the implant and the daily drug release amount was calculated using the formula y = 4.2459x + 0.3967, R 2=0.9957, and the approximation equation shows that there is a linear relationship between the daily drug release amount and the drug core side area, and the drug release amount increases with the increase of the drug core side area. Based on this relationship, the drug release amount can be adjusted by fixing the outer diameter and wall thickness of the silicone tube and adjusting the length of the drug core, or by fixing the length of the drug core and adjusting the inner and outer diameters of the silicone tube. In the actual use of the implant, there are large individual differences and large differences in body weight, so that levonorgestrel implants with different specifications can be manufactured to realize individual administration, which can ensure the contraceptive effect while greatly reducing side effects.

[0775] (2) Amount of hydrogen-containing silicone oil used The implant was manufactured using a silicone tube with a molar ratio of hydrogen-containing silicone oil:methyl vinyl silicone rubber of 1.2:1, and the rest was the same as in Example 28. The effect of silicone tubes manufactured with different molar ratios on the extracorporeal release of levonorgestrel was...

Claims

1. In parts by weight R-vinyl silicone rubber: 100 parts; Reinforcing agent: 20-80 parts; Hydrogenated silicone oil: 0.3 to 3.0 parts; Catalyst: ≧0.000002 parts, preferably 0.000002-0.00005 parts; Includes however, R in the R-vinyl silicone rubber is a substituted or unsubstituted C １ ~C ５ linear or branched alkanes of substituted or unsubstituted C ６ ~C ２０ It is an aromatic hydrocarbon, The vinyl content in the R-vinyl silicone rubber is 0.10 to 0.50 mol %, The hydrogen-containing silicone oil has a Si—H group content of 0.18 to 1.6 mol %, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-4):1; Optionally, further comprising an inhibitor, said inhibitor being capable of inhibiting the addition reaction between said R-vinyl silicone rubber and said hydrogen-containing silicone oil; A raw material composition for a silicone material.

2. The raw material composition of the silicone material is (1) The R-vinyl silicone rubber is a methyl vinyl silicone rubber, and the methyl vinyl silicone rubber may be a methyl vinyl silicone rubber having a relative molecular weight of 100,000 to 800,000 g / mol; (2) The vinyl content in the R-vinyl silicone rubber is 0.10 to 0.23 mol %, for example, 0.17 mol % or 0.23 mol %, and preferably 0.17 to 0.23 mol %; (3) The reinforcing agent is one or more of white carbon black, diatomaceous earth, quartz powder, silica fine powder, calcium carbonate, aluminum hydroxide, magnesium oxide, white titanium powder, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate, and calcium carbonate, for example, white carbon black, and the white carbon black may be gas-phase white carbon black, precipitated white carbon black, gel white carbon black, or surface-treated white carbon black; (4) The amount of the reinforcing agent used is 30 to 80 parts, for example, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts, or 60 parts; (5) The amount of the hydrogen-containing silicone oil used is 0.4 to 2.8 parts, for example, 0.42 parts, 0.67 parts, 0.84 parts, 1.01 parts, 1.26 parts, 1.36 parts, 1.51 parts, 1.68 parts, or 2.52 parts; (6) The content of Si—H groups in the hydrogen-containing silicone oil is 0.36 to 1.6 mol%, for example, 0.36 mol%, 0.5 mol%, 0.75 mol%, 1.0 mol%, or 1.6 mol%; (7) the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is (0.8 to 4.0):1, for example, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1 or 3.0:1, preferably (1.2 to 1.8):1 or (1.2 to 1.5):1; (8) The inhibitor is an alkynol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol, or 2-methyl-3-butyn-2-ol; (9) The amount of the inhibitor used is 0.03 to 2.0 parts, for example, 0.3 to 1.0 parts, and for example, 0.3 parts, 0.5 parts, 0.7 parts, or 0.9 parts; (10) The catalyst is a rhodium catalyst, a palladium catalyst, or a platinum catalyst, and is preferably a platinum catalyst; the platinum catalyst may have a platinum concentration of 3000 ppm, where 3000 ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million; and (11) The amount of the catalyst used is 0.000005 to 0.00005 parts, for example, 0.000005 parts, 0.00001 parts, 0.00002 parts, or 0.00003 parts; The silicone material raw material composition according to claim 1 , characterized in that it satisfies one or more of the above.

3. (1) parts by weight of the silicone material raw material composition, Methylvinylsilicone rubber: 100 parts; Reinforcing agent: 20-80 parts; Hydrogenated silicone oil: 0.3 to 3.0 parts; Catalyst: 0.000002-0.00005 parts; Inhibitor: 0.03-2.0 parts; Including, however, The vinyl content in the methyl vinyl silicone rubber is 0.10 to 0.50 mol %, The hydrogen-containing silicone oil has a Si—H group content of 0.18 to 1.6 mol %, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinylsilicone rubber is (0.5-4):1; Or, (2) parts by weight of the silicone material raw material composition, Methylvinylsilicone rubber: 100 parts; Reinforcing agent: 30-60 parts; Hydrogenated silicone oil: 0.4 to 2.8 parts; Catalyst: 0.000002-0.00005 parts; Inhibitor: 0.3-1.0 parts; Including, however, The vinyl content in the methyl vinyl silicone rubber is 0.17 to 0.23 mol %, The hydrogen-containing silicone oil has a Si—H group content of 0.18 to 1.6 mol %, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methylvinyl silicone rubber is (0.8-2):1; Or, (3) parts by weight of the silicone material raw material composition, Methylvinylsilicone rubber: 100 parts; Reinforcing agent: 30-45 parts; Hydrogenated silicone oil: 0.42 to 2.52 parts; Catalyst: 0.000002-0.00005 parts; Inhibitor: 0.3-0.9 parts; Including, however, The vinyl content in the methyl vinyl silicone rubber is 0.17 to 0.23 mol %, The hydrogen-containing silicone oil has a Si—H group content of 0.5 to 1.0 mol %, The molar ratio of the Si-H groups in the hydrogen-containing silicone oil and the vinyl in the methylvinylsilicone rubber is (1.2-1.8):

1. The raw material composition for a silicone material according to claim 1 or 2.

4. (1) Method 1 When the raw material composition for a silicone material according to any one of claims 1 to 3 does not contain an inhibitor, A step S1 of uniformly mixing the R-vinyl silicone rubber according to any one of claims 1 to 3 and the reinforcing agent according to any one of claims 1 to 3 to obtain a mixture A; Step S2, in the presence of a catalyst according to any one of claims 1 to 3, by mixing the mixture A and the hydrogen-containing silicone oil according to any one of claims 1 to 3 to obtain a mixture B, and performing catalyst addition; A method for producing a silicone material comprising the steps of: (2) Method 2 When the raw material composition for a silicone material according to any one of claims 1 to 3 further contains an inhibitor, A step S1 of uniformly mixing the R-vinyl silicone rubber according to any one of claims 1 to 3 and the reinforcing agent according to any one of claims 1 to 3 to obtain a mixture A; Step S2 of dividing the mixture A into components A1 and A2, mixing the component A1 with the catalyst according to any one of claims 1 to 3 to obtain component B1, and mixing the component A2 with the hydrogen-containing silicone oil according to any one of claims 1 to 3 and the inhibitor according to any one of claims 1 to 3 to obtain component B2; Step S3: mixing the component B1 and the component B2 to obtain a mixture B and carrying out a catalyst addition; A method for producing a silicone material comprising the steps of:

13. A method for producing a silicone material, comprising the steps of:

5. The method for producing the silicone material includes the steps of: (1) In the method 1 and method 2, the reinforcing agent is pretreated by drying it at 100 to 210° C. for 1 to 24 hours; (2) In the above-mentioned methods 1 and 2, the R-vinyl silicone rubber is pretreated by drying it at 30 to 60° C. for 1 to 24 hours. (3) In the above-mentioned methods 1 and 2, the mixing step in S1 is a step of enveloping the reinforcing agent with the R-vinyl silicone rubber, thinly extruding the mixture with an open mill, and tableting the mixture. Alternatively, in the method 1 and method 2, the mixing step in S1 is a step in which the R-vinyl silicone rubber and the reinforcing agent are kneaded in a kneader under a condition of 30° C. for 30 minutes, then removed, triangularly spread on an open mill with a roll spacing of 1 to 10 mm, milled five times, wound into a roll, and then left to stand for 24 hours to obtain the mixture A; (4) In the method 1, before the addition of the oxidizing agent, the mixture B is milled in an open mill 4 to 6 times in a triangular pattern, and then uniformly sliced ​​and taken out. (5) In the method 2, the mixing step of the component B1 and the component B2 is a step of putting the component B1 and the component B2 into an open mill in a ratio of 1:1, milling the component B1 and the component B2 4 to 6 times with a triangular mill, and taking out the mixture by slicing it uniformly; (6) In the method 1 and method 2, the step of adding a catalyst is a step of sequentially subjecting the mixture B to a first heat treatment and a second heat treatment, and preferably includes a third heat treatment after the second heat treatment, in which the temperature of the first heat treatment may be 250 to 360° C., for example, 270 to 300° C., and for example, 270° C., 280° C., or 300° C., the time of the first heat treatment may be 5 seconds, the temperature of the second heat treatment may be 120 to 300° C., for example, 180 to 280° C., and for example, 180° C., 260° C., or 280° C., the time of the second heat treatment may be 2 minutes, the temperature of the third heat treatment may be 180° C., and the time of the third heat treatment may be 24 to 48 hours, for example, 48 hours; The method for producing a silicone material according to claim 4, characterized in that one or more of the following are satisfied:

6. The silicone material composition according to any one of claims 1 to 3 is molded by a catalytic addition process. Wherein, the catalyst addition process includes a first heat treatment and a second heat treatment in sequence, the temperature of the first heat treatment is 250-360°C, and the temperature of the second heat treatment is 120-300°C, for example, 120-280°C; 1. A method for producing a silicone material, comprising:

7. The mixture of raw material compositions of the silicone material is (1) Method 1 When the raw material composition for a silicone material according to any one of claims 1 to 3 does not contain an inhibitor, A step S1 of uniformly mixing the R-vinyl silicone rubber according to any one of claims 1 to 3 and the reinforcing agent according to any one of claims 1 to 3 to obtain a mixture A; Step S2 of obtaining a mixture B by mixing the mixture A and the hydrogen-containing silicone oil according to any one of claims 1 to 3 in the presence of the catalyst according to any one of claims 1 to 3; A method for producing a mixture of a raw composition of a silicone material, comprising: (2) Method 2: When the raw material composition for the silicone material according to any one of claims 1 to 3 further contains an inhibitor, A step S1 of uniformly mixing the R-vinyl silicone rubber according to any one of claims 1 to 3 and the reinforcing agent according to any one of claims 1 to 3 to obtain a mixture A; Step S2 of dividing the mixture A into components A1 and A2, mixing the component A1 and the catalyst according to any one of claims 1 to 3 to obtain component B1, and mixing the component A2 and the hydrogen-containing silicone oil according to any one of claims 1 to 3 and the inhibitor according to any one of claims 1 to 3 to obtain component B2; Step S3 of mixing the component B1 and the component B2 to obtain a mixture B; A method for producing a mixture of a raw composition of a silicone material, comprising: The method for producing the silicone material according to claim 6, characterized in that the silicone material is produced by using any one of the following:

8. The method for producing the mixture of raw material compositions for silicone materials includes the steps of: (1) In the method 1 and method 2, the reinforcing agent is pretreated by drying it at 100 to 210° C. for 1 to 24 hours; (2) In the above-mentioned methods 1 and 2, the R-vinyl silicone rubber is pretreated by drying it at 30 to 60° C. for 1 to 24 hours. (3) In the above-mentioned methods 1 and 2, the mixing step in S1 is a step of enveloping the reinforcing agent with the R-vinyl silicone rubber, thinly extruding the mixture with an open mill, and tableting the mixture. Alternatively, in the above-mentioned methods 1 and 2, the mixing step in S1 is a step in which the R-vinyl silicone rubber and the reinforcing agent are kneaded in a kneader under conditions of 30° C. for 30 minutes, then removed, triangularly spread on an open mill with a roll spacing of 1 to 10 mm, milled five times, wound into a roll, and then left to stand for a further 24 hours to obtain the above-mentioned mixture A, (4) In the method 1, the mixture B is milled 4 to 6 times in an open mill using a triangular mill before the addition of the oxidizing agent, and then uniformly sliced ​​and taken out. (5) In the method 2, the mixing step of the component B1 and the component B2 is a step of putting the component B1 and the component B2 into an open mill in a ratio of 1:1, milling the component B1 and the component B2 4 to 6 times with a triangular mill, and taking out the mixture by slicing it uniformly; 8. The method for producing a silicone material according to claim 6 or 7, characterized in that one or more of the following are satisfied:

9. The temperature of the first heat treatment is 250 to 330° C., for example, 270° C., 280° C., 300° C., or 330° C.; and / or the temperature of the second heat treatment is 150 to 300° C., for example, 150 to 280° C., for example, 150° C., 180° C., 210° C., 260° C. or 280° C.; and / or a third heat treatment is further carried out after the second heat treatment, the temperature of the third heat treatment may be 100-280°C, for example 180°C, and the time of the third heat treatment is preferably 0-72 hours, but is not 0 hours, for example 24 hours, 48 ​​hours or 72 hours.

10. A silicone material produced by the method for producing a silicone material according to at least one of claims 4 to 9.

11. A method for forming the silicone material according to claim 10 into a tube shape by an extrusion process, for example, a method for forming the mixture B according to any one of the methods 1 and 2 according to claims 4 to 5 and 7 to 9 into a tube shape by an extrusion process, and further carrying out the addition of a catalyst; Alternatively, in the method for producing a silicone material according to any one of claims 4 to 9, the catalyst addition process is carried out in a tubular mould to obtain the silicone tube, for example, in the method 1 or 2 according to any one of claims 4 to 5 and 7 to 9, the catalyst addition process is carried out in a tubular mould to obtain the silicone tube. A silicone tube, characterized in that it is manufactured using the following:

12. 12. A silicone tubing according to claim 11, comprising a drug core containing a pharmaceutical active ingredient, The pharmaceutical active ingredient may include a pharmaceutical active ingredient acting on the reproductive system, the pharmaceutical active ingredient acting on the reproductive system may include a pharmaceutical active ingredient used in contraception, and may include levonorgestrel, gestodene, gestrinone, the pharmaceutical active ingredient acting on the reproductive system may include a steroidal estrogen, such as estradiol; The pharmaceutical active ingredient may be a pharmaceutical active ingredient with a drug solubility of ≦100 mg / mL and a drug molecular weight of less than 1000 Da, and may be, for example, one or more of levonorgestrel, gestodene, gestrinone, estradiol, ibuprofen, paliperidone, meloxicam, and puerarin; The pharmaceutical active ingredient may be a pharmaceutical active ingredient having a solubility of ≦60 mg / mL and a drug molecular weight of less than 1000 Da; The pharmaceutical active ingredient may be a pharmaceutical active ingredient having a solubility of ≦50 mg / mL and a drug molecular weight of 1000 Da; The pharmaceutical active ingredient may be a pharmaceutical active ingredient having a solubility of ≦10 mg / mL and a drug molecular weight of less than 1000 Da; The pharmaceutical active ingredient may be a pharmaceutical active ingredient having a solubility of ≦5 mg / mL and a drug molecular weight of less than 1000 Da; The drug core may be a powdered drug core, The outer diameter of the silicone tube is preferably 2.0 to 5.0 mm, for example, 2.4 mm or 2.6 mm; The length of the silicone tube is preferably 1.5 to 4.5 cm, for example 1.9 cm or 4.4 cm; the wall thickness of the silicone tube is preferably 0.2-0.5 mm, for example 0.3 mm, 0.4 mm or 0.5 mm; The drug release area of ​​the silicone tube is preferably 0.4 to 15.0 cm ２ For example, 0.69 cm ２ , 1.38 cm ２ , 2.07 cm ２ , 2.76 cm ２ or 3.45 cm ２ and The diameter of the drug core is preferably 1.5 to 4.0 mm, e.g., 1.6 mm or 2.0 mm; The length of the drug core is preferably 1.0-4.0 cm, for example 1.5 cm or 3.9 cm.

13. Contains active pharmaceutical ingredients and poorly soluble auxiliary materials, The pharmaceutical composition, wherein the poorly soluble auxiliary material comprises a silicone material.

14. The density of the poorly soluble auxiliary material is 1 to 10,000 g / L, for example, 1,000 g / L; and / or the particle size of the poorly soluble auxiliary material is 1 to 200 μm; and / or the pore size of the silicon material is less than 1 μm, e.g., 0 nm, 5 nm, 10 nm, 18 nm, 50 nm or 100 nm; and / or in said silicon material, the silica content is more than 50%, preferably 80%, 90%, 95%, 99% or 99.8%, and / or the refractory auxiliary material comprises one or more of white carbon black, AL-1FP mesoporous silicon, XDP3050 mesoporous silicon and XDP3150 mesoporous silicon, where the white carbon black is preferably gas phase white carbon black, precipitated white carbon black, gel white carbon black or white carbon black obtained by surface treatment; Preferably, the refractory auxiliary material is one or more of white carbon black, AL-1FP mesoporous silicon, XDP3050 mesoporous silicon and XDP3150 mesoporous silicon; More preferably, the sparingly soluble auxiliary material is one or more of white carbon black, AL-1FP mesoporous silicon and XDP3050 mesoporous silicon; And / or the poorly soluble auxiliary material further comprises a poorly soluble weak acid and / or a poorly soluble weak base; The poorly soluble weak acid preferably comprises one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, more preferably boric acid and / or fumaric acid; 14. The pharmaceutical composition according to claim 13, characterized in that the poorly soluble weak base preferably comprises one or more of magnesium hydroxide, aluminium hydroxide, zinc hydroxide, ferrous hydroxide and magnesium oxide, more preferably one or more of magnesium hydroxide, aluminium hydroxide and zinc hydroxide.

15. The poorly soluble auxiliary material is a, white carbon black; b, white carbon black and magnesium hydroxide; c, white carbon black and aluminum hydroxide; d, white carbon black and zinc hydroxide; e. white carbon black and fumaric acid; f, white carbon black and boric acid; g, AL-1FP mesoporous silicon; h, AL-1FP mesoporous silicon and XDP3050 mesoporous silicon; i, AL-1FP mesoporous silicon and XDP3150 mesoporous silicon; j, AL-1FP mesoporous silicon and magnesium hydroxide; k, AL-1FP mesoporous silicon and aluminum hydroxide; l, AL-1FP mesoporous silicon and zinc hydroxide; m, AL-1FP mesoporous silicon and fumaric acid; n, AL-1FP mesoporous silicon and boric acid; o, XDP3050 mesoporous silicon; p, XDP3050 mesoporous silicon and magnesium hydroxide; q, XDP3050 mesoporous silicon and aluminum hydroxide; r, XDP3050 mesoporous silicon and zinc hydroxide; s, XDP3050 mesoporous silicon and fumaric acid; t, XDP3050 mesoporous silicon and boric acid; u, XDP3150 mesoporous silicon; v, XDP3150 mesoporous silicon and magnesium hydroxide; w, XDP3150 mesoporous silicon and aluminum hydroxide; x, XDP3150 mesoporous silicon and zinc hydroxide; y, XDP3150 mesoporous silicon and fumaric acid; z, XDP3150 mesoporous silicon and boric acid; The pharmaceutical composition according to claim 13 or 14, characterized in that it is one of the above a to z.

16. the content of the drug substance is 10%-99.9%, for example, 50%-99.5%, for example, 95%, the percentage being the mass percentage of the drug substance in the pharmaceutical composition; and / or the content of the poorly soluble auxiliary material is 0.1%-90%, for example, 0.1%-50%, for example, 0.5%-5%, the percentage being the mass percentage of the poorly soluble auxiliary material in the pharmaceutical composition; and / or the density of the poorly soluble auxiliary material is 1 to 10,000 g / L, for example, 1,000 g / L; and / or the particle size of the poorly soluble auxiliary material is 1 to 200 μm; and / or the drug substance is a small molecule drug with a solubility of less than 100 mg / mL; and / or the molecular weight of the drug substance is less than 1000 Da; and / or the active pharmaceutical ingredient in the drug substance includes an active pharmaceutical ingredient acting on the reproductive system, or an active pharmaceutical ingredient acting on the urinary system, or an active pharmaceutical ingredient acting on chronic diseases related to metabolism and nutrition, or an active pharmaceutical ingredient used in the treatment of chronic diseases related to connective tissue and rheumatism, or an active pharmaceutical ingredient used in the treatment of hyperlipidemia, tumor treatment, neuropsychiatric disease treatment, chronic dental disease treatment, simple obesity treatment, chronic lower back pain treatment, or leukemia treatment, or an active pharmaceutical ingredient acting on the circulatory system; wherein the pharmaceutical active ingredient acting on the reproductive system preferably comprises a pharmaceutical active ingredient used for contraception, and the pharmaceutical active ingredient used for contraception preferably comprises levonorgestrel, gestodene or gestrinone; wherein the active pharmaceutical ingredient acting on the urinary system preferably includes an active pharmaceutical ingredient used for treating chronic nephritis, chronic renal failure, or chronic prostatitis, and the active pharmaceutical ingredient used for treating chronic prostatitis is preferably a nonsteroidal anti-inflammatory drug, more preferably ibuprofen; Wherein, the active pharmaceutical ingredient acting on chronic diseases related to metabolism and nutrition preferably includes an active pharmaceutical ingredient for anti-diabetes, nutritional deficiency, gout suppression, or osteoporosis treatment, and the active pharmaceutical ingredient used for gout suppression is preferably a gout attack suppressant, more preferably ibuprofen; wherein the active pharmaceutical ingredient used in the treatment of chronic diseases involving connective tissue and rheumatism preferably includes an active pharmaceutical ingredient used in the treatment of rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjogren's syndrome, vasculitis, idiopathic inflammatory myopathy, systemic sclerosis, or osteoarthritis; the active pharmaceutical ingredient used in the treatment of rheumatoid arthritis is preferably a nonsteroidal anti-inflammatory drug, more preferably meloxicam or ibuprofen; the active pharmaceutical ingredient used in the treatment of osteoarthritis is preferably an analgesic, more preferably ibuprofen or meloxicam; wherein the active pharmaceutical ingredient used in the treatment of said neuropsychiatric disorder is preferably a drug used in the treatment of schizophrenia, more preferably a benzisoxazole, for example, paliperidone; Wherein, the active pharmaceutical ingredient used for treating said chronic lower back pain is preferably a non-steroidal analgesic, more preferably ibuprofen or meloxicam; Here, the pharmaceutical active ingredient acting on the circulatory system preferably includes a pharmaceutical active ingredient used in the treatment of chronic heart failure, coronary heart disease, congenital heart disease, chronic infective endocarditis, or chronic pericarditis, and the pharmaceutical active ingredient used in the treatment of coronary heart disease is preferably a drug that improves the symptoms of angina pectoris, more preferably puerarin; More preferably, the pharmaceutical composition according to at least one of claims 13 to 15, characterized in that the drug substance is levonorgestrel drug substance, gestodene drug substance, ibuprofen drug substance, paliperidone drug substance, meloxicam drug substance or puerarin drug substance.

17. When the drug substance is a Gestodene drug substance, the Gestodene drug substance is in a powder form, and the particle size of the Gestodene drug substance is preferably 1 to 180 μm, more preferably 2.81 μm; and / or, when the drug substance is a levonorgestrel drug substance, the levonorgestrel drug substance is in a powder form, and the particle size of the levonorgestrel drug substance is preferably 1 to 180 μm, for example, 2.12 μm; and / or, when the drug substance is an ibuprofen drug substance, the ibuprofen drug substance is in a powder form, and the particle size of the ibuprofen drug substance is preferably 1 to 200 μm, for example, 80 μm; and / or, when the drug substance is a paliperidone drug substance, the paliperidone drug substance is in a powder form, and the particle size of the paliperidone drug substance is preferably 1 to 200 μm, for example, 1 μm, 10 μm, 50 μm, 80 μm, 120 μm, 150 μm, or 180 μm; and / or, when the drug substance is a meloxicam drug substance, the meloxicam drug substance is in a powder form, and the particle size of the meloxicam drug substance is preferably 1 to 200 μm, for example, 1 μm, 10 μm, 50 μm, 80 μm, 120 μm, 150 μm or 180 μm; And / or, when the drug substance is a puerarin drug substance, the puerarin drug substance is in a powder form, and the particle size of the puerarin drug substance is preferably 1 to 200 μm, for example, 1 μm, 10 μm, 50 μm, 80 μm, 120 μm, 150 μm or 180 μm; And / or the pharmaceutical composition according to at least one of claims 13 to 16, characterized in that the pharmaceutical composition is in powder form.

18. The implant comprises a pharmaceutical composition according to at least one of claims 13 to 17 and a silicone tube, Preferably, the silicone tube is a silicone tube according to claim 11.

19. a drug core and a silicone tube; The drug core contains an active pharmaceutical ingredient and has a particle size D of the active pharmaceutical ingredient. ５０ is 180 μm or less, The raw material composition of the silicone tube comprises, in parts by weight: R-vinyl silicone rubber: 100 parts; Hydrogen-containing silicone oil: 0.3 to 3.0 parts; Reinforcing agent: 20-80 parts; Catalyst: ≧0.000002 parts, preferably 2×10 －６ -5 x 10 －５ Department; Including, however, R in the R-vinyl silicone rubber is a substituted or unsubstituted C １ ~C ５ linear or branched alkanes of substituted or unsubstituted C ６ ~C ２０ It is an aromatic hydrocarbon, The vinyl content in the R-vinyl silicone rubber is 0.05 to 0.50 mol %, the content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol %, and the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-4):1; An implant, characterized in that a manufacturing method of the silicone tube includes a step of extruding a raw material mixture of the silicone tube.

20. The pharmaceutical active ingredient includes a pharmaceutical active ingredient acting on the reproductive system, and the pharmaceutical active ingredient acting on the reproductive system may include a pharmaceutical active ingredient used in contraception, such as levonorgestrel, gestodene, gestrinone, and the pharmaceutical active ingredient acting on the reproductive system may include a steroidal estrogen, such as estradiol; and / or the pharmaceutical active ingredient has a solubility of ≦100 mg / mL; and / or the molecular weight of the pharmaceutical active ingredient is less than 1000 Da; and / or the particle size D of the pharmaceutical active ingredient. ５０ is 1 to 180 μm, for example, 2.12 μm, 2.81 μm, 10 μm, 43.24 μm, 80 μm, 80.3 μm, or 100 μm; and / or, when the pharmaceutical active ingredient is Gestodene, the mass of the pharmaceutical active ingredient is 10-100 mg, for example, 12.5 mg, 22.8 mg, 29.6 mg, 42 mg, 60 mg, or 84 mg; and / or, when the active pharmaceutical ingredient is levonorgestrel, the mass of the active pharmaceutical ingredient is 15-300 mg, e.g., 15 mg, 36 mg, 72 mg, 75 mg, 100 mg, 150 mg, 180 mg, 216 mg, or 252 mg; and / or, when the pharmaceutical active ingredient is estradiol, the mass of the pharmaceutical active ingredient is 10-300 mg, for example, 75 mg; and / or, when the active pharmaceutical ingredient is ibuprofen, the mass of the active pharmaceutical ingredient is between 10 and 2000 mg, e.g., 40 mg; and / or, when the active pharmaceutical ingredient is meloxicam, the mass of the active pharmaceutical ingredient is 10-2000 mg, for example, 40 mg; and / or, when the active pharmaceutical ingredient is paliperidone, the mass of the active pharmaceutical ingredient is 10-2000 mg, e.g., 40 mg; And / or the implant according to claim 19, characterized in that when the pharmaceutical active ingredient is puerarin, the mass of the pharmaceutical active ingredient is 10-2000 mg, for example 40 mg.

21. The R-vinyl silicone rubber is a methyl vinyl silicone rubber, and / or the vinyl content in the R-vinyl silicone rubber is 0.10 to 0.5 mol %, for example, 0.17 to 0.23 mol %, and / or the weight part of the hydrogen-containing silicone oil is 0.5 to 1 part, for example, 0.75 parts; and / or the molar ratio of Si—H groups in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (1-1.8):1, e.g., 1:1, 1.2:1, or 1.5:1; and / or the content of Si—H groups in the hydrogen-containing silicone oil is 0.5 to 1 mol %, for example, 0.75 mol %, and / or the weight parts of the reinforcing agent are 30 to 50 parts, for example 35 parts or 40 parts; and / or the reinforcing agent is one or more of white carbon black, diatomaceous earth, quartz powder, fine silica powder, calcium carbonate, aluminum hydroxide, magnesium oxide, white titanium powder, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate and calcium carbonate, e.g. white carbon black, e.g. gaseous white carbon black, precipitated white carbon black, gel white carbon black or surface-treated white carbon black; and / or the drug core further comprises an auxiliary material, the auxiliary material comprising a silicone material and a pH adjusting agent; Wherein, the silicon material is preferably white carbon black and / or mesoporous silicon, the white carbon black being, for example, gas phase white carbon black, the mesoporous silicon being, for example, one or more of mesoporous silicon AL-1FP, mesoporous silicon XDP 3050 and XDP3150; wherein the pH adjuster preferably comprises one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid, germanic acid, magnesium hydroxide, aluminum hydroxide, zinc hydroxide, ferrous hydroxide and magnesium oxide; wherein the mass ratio of the auxiliary material to the active pharmaceutical ingredient is preferably 1:1; And / or an implant according to claim 19 or 20, characterized in that the active pharmaceutical ingredient is one or more of gestodene, levonorgestrel, estradiol, ibuprofen, meloxicam, paliperidone and puerarin.

22. The weight parts of the catalyst are 5×10 －６ ~3×10 －５ For example, 1×10 －５ Department, and / or the type of catalyst is a platinum catalyst; And / or, the raw material mixture of the silicone tube further comprises an inhibitor, the inhibitor being a hydrocarbon compound; The molecular structure of the hydrocarbon compound preferably contains at least one alkynyl and one hydroxyl, for example, 2-methyl-3-butyn-2-ol; Implant according to at least one of claims 19 to 21, characterized in that the parts by weight of inhibitor are between 0.03 and 2 parts, preferably between 0.1 and 1 part, for example 0.7 part.

23. The extrusion process includes sequentially performing a first heat treatment and a second heat treatment; Wherein, the temperature of the first heat treatment is preferably 250-360°C, for example 270°C, 300°C, 330°C or 360°C, the first heat treatment is preferably carried out in a front vulcanization tunnel, the length of the front vulcanization tunnel is, for example, 0.8m; wherein the temperature of the second heat treatment is preferably 120-280°C, for example 120°C, 150°C, 180°C or 210°C, the second heat treatment is preferably carried out in a rear vulcanization tunnel, the length of the rear vulcanization tunnel being, for example, 2.5m; And / or further comprising a third heat treatment after the extrusion, The temperature of the third heat treatment is 100 to 280° C., preferably 120 to 200° C., and more preferably 180° C.; Implant according to at least one of claims 19 to 22, characterized in that the duration of said third heat treatment is between 0 and 72 hours but not 0 hours, for example 24 hours or 48 hours.

24. A method of manufacturing the implant includes the steps of filling the drug core into the silicone tube, end sealing and curing to obtain an implant; However, the curing time is preferably 0 to 72 hours, but not 0 hours, for example 24 hours or 48 hours; And / or the implant according to at least one of claims 19 to 23, characterized in that the implant further comprises a blast removal treatment.

25. A simulation is performed with the implant having different drug core lateral areas and daily drug release amounts, and a mathematical model formula: y = kx + b is obtained; y is the daily drug release amount in μg / d, and x is the lateral area of ​​the drug core in cm ２ The method for measuring the amount of drug released from an implant according to at least one of claims 19 to 24, characterized in that x = πDL, D: diameter of the drug core, and L: length of the drug core.

26. When the drug core is gestodene, k ranges from 4 to 16, e.g., 6.257, 7.520, 8.7363, 8.8140, 9.057, 10.229, or 11.591, and b ranges from (-4) to 4, e.g., 0.0802, 0.1767, 0.498, 0.561, 0.587, 0.708, or 0.802; R ２ >0.99, When the active pharmaceutical ingredient is Gestodene, the mathematical model formula is: y=11.591x+0.561, R ２ = 0.9947, Or, y = 6.257x + 0.498, R ２ = 0.998, Or, y = 7.520x + 0.587, R ２ = 0.9987, Or, y = 10.229x + 0.802, R ２ = 0.9982, Or, y = 9.057x + 0.708, R ２ = 0.9987, Or, y = 8.7363x + 0.0802, R ２ = 0.9999, Or, y = 8.8140x + 0.1767, R ２ The method for quantitatively measuring the amount of drug released from an implant according to claim 25, wherein:

27. When the drug core is levonorgestrel, k ranges from 1 to 10, e.g., 3.412, 4.2459, 5.0172, 5.6294, 5.6865, 5.8036, 6.4689, 6.4978, or 6.6085; and from (-6) to 6, e.g., -1.7641, -1.919, -0.2767, -0.2482, -0.9893, -0.3064, 0.3281, 0.3967, or 0.5; When the active pharmaceutical ingredient is levonorgestrel, the mathematical model formula is: y=4.2459x+0.3967, R ２ = 0.9957, Or, y = 6.4978x - 1.9190, R ２ = 0.9979, Or, y = 6.4689x - 0.2767, R ２ = 0.9973, Or, y = 5.8036x - 0.2482, R ２ = 0.9973, Or, y = 3.4120x - 0.9893, R ２ = 0.9978, Or, y = 6.6085x + 0.3064, R ２ = 0.997, Or, y = 5.0172x + 0.3281, R ２ = 0.998, Or, y = 5.6865x - 1.7641, R ２ = 0.9951, Or, y = 5.6294x + 0.5000, R ２ The method for quantitatively measuring the amount of drug released from an implant according to claim 26, wherein:

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