Silica gel material and preparation method thereof, silica gel tube, implant and preparation method and application of implant

Abstract

The invention discloses a silica gel material and a preparation method thereof, a silica gel tube, an implant and a preparation method and application thereof. The silica gel material comprises the following components in parts by weight: 100 parts of R-vinyl polysiloxane; 10 to 80 parts of a reinforcing agent; 0.000002 to 1 part of a catalyst; wherein R in the R-vinyl polysiloxane is substituted or unsubstituted straight-chain alkane or branched alkane of C1-C5, and substituted or unsubstituted aromatic hydrocarbon of C6-C20, and R in the R-vinyl polysiloxane is substituted or unsubstituted straight-chain alkane or branched alkane of C1-C5, or substituted or unsubstituted aromatic hydrocarbon of C6-C20; the content of vinyl in the R-vinyl polysiloxane ranges from 0.1 mol% to 0.5 mol%; the components contained in the reinforcing agent comprise hydrophilic groups; the content of Si-H groups in the hydrogen-containing silicone oil is 0.18 mol% to 1.6 mol%; the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl group in the R-vinyl polysiloxane is (0.5-10): 1; optionally, the composition also comprises an inhibitor. According to the silica gel material provided by the invention, the permeability of water to the silica gel tube is increased while the mechanical property is met, so that the release amount of a medicine is increased, and the defect of low in-vitro release degree in the prior art is improved.

Description

Technical Field

[0001] The invention relates to a silica gel material and a preparation method thereof, a silica gel tube and an implant and a preparation method and application thereof. Background Art

[0002] Silicone subcutaneous implants are mainly made by filling drugs into silicone tubes and implanting them under the skin. Water penetrates into the silicone tubes to form drug solutions, which are stably released through the silicone tubes to achieve long-term effects. Currently on the market are levonorgestrel implants, which can achieve long-term contraceptive effects. This preparation avoids the first-pass effect in the gastrointestinal tract, thereby greatly improving the bioavailability of the drug.

[0003] The silicone subcutaneous implant in the prior art mainly uses methylvinyl polysiloxane and hydrophobic silica as the base material. Among them, hydrophobic silica has better reinforcing properties, and the prepared silicone tube can better meet the mechanical conditions of implantation. However, it has low permeability to water and is a hydrophobic substance, which makes it difficult for water to penetrate the silicone tube well and dissolve the drug to form a solution, resulting in a low drug release of the implant, which cannot meet the requirements of large-dose drugs and has a narrow clinical application range. Summary of the invention

[0004] The present invention is mainly to overcome the defect that the mechanical properties and water permeability of the silica gel material in the prior art are difficult to be achieved at the same time, and provides a silica gel material and a preparation method thereof, a silica gel tube and an implant and a preparation method and application thereof. The silica gel material provided by the present invention increases the permeability of water to the silica gel tube while meeting the mechanical properties, thereby increasing the release amount of the drug and improving the defect of low in vitro release in the prior art.

[0005] The present invention solves the above technical problems through the following technical solutions.

[0006] The present invention provides a raw material composition of silica gel material, which comprises the following components in parts by weight:

[0007] R-vinyl polysiloxane: 100 parts;

[0008] Reinforcing agent: 10-80 parts;

[0009] Catalyst: 0.000002-1 part;

[0010] Wherein, R in the R-vinyl polysiloxane is substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0011] The content of vinyl in the R-vinyl polysiloxane is 0.1 mol%-0.5 mol%;

[0012] The reinforcing agent contains a hydrophilic group in its components;

[0013] The content of Si-H groups in the hydrogen-containing silicone oil is 0.18 mol%-1.6 mol%;

[0014] The molar ratio of Si-H groups in the hydrogen silicone oil to vinyl groups in the R-vinyl polysiloxane is (0.5-10):1;

[0015] Optionally, an inhibitor is also included, and the inhibitor is a substance that can inhibit the addition reaction between the R-vinyl polysiloxane and the hydrogen-containing silicone oil.

[0016] In the present invention, R in the R-vinyl polysiloxane may be a substituted or unsubstituted C 1 -C 5 A straight chain alkane such as methyl.

[0017] When the R is a methyl group, the R-vinyl polysiloxane is a methyl vinyl polysiloxane.

[0018] In the present invention, the structural formula of the R-vinyl polysiloxane may be as follows:

[0019]

[0020] Among them, m, n, p are natural numbers, R 1 , R 2 It can be a conventional substituent group in the art, and R and R' can be a conventional end-capping group in the art.

[0021] For example, when R 1 =R 2 =CH 3 When , it corresponds to dimethyl polysiloxane;

[0022] For example, when R 1 =CH 3 , R 2 =CH=CH 2 When , its corresponding is methyl vinyl polysiloxane;

[0023] For example, when R 1 =Ph, R 2 =CH=CH 2 When , its corresponding is methylphenyl vinyl polysiloxane;

[0024] For example, when R 1 =CH 3 CH 2 CF3 , R 2 =CH=CH 2 When , it corresponds to fluorosilicone polysiloxane;

[0025] For example, when R 1 =CH 3 CH 2 CN, R 2 =CH=CH 2 When , it corresponds to nitrile polysiloxane.

[0026] In the present invention, the vinyl content in the R-vinyl polysiloxane is preferably 0.15 mol% to 0.3 mol%, such as 0.18 mol% or 0.23 mol%.

[0027] In the present invention, the content of vinyl groups in the R-vinyl polysiloxane refers to the molar percentage of vinyl groups in the R-vinyl polysiloxane.

[0028] In the present invention, the polysiloxane may be any one of silicone rubber, silicone oil and silicone resin, preferably silicone rubber.

[0029] In the present invention, the weight proportion of the reinforcing agent may be 20-70 parts, such as 30 parts, 40 parts, 45 parts or 50 parts.

[0030] In the present invention, the water contact angle of the reinforcing agent may be ≤90°, for example, 14-90°, 16-35° or ≤25°. The water contact angle in the present invention is the static water contact angle of the material, and its measurement utilizes the principle of optical appearance projection to test. During use, the volume of the water drop is set using the test software, and then the syringe needle drops the water drop of the set volume on the surface of the sample to be tested. The image of the drop is projected onto the automatic image analysis system using a screen micrometer under the background of an LED light source for measurement. In the present invention, the hydrophilic group may be a conventional atomic group in the art that is soluble in water or easily affinity with water. For example, one or more of hydroxyl, thiol, aldehyde, ketone, ether bond, block polyether, carboxylic acid, carboxylate, sulfate, sulfone, sulfinic acid, sulfonic acid, sulfonamide, sulfonate, thioether, phosphate, phosphoramide, phosphorimide, phosphate, phosphite, phosphine, amino, imino, tertiary amine, quaternary ammonium, nitrile, cyanate, thiocyanate, amide and other oxygen-containing groups that can form hydrogen bonds with water molecules.

[0031] Wherein, the hydroxyl group may be an alcoholic hydroxyl group or a phenolic hydroxyl group.

[0032] In the present invention, the reinforcing agent can be one or more of white carbon black, hydroxyapatite, diatomaceous earth, quartz powder, silicon powder, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, titanium dioxide, clay, lignin, carbonate and kaolin. The reinforcing agent can increase the water permeability of the silica gel material while ensuring the mechanical properties of the silica gel material.

[0033] The white carbon black is preferably hydrophilic white carbon black or a mixture of hydrophilic white carbon black and hydrophobic white carbon black.

[0034] The hydrophilic silica is preferably hydrophilic fumed silica, such as one or more of hydrophilic fumed silica N20, hydrophilic fumed silica TH-a200, hydrophilic fumed silica A380, hydrophilic fumed silica A300, T30 hydrophilic fumed silica, T40 hydrophilic fumed silica and V15 hydrophilic fumed silica.

[0035] As a reinforcing agent for addition-type polysiloxane, hydrophilic fumed silica is a white fluffy powder with active hydroxyl groups on its surface. The hydroxyl groups on its surface are easily connected and adsorbed with polysiloxane through hydrogen bonds and van der Waals forces, which indirectly increases the cross-linking density between the reaction molecules, thereby achieving a reinforcing effect. However, compared with hydrophobic silica, hydrophilic silica is not conducive to the mechanical properties of silicone tubes. Hydrophilic silica has not undergone silanization reaction, and the silanol groups on its surface are easily introduced into moisture during the preparation process. The prepared silicone tube will produce bubbles, which will affect the mechanical properties and release of the silicone tube. The present invention greatly improves the drug release amount of the silicone material while meeting the mechanical properties of the silicone tube by changing the prescription of the silicone material and optimizing the preparation process.

[0036] The hydrophobic silica may be HB-615 hydrophobic silica, hydrophobic silica R106, hydrophobic silica R202, hydrophobic silica R812, hydrophobic silica R974, or hydrophobic silica AEROSIL R972.

[0037] In the present invention, the hydrogen-containing silicone oil can be a conventional hydrogen-containing silicone oil in the art, for example. The hydrogen-containing silicone oil in the present invention can be used as a crosslinking agent to react with R-vinyl polysiloxane to form a crosslinking reaction. 2 - An addition reaction occurs, causing the linear R-vinyl polysiloxane macromolecules to bond and cross-link to form a three-dimensional network structure.

[0038] In the present invention, the mass of the hydrogen-containing silicone oil is calculated by the following formula (1):

[0039]

[0040] In formula (1):

[0041] W: quality of hydrogen-containing silicone oil;

[0042] A: The molar ratio of Si-H in hydrogen silicone oil to the vinyl content in R-vinyl polysiloxane;

[0043] ω(Vi): mass percentage of vinyl groups in R-vinyl polysiloxane;

[0044] ω(H): The content of Si-H groups in hydrogen-containing silicone oil;

[0045] 27: molar mass of vinyl;

[0046] W 1 : The quality of R-vinyl polysiloxane.

[0047] In the present invention, the amount of the hydrogen-containing silicone oil is 0.3-5 parts, preferably 0.3-3 parts, such as 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts or 1.70 parts.

[0048] In the present invention, the content of Si-H groups in the hydrogen-containing silicone oil may be 0.18-1.2 mol%, for example 0.75 mol%.

[0049] In the present invention, the molar ratio of Si-H groups in the hydrogen silicone oil to vinyl groups in the R-vinyl polysiloxane may be (0.5-8):1, preferably (0.8-5):1, for example 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1 or 3:1.

[0050] In the present invention, the catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between methylvinyl polysiloxane and hydrogen-containing silicone oil, such as a platinum catalyst.

[0051] Wherein, the concentration of platinum in the platinum catalyst may be 1×10 3 -1×10 5 ppm, for example 1×10 3 ppm, 1×10 4 ppm, ppm refers to the mass concentration of platinum in the platinum catalyst as one part per million.

[0052] In the present invention, the amount of the catalyst is preferably 0.00001-0.5 parts, such as 0.00001 parts, 0.0098 parts or 0.21 parts.

[0053] In the present invention, the raw material composition of the silica gel material may further include an inhibitor, and the inhibitor is used to inhibit the addition reaction between R-vinyl polysiloxane and hydrogen-containing silicone oil at room temperature.

[0054] In the present invention, the inhibitor may be an acetylenic alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, and another example is 2-methyl-3-butyn-2-ol.

[0055] In the present invention, the weight proportion of the inhibitor may be 0.03-2.0 parts, such as 0.69 parts or 0.7 parts.

[0056] In the present invention, PHR refers to the mass fraction of each specific component per 100 mass fractions of R-vinyl polysiloxane (eg, methyl vinyl polysiloxane).

[0057] In some specific embodiments, the raw material composition of the silica gel material may include the following components: wherein the content of Si-H groups in the hydrogen-containing silicone oil is 0.75%:

[0058]

[0059] In some specific embodiments, the raw material composition of the silica gel material may include the following components: wherein the content of Si-H groups in the hydrogen-containing silicone oil is 0.75%:

[0060]

[0061] In some specific embodiments, the raw material composition of the silica gel material may include the following components: wherein the content of Si-H groups in the hydrogen-containing silicone oil is 0.75%:

[0062]

[0063]

[0064] In some preferred embodiments, the raw material composition of the silica gel material may include the following components:

[0065] Methylvinyl polysiloxane: 100 parts; the vinyl content in the methylvinyl polysiloxane is 0.18 mol%;

[0066] Hydrophilic white carbon black: 30 parts;

[0067] Hydrogenated silicone oil: 1.33 parts; the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in methyl vinyl polysiloxane is 1.5:1;

[0068] Platinum catalyst (concentration 3000ppm): 0.0098 parts;

[0069] 2-Methyl-3-butyn-2-ol: 0.69 parts.

[0070] In some preferred embodiments, the raw material composition of the silica gel material may include the following components:

[0071] Methylvinyl polysiloxane: 100 parts; the vinyl content in the methylvinyl polysiloxane is 0.18 mol%;

[0072] Hydrophilic white carbon black: 30 parts;

[0073] Hydrogenated silicone oil: 1.33 parts; the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in methyl vinyl polysiloxane is 1.5:1;

[0074] Platinum catalyst (concentration 3000ppm): 0.01 parts;

[0075] 2-Methyl-3-butyn-2-ol: 0.69 parts.

[0076] In some preferred embodiments, the raw material composition of the silica gel material may include the following components:

[0077] Methylvinyl polysiloxane: 100 parts; the vinyl content in the methylvinyl polysiloxane is 0.18 mol%;

[0078] Hydroxyapatite: 20 parts;

[0079] HB-615 hydrophobic fumed silica: 20 parts;

[0080] Hydrogenated silicone oil: 1.33 parts; the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in methyl vinyl polysiloxane is 1.5:1;

[0081] Platinum catalyst (concentration 3000ppm): 0.21 parts;

[0082] 2-Methyl-3-butyn-2-ol: 0.98 parts.

[0083] In some specific embodiments, the raw material composition of the silica gel material may include the following components:

[0084] Methylvinyl polysiloxane: 100 parts; the vinyl content in the methylvinyl polysiloxane is 0.17 mol%;

[0085] Hydrophilic fumed silica N20: 20 parts;

[0086] Hydrophobic fumed silica R106: 20 parts;

[0087] The content of Si-H groups in the hydrogen-containing silicone oil is 0.75%; the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in methyl vinyl polysiloxane is 1.2:1;

[0088] Platinum catalyst: 0.00001 parts;

[0089] 2-Methyl-3-butyn-2-ol: 0.7 parts.

[0090] The present invention also provides a method for preparing a silica gel material, which adopts any of the following methods:

[0091] Method 1:

[0092] S1. mixing the R-vinyl polysiloxane and the reinforcing agent to obtain a mixture A;

[0093] S2. The mixture A is divided into component A1 and component A2, the component A1 and the hydrogen-containing silicone oil are mixed to obtain component B1, and the component A2 and the catalyst are mixed to obtain component B2; optionally, the component B1 further includes an inhibitor;

[0094] S3. The component B1 and the component B2 are mixed to obtain a mixture B, and catalytic addition is performed to obtain the silica gel material.

[0095] Method 2:

[0096] The silica gel material is obtained by catalytic addition of the raw material composition; the raw material composition comprises: R-vinyl polysiloxane, a reinforcing agent, hydrogen-containing silicone oil and a catalyst; and optionally, an inhibitor may also be included.

[0097] In the present invention, the reinforcing agent can be pretreated by conventional methods in the art, and the pretreatment method is preferably drying at 90-220°C (for example, 130°C) for 1-24h (for example, 24h) for standby use; for example, the pretreatment method is drying at 130°C for 24h.

[0098] In the present invention, the R-vinyl polysiloxane can be pretreated by conventional methods in the art, and the pretreatment method is preferably drying at 20-90° C. for 1-24 hours for use; for example, the pretreatment method is drying at 40° C. for 12 hours.

[0099] In step S1, the mixing step may be to add the reinforcing agent into the R-vinyl polysiloxane in small amounts and multiple times for kneading, and then to thinly pass the mixture by extrusion.

[0100] In step S2, the preparation method of component B1 can be to re-refine component A1 in an open mill with a roller distance parameter of 1 unit, and add the hydrogen-containing silicone oil and the inhibitor dropwise, set different roller distances after adding, perform triangular packaging, thin pass, take out and park for 24 hours for standby use.

[0101] In step S2, the preparation method of component B2 can be to re-refine component A2 in an open mill with a roller distance parameter of 1 unit, and add the catalyst dropwise, continuously shorten the roller distance, perform thin pass, take out and park for 24 hours for standby use.

[0102] In step S3, the mass ratio of the component B1 to the component B2 in the mixture B may be 1:1.

[0103] In step S3, the preparation method of the mixture B can be as follows: placing component B1 and component B2 in an open mill for mixed extrusion, and performing 6 thin passes to obtain the mixture.

[0104] In step S3, the catalytic addition step may be to subject the mixture B to a first sulfurization treatment and a second sulfurization treatment in sequence, and preferably also includes a third sulfurization treatment.

[0105] The temperature of the first vulcanization treatment can be 200℃-340℃, for example, 250℃. The temperature of the first vulcanization treatment is also called the pre-drying tunnel temperature. After the silicone material is extruded from the extruder die, it will pass through a short pre-drying tunnel (0.8m long vertical hot air vulcanization tunnel). This is the first vulcanization treatment. The inhibitor in the silicone material decomposes into gas volatilization when it encounters high temperature. At this time, the catalyst begins to work and the catalytic addition reaction proceeds. At this time, the silicone material is initially vulcanized and shaped. The length of the pre-drying tunnel is relatively short. Its main function is to quickly vulcanize and shape the silicone material in a short time to prevent the silicone material from being squeezed and deformed due to the gravity of the tube itself during the conveyor belt transportation, resulting in tube flatness and dimensional errors.

[0106] The time of the first vulcanization treatment may be 2s-30s.

[0107] The first vulcanization treatment can be performed in a vertical hot air vulcanization channel. The first vulcanization treatment can initially set the rubber material at high temperature.

[0108] The temperature of the second vulcanization treatment can be 180°C-280°C, such as 220°C, 240°C, 260°C or 280°C. The temperature of the second vulcanization treatment can also be called the post-drying tunnel temperature. After the silicone material is initially vulcanized and finalized in the front drying tunnel, due to its short reaction time, the cross-linking of the silicone material is not complete. Therefore, it is then pulled by a conveyor belt and passed through a long post-drying tunnel (a 2.5m long horizontal hot air vulcanization channel) for the second vulcanization treatment, so that the addition reaction is more complete, the silicone material is further vulcanized, and good mechanical properties are achieved.

[0109] The second vulcanization treatment may be performed for 0.1 min to 5 min.

[0110] The second vulcanization treatment can be performed in a horizontal hot air vulcanization channel. The second vulcanization treatment can fully vulcanize the rubber material.

[0111] The temperature of the third vulcanization treatment may be 150°C-240°C, for example, 180°C. The vulcanization temperature has a great influence on the mechanical properties and appearance of the silicone material. If the temperature is too low, the vulcanization is insufficient, the silicone material is too soft and easy to deform, and the mechanical properties are poor. If the temperature is too high, the silicone material is prone to over-vulcanization, brittle and easy to break, and poor elasticity.

[0112] In the present invention, the vulcanization principle of two-component addition-type polysiloxane is as follows: two-component addition-type room temperature vulcanized polysiloxane, for example, is based on vinyl polydimethylsiloxane as a polymer and hydrogen-containing silicone oil as a cross-linking agent. Under the catalytic action of a catalyst (such as a platinum catalyst), the vinyl group and the hydrogen group undergo a silylation reaction to form a cross-linked network structure, and the cross-linked structure can control the release of the drug. The reaction formula is shown below.

[0113]

[0114] After mixing with crosslinking agent and catalyst, raw rubber can react at room temperature, but the mixing and processing of rubber materials require a certain amount of time. If the reactants are cured in advance during operation, the desired shape and properties cannot be obtained. This is especially true for addition-type polysiloxanes. Therefore, it is generally required that the catalytic reaction has almost no effect before vulcanization (mixing at room temperature), and reacts rapidly when the vulcanization temperature is reached. The method of inhibiting the reaction is usually to add inhibitors. Inhibitors can form a certain form of complex with platinum catalysts. Effective inhibitors can be placed with rubber materials for a considerable period of time, and can only be vulcanized when heated to a certain vulcanization temperature. Commonly used are acetylenic alcohol compounds, nitrogen-containing compounds, organic peroxides, etc. with good compatibility.

[0115] The present invention also provides a silica gel material, which is prepared by the above-mentioned preparation method.

[0116] The present invention also provides a method for preparing a silicone tube, wherein the mixture B as described above is formed into a tube through an extrusion process, and then subjected to catalytic addition to obtain the silicone tube;

[0117] Alternatively, the aforementioned catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

[0118] The present invention also provides a silicone tube, which is prepared by the preparation method as described above.

[0119] The present invention also provides an implant, which comprises the silicone tube and a medicine core as described above, wherein the medicine core contains active pharmaceutical ingredients.

[0120] In the present invention, the active pharmaceutical ingredient may be a conventional sustained-release pharmaceutical ingredient in the art that requires long-term drug release, preferably an active pharmaceutical ingredient with a solubility of ≤100 mg / mL (with water as solvent).

[0121] In the present invention, the active pharmaceutical ingredients may include active pharmaceutical ingredients that act on the reproductive system, or active pharmaceutical ingredients that act on the urinary system, or active pharmaceutical ingredients that act on chronic diseases related to metabolism and nutrition, or active pharmaceutical ingredients used to treat chronic diseases related to connective tissue and rheumatism, or active pharmaceutical ingredients used to treat hyperlipidemia, tumors, neuropsychiatric diseases, chronic dental diseases (caries, periodontal disease), simple obesity, chronic low back pain or leukemia, or active pharmaceutical ingredients that act on the circulatory system, or active pharmaceutical ingredients that act on the respiratory system, or active pharmaceutical ingredients that act on the digestive system, or active pharmaceutical ingredients that act on the blood system, or active pharmaceutical ingredients that act on the endocrine system.

[0122] The active pharmaceutical ingredients acting on the reproductive system may include active pharmaceutical ingredients for contraception, or steroidal estrogens.

[0123] The active ingredients of the contraceptive drugs may be conventional ones in the art, and preferably include levonorgestrel, gestodene or gestrinone.

[0124] The steroidal estrogen is preferably estradiol.

[0125] Among them, the active pharmaceutical ingredients acting on the urinary system preferably include active pharmaceutical ingredients for treating chronic nephritis, treating chronic renal failure, or treating chronic prostatitis.

[0126] The active ingredient of the drug for treating chronic prostatitis is preferably a non-steroidal anti-inflammatory drug, more preferably ibuprofen. Generally, the drug for treating chronic prostatitis can be: antibiotics (such as fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracycline), α receptor blockers (such as doxazosin, terazosin, etc.), non-steroidal anti-inflammatory drugs (such as ibuprofen, diclofenac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib, etc.), analgesics (such as acetaminophen, etc.), opioids (such as morphine, fentanyl, nalbuphine, pentazocine, etc.), anti-neuropathic pain drugs (such as 5-hydroxytryptamine, duloxetine, venlafaxine), anti-epileptics (such as pregabalin, etc.), M receptor blockers (such as solifenacin, tolterodine, etc.).

[0127] The drugs for treating chronic nephritis can generally be: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan, etc.), calcium channel blockers (such as amlodipine, felodipine, nifedipine, etc.), beta-receptor blockers (such as atenolol, bisoprolol, carvedilol, propranolol, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide, etc.), immunosuppressants (such as prednisone, Enova, methylprednisolone, cyclophosphamide, dexamethasone, etc.), statins lipid-lowering drugs (such as fluvastatin, simvastatin, pravastatin).

[0128] The drugs for treating chronic renal failure generally include: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide, etc.), iron preparations (ferrous fumarate, etc.), compound amino acids, α-keto acids, and recombinant human erythropoietin.

[0129] Among them, the active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition preferably include active pharmaceutical ingredients for treating diabetes, nutritional deficiency diseases, gout, or osteoporosis.

[0130] The anti-gout active ingredient is preferably an anti-gout attack drug, such as colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, aminosalicylic acid, salsalate, benolate, more preferably ibuprofen. Generally, the anti-gout drug can also be a uricosuric agent drug (such as benzbromarone, probenecid), a uric acid synthesis blocker drug (such as allopurinol).

[0131] The anti-diabetic drugs can generally be anti-type 1 diabetes drugs (such as insulin) and anti-type 2 diabetes drugs. The anti-type 2 diabetes drugs can be sulfonylurea drugs (such as glimepiride, gliquidone), glinides (such as repaglinide, nateglinide), metformin drugs (such as metformin), α-glucosidase inhibitors (such as acarbose, voglibose), DPP-4 inhibitors (such as sitagliptin), GLP-1 receptor agonists (such as liraglutide, exenatide) or SGLT-2 inhibitors (such as dapagliflozin, empagliflozin).

[0132] The drugs for treating nutritional deficiency diseases can generally be drugs for gastrointestinal diseases (such as omeprazole, mosapride) and nutritional supplements (such as vitamin E).

[0133] The anti-osteoporosis drugs can generally be bisphosphonates (e.g., alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonates, clodronate disodium, zoledronic acid sodium, risedronate sodium), calcitonin drugs (e.g., salmon calcitonin), estrogen drugs (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) drugs (e.g., raloxifene, benzothiophene), RANKL inhibitor drugs, parathyroid hormone drugs, monofluoroglutamine drugs, strontium salt drugs (e.g., strontium ranelate), active vitamin D and analogs (e.g., calcitriol, α-calciferol), vitamin K (e.g., menatetrenone).

[0134] Among them, the active pharmaceutical ingredients for treating chronic diseases involving connective tissue and rheumatism preferably include active pharmaceutical ingredients for treating rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, vasculitis, idiopathic inflammatory myopathy, systemic sclerosis, or osteoarthritis.

[0135] The active ingredient of the drug for treating rheumatoid arthritis is preferably a non-steroidal anti-inflammatory drug, such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, nabumetone, more preferably meloxicam or ibuprofen. Generally, the drug for treating rheumatoid arthritis can be a glucocorticoid drug (such as hydrocortisone, dexamethasone, prednisone), a slow-acting antirheumatic drug (such as methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide).

[0136] The active ingredient of the drug for treating osteoarthritis is preferably an analgesic, such as ibuprofen, Voltaren, meloxicam, celecoxib, loxoprofen sodium nimesulide, more preferably ibuprofen or meloxicam. Generally, the drug for treating osteoarthritis can be a drug for nourishing cartilage, an opioid (such as oxycodone, chimantin).

[0137] The drugs for treating systemic lupus erythematosus can generally be non-steroidal anti-inflammatory drugs (such as naproxen, ibuprofen), antimalarial drugs, glucocorticoid drugs (such as prednisone acetate, methylprednisolone), immunosuppressant drugs (such as methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), and biological drugs (such as rituximab, belimumab).

[0138] The drugs for treating ankylosing spondylitis can generally be non-steroidal drugs (such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, and ericoxib), disease-modifying antirheumatic drugs (such as pyridine sulfamethoxazole, methotrexate, and hydroxychloroquine), glucocorticoid drugs (such as prednisone, prednisolone, and diprosone), and biological TNF-a antagonists (such as etanercept).

[0139] The drugs for treating Sjögren's syndrome can generally be systemic therapeutic drugs (such as levamisole, transfer factor coenzyme Q10, thymosin), glucocorticoid drugs (such as prednisone), and immunosuppressive drugs (such as hydroxychloroquine, azathioprine, and ilamod).

[0140] The drugs for treating vasculitis can generally be glucocorticoid drugs (such as prednisone, methylprednisolone, dexamethasone) and immunosuppressant drugs (such as cyclophosphamide, cyclosporine, azathioprine).

[0141] The drugs for treating idiopathic inflammatory myopathy can generally be glucocorticoid drugs (such as dexamethasone, prednisone, hydrocortisone, methylprednisolone), immunosuppressant drugs (such as cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolate mofetil).

[0142] The drugs for treating systemic sclerosis can generally be anti-fibrotic drugs (such as colchicine), vasoactive drugs (such as nifedipine, benzathine) and several other commonly used drugs (such as naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, tocilizumab).

[0143] Among them, the active ingredients of the drugs for treating neuropsychiatric disorders can generally be drugs for treating schizophrenia, antidepressants, drugs for treating opioid abuse or drugs for treating anxiety disorders; preferably, drugs for treating schizophrenia, more preferably, phenothiazines (such as chlorpromazine), thioxanthenes (such as chlorprothixene), butyrophenones (such as haloperidol), dibenzodiazepines (such as olanzapine, clozapine), benzisoxazoles (such as risperidone, paliperidone), benzisothiazoles (such as ziprasidone), diphenylthiazepines (such as quetiapine), quinolones (such as aripiprazole), and further preferably, benzisoxazoles (such as paliperidone).

[0144] The antidepressant drugs can generally be tricyclic antidepressants (such as imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (such as moclobemide), selective serotonin reuptake inhibitors (such as sertraline), serotonin and norepinephrine reuptake inhibitors (such as venlafaxine), serotonin block and reuptake inhibitors (such as trazodone), norepinephrine and dopamine reuptake inhibitors (such as bupropion), norepinephrine inhibitors (such as reboxetine), α2 adrenergic receptor blockers (such as mirtazapine).

[0145] The drug for treating opioid abuse may generally be buprenorphine or methadone.

[0146] The anxiety-treating drugs generally include benzodiazepines (eg, diazepam), 5-HT1A receptor partial agonists (eg, buspirone), beta-adrenergic receptor blockers (eg, propranolol), and valproate.

[0147] Among them, the therapeutic drugs for treating hyperlipidemia can generally be statins (such as simvastatin, atorvastatin, pravastatin), fibrates (such as fenofibrate, bezafibrate, gemfibrozil), and nicotinic acids (such as niacin).

[0148] Among them, the anti-tumor drug can generally be an anti-breast cancer drug (such as azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol acetate, cetuximab or leuprolide), an anti-prostate cancer drug (such as degarelix, leuprolide, histrelin, flunitrium, estramustine, cyproterone acetate), an anti-ovarian cancer drug (such as carboplatin, topotecan, methotrexate), an anti-rectal cancer drug (such as panitumumab), an anti-colon cancer drug (such as bevacizumab, oxaliplatin), an anti-liver cancer drug (such as sorafenib), an anti-lung cancer drug (such as erlotinib, gefitinib, docetabine) , anti-renal cancer drugs (e.g. pazopanib, everolimus, temsirolimus), anti-gastric cancer drugs (e.g. 5-fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), anti-pancreatic cancer drugs (e.g. nimotuzumab), anti-esophageal cancer drugs (e.g. docetaxel, paclitaxel, cisplatin, gemcitabine, tegafur, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), anti-skin cancer drugs (e.g. 5-fluorouracil), anti-lymphoma drugs (e.g. vincristine, bexarotene, dacarbazine, etoposide), anti-myeloma drugs (e.g. bortezomib), anti-cervical cancer drugs (e.g. bleomycin) or anti-bladder cancer drugs (e.g. epirubicin, bacillus Calmette-Guérin).

[0149] Among them, the drugs for treating chronic dental diseases (such as caries and periodontal disease) can generally be divided into nitroimidazole drugs (such as metronidazole, tinidazole, ornidazole), penicillin drugs, and other commonly used drugs (minocycline, chlorhexidine acetate).

[0150] Wherein, the drug for treating simple obesity can generally be orlistat.

[0151] Wherein, the active ingredient of the drug for treating chronic low back pain is preferably a non-steroidal analgesic drug, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen, voltaren, more preferably ibuprofen or meloxicam;

[0152] The drugs for treating leukemia are generally drugs that interfere with nucleic acid biosynthesis (such as cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect the DNA structure and function of cancer cells (such as busulfan, mitomycin, chlorambucil, phenylalanine mustard, cyclophosphamide), drugs that interfere with the transcription process and prevent RNA synthesis (such as daunorubicin, doxorubicin, adriamycin, aclarubicin), drugs that inhibit protein synthesis and function (such as vindesine, vincristine, L-aspartate, homoharringtonine), and other commonly used drugs (such as interferon, fludarabine, arsenite, etoposide, and carmustine).

[0153] Wherein, the active pharmaceutical ingredients acting on the circulatory system preferably include active pharmaceutical ingredients for treating chronic heart failure, coronary heart disease, congenital heart disease, or chronic infective endocarditis or chronic pericarditis;

[0154] The active ingredients of the drugs for treating coronary heart disease can generally be drugs for improving angina symptoms (such as puerarin, isosorbide mononitrate), drugs for antiplatelet aggregation (such as aspirin, clopidogrel bisulfate, ticagrelor), drugs for lipid-lowering and plaque-stabilizing (such as atorvastatin, rosuvastatin, pravastatin), drugs for inhibiting sympathetic nerve activity (such as metoprolol, bisoprolol fumarate), and drugs for improving myocardial remodeling (such as angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists); preferably, the drugs for improving angina symptoms are puerarin; the active ingredients of the drugs for treating chronic heart failure can generally be cardiotonic drugs (such as digitalis, digoxin, cedilanid), vasodilator drugs (such as sodium nitroprusside, nitroglycerin, converting enzyme inhibitors (such as enalapril, lenoprolol, etc.), and diuretics (such as furosemide, hydrochlorothiazide, spironolactone).

[0155] The active ingredient of the drug for treating congenital heart disease can generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide or coenzyme Q10.

[0156] The active ingredient of the drug for treating chronic infective endocarditis can generally be an antibiotic (eg, vancomycin, cephalosporin, penicillin, aminoglycoside).

[0157] The active ingredient of the medicine for treating chronic pericarditis can generally be digitalis.

[0158] Among them, the active pharmaceutical ingredients acting on the respiratory system may generally include active pharmaceutical ingredients for treating chronic obstructive pulmonary emphysema, treating asthma, treating chronic cor pulmonale, treating chronic respiratory failure, treating silicosis or treating pulmonary fibrosis.

[0159] The active ingredients of the drugs for treating chronic obstructive pulmonary emphysema can generally be bronchodilators (including beta-receptor agonists and anticholinergic drugs), inhaled hormones (such as budesonide and fluticasone), theophylline antiasthmatics (such as theophylline), expectorants (such as carbocysteine ​​and fudosteine), and glucocorticoids and antibiotics (such as penicillins, glycosides and cephalosporins) can also be appropriately selected when the condition requires.

[0160] The active ingredients of the asthma-treating drugs are generally commonly used inhaled drugs (e.g., beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (e.g., salbutamol), sustained-release theophylline, leukotriene modifiers (which can be used in combination), anticholinergics (e.g., isoproscopolamine), and antihistamines (e.g., astemizole, ketotifen).

[0161] The active ingredients of the drugs for treating chronic cor pulmonale can generally be antibiotics (such as amoxicillin, cefuroxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (such as selective β2 receptor stimulants, theophylline drugs), drugs that eliminate nonspecific airway inflammation (such as prednisone), inhaled drugs (such as beconazole), respiratory stimulants (such as lobeline, doxapram, duloxetine, etc.).

[0162] The active ingredients of the drug for treating chronic respiratory failure can generally be drugs for relieving bronchospasm and removing phlegm (such as salbutamol, acetylcysteine, etc.).

[0163] The active ingredients of the medicine for treating silicosis can generally be siping, acetylcysteine, aluminum preparations, closiperine, and salvia miltiorrhiza.

[0164] The active ingredients of the drug for treating pulmonary fibrosis can generally be pirfenidone, nintedanib, glucocorticoids (such as methylprednisolone, prednisone), immunosuppressants (such as azathioprine, methotrexate, etc.), colchicine, interferon, ACEI or statins, etc.

[0165] Among them, the active pharmaceutical ingredients acting on the digestive system generally include active pharmaceutical ingredients for treating chronic gastritis, treating peptic ulcers, treating intestinal tuberculosis, treating chronic enteritis, treating chronic diarrhea, treating chronic hepatitis, treating cirrhosis, treating chronic pancreatitis, and treating chronic cholecystitis.

[0166] The active ingredients of the drugs for treating chronic gastritis can generally be used to relieve pain (atropine, propantheline, etc. can be used), PPI proton pump inhibitors (such as lansoprazole, omeprazole, etc.) can be used for increased gastric acid, H2 receptor blockers (such as cimetidine, ranitidine, aluminum hydroxide ammonium, etc.) can be used for those with milder symptoms, digestive aids (pancreatic enzymes can be added), and bile reflux (metoclopramide and metoclopramide, cholestyramine, and sucralfate can bind to bile acid).

[0167] The active ingredients of the drug for treating peptic ulcer are generally levofloxacin, metronidazole and omeprazole.

[0168] The active ingredient of the drug for treating intestinal tuberculosis can generally be rifampicin.

[0169] The active ingredients of the medicine for treating chronic enteritis can generally be anti-inflammatory analgesics, probiotics, antispasmodics and analgesics (such as atropine and propantheline).

[0170] The active ingredients of the medicine for treating chronic diarrhea can generally be antidiarrheal drugs (such as montmorillonite powder, diphenoxylate, loperamide), intestinal microbial preparations (such as lactobacillus, bifidobacterium), and spasmodic analgesics (such as pinaverium bromide).

[0171] The active ingredients of the drugs for treating chronic hepatitis can generally be liver-protecting drugs (such as silymarin preparations, schisandra preparations, etc.), anti-fibrosis drugs (such as oral Chinese patent medicine preparations), antivirals (such as conventional interferons and pegylated interferons), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine, entecavir), and immunosuppressants (azathioprine).

[0172] The active ingredients of the drug for treating liver cirrhosis can generally be drugs for treating hepatitis B (such as nucleoside analogs), drugs for treating autoimmune hepatitis (such as glucocorticoids), anti-inflammatory drugs, liver-protecting drugs, anti-liver fibrosis drugs (such as reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, etc.), drugs for treating spontaneous bacterial peritonitis (such as antibiotics), and drugs for treating portal hypertension (such as carvedilol).

[0173] The active ingredients of the medicine for treating chronic pancreatitis can generally be analgesics (such as buprenorphine and fentanyl) and pancreatic enzyme treatment drugs (such as pancreatic enzymes).

[0174] The active ingredients of the drug for treating chronic cholecystitis can generally be antibacterial and anti-inflammatory drugs (such as levofloxacin, ciprofloxacin, amoxicillin), antispasmodics and analgesics, and choleretics (such as ursodeoxycholic acid).

[0175] Among them, the active pharmaceutical ingredients acting on the blood system generally include active pharmaceutical ingredients for treating chronic anemia, treating chronic myeloid leukemia, and treating chronic lymphocytic leukemia.

[0176] The drugs for treating chronic anemia generally include: trace elements (such as folic acid, vitamin B12, etc.), bone marrow stimulants (such as strychnine nitrate, scopolamine, hyoscyamine, etc.), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight dextran iron, carboxymaltose iron, isomaltose iron, glucuronic acid iron, nano iron oxide, sorbitol iron, etc.), and erythropoiesis-stimulating agents (recombinant human erythropoietin α, darbepoetin α, etc.).

[0177] The drugs for treating chronic myeloid leukemia generally include: tyrosine kinase inhibitors (such as imatinib, nilotinib, bosutinib, ponatinib, etc.), homoharringtonine.

[0178] The drugs for treating chronic lymphocytic leukemia generally include: chemotherapy drugs (such as nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted drugs (such as adranib, venetola, ibrutinib, imatinib, dasatinib, etc.), and monoclonal antibodies (such as ofatumumab, rituximab, atozumab, alemtuzumab, etc.).

[0179] Among them, the active pharmaceutical ingredients acting on the endocrine system may generally include active pharmaceutical ingredients for treating chronic lymphocytic thyroiditis, hyperthyroidism, and hypothyroidism.

[0180] The drugs for treating chronic lymphocytic thyroiditis generally include: thyroid hormones (such as levothyroxine, thyroxine), glucocorticoids (such as prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0181] The drugs for treating hyperthyroidism generally include: thiouracils (such as propylthiouracil, methylthiouracil, etc.), imidazoles (such as methimazole, carbimazole, etc.), iodine and iodide (such as Lugol's solution, etc.), radioactive iodine (such as 131 iodine, etc.), beta-receptor blockers (such as metoprolol, atenolol, bisoprolol, carvedilol, propranolol, etc.).

[0182] The drugs for treating hypothyroidism generally include: thyroxine (eg, levothyroxine, levothyroxine sodium, thyroxine, etc.).

[0183] In the present invention, the preparation method of the drug core can be to mix, extrude and vulcanize the drug active component and polysiloxane in sequence to obtain the drug core.

[0184] The polysiloxane comprises R-vinyl polysiloxane, hydrogen-containing silicone oil, a catalyst and an inhibitor.

[0185] Wherein, the temperature of the vulcanization treatment may be 70°C-160°C.

[0186] Wherein, the time of the vulcanization treatment can be 0.5-10h.

[0187] Among them, the raw material composition of the drug core can be: in parts by weight, 100 parts of active pharmaceutical ingredients, 100 parts of R-vinyl polysiloxane, 0.21 parts of catalyst, 0.98 parts of inhibitor, and the molar ratio of Si-H in hydrogenated silicone oil to vinyl in R-vinyl polysiloxane is 4.5:1.

[0188] The present invention provides a method for preparing the implant as described above, which comprises the following steps: filling the drug core into the silicone tube and then sealing the end to obtain the implant.

[0189] In the present invention, the drug core may be a skeleton-type rod core or a powder-type drug core.

[0190] When the drug core is a skeleton-type rod core, the length of the silicone tube is 0.4 cm longer than the length of the skeleton-type rod core. 0.2 cm is reserved at both ends of the silicone tube to facilitate the sealing of the implant.

[0191] When the drug core is a skeleton-type stick core, the filling method is preferably to quickly insert the skeleton-type stick core into the silicone tube when it is in a swollen state; the swelling can be achieved by soaking the silicone tube in petroleum ether for 1-2 minutes. After the filling is completed, it is preferably naturally air-dried for 12-24 hours; the purpose of natural air-drying is to evaporate the residual petroleum ether.

[0192] When the drug core is a powder type drug core, the filling method is preferably to seal one end of the silicone tube first and then fill it through a drug filling funnel.

[0193] In the present invention, the end-capping can be sealed with a sealing glue; the sealing glue is preferably silica gel.

[0194] In the present invention, after the end-capping is completed, it is preferably placed at room temperature for 12-24 hours to allow the sealing glue to solidify.

[0195] In the present invention, the silicone tube is preferably pretreated by soaking it in 75% ethanol for 15 minutes, then repeatedly rinsing it with 75% ethanol for several times and then air-drying it naturally.

[0196] The present invention also provides a use of the aforementioned silica gel material or the aforementioned silica gel tube as a release rate regulating medium in a sustained-release preparation.

[0197] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0198] The reagents and raw materials used in the present invention are commercially available.

[0199] The positive and progressive effects of the present invention are:

[0200] The silicone tube made of the silicone material in the present invention has excellent mechanical properties and increases the water permeability to the silicone tube, so that when used, the drug can be more easily formed into a drug solution and released from the implant, thereby increasing the release amount of the drug. The drug release can reach several to dozens of times that of the traditional silicone tube, thereby expanding the range of drug selection and greatly expanding the application range of the implant. BRIEF DESCRIPTION OF THE DRAWINGS

[0201] Figure 1 The in vitro release profiles of the improved gestodene reservoir skeleton implants with different wall thicknesses prepared in Examples 8-1, 8-2 and 8-3.

[0202] Figure 2 The in vitro release diagram of the improved gestodene reservoir skeleton implant prepared by using different amounts of white carbon black in Examples 8-1, 9-1 and 9-2.

[0203] Figure 3 The in vitro release profiles of the improved gestodene reservoir matrix implants prepared using methylvinyl polysiloxane with different vinyl contents in Examples 8-1 and 10.

[0204] Figure 4 The in vitro release profiles of the improved gestodene reservoir skeleton implants prepared in Examples 8-1, 11-1 and 11-2 using different molar ratios of Si—H in hydrogen-containing silicone oil to vinyl in methylvinylpolysiloxane.

[0205] Figure 5 This is a data chart showing the 150-day in vitro release effect of the improved gestodene reservoir skeleton implant prepared in Example 8-1.

[0206] Figure 6 This is a data chart of the 150-day in vitro release effect of the gestodene reservoir skeleton implant prepared in Comparative Example 1.

[0207] Figure 7 This is a comparison chart of the 150-day in vitro release effect data of the improved gestodene reservoir skeleton type implant prepared in Example 8-1 and the gestodene reservoir skeleton type implant prepared in Comparative Example 1.

[0208] Figure 8 The in vitro release data of the improved paliperidone reservoir implants prepared with different contents of hydroxyapatite in Examples 12-1, 12-2 and 12-3 are shown.

[0209] Fig. 9 The in vitro release data of the improved paliperidone reservoir implant prepared by using methylvinyl polysiloxane with different vinyl contents in Examples 12-1 and 13 are shown.

[0210] Fig.10 The in vitro release data of the improved paliperidone reservoir implant prepared by using different molar ratios of Si—H in hydrogen-containing silicone oil to vinyl in methylvinylpolysiloxane in Examples 12-1, 14-1 and 14-2 are shown.

[0211] Fig.11 This is the in vitro release data of the improved paliperidone reservoir implant prepared in Example 14-1.

[0212] Fig.12 This is the in vitro release data of the paliperidone reservoir implant prepared in Comparative Example 2.

[0213] Fig.13 This is a comparison chart of the in vitro release data of the improved paliperidone reservoir implant prepared in Example 14-1 and the paliperidone reservoir implant prepared in Comparative Example 2.

[0214] Fig.14 The in vitro release data of the improved estradiol reservoir implants prepared by using different vulcanization treatment temperatures in Examples 17-1, 17-2 and 17-3 are shown.

[0215] Fig.15 The in vitro release data of the improved estradiol reservoir implants with different wall thicknesses prepared in Examples 18-1, 18-2 and 18-3 are shown.

[0216] Fig.16 This is the in vitro release data of the improved estradiol reservoir implant prepared in Example 17-2.

[0217] Fig.17 This is the in vitro release data of the estradiol reservoir implant prepared in Comparative Example 3.

[0218] Fig.18This is a comparison chart of the long-term in vitro release effect data of the improved estradiol reservoir implant of Example 17-2 and the estradiol reservoir implant prepared in Comparative Example 3. DETAILED DESCRIPTION

[0219] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0220] The sources of the components in the embodiments and comparative examples are shown in the following table.

[0221] Components Commercial Source Methylvinyl polysiloxane, 100000-800000 g / mol Dongjue Silicone Group Co., Ltd. Hydrogenated silicone oil (Si-H content is 0.75 mol%) Guangdong Guiye New Material Technology Co., Ltd. Hydrophilic fumed silica N20 (contact angle 14-90°) Wacker International AG Hydrophilic white carbon black TH-a200 (contact angle is <90°) Shandong Wanhua Tianhe New Materials Co., Ltd. Hydrophilic fumed silica A380 (contact angle 16-35°) Evonik Degussa Hydrophobic fumed silica R106 (contact angle > 90°) Evonik Degussa HB-615 hydrophobic fumed silica (contact angle > 138°) Dalian Shengsen Nanomaterials Co., Ltd. Hydroxyapatite (contact angle 0-25°) Shanghai Aladdin Biochemical Technology Co., Ltd. Platinum catalyst (3000ppm) Guangdong Guiye New Material Technology Co., Ltd. 2-Methyl-3-butyn-2-ol Jiuding Chemical Technology Co., Ltd. Paliperidone Shanghai Aladdin Biochemical Technology Co., Ltd. Gestodene (purity 98%, batch number: 190327) Hebei Mokai Technology Co., Ltd. Estradiol (purity 99%, batch number: 190327) Hebei Mokai Technology Co., Ltd. KN-300N Adhesive Kanglibang Polymer New Materials Co., Ltd. Anhydrous ethanol (analytical grade) Shandong Yuwang Chemical Reagent Co., Ltd. Chromatography Methanol Shandong Yuwang Chemical Reagent Co., Ltd. Petroleum ether (boiling range 60-90℃) Shandong Yuwang Chemical Reagent Co., Ltd.

[0222] The equipment and instruments used in the preparation and testing process are shown in the following table:

[0223]

[0224]

[0225] 1. Silicone tube

[0226] 1.1 Preparation method of silicone tube

[0227] (1) drying the methyl vinyl polysiloxane raw rubber at 40° C. for 12 h for later use; drying the hydrophilic fumed silica at 130° C. for 24 h for later use;

[0228] (2) mixing methyl vinyl polysiloxane rubber and hydrophilic fumed silica according to a prescribed amount to obtain a mixture A;

[0229] (3) The mixture A is divided into component A1 and component A2, and component A1 is re-refined in an open mill with a roller distance parameter of 1 unit, and the prescribed amount of the hydrogen-containing silicone oil and the inhibitor 2-methyl-3-butyn-2-ol are added dropwise. After the addition, different roller distances are set, and the components are triangularly packaged, thinned, taken out and left for 24 hours to obtain component B1 for standby; component A2 is re-refined in an open mill with a roller distance parameter of 1 unit, and the prescribed amount of platinum catalyst is added dropwise, the roller distance is continuously shortened, thinned, taken out and left for 24 hours to obtain component B2 for standby;

[0230] (4) placing B1 and B2 obtained in step (3) in a ratio of 1:1 in an open mill for mixed extrusion, and performing 4-6 thin passes to obtain a mixture B;

[0231] (5) The mixture B obtained in step (4) is unloaded from the open mill in the form of a thin sheet and then cut into strips; a mold of suitable size is installed on the extruder, the extruder screw speed is set, and the cut silicone strips are put into the extruder. The rubber material is continuously extruded into a silicone tube through the die mouth under the push of the screw rotation. The outer diameter of the silicone tube is determined by the extruder screw speed, the speed of the post-drying channel conveyor belt, and the mold size, and the wall thickness is determined by the mold size.

[0232] (6) subjecting the silicone tube obtained in step (5) to a first vulcanization treatment and a second vulcanization treatment, thereby obtaining a silicone tube finished product;

[0233] Among them, the first vulcanization treatment: the silicone tube extruded from the mold mouth first passes through a front drying channel (vertical hot air vulcanization channel) for rapid high-temperature vulcanization, which is the first vulcanization treatment, so that the silicone tube quickly changes from a sticky and soft state to an elastic state and is initially shaped.

[0234] Among them, the second vulcanization treatment: after the first vulcanization, it enters the post-drying tunnel (horizontal hot air vulcanization channel) to continue vulcanization, which is the second vulcanization treatment, so that the vulcanization reaction of the silicone tube is more complete and reaches the optimal cross-linking state, and then the finished silicone tube is continuously transported out through the conveyor belt of the post-drying tunnel.

[0235] 1.2 Investigation of the prescription and process of silicone tube

[0236] (1) Effects of vinyl content in methyl vinyl polysiloxane, amount of reinforcing agent, and molar ratio of Si-H in hydrogenated silicone oil to vinyl in methyl vinyl polysiloxane on the mechanical properties of silicone tubes

[0237] A. Prescription: The concentration of the platinum catalyst is 3000 ppm; the dosage of the platinum catalyst is 0.0098 PHR; the dosage of the inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR. Other prescription parameters are shown in Table 1.

[0238] Table 1

[0239]

[0240] B. Preparation method: The preparation method described in 1.1 is adopted, and the specific process parameters are: the temperature of the first vulcanization treatment is 250°C; the time of the first vulcanization treatment is 3s; the temperature of the second vulcanization treatment is 240°C; the time of the second vulcanization treatment is 4min; the diameter of the die is 3mm; the diameter of the core die is 2.6mm; the wall thickness of the obtained silicone tube is 0.2mm; the screw speed is 5r·min -1 .

[0241] (2) Effect of the temperature of the second vulcanization treatment on the mechanical properties of silicone tubes

[0242] A. Prescription: The concentration of platinum catalyst is 3000ppm; the dosage of platinum catalyst is 0.0098PHR; the dosage of inhibitor 2-methyl-3-butyn-2-ol is 0.69PHR; the vinyl content in methyl vinyl polysiloxane is 0.18%; the dosage of hydrophilic white carbon black TH-a200 is 30PHR; the molar ratio of Si-H in hydrogen silicone oil to vinyl in methyl vinyl polysiloxane is 1.5:1.

[0243] B. Preparation method: The preparation method described in 1.1 is adopted, except that the temperature of the vulcanization treatment is set according to the setting recorded in Table 2; the time of the first vulcanization treatment is 3s, and the time of the second vulcanization treatment is 4min; and the diameter of the die is 3mm; the diameter of the core die is 2.6mm; the wall thickness of the obtained silicone tube is 0.2mm; the screw speed is 5r·min -1 .

[0244] Table 2

[0245] serial number First vulcanization temperature / ℃ Second vulcanization temperature / ℃ Example 4-1 250 220 Example 4-2 250 240 Example 4-3 250 260 Example 4-4 250 280

[0246] (3) The influence of mold size and screw speed on the outer diameter of silicone tube

[0247] A. Prescription: The concentration of platinum catalyst is 3000ppm; the dosage of platinum catalyst is 0.0098PHR; the dosage of inhibitor 2-methyl-3-butyn-2-ol is 0.69PHR; the vinyl content in methyl vinyl polysiloxane is 0.18%; the dosage of hydrophilic white carbon black TH-a200 is 30PHR; the molar ratio of Si-H in hydrogen silicone oil to vinyl in methyl vinyl polysiloxane is 1.5:1.

[0248] B. Preparation process: The preparation method described in 1.1 is adopted, and the temperature of the first vulcanization treatment is 250°C; the time of the first vulcanization treatment is 3s; the temperature of the second vulcanization treatment is 240°C; the time of the second vulcanization treatment is 4min; the mold size and screw speed are shown in Table 3. (Note: Ring width = (die inner diameter - core mold diameter) / 2)

[0249] Table 3

[0250] serial number Die inner diameter / mm Core mold diameter / mm Ring width / mm Screw speed / r / min Silicone tube outer diameter / mm Example 5-1 3.30 2.50 0.40 5.0 2.23 Example 5-2 3.30 2.50 0.40 6.0 2.30 Example 5-3 3.30 2.50 0.40 7.0 2.35 Example 5-4 3.30 2.50 0.40 8.0 2.45 Example 5-5 3.30 2.50 0.40 9.0 2.61 Embodiment 5-6 3.30 2.50 0.40 10.0 2.74 Example 6-1 3.90 3.00 0.45 5.0 2.32 Example 6-2 3.90 3.00 0.45 6.0 2.37 Example 6-3 3.90 3.00 0.45 7.0 2.40 Example 6-4 3.90 3.00 0.45 8.0 2.52 Example 6-5 3.90 3.00 0.45 9.0 2.66 Example 6-6 3.90 3.00 0.45 10.0 2.79 Example 7-1 3.50 2.50 0.50 5.0 2.47 Example 7-2 3.50 2.50 0.50 6.0 2.55 Example 7-3 3.50 2.50 0.50 7.0 2.62 Example 7-4 3.50 2.50 0.50 8.0 2.67 Example 7-5 3.50 2.50 0.50 9.0 2.71 Example 7-6 3.50 2.50 0.50 10.0 2.78

[0251] The results in Table 3 show that when the screw speed reaches 5 r·min -1 When the screw speed is constant, the larger the ring width between the inner diameter of the die and the core diameter, the thicker the silicone tube wall will be. The outer diameter of the silicone tube has no direct relationship with the ring width, but is affected by the combined effect of the size of the die and core, the ring width, and the screw speed.

[0252] When using the same mold, the greater the screw speed, the larger the outer diameter of the silicone. This is because when the screw speed is higher, the speed of silicone tube extrusion is higher, and the stretching effect of the conveyor belt on the silicone tube is smaller, so the outer diameter is larger. When the screw speed is lower, the speed of silicone tube extrusion is lower, the stretching effect of the conveyor belt on the silicone tube is greater, and the outer diameter of the silicone tube is smaller.

[0253] In summary, the outer diameter of the silicone tube is greatly affected by the screw speed. By using molds of different sizes and matching the corresponding screw speeds, silicone tubes with different outer diameters can be prepared, laying the foundation for the subsequent preparation of implants of different specifications and their drug release research.

[0254] 2. Improved gestodene storage skeleton implant

[0255] 2.1 Preparation method of implant

[0256] (1) Silicone tube preparation method A silicone tube is prepared according to steps (1) to (6) of the preparation method in 1.1;

[0257] (2) Basic formula and preparation process of drug core: gestodene, particle size is 2-3 μm, added amount is 100 PHR; methyl vinyl polysiloxane, vinyl content range is 0.18% to 0.23%; hydrogen-containing silicone oil, Si-H content is 0.75%, added amount range is 0.3 to 5.0 PHR; platinum catalyst, platinum concentration is 10000 ppm, added amount range is 0.000002 to 0.5 PHR; 2-methyl-3-butyn-2-ol is an inhibitor, added amount range is 0.03 to 2.0 PHR;

[0258] The vulcanization temperature is 90°C; the vulcanization time is 1h; the diameter of the core is 0.2cm and the length is 1.5cm.

[0259] (3) Soak the silicone tube in petroleum ether for 1-2 minutes, quickly shake off the petroleum ether remaining on the surface of the silicone tube by hand, and immediately insert the cut drug core into the middle position of the silicone tube with tweezers, so that the same length of space is reserved at both ends of the silicone tube for sealing. After assembly, the implant is naturally air-dried for 12-24 hours to evaporate the residual petroleum ether, and then the two ends of the naturally air-dried implant are sealed with sealing glue and left at room temperature for 12-24 hours to solidify the sealing glue, thereby obtaining a modified gestodene reservoir skeleton implant.

[0260] 2.2 Effect of preparation process or prescription on silicone tube performance

[0261] (1) The effects of the vinyl content in methylvinylpolysiloxane, the amount of reinforcing agent, the molar ratio of Si-H in hydrogenated silicone oil to the vinyl in methylvinylpolysiloxane, and the wall thickness of the silicone tube on the in vitro release of the silicone tube.

[0262] A. Prescription: The concentration of the platinum catalyst is 10000 ppm; the dosage of the platinum catalyst is 0.01 PHR; the dosage of the inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR. Other prescription parameters are shown in Table 1.

[0263] Table 4

[0264] serial number Vinyl Content Hydrophilic fumed silica A380 dosage Molar ratio of hydrogen silicone oil Silicone tube wall thickness / mm Example 8-1 0.18％ 30PHR 1.5:1 0.2 Example 8-2 0.18％ 30PHR 1.5:1 0.3 Example 8-3 0.18％ 30PHR 1.5:1 0.4 Example 9-1 0.18％ 20PHR 1.5:1 0.2 Example 9-2 0.18％ 40PHR 1.5:1 0.2 Example 10 0.23％ 30PHR 1.5:1 0.2 Example 11-1 0.18％ 30PHR 1.2:1 0.2 Example 11-2 0.18％ 30PHR 1.8:1 0.2

[0265] B. It adopts the preparation method as described in 2.1, and the specific process parameters are: the temperature of the first vulcanization treatment is 250°C; the time of the first vulcanization treatment is 3s; the temperature of the second vulcanization treatment is 240°C; the time of the second vulcanization treatment is 4min; the diameter of the fixed core is 0.2cm and the length is 1.5cm, and the outer diameter of the fixed silicone tube is 2.4mm and the length is 1.9cm.

[0266] 3. Improved paliperidone reservoir implant

[0267] 3.1 Preparation of implants

[0268] A silicone tube is prepared according to steps (1) to (6) of the preparation method in 1.1, and then a paliperidone reservoir implant is prepared through the following step (7);

[0269] (7) Preparation of paliperidone reservoir implant: seal one end with KN-300N adhesive and fill the implant with drug through a drug filling funnel after curing for 24 hours. After filling, seal the other end with KN-300N adhesive and cure for 24 hours. After curing, check for drug leakage. After confirming that there is no leakage, wash repeatedly with anhydrous ethanol for 30 seconds. The preparation is complete to obtain a modified paliperidone reservoir implant.

[0270] 3.2 Effects of the dosage of hydroxyapatite, vinyl content of methylvinylpolysiloxane, and the dosage of hydrogenated silicone oil on the in vitro drug release

[0271] A. Prescription: The amount of paliperidone added is 100 PHR; the amount of HB-615 hydrophobic fumed silica is 20 PHR; the concentration of the platinum catalyst is 3000 ppm; the amount of the platinum catalyst is 0.21 PHR; the amount of the inhibitor 2-methyl-3-butyn-2-ol is 0.98 PHR. Other prescription parameters are shown in Table 5.

[0272] Table 5

[0273] serial number Vinyl Content Hydroxyapatite Molar ratio of hydrogen silicone oil Example 12-1 0.18％ 20PHR 1.2:1 Example 12-2 0.18％ 30PHR 1.2:1 Example 12-3 0.18％ 40PHR 1.2:1 Embodiment 13 0.23％ 20PHR 1.2:1 Example 14-1 0.18％ 20PHR 1.5:1 Example 14-2 0.18％ 20PHR 1.8:1

[0274] B. Preparation method: The preparation method described in 2.1 is adopted, and the specific process parameters are: the temperature of the first vulcanization treatment is 250℃; the time of the first vulcanization treatment is 5s; the temperature of the second vulcanization treatment is 240℃; the time of the second vulcanization treatment is 2min; the wall thickness of the prepared implant is 0.2mm; the outer diameter is 2.2-2.3mm; the drug release area is 2.7±0.5cm 2 .

[0275] 4. Improved estradiol reservoir implant

[0276] 4.1 Preparation of implants

[0277] Same as the implant preparation method described in 3.1

[0278] 4.2 Effects of curing temperature, silicone tube wall thickness and drug release area on in vitro release of implants

[0279] A. Prescription: As shown in the following table:

[0280] Table 6

[0281] Material Name Dosage Methyl vinyl polysiloxane 100PHR Vinyl Content of Methyl Vinyl Polysiloxane 0.17％ Hydrophilic fumed silica N20 20PHR Hydrophobic fumed silica R106 20PHR Molar ratio of Si-H groups in hydrogen silicone oil to vinyl groups in methylvinyl polysiloxane 1.2:1 The content of Si-H groups in hydrogen silicone oil 0.75％ 2-Methyl-3-butyn-2-ol 0.7PHR Platinum catalyst (3000ppm) 0.00001PHR

[0282] B. Preparation process: The first vulcanization treatment time is 5s; the second vulcanization treatment time is 2min; the third vulcanization treatment time is 48h; other parameters are shown in the table below:

[0283] Table 7

[0284] serial number First vulcanization temperature / ℃ Second vulcanization temperature / ℃ The third vulcanization temperature / °C Example 17-1 250 220 180 Example 17-2 250 240 180 Example 17-3 250 260 180

[0285] Table 8

[0286] serial number Silicone tube outer diameter / mm Silicone tube wall thickness / mm Length containing medicine / cm Example 18-1 2.2 0.2 4 Example 18-2 2.2 0.4 4 Example 18-3 2.2 0.6 4

[0287] Table 9

[0288] serial number Silicone tube outer diameter / mm Silicone tube wall thickness / mm <![CDATA[Drug release area / cm 2 > Example 19-1 2.2 0.2 0.69 Example 19-2 2.2 0.2 1.38 Example 19-3 2.2 0.2 2.07 Example 19-4 2.2 0.2 2.76 Example 19-5 2.2 0.2 3.45

[0289] Comparative Example 1 Gestodene Depot Frame Implant

[0290] A. Prescription: Compared with the prescription of the modified gestodene skeleton implant, the difference is that the reinforcing agent is only HB-615 hydrophobic fumed silica.

[0291] B. Preparation process: The preparation method is the same as described in 2.1.

[0292] Comparative Example 2 Paliperidone Depot Implant

[0293] A. Formulation: Compared with the formulation of the modified paliperidone reservoir implant, the difference is that the reinforcing agent is only HB-615 hydrophobic fumed silica and does not contain hydroxyapatite.

[0294] B. Preparation process: The preparation method is the same as described in 3.1.

[0295] Comparative Example 3 Estradiol Depot Implant

[0296] A. Prescription: Compared with the prescription of the modified estradiol reservoir implant, the difference is that the reinforcing agent is only hydrophobic fumed silica R106, and does not contain N20 hydrophilic silica.

[0297] B. Preparation process: The preparation method is the same as described in 4.1.

[0298] Effect Example

[0299] The mechanical properties and in vitro release properties of the embodiments of the present invention and the comparative examples were studied.

[0300] 1. Mechanical properties

[0301] Subcutaneous implants should meet the national standard GB / T528 (ISO37) "Determination of tensile stress-strain properties of vulcanized rubber or thermoplastic rubber" to have good mechanical properties to ensure that the shape can be maintained unchanged during implantation and removal.

[0302] 1. Elongation at break (%): The elongation of the sample at break.

[0303] 2. Tensile strength (MPa) refers to the maximum tensile stress that the sample is subjected to when stretched to fracture during the tensile test.

[0304] 3. Tear strength (KN·m -1 )The strength required for the sample to be torn.

[0305] Specific test method: Prepare samples of about 5 cm in length, prepare three copies of each sample in parallel, use a tensile tester to test the samples, set the test parameters to a clamping distance of 50 mm and a tensile speed of 200 mm min -1 , wait for the sample test to be completed and record the data.

[0306] Table 10

[0307] Elongation at break / % Tensile strength / MPa <![CDATA[Tear strength / KN·m -1 > Example 1-1 131.0 2.54 16.90 Example 1-2 163.7 3.06 23.17 Example 2-1 151.5 1.79 10.98 Example 2-2 185.6 2.25 13.74 Example 2-3 194.8 2.68 13.80 Embodiment 2-4 167.9 2.03 9.96 Example 3-1 211.7 3.87 26.55 Example 3-2 210.8 3.79 26.07 Example 4-1 187.4 3.19 23.94 Example 4-2 223.7 3.75 27.87 Example 4-3 148.7 2.88 19.56 Example 4-4 100.9 1.97 11.33

[0308] According to the effect data of Examples 1-1 and 1-2, it can be seen that when the vinyl content is 0.18% and 0.23%, the elongation at break, tensile strength, and tear strength of the vulcanized silicone tube are not much different overall, and both show good mechanical properties. It shows that the vinyl content of the above two is within a suitable range. After the addition reaction, the cross-linked chain lengths in the network structure are appropriate, and the cross-linking points are distributed in an orderly manner. Therefore, the prepared silicone tube has good elasticity, certain tensile and tear resistance, and meets the requirements for the preparation of implants and clinical applications.

[0309] It can be seen from the effect data of Examples 2-1 to 2-4 that when the amount of hydrophilic silica is within the range of 30-50 PHR, the mechanical properties of the silicone tube after vulcanization are good.

[0310] According to the effect data of Examples 2-1, 3-1 and 3-2, it can be seen that when the molar ratio of Si-H in hydrogen-containing silicone oil to vinyl in methylvinyl polysiloxane increases from 1.2:1 to 1.5:1, the tensile strength and tear strength of the silicone tube are enhanced. When the molar ratio increases from 1.5 to 1.8, the overall difference in the elongation at break, tensile strength and tear strength of the silicone tube after vulcanization is not large, and the mechanical properties of the silicone tube are good. When the addition reaction occurs, the hydrogen of the hydrogen-containing silicone oil and the vinyl in the methylvinyl polysiloxane theoretically participate in the reaction at a molar ratio of 1:1. However, in the actual reaction, Si-H will be lost due to side reactions, so it is usually necessary to make the hydrogen-containing silicone oil slightly excessive, so that the addition reaction can be fully carried out, the cross-linking is getting closer and closer to complete, and the mechanical properties of the silicone tube reach the best state.

[0311] According to the effect data of Examples 4-1 to 4-4, it can be seen that with the increase of the second vulcanization temperature, the elongation at break, tensile strength and tear strength of the silicone tube after vulcanization show a trend of first increasing and then decreasing. When the second vulcanization temperature is 240°C, the values ​​of various indicators reach the maximum. The second vulcanization treatment is mainly to allow the silicone tube to continue to vulcanize and the cross-linking reaction to continue. The appropriate temperature can make the cross-linking reaction complete and the mechanical indicators better. However, too high a temperature will cause the silicone tube to be over-vulcanized and the internal cross-linking bonds to undergo thermal cracking, resulting in performance degradation.

[0312] 2. In vitro release effect

[0313] 1. In vitro release characterization of the modified gestodene reservoir skeleton implant

[0314] 1.1 Test Method

[0315] (1) Chromatographic conditions

[0316] Chromatographic column: C18 column (4.6 mm × 250 mm, 5 μm);

[0317] Mobile phase: methanol: water (80:20, v / v);

[0318] Column temperature: 30°C;

[0319] Detection wavelength: 239nm;

[0320] Flow rate: 1.0 mL min-1;

[0321] Injection volume: 20 μL

[0322] (2) In vitro release test method

[0323] The release experiment adopts the horizontal oscillation method. Take one implant and fix the two ends of the implant to the bottom and wall of a 50mL stoppered conical flask with a silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it for 12 hours to allow the silicone adhesive to cure completely. Accurately measure 50mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it. The temperature is set to 37℃ and the amplitude is 100r·min-1. Replace the same volume of medium every 24 hours. The release liquid is filtered with a 0.22μm microporous filter membrane and detected according to chromatographic conditions. The injection volume is 20μL.

[0324] 1.2 Effect data

[0325] (1) 30-day in vitro release effect data

[0326] Examples 8-1 to 8-3 are implants with different silicone tube wall thicknesses, and their in vitro release effect data are as follows: Figure 1 As shown in the figure, it can be seen that the thicker the silicone tube wall thickness, the lower the daily drug release of the implant. The average daily drug release of the implant with a silicone tube wall thickness of 0.2 mm is about 55 μg in 30 days; the average daily drug release of the implant with a wall thickness of 0.3 mm is about 48 μg in 30 days; the average daily drug release of the implant with a wall thickness of 0.4 mm is about 42 μg in 30 days. That is, for every 0.1 mm increase in the thickness of the silicone tube, its average daily drug release decreases by about 5-8 μg. From the above data, it can be seen that when the outer diameter and length of the silicone tube, the diameter and length of the drug core are fixed, the wall thickness of the silicone tube can slightly affect the in vitro release of the implant. In the actual preparation process of the implant, when the outer diameter of the silicone tube remains unchanged, the thicker the wall thickness, the smaller the inner diameter, and the more difficult it is to assemble the drug core and the silicone tube, while the inner diameter of the silicone tube with a wall thickness of 0.2 mm is relatively large, and it cooperates better with the drug core.

[0327] Examples 8-1, 9-1 and 9-2 are different dosages of hydrophilic white carbon black, and their in vitro release effect data are as follows: Figure 2 As shown in the figure, it can be seen that the amount of hydrophilic silica has a slight effect on the release of the implant. With the increase of the amount of hydrophilic silica, the average daily release of the implant in 30 days increases slightly. When the amount of hydrophilic silica is 40PHR, the daily release is high, about 55μg. Figure 5 It can be seen that the drug release curve in the 1-15d time period is significantly higher than that of 30PHR and 20PHR. The average daily drug release of hydrophilic silica dosages of 30PHR and 20PHR is not much different, both around 48μg, and the fluctuations of the two drug release curves are smaller than that of 40PHR, and the drug release stability is better. In addition, during the silicone tube extrusion process, the extrusion stability and smoothness are better when the amount of fumed silica is 30PHR.

[0328] Examples 8-1 and 10 are implants with different vinyl contents. The in vitro release effect data are as follows: Figure 3 As shown, it can be seen that the vinyl content of the silicone tube has little effect on the release of the implant. The average daily release of the two groups of implants within 30 days is between 47-50μg. Methyl vinyl polysiloxane with a vinyl content of 0.18% is more in line with the requirements of mechanical properties and cost.

[0329] The in vitro release effect data of the implants of Examples 8-1, 11-1 and 11-2 with different amounts of hydrogenated silicone oil are as follows Figure 4 As shown, it can be seen that when the molar ratio of hydrogenated silicone oil is 1.2 and 1.8, the release amount of the implant in the first 3 days is relatively high, there is an early burst release phenomenon, and the overall release curve fluctuates greatly, while the release curve when the molar ratio is 1.5 fluctuates relatively little. It can be seen that the release curve when the molar ratio is 1.5 is already relatively stable and the mechanical indicators of the silicone tube shown in previous studies are also good.

[0330] (3) In vitro release experiment

[0331] The implants of Example 8-1 and Comparative Example 1 were subjected to a 150-day long-term in vitro release experiment. The results are shown in Tables 11 and 12, respectively.

[0332] Table 11

[0333]

[0334] Table 12

[0335]

[0336]

[0337] Figure 5 This is a data chart showing the 150-day in vitro release effect of the improved gestodene reservoir skeleton implant prepared in Example 8-1. Figure 6 This is a data chart of the 150-day in vitro release effect of the gestodene reservoir skeleton implant prepared in Comparative Example 1. Figure 7 This is a comparison chart of the in vitro release effect data of Example 8-1 and Comparative Example 1. Figure 5 , Figure 6 and Figure 7 It can be seen that under the premise of meeting the mechanical properties of the implant, compared with hydrophobic silica, hydrophilic silica increases the release of silicone tubes by 18-23μg, indicating that the release of the implant meets the requirements and has good drug release stability, and can achieve stable drug release for at least 5 months. And compared with the gestodene skeleton reservoir implant, the in vitro release of the improved gestodene skeleton reservoir implant can be increased by 192%.

[0338] 2. In vitro release characterization of the modified paliperidone reservoir implant

[0339] 2.1 Test Method

[0340] (1) Chromatographic conditions

[0341] Column: InfinityLab Poroshell HPH-C8 (4.6×100mm, 2.7μm)

[0342] Mobile phase: methanol: acetonitrile: phosphate 1:4:15 isocratic elution

[0343] Flow rate: 1mL / min

[0344] Column temperature: 35°C

[0345] Injection volume: 20 μL

[0346] Detection wavelength: 280nm

[0347] (2) In vitro release test method

[0348] Take a modified paliperidone reservoir implant and fix it in a 20mL sample bottle with a silicone adhesive; accurately measure an appropriate amount of distilled water into the sample bottle so that the preparation is always below the liquid surface of the release medium, and place it in a constant temperature oscillator with an amplitude of 100r·min-1 and a temperature of 37°C for release. Take samples every 24 hours, replace the release medium, and filter the solution through a 0.22μm filter membrane before keeping the sample for testing.

[0349] 2.2 Effect data

[0350] (1) 30-day in vitro release effect data

[0351] Examples 12-1 to 12-3 are implants prepared with different amounts of hydroxyapatite, and their in vitro release effect data are as follows: Figure 8 As shown, the in vitro release of the silicone tube after vulcanization increased with the increase of hydroxyapatite dosage.

[0352] Example 12-1 and Example 13 studied the effect of the vinyl content of methylvinylpolysiloxane on the in vitro release of silicone tubes. The effect data are as follows: Fig. 9 It can be seen that the vinyl content in the silicone tube has little effect on the release of the implant. The daily release of the two groups of implants within 30 days is between 20-25μg, and the difference between the two is not large. However, when the raw rubber vinyl content of the silicone tube is 0.18%, the overall release curve of the implant is more stable.

[0353] Examples 12-1, 14-1 and 14-2 studied the effect of the molar ratio of hydrogen-containing silicone oil on the in vitro release of silicone tubes. The effect data are as follows: Fig.10 As shown, it can be seen that the release curves of the implants are not much different when the molar ratio of hydrogenated silicone oil is different, because when the addition reaction occurs, the hydrogen of hydrogenated silicone oil and the vinyl group in methyl vinyl polysiloxane theoretically participate in the reaction at a molar ratio of 1:1. However, in the actual reaction, Si-H will be lost due to side reactions, so it is usually necessary to make the hydrogenated silicone oil slightly excessive so that the addition reaction can proceed fully and the cross-linking is getting closer and closer to complete.

[0354] (2) Long-term in vitro release results data

[0355] At 37°C, shaking speed 100 r / min -1 The long-term in vitro release test of Example 14-1 and Comparative Example 2 was carried out under the following conditions. The long-term in vitro release results of Example X are shown in Table 13. The long-term in vitro release results of Comparative Example 2 are shown in Table 14.

[0356] Table 13

[0357]

[0358] Table 14

[0359]

[0360] Fig.11 This is a data graph of the in vitro release effect of the improved paliperidone reservoir implant prepared in Example 14-1. Fig.12 This is a data chart of the in vitro release effect of the paliperidone reservoir implant prepared in Comparative Example 2. Fig.13 The in vitro release effect data comparison diagram of Example 14-1 and Comparative Example 2. According to the effect data in the above table, the in vitro release study of the improved paliperidone reservoir implant prepared by the silicone tube provided by the present invention shows that the drug release is stable within 150 days, and compared with the paliperidone reservoir implant, the in vitro release amount of the improved paliperidone reservoir implant is increased by 260%.

[0361] 3. In vitro release characterization of the modified estradiol reservoir implant

[0362] 3.1 Test Method

[0363] (1) Take one modified estradiol reservoir implant, split the silicone tube, cut the drug core into several small pieces, place it in a 100mL volumetric flask, add 10mL of methanol to soak, let it stand for 3 hours, dilute to the mark with anhydrous ethanol, shake well and filter, accurately measure 0.2mL of the filtrate and place it in a 50mL volumetric flask, dilute to the mark with the mobile phase, shake well, inject into HPLC, inject 20μL, calculate according to the standard curve, and obtain the drug content. The chromatographic conditions are as follows:

[0364] Chromatographic conditions

[0365] Chromatographic column: C18 column (250mm×4mm, 5μm)

[0366] Mobile phase: acetonitrile-water (55:45, v / v)

[0367] Column temperature: 25°C

[0368] Detection wavelength: 202nm

[0369] Flow rate: 0.8 mL min-1

[0370] Injection volume: 20 μL

[0371] (2) Release determination method

[0372] The release rate was determined by the horizontal oscillation method: take one modified estradiol reservoir implant and fix it in a 100 mL stoppered conical bottle with an adhesive. Accurately measure 100 mL of distilled water as the release medium. Place the stoppered conical bottle in a constant temperature oscillator and set the amplitude to 100 r·min. -1 , temperature 37°C, ensure that the implant is always below the liquid surface, sample every 24 hours and replace the release medium with an equal volume, the sample solution is filtered through a 0.22 μm microporous filter membrane and injected according to the content determination method (1), and the drug release amount is calculated based on the standard curve.

[0373] 3.2 Effect data

[0374] 3.2.1 Effect of curing conditions on in vitro release

[0375] Table 15

[0376]

[0377]

[0378] Fig.14 The in vitro release data of the modified estradiol reservoir implant prepared at different vulcanization temperatures are shown in the table above. Fig.14 It shows that the change of the vulcanization temperature of the silicone tube has little effect on the average daily drug release of the implant and the fluctuation is not large. Therefore, silicone tubes with better mechanical properties are selected for the preparation of implants, that is, the vulcanization conditions are the first vulcanization treatment temperature of 250°C and the second vulcanization treatment temperature of 240°C.

[0379] 3.3.2 Silicone tube wall thickness

[0380] Table 16

[0381]

[0382]

[0383] Fig.15 The in vitro release data of modified estradiol reservoir implants with different wall thicknesses are shown in Figure 2. The results show that when the outer diameter and release area are kept constant, the in vitro release of modified estradiol reservoir implants prepared from three silicone tubes with different wall thicknesses gradually decreases with the increase of wall thickness. In order to ensure the drug release, the wall thickness should be reduced as much as possible. However, in actual operation, a silicone tube with a wall thickness of 0.2 mm is already the limit. If the wall thickness is reduced further, it is difficult to ensure the smooth extrusion of the silicone tube. Therefore, it is recommended to use a silicone tube with a wall thickness of 0.2 mm.

[0384] 3.3.3 Investigation of the drug release area of ​​silicone tube

[0385] The effect of the length of the drug core in the silicone tube on the in vitro release is shown in the following table.

[0386] Table 17

[0387] <![CDATA[Drug release area (cm 2 )]]> <![CDATA[Average daily release dose (μg·d -1 )]]> 0.69 6.63±0.42 1.38 12.67±1.18 2.07 19.37±2.08 2.76 25.68±1.79 3.45 32.02±2.78

[0388] The results showed that the daily drug release of the modified estradiol reservoir implant increased with the increase of the release area. In practical applications, due to the large individual differences among patients, different specifications of modified estradiol reservoir implants can be produced during production to achieve personalized drug delivery according to different needs, reduce side effects, and achieve maximum benefits.

[0389] 3.4 Long-term in vitro release experiment of estradiol reservoir implant

[0390] The estradiol reservoir implant prepared in Example 17-2 and Comparative Example 3 was placed at a temperature of 37°C and a shaking speed of 100 r·min. -1 Long-term in vitro release experiments were carried out under the following conditions, and the results are shown in the figure below the table.

[0391] Table 18

[0392]

[0393]

[0394] The above table and Fig.16 The results showed that the average daily in vitro drug release of the implant prepared with hydrophilic silica was stable in the range of 20-35 μg, with good stability.

[0395] Table 19

[0396]

[0397] The above table and Fig.17The results showed that the average daily release of estradiol reservoir implant was about 12 μg, with a burst release in the early stage and a stable release in the later stage.

[0398] The in vitro release of the modified estradiol reservoir implant was compared with that of the estradiol reservoir implant. Fig.18 The results showed that, under the premise of meeting the mechanical properties of the implant, the in vitro release of the improved estradiol implant was increased by 245% compared with that of hydrophobic silica, and the problem of sudden release of the original estradiol reservoir implant was improved.

Claims

1. A raw material composition of silica gel material, characterized in that: In parts by weight, it comprises the following components: R-vinyl polysiloxane: 100 parts; Reinforcing agent: 10-80 parts; Catalyst: 0.000002-1 part; Wherein, R in the R-vinyl polysiloxane is a substituted or unsubstituted C1-C5 straight chain alkane or branched chain alkane, a substituted or unsubstituted C6-C 20 Aromatics; The content of vinyl in the R-vinyl polysiloxane is 0.1 mol%-0.5 mol%; The reinforcing agent contains a hydrophilic group in its components; The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%; The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl polysiloxane is (0.5-10):1; Optionally, an inhibitor is also included, and the inhibitor is a substance that can inhibit the addition reaction between the R-vinyl polysiloxane and the hydrogen-containing silicone oil.

2. The raw material composition of silica gel material according to claim 1, characterized in that: The raw material composition of the silica gel material satisfies one or more of the following conditions am: a. R in the R-vinyl polysiloxane is a substituted or unsubstituted C1-C5 straight chain alkane, such as a methyl group; b. The vinyl content of the R-vinyl polysiloxane is 0.15 mol% to 0.3 mol%, for example 0.18 mol% or 0.23 mol%; c. The weight proportion of the reinforcing agent is 20-70 parts, for example 30 parts, 40 parts, 45 parts or 50 parts; d. The water contact angle of the reinforcing agent is ≤90°, for example 14-90°, 16-35° or ≤25°; e. the hydrophilic group is selected from one or more of hydroxyl, thiol, aldehyde, ketone, ether bond, block polyether, carboxylic acid, carboxylate, sulfate, sulfone, sulfinic acid, sulfonic acid, sulfonamide, sulfonate, thioether, phosphoric acid, phosphoramide, phosphorimide, phosphate, phosphite, phosphine, amino, imino, tertiary amine, quaternary ammonium, nitrile, cyanate, thiocyanate, amide and other oxygen-containing groups capable of forming hydrogen bonds with water molecules; f. The reinforcing agent is one or more of white carbon black, hydroxyapatite, diatomaceous earth, quartz powder, silica powder, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, titanium dioxide, clay, lignin, carbonate and kaolin; the white carbon black is preferably hydrophilic white carbon black or a mixture of "hydrophilic white carbon black and hydrophobic white carbon black"; the hydrophilic white carbon black is preferably hydrophilic fumed white carbon black, such as hydrophilic fumed white carbon black N20, hydrophilic fumed white carbon black TH-a200, hydrophilic fumed white carbon black A380, hydrophilic fumed white carbon black A300, T30 hydrophilic fumed white carbon black, T40 hydrophilic fumed white carbon black and V15 hydrophilic fumed white carbon black. g. The amount of the hydrogen-containing silicone oil is 0.3-5 parts, preferably 0.3-3 parts, for example 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts or 1.70 parts; h. The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl polysiloxane is (0.5-8):1, preferably (0.8-3):1, for example 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1 or 3:1; i. The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%, preferably 0.15-1.2 mol%, for example 0.75 mol%; j. The catalyst is a platinum catalyst; wherein the concentration of platinum in the platinum catalyst is preferably 1×10 3 -1×10 5 ppm, for example 1×10 3 ppm, 1×10 4 ppm, ppm refers to the mass concentration of platinum in the platinum catalyst as one part per million; k. The amount of the catalyst is 0.00001-0.5 parts, for example 0.00001 parts, 0.0098 parts or 0.21 parts; l. The inhibitor is an alkynol compound, a nitrogen-containing compound or an organic peroxide, such as methyl butynol, and another example is 2-methyl-3-butyn-2-ol; m. The weight proportion of the inhibitor is 0.03-2.0 parts, for example 0.69 parts.

3. The raw material composition of silica gel material according to claim 1, characterized in that: The raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.18 mol%; 30 parts of hydrophilic white carbon black; 1.33 parts of hydrogenated silicone oil; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.5:1; 0.0098 parts of platinum catalyst (concentration is 3000 ppm); 0.69 parts of 2-methyl-3-butyn-2-ol; Or, the raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.18 mol%; 30 parts of hydrophilic white carbon black; 1.33 parts of hydrogenated silicone oil; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.5:1; 0.01 parts of platinum catalyst (concentration is 3000 ppm); 0.69 parts of 2-methyl-3-butyn-2-ol; Or, the raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.18 mol%; 20 parts of hydroxyapatite; 20 parts of HB-615 hydrophobic fumed silica; 1.33 parts of hydrogenated silicone oil; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.5:1; 0.21 parts of platinum catalyst (concentration is 3000 ppm); 0.98 parts of 2-methyl-3-butyn-2-ol; Or, the raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.17 mol%; 20 parts of hydrophilic fumed silica N20; 20 parts of hydrophobic fumed silica R106; the Si-H content of hydrogenated silicone oil is 0.75%; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.2:1; Platinum catalyst: 0.00001 parts; 2-methyl-3-butyn-2-ol: 0.7 parts.

4. A method for preparing a silica gel material, characterized in that: It includes the following steps: S1. The R-vinyl polysiloxane and the reinforcing agent are mixed to obtain a mixture A; S2. The mixture A is divided into component A1 and component A2, the component A1 is mixed with hydrogen-containing silicone oil to obtain component B1, and the component A2 is mixed with a catalyst to obtain component B2; optionally, the component B1 further includes an inhibitor; S3. The component B1 and the component B2 are mixed to obtain a mixture B, and catalytic addition is performed to obtain the silica gel material.

5. The method for preparing the silica gel material according to claim 4, characterized in that: The preparation method of the silica gel material meets one or more of the following conditions: ① The reinforcing agent is pretreated, and the pretreatment method is drying at 90-220°C for 1-24h; for example, drying at 130°C for 24h; ② The R-vinyl polysiloxane is pretreated by drying at 20-90° C. for 1-24 hours; for example, drying at 40° C. for 12 hours; ③ In step S1, the mixing step is to add the reinforcing agent into the R-vinyl polysiloxane in small amounts and multiple times for kneading, and then to thin through by extrusion; ④ In step S2, the preparation method of component B1 is to re-refine component A1 in an open mill with a roller distance parameter of 1 unit, and add the hydrogen-containing silicone oil and the inhibitor dropwise, set different roller distances after addition, perform triangular packaging, thin pass, take out and park for 24 hours; ⑤ In step S2, the preparation method of component B2 is to re-refine component A2 in an open mill with a roller distance parameter of 1 unit, and add the catalyst dropwise, continuously shorten the roller distance, perform thin pass, and take out and park for 24 hours; ⑥ In step S3, the mass ratio of the component B1 to the component B2 in the mixture B is 1:1; ⑦ In step S3, the preparation method of the mixture B is to place component B1 and component B2 in an open mill for mixed extrusion, and perform thin passes 6 times to obtain; ⑧ In step S3, the catalytic addition step is to subject the mixture B to a first vulcanization treatment and a second vulcanization treatment in sequence, and preferably also includes a third vulcanization treatment; wherein the temperature of the first vulcanization treatment is preferably 200°C-340°C, for example, 250°C; the time of the first vulcanization treatment is preferably 2s-30s; wherein the first vulcanization treatment is preferably carried out in a vertical hot air vulcanization channel; the temperature of the second vulcanization treatment is preferably 180°C-280°C, for example, 220°C, 240°C, 260°C or 280°C; the time of the second vulcanization treatment is preferably 0.1min-5min; the second vulcanization treatment is preferably carried out in a horizontal hot air vulcanization channel; the temperature of the third vulcanization treatment is preferably 150°C-240°C, for example, 180°C.

6. A silica gel material, characterized in that: It is prepared by the preparation method as claimed in claim 4 or 5.

7. A method for preparing a silicone tube, characterized in that: The mixture B as claimed in claim 4 or 5 is formed into a tube by extrusion process, and then catalytic addition is performed to obtain the silicone tube; Alternatively, the aforementioned catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

8. A silicone tube, characterized in that: It is prepared by the preparation method as claimed in claim 7.

9. An implant, characterized in that: It comprises a medicine core and the silicone tube as claimed in claim 8, wherein the medicine core contains active pharmaceutical ingredients.

10. Use of the silica gel material according to claim 6 or the silica gel tube according to claim 8 as a release rate regulating medium in a sustained-release preparation.

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