Silicone material and method for its production, silicone tube and implant and method for its production, use

Abstract

This invention discloses silicone materials and their preparation methods, silicone tubes and implantation agents and their preparation methods, and applications. The silicone material, by weight, 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, or a substituted or unsubstituted C6-C5... 20 The invention comprises: aromatic hydrocarbons; the vinyl content in the R-vinyl polysiloxane is 0.1 mol%-0.5 mol%; the reinforcing agent contains hydrophilic groups; the Si-H group content in the hydrogen-containing silicone oil is 0.18 mol%-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, it also includes inhibitors. The silicone material provided by this invention, while satisfying mechanical properties, increases the permeability of water to the silicone tube, thereby increasing the drug release and overcoming the deficiency of low in vitro release in the prior art.

Description

Technical Field

[0001] This invention relates to silicone materials and their preparation methods, silicone tubes and implantation agents and their preparation methods and applications. Background Technology

[0002] Silicone subdermal implants involve filling a silicone tube with medication and implanting it under the skin. Water permeates into the silicone tube to form a drug solution, which is then stably released through the tube, achieving a long-term effect. Currently available on the market is a levonorgestrel implant, which provides long-term contraception. This formulation avoids the first-pass effect of the gastrointestinal tract, thus significantly improving drug bioavailability.

[0003] Existing silicone subdermal implants primarily use methyl vinyl polysiloxane and hydrophobic fumed silica as base materials. Hydrophobic fumed silica offers good reinforcing properties, and the resulting silicone tubes generally meet the mechanical requirements for implantation. However, its low water permeability, being a hydrophobic substance, prevents water from effectively permeating the silicone tube to dissolve the medication, resulting in a lower drug release rate. This limits its clinical application and cannot support high-dose, effective medications. Summary of the Invention

[0004] This invention aims to overcome the limitation of existing silicone materials in simultaneously achieving both mechanical properties and water permeability. It provides silicone materials, their preparation methods, silicone tubes, and implantation agents, along with their preparation methods and applications. The silicone material provided by this invention increases water permeability to the silicone tube while satisfying mechanical properties, thereby improving drug release and overcoming the low in vitro release rate of existing technologies.

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

[0006] This invention provides a raw material composition for silicone material, comprising 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 a substituted or unsubstituted C1-C5 straight-chain alkane or branched-chain alkane, or a substituted or unsubstituted C6-C5 alkane. 20 Aromatic hydrocarbons;

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

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

[0013] The Si-H group content in the hydrogen-containing silicone oil is 0.18 mol%-1.6 mol%.

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

[0015] Optionally, it may also include an inhibitor, which is a substance capable of inhibiting the addition reaction between the R-vinyl polysiloxane and the hydrogen-containing silicone oil.

[0016] In this invention, R in the R-vinyl polysiloxane can be a substituted or unsubstituted C1-C5 straight-chain alkane, such as methyl.

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

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

[0019]

[0020] Where m, n, and p are natural numbers, R1 and R2 can be conventional substituents in the art, and R and R' can be conventional end-capping groups in the art.

[0021] For example, when R1 = R2 = CH3, it corresponds to dimethylpolysiloxane;

[0022] For example, when R1 = CH3 and R2 = CH = CH2, it corresponds to methyl vinyl polysiloxane;

[0023] For example, when R1 = Ph and R2 = CH = CH2, it corresponds to methylphenyl vinyl polysiloxane;

[0024] For example, when R1 = CH3CH2CF3 and R2 = CH = CH2, it corresponds to fluorosilicone polysiloxane;

[0025] For example, when R1 = CH3CH2CN and R2 = CH = CH2, it corresponds to nitrile polysiloxane.

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

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

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

[0029] In this invention, the reinforcing agent can be 20-70 parts by weight, for example 30 parts, 40 parts, 45 parts or 50 parts.

[0030] In this invention, the water contact angle of the reinforcing agent can be ≤90°, for example, 14-90°, 16-35°, or ≤25°. The water contact angle in this invention is the static water contact angle of the material, which is measured using the principle of optical projection. During the process, the water droplet volume is set using testing software, and the syringe needle drops the set volume of water onto the surface of the sample to be tested. Under an LED light source background, a micrometer on a screen projects the image of the droplet onto an automatic image analysis system for measurement. In this invention, the hydrophilic group can be a group of atoms that are conventionally soluble in water or readily affinity for water. For example, one or more of the following groups: hydroxyl, mercapto, aldehyde, ketone, ether, block polyether, carboxylic acid, carboxylic acid ester, sulfate, sulfone, sulfinic acid, sulfonic acid, sulfonamide, sulfonate, thioether, phosphate, phosphoramide, phosphorimide, phosphate ester, phosphite, amino, imino, tertiary amine, quaternary ammonium, nitrile, cyanate, thiocyanate, amide, and other oxygen-containing groups that can form hydrogen bonds with water molecules.

[0031] The hydroxyl group can be an alcohol hydroxyl group or a phenolic hydroxyl group.

[0032] In this invention, the reinforcing agent may be one or more of the following: silica, hydroxyapatite, diatomaceous earth, quartz powder, silica fume, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, titanium dioxide, kaolin, lignin, carbonates, and kaolin. The reinforcing agent increases the water permeability of the silicone material while maintaining its mechanical properties.

[0033] Preferably, the silica is hydrophilic silica or a mixture of hydrophilic silica and hydrophobic silica.

[0034] The hydrophilic fumed silica is preferably a 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 polysiloxanes, hydrophilic fumed silica is a white, fluffy powder with active hydroxyl groups on its surface. These hydroxyl groups readily connect and adsorb with polysiloxanes through hydrogen bonds and van der Waals forces, indirectly increasing the cross-linking density between reactant molecules and thus achieving a reinforcing effect. However, compared to hydrophobic fumed silica, hydrophilic fumed silica is detrimental to the mechanical properties of silicone tubing. Since hydrophilic fumed silica has not undergone silanization, the silanol groups on its surface easily introduce moisture during the preparation process, leading to the formation of bubbles in the prepared silicone tubing, which affects the mechanical properties and drug release. This invention, by modifying the silicone material formulation and optimizing the preparation process, significantly improves the drug release capacity of the silicone material while satisfying the mechanical properties of the silicone tubing.

[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 this 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 this invention can act as a crosslinking agent to undergo a crosslinking reaction with R-vinyl polysiloxane. Through the addition reaction between the Si-H in the crosslinking agent and the -CH=CH2- of R-vinyl polysiloxane, the linear R-vinyl polysiloxane macromolecules are bonded and crosslinked to form a three-dimensional network structure.

[0038] In this invention, the mass of the hydrogen-containing silicone oil is calculated using 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 content in hydrogen-containing 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 group;

[0046] W1: Mass of R-vinyl polysiloxane.

[0047] In this invention, 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.

[0048] In this invention, the Si-H group content in the hydrogen-containing silicone oil can be 0.18-1.2 mol%, for example, 0.75 mol%.

[0049] In this invention, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in R-vinyl polysiloxane can 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 this invention, the catalyst can be a conventional catalyst in the art that can catalyze the addition reaction between methyl vinyl polysiloxane and hydrogen-containing silicone oil, such as a platinum catalyst.

[0051] The concentration of platinum in the platinum catalyst can be 1×10⁻⁶. 3 -1×10 5 ppm, for example 1×10 3 ppm, 1×10 4 ppm refers to the concentration of platinum in a platinum catalyst being one part per million.

[0052] In this invention, the amount of catalyst used is preferably 0.00001-0.5 parts, for example 0.00001 parts, 0.0098 parts or 0.21 parts.

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

[0054] In this invention, the inhibitor may be an alkynol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol, or 2-methyl-3-butyn-2-ol.

[0055] In this invention, the weight fraction of the inhibitor can be 0.03-2.0 parts, for example 0.69 parts or 0.7 parts.

[0056] In this invention, PHR refers to the number of mass parts of each specific component corresponding to 100 parts by mass of R-vinyl polysiloxane (e.g., methyl vinyl polysiloxane).

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

[0058]

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

[0060]

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

[0062]

[0063]

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

[0065] Methyl vinyl polysiloxane: 100 parts; the vinyl content in methyl vinyl polysiloxane is 0.18 mol%.

[0066] Hydrophilic silica: 30 parts;

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

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

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

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

[0071] Methyl vinyl polysiloxane: 100 parts; the vinyl content in methyl vinyl polysiloxane is 0.18 mol%.

[0072] Hydrophilic silica: 30 parts;

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

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

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

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

[0077] Methyl vinyl polysiloxane: 100 parts; the vinyl content in methyl vinyl polysiloxane is 0.18 mol%.

[0078] Hydroxyapatite: 20 parts;

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

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

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

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

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

[0084] Methyl vinyl polysiloxane: 100 parts; the vinyl content in methyl vinyl 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] This invention also provides a method for preparing a silicone material, which employs any of the following methods:

[0091] Method 1:

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

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

[0094] S3. Mix component B1 and component B2 to obtain mixture B, and then perform catalytic addition to obtain the silica gel material.

[0095] Method 2:

[0096] The silicone material is obtained by catalytic addition of the raw material composition; the raw material composition includes: R-vinyl polysiloxane, reinforcing agent, hydrogen-containing silicone oil and catalyst; optionally, it may also include inhibitor.

[0097] In this invention, the reinforcing agent can be pretreated using conventional methods in the art. The pretreatment method is preferably drying at 90-220°C (e.g., 130°C) for 1-24 hours (e.g., 24 hours) for later use; for example, the pretreatment method is drying at 130°C for 24 hours.

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

[0099] In step S1, the mixing step can be achieved by adding the reinforcing agent to the R-vinyl polysiloxane in small amounts multiple times for kneading, followed by extrusion through a thin tube.

[0100] In step S2, the preparation method of component B1 can be as follows: component A1 is refining in a two-roll mill with a roller distance parameter of 1 unit, and the hydrogen-containing silicone oil and the inhibitor are added dropwise. After addition, different roller distances are set, and the mixture is triangularly packaged, thin-passed, taken out and left to stand for 24 hours for later use.

[0101] In step S2, the preparation method of component B2 can be as follows: refining component A2 in a two-roll mill with a roller distance parameter of 1 unit, adding the catalyst dropwise, continuously shortening the roller distance, performing thin-pass milling, taking it out and letting it stand for 24 hours for later use.

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

[0103] In step S3, the mixture B can be prepared by placing component B1 and component B2 in an open mill for mixing and extrusion, and performing six thin passes to obtain the mixture.

[0104] In step S3, the catalytic addition step can be performed by subjecting the mixture B to a first sulfidation treatment and a second sulfidation treatment in sequence, and preferably also includes a third sulfidation treatment.

[0105] The temperature of the first vulcanization treatment can be 200℃-340℃, for example, 250℃. This first vulcanization temperature is also known as the pre-drying tunnel temperature. After the silicone material is extruded from the extruder die, it passes through a short pre-drying tunnel (a 0.8m long vertical hot air vulcanization channel). This is the first vulcanization treatment. The inhibitors in the silicone material decompose and volatilize at high temperatures, while the catalyst begins to function, initiating the catalytic addition reaction. At this point, the silicone material is initially vulcanized and shaped. The short pre-drying tunnel's main function is to allow the silicone material to quickly vulcanize and shape within a short time, preventing deformation due to the tube's own weight during conveyor belt transport, which could lead to tube flattening and dimensional errors.

[0106] The time for the first vulcanization treatment can be 2s-30s.

[0107] The first vulcanization process can be carried out in a vertical hot air vulcanization channel. The first vulcanization process can initially set the rubber compound at high temperature.

[0108] The temperature of the second vulcanization treatment can be 180℃-280℃, for example, 220℃, 240℃, 260℃ or 280℃. The temperature of the second vulcanization treatment can also be called the post-drying tunnel temperature. After the silicone material is initially vulcanized and shaped in the pre-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 through a long post-drying tunnel (a 2.5m long horizontal hot air vulcanization channel) for a second vulcanization treatment, so that the addition reaction is more complete and the silicone material is further vulcanized to achieve good mechanical properties.

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

[0110] The second vulcanization process can be carried out in a horizontal hot air vulcanization channel. This second vulcanization process ensures the rubber compound is fully vulcanized.

[0111] The temperature of the third vulcanization treatment can be between 150℃ and 240℃, for example, 180℃. Vulcanization temperature has a significant impact on the mechanical properties and appearance of silicone materials. If the temperature is too low, vulcanization is insufficient, resulting in overly soft and easily deformable silicone materials with poor mechanical properties. If the temperature is too high, over-vulcanization can occur, making the silicone material brittle, prone to breakage, and with poor elasticity.

[0112] In this invention, the vulcanization principle of the two-component addition-type polysiloxane is as follows: the two-component addition-type room temperature vulcanized polysiloxane, for example, uses vinyl polydimethylsiloxane as the base polymer and hydrogen-containing silicone oil as the crosslinking agent. Under the catalytic action of a catalyst (e.g., a platinum catalyst), the vinyl group and the hydrogen group undergo a hydrosilylation reaction to form a crosslinked network structure. The crosslinked structure can control the release of drugs. The reaction formula is shown below.

[0113]

[0114] Raw rubber, when mixed with crosslinking agents and catalysts, can react at room temperature. However, the compounding and processing of the rubber require a certain amount of time. If the reactants cure prematurely during operation, the desired shape and properties will not be achieved. This is especially true for addition-type polysiloxanes. Therefore, it is generally required that the catalytic reaction be almost inactive before vulcanization (mixed at room temperature), and react rapidly once the vulcanization temperature is reached. The method to inhibit the reaction is usually to add inhibitors. Inhibitors can form certain complexes with platinum catalysts. Effective inhibitors can stand with the rubber compound for a considerable period of time, and vulcanization can only occur when heated to a certain vulcanization temperature. Commonly used inhibitors include compatible alkynyl alcohols, nitrogen-containing compounds, and organic peroxides.

[0115] The present invention also provides a silicone material, which is prepared by the preparation method described above.

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

[0117] Alternatively, the catalytic addition process described above can be 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 described above.

[0119] The present invention also provides an implantation agent comprising a silicone tube and a core as described above, wherein the core contains a pharmaceutically active ingredient.

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

[0121] In this invention, the active pharmaceutical ingredient may include an active pharmaceutical ingredient acting on the reproductive system, or an active pharmaceutical ingredient acting on the urinary system, or an active pharmaceutical ingredient acting on chronic diseases involving metabolism and nutrition, or an active pharmaceutical ingredient used to treat chronic diseases involving connective tissue and rheumatism, or an active pharmaceutical ingredient used to treat hyperlipidemia, tumors, neuropsychiatric disorders, chronic dental diseases (dental caries, periodontal disease), simple obesity, chronic lower back pain, or leukemia, or an active pharmaceutical ingredient acting on the circulatory system, or an active pharmaceutical ingredient acting on the respiratory system, or an active pharmaceutical ingredient acting on the digestive system, or an active pharmaceutical ingredient acting on the blood system, or an active pharmaceutical ingredient acting on the endocrine system.

[0122] The active pharmaceutical ingredient acting on the reproductive system may include a contraceptive active pharmaceutical ingredient, or a steroidal estrogen.

[0123] The active pharmaceutical ingredient used for contraception may be conventional in the art, and preferably includes levonorgestrel, pregnadienone, or pregnatrinone.

[0124] The steroidal estrogen is preferably estradiol.

[0125] The active pharmaceutical ingredient acting on the urinary system preferably includes an active pharmaceutical ingredient for treating chronic nephritis, chronic renal failure, or chronic prostatitis.

[0126] The active ingredient of the drug for treating chronic prostatitis is preferably a nonsteroidal anti-inflammatory drug (NSAID), more preferably ibuprofen. Generally, the drug for treating chronic prostatitis may be: antibiotics (e.g., fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracycline), alpha-receptor blockers (e.g., doxazosin, terazosin, etc.), NSAIDs (e.g., ibuprofen, diclofenac, loxoprofen, flurbiprofen ester, ketorolac, celecoxib, etc.), analgesics (e.g., acetaminophen, etc.), opioids (e.g., ibuprofen, fentanyl, nalbuphine, pentazocine, etc.), anti-neuropathic pain drugs (e.g., serotonin, duloxetine, venfalacin), antiepileptics (e.g., pregabalin, etc.), and M-receptor blockers (e.g., solifenacin, tolterodine, etc.).

[0127] The medications used to treat chronic nephritis 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.), calcium channel blockers (such as amlodipine, felodipine, nifedipine, etc.), beta-blockers (such as atenolol, bisoprolol, carvedalol, propranolol, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, benzfluthiazide, bumetanide, etc.), immunosuppressants (such as prednisone, enrofloxacin, methylprednisolone, cyclophosphamide, dexamethasone, etc.), and statins (such as fluvastatin, simvastatin, pravastatin).

[0128] The medications used to treat 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, benzfluthiazide, bumetanide, etc.), iron supplements (such as ferrous fumarate), compound amino acids, α-keto acids, and recombinant human erythropoietin.

[0129] The active pharmaceutical ingredients that act on chronic diseases related to metabolism and nutrition preferably include active pharmaceutical ingredients for treating diabetes, nutritional deficiencies, gout, or osteoporosis.

[0130] The active pharmaceutical ingredient for treating gout is preferably an anti-gout medication, such as colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, para-aminosalicylic acid, disalicylate, benorilate, and more preferably ibuprofen. Generally, the anti-gout medication may also be a uric acid excretion agent (e.g., benzbromarone, probenecid) or a uric acid synthesis blocker (e.g., allopurinol).

[0131] The antidiabetic drugs mentioned can generally be anti-type 1 diabetes drugs (e.g., insulin) or anti-type 2 diabetes drugs. The anti-type 2 diabetes drugs can be sulfonylureas (e.g., glimepiride, glibenclamide), meglitinides (e.g., repaglinide, nateglinide), metformin drugs (e.g., metformin), alpha-glucosidase inhibitors (e.g., acarbose, voglibose), DPP-4 inhibitors (e.g., sitagliptin), GLP-1 receptor agonists (e.g., liraglutide, exenatide), or SGLT-2 inhibitors (e.g., dapagliflozin, empagliflozin).

[0132] The medications used to treat nutritional deficiencies can generally be drugs for gastrointestinal diseases (such as omeprazole and mosapride) or nutritional supplements (such as vitamin E).

[0133] The aforementioned anti-osteoporosis drugs can generally be bisphosphonates (e.g., alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonates, disodium chlorophosphate, zoledronic acid sodium, risedronate sodium), calcitonin (e.g., salmon calcitonin), estrogen (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) (e.g., raloxifene, benzothiophene), RANKL inhibitors, parathyroid hormone, monofluorophosphate glutamine, strontium salts (e.g., strontium ranelate), active vitamin D and analogues (e.g., calcitriol, alpha-calciferol), and vitamin K (e.g., tetraene-menaquinone).

[0134] The active pharmaceutical ingredient used to treat chronic diseases involving connective tissue and rheumatism preferably includes 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 pharmaceutical ingredient for treating rheumatoid arthritis is preferably a nonsteroidal anti-inflammatory drug (NSAID), such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, or nabumetone, and more preferably meloxicam or ibuprofen. Generally, the drug for treating rheumatoid arthritis may be a glucocorticoid (e.g., hydrocortisone, dexamethasone, prednisone) or a slow-acting antirheumatic drug (e.g., methotrexate, cyclophosphamide, azathioprine, cyclosporine, or leflunomide).

[0136] The active pharmaceutical ingredient for treating osteoarthritis is preferably an analgesic, such as ibuprofen, diclofenac, meloxicam, celecoxib, loxoprofen sodium, or nimesulide, and more preferably ibuprofen or meloxicam. Generally, the drug for treating osteoarthritis may be a cartilage-nourishing drug or an opioid (e.g., oxycodone, tamsulosin).

[0137] The drugs used to treat systemic lupus erythematosus generally include nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen and ibuprofen, antimalarial drugs, glucocorticoids such as prednisolone acetate and methylprednisolone, immunosuppressants such as methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, and tacrolimus, and biologics such as rituximab and belimumab.

[0138] The medications used to treat ankylosing spondylitis generally include nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, and etoricoxib, disease-modifying antirheumatic drugs (DMARDs such as pyridine salinomycin, methotrexate, and hydroxychloroquine), glucocorticoids (such as prednisone, prednisolone, and betamethasone), and biological agents such as TNF-α antagonists (such as etanercept).

[0139] The medications used to treat Sjögren's syndrome can generally be systemic drugs (such as levamisole, transfer factor coenzyme Q10, thymosin), glucocorticoids (such as prednisone), or immunosuppressants (such as hydroxychloroquine, azathioprine, alamod).

[0140] The medications used to treat vasculitis are generally glucocorticoids (such as prednisone, methylprednisolone, and dexamethasone) and immunosuppressants (such as cyclophosphamide, cyclosporine, and azathioprine).

[0141] The medications used to treat idiopathic inflammatory myopathy are generally glucocorticoids (such as dexamethasone, prednisone, hydrocortisone, and methylprednisone) and immunosuppressants (such as cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, and mycophenolate mofetil).

[0142] The drugs used to treat systemic sclerosis can generally be antifibrotic drugs (such as colchicine), vasoactive drugs (such as nifedipine, aspirin), and several other commonly used drugs (such as naproxen, nifedipine, bosentan, sildenafil, eprostol, nintedanib, tocilizumab).

[0143] The active pharmaceutical ingredient used to treat neuropsychiatric disorders is generally a drug for treating schizophrenia, an antidepressant, a drug for treating opioid abuse, or a drug for treating anxiety disorders; preferably a drug for treating schizophrenia, more preferably a phenothiazine (e.g., chlorpromazine), a thioxanthracene (e.g., chlorprothixol), a butyrophenone (e.g., haloperidol), a benzodiazepine (e.g., olanzapine, clozapine), abenisoxazole (e.g., risperidone, paliperidone), abenisothioazole (e.g., ziprasidone), abenisothioazole (e.g., quetiapine), a quinolone (e.g., aripiprazole), and even more preferably a benisoxazole (e.g., paliperidone).

[0144] The aforementioned antidepressants generally include tricyclic antidepressants (e.g., imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (e.g., moclobemide), selective serotonin reuptake inhibitors (e.g., sertraline), serotonin and norepinephrine reuptake inhibitors (e.g., venlafaxine), serotonin blockers and reuptake inhibitors (e.g., trazodone), norepinephrine and dopamine reuptake inhibitors (e.g., bupropion), norepinephrine inhibitors (e.g., reboxetine), and α2-adrenergic receptor blockers (e.g., mirtazapine).

[0145] The medications used to treat opioid abuse are generally buprenorphine or methadone.

[0146] The medications used to treat anxiety disorders are generally benzodiazepines (e.g., diazepam), 5-HT1A receptor partial agonists (e.g., buspirone), β-adrenergic receptor blockers (e.g., propranolol), and valproate.

[0147] The drugs mentioned for treating hyperlipidemia can generally be statins (such as simvastatin, atorvastatin, pravastatin), fibrates (such as fenofibrate, bezafibrate, gemfibrozil), or niacin (such as niacin).

[0148] The antitumor drugs mentioned generally include anti-breast cancer drugs (such as azacitidine, docetaxel, busherin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol acetate, cetuximab, or leuprorelin), anti-prostate cancer drugs (such as degarelix, leuprorelin, histamine, flunitrazepam, estradiol, cyproterone acetate), anti-ovarian cancer drugs (such as carboplatin, topotecan, methotrexate), anti-rectal cancer drugs (such as panitumumab), anti-colon cancer drugs (such as bevacizumab, oxaliplatin), anti-liver cancer drugs (such as sorafenib), and anti-lung cancer drugs (such as erlotinib, gefitinib, docetaxel). Anti-renal cancer drugs (e.g., pazopanib, everolimus, tamsulosin), anti-gastric cancer drugs (e.g., 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., fluorouracil), anti-lymphoma drugs (e.g., vincristine, bexarotin, dacarbazine, etoposide), anti-myeloma drugs (e.g., bortezomib), anti-cervical cancer drugs (e.g., bleomycin), or anti-bladder cancer drugs (e.g., epirubicin, BCG).

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

[0150] Orlistat is a common drug used to treat simple obesity.

[0151] The active pharmaceutical ingredient for treating chronic low back pain is preferably a nonsteroidal analgesic drug, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen codeine, diclofenac sodium, and more preferably ibuprofen or meloxicam.

[0152] The drugs used to treat leukemia are generally those that interfere with nucleic acid biosynthesis (e.g., cytarabine, methotrexate, 6-mercaptopurine), those that directly affect the DNA structure and function of cancer cells (e.g., busulfan, mitomycin, chlorambucil, phenylalanine mustard, cyclophosphamide), those that interfere with transcription and inhibit RNA synthesis (e.g., daunorubicin, doxorubicin, doxorubicin, aclarubicin), those that inhibit protein synthesis and function (e.g., vincristine, vinblastine, L-aspartate, homoharringtonine), and other commonly used drugs (e.g., interferon, fludarabine, arsenic trioxide, etoposide, carmustine).

[0153] The active pharmaceutical ingredient acting on the circulatory system preferably includes active pharmaceutical ingredients for treating chronic heart failure, coronary heart disease, congenital heart disease, chronic infective endocarditis, or chronic pericarditis.

[0154] The active pharmaceutical ingredient for treating coronary heart disease can generally be a drug that improves angina symptoms (e.g., puerarin, isosorbide mononitrate), an antiplatelet aggregation drug (e.g., aspirin, clopidogrel bisulfate, ticagrelor), a lipid-lowering and plaque-stabilizing drug (e.g., atorvastatin, rosuvastatin, pravastatin), a drug that inhibits sympathetic nerve activity (e.g., metoprolol, bisoprolol fumarate), or a drug that improves myocardial remodeling (e.g., angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists); preferably a drug that improves angina symptoms, more preferably puerarin; the active pharmaceutical ingredient for treating chronic heart failure can generally be a cardiotonic drug (e.g., digitalis, digoxin, digoxin), a vasodilator (e.g., sodium nitroprusside, nitroglycerin), an angiotensin-converting enzyme inhibitor (e.g., enalapril, linoleic acid), or a diuretic (e.g., furosemide, hydrochlorothiazide, spironolactone).

[0155] The active ingredients of the drugs used to treat congenital heart disease may generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide, or coenzyme Q10.

[0156] The active ingredient in the drugs used to treat chronic infective endocarditis is generally an antibiotic (e.g., vancomycin, cephalosporins, penicillin, aminoglycosides).

[0157] The active ingredient in drugs used to treat chronic pericarditis is generally digitalis.

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

[0159] The active ingredients of the drugs used to treat chronic obstructive pulmonary emphysema are generally bronchodilators (including beta-receptor agonists and anticholinergic drugs), inhaled corticosteroids (such as budesonide and fluticasone), theophylline bronchodilators (such as theophylline), expectorants (such as carbocysteine ​​and fodocysteine), and glucocorticoids and antibiotics (such as penicillins, glycosides, and cephalosporins) may also be used as appropriate when the condition requires them.

[0160] The active ingredients of the drugs used to treat asthma can generally be commonly used inhaled medications (such as beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (such as salbutamol), sustained-release theophylline, leukotriene modifiers (which can be used in combination therapy), anticholinergic drugs (such as isoproscolamine), and antihistamines (such as astemizole, ketotifen).

[0161] The active ingredients of the drugs used to treat chronic cor pulmonale can generally be antibiotics (such as amoxicillin, cefazolin, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (such as selective β2 receptor agonists, theophylline), drugs to eliminate non-specific airway inflammation (such as prednisone), inhaled drugs (such as beclomethasone), and respiratory stimulants (such as lobeline, doxapram, and clomethasone).

[0162] The active ingredients of the drugs used to treat chronic respiratory failure are generally bronchospasm relievers and expectorants (such as salbutamol, acetylcysteine, etc.).

[0163] The active ingredients of the drugs used to treat silicosis can generally be tetrahydropalmatine, acetylcysteine, aluminum preparations, silicone, and danshen.

[0164] The active ingredients of the drugs used to treat pulmonary fibrosis can generally be pirfenidone, nintedanib, glucocorticoids (such as methylprednisolone, prednisone), immunosuppressants (such as azathioprine, methotrexate, etc.), colchicine, interferon, ACEIs or statins, etc.

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

[0166] The active ingredients of the drugs used to treat chronic gastritis can generally be used to relieve pain (such as atropine, propantheline bromide, etc.), to treat increased gastric acid (such as proton pump inhibitors, such as lansoprazole, omeprazole, etc.), to treat milder symptoms (such as cimetidine, ranitidine, aluminum hydroxide, etc.), to treat digestive aids (pancreatic enzymes can be added), and to treat bile reflux (such as metoclopramide, domperidone, cholestyramine, sucralfate, etc., which can bind to bile acids).

[0167] The active ingredients in drugs used to treat peptic ulcers are generally levofloxacin, tinidazole, or omeprazole.

[0168] The active ingredient in the drug used to treat intestinal tuberculosis is generally rifampin.

[0169] The active ingredients in drugs used to treat chronic enteritis are generally anti-inflammatory analgesics, probiotics, and antispasmodic analgesics (such as atropine and propantheline).

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

[0171] The active ingredients of the drugs used to treat chronic hepatitis can generally be hepatoprotective drugs (such as silymarin preparations, schisandra preparations, etc.), antifibrotic drugs (such as oral preparations of traditional Chinese medicine), antiviral drugs (such as ordinary interferon and pegylated interferon), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine, entecavir), and immunosuppressants (azotine).

[0172] The active pharmaceutical ingredients used to treat cirrhosis can generally be drugs for treating hepatitis B (e.g., nucleoside analogs), drugs for treating autoimmune hepatitis (e.g., glucocorticoids), anti-inflammatory drugs, hepatoprotective drugs, anti-hepatic fibrosis drugs (e.g., reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, etc.), drugs for treating spontaneous bacterial peritonitis (e.g., antibiotics), or drugs for treating portal hypertension (e.g., carvedilol).

[0173] The active pharmaceutical ingredients used to treat chronic pancreatitis are generally analgesics (such as buprenorphine and fentanyl) or pancreatic enzyme therapy drugs (such as pancreatic enzymes).

[0174] The active ingredients of the drugs used to treat chronic cholecystitis are generally antibacterial and anti-inflammatory drugs (such as levofloxacin, ciprofloxacin, and amoxicillin), antispasmodic and analgesic drugs, and choleretic drugs (such as ursodeoxycholic acid).

[0175] The active pharmaceutical ingredients that act on the blood system may generally include active pharmaceutical ingredients for treating chronic anemia, chronic myeloid leukemia, and chronic lymphocytic leukemia.

[0176] The medications used to treat chronic anemia generally include: trace elements (such as folic acid, vitamin B12, etc.), bone marrow stimulants (such as strychnine nitrate, hyoscyamine, scopolamine, etc.), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron supplements (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, ferrous sucrose, low molecular weight dextran iron, carboxymaltose iron, isomaltose iron, ferrous glucuronide, nano iron oxide, sorbitol iron, etc.), and erythropoietin-stimulating agents (recombinant human erythropoietin-α, dapoxetine-α, etc.).

[0177] The drugs used to treat chronic myeloid leukemia are generally: tyrosine kinase inhibitors (such as imatinib, nilotinib, bosutinib, ponatinib, etc.) and homoharringtonine.

[0178] The drugs used to treat chronic lymphocytic leukemia generally include: chemotherapy drugs (such as nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted drugs (such as edarab, venetumab, ibrutinib, imatinib, dasatinib, etc.), and monoclonal antibody drugs (such as oflamb, rituximab, atoruzumab, alenzusmab, etc.).

[0179] The active pharmaceutical ingredients that act on the endocrine system may generally include active pharmaceutical ingredients for treating chronic lymphocytic thyroiditis, hyperthyroidism, and hypothyroidism.

[0180] The medications used to treat chronic lymphocytic thyroiditis generally include: thyroid hormones (such as levothyroxine, thyroxine), and glucocorticoids (such as prednisone, methylprednisolone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0181] The medications used to treat hyperthyroidism generally include: thiouracil (e.g., propylthiouracil, methiouracil, etc.), imidazoles (e.g., methimazole, carbimazole, etc.), iodine and iodides (e.g., Lugol solution, etc.), radioactive iodine (e.g., iodine-131, etc.), and beta-blockers (e.g., metoprolol, atenolol, bisoprolol, carvedalol, propranolol, etc.).

[0182] The medications used to treat hypothyroidism are generally thyroid hormones (such as levothyroxine, levothyroxine sodium, thyroxine, etc.).

[0183] In this invention, the preparation method of the drug core can be to sequentially mix the active pharmaceutical ingredient with polysiloxane, extrude and vulcanize it.

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

[0185] The temperature of the vulcanization treatment can be 70℃-160℃.

[0186] The vulcanization treatment time can be 0.5-10 hours.

[0187] The raw material composition of the core may be as follows: by weight, 100 parts of active pharmaceutical ingredient, 100 parts of R-vinyl polysiloxane, 0.21 parts of catalyst, 0.98 parts of inhibitor, and the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the R-vinyl polysiloxane is 4.5:1.

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

[0189] In this invention, the core can be a skeleton-type rod core or a powder-type core.

[0190] When the core material 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. A 0.2 cm margin is left at each end of the silicone tube to facilitate sealing with the implanting agent.

[0191] When the core is a matrix-type rod, the filling method is preferably to quickly insert the matrix-type rod into the silicone tube while it is in a swollen state; the swelling can be achieved by immersing the silicone tube in petroleum ether for 1-2 minutes. After filling, it is preferably air-dried for 12-24 hours; the purpose of air-drying is to allow any residual petroleum ether to evaporate completely.

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

[0193] In this invention, the sealing end can be sealed with sealing adhesive; the sealing adhesive is preferably silicone.

[0194] In this invention, after the sealing is completed, it is preferably placed at room temperature for 12-24 hours to allow the sealing adhesive to cure.

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

[0196] The present invention also provides the application of the aforementioned silicone material or the aforementioned silicone tube as a release rate regulating medium in sustained-release formulations.

[0197] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0198] The reagents and raw materials used in this invention are all commercially available.

[0199] The positive and progressive effects of this invention are as follows:

[0200] The silicone tubes made from the silicone material of this invention exhibit excellent mechanical properties and increased water permeability. This allows for easier release of drugs from the implant during application, resulting in a higher drug release rate—several times to tens of times greater than that of traditional silicone tubes. This expands the range of drugs that can be selected and significantly broadens the application scope of the implant. Attached Figure Description

[0201] Figure 1 The images show the in vitro release of modified pregnadienone reservoir skeleton implants with different wall thicknesses prepared in Examples 8-1, 8-2 and 8-3.

[0202] Figure 2 The images show the in vitro release of the modified pregnadienone reservoir skeleton implants prepared with different amounts of silica in Examples 8-1, 9-1, and 9-2.

[0203] Figure 3 The images show the in vitro release of modified pregnadienone reservoir skeleton implants prepared with methyl vinyl polysiloxanes of different vinyl contents in Examples 8-1 and 10.

[0204] Figure 4 The in vitro release diagrams are for the modified pregnadienone reservoir skeleton implants prepared in Examples 8-1, 11-1, and 11-2 using different molar ratios of Si-H in hydrogen-containing silicone oils to vinyl groups in methyl vinyl polysiloxanes.

[0205] Figure 5 This is a graph showing the 150-day in vitro release effect of the modified pregnadienone reservoir framework implant prepared in Example 8-1.

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

[0207] Figure 7 This is a comparison chart of the 150-day in vitro release data of the modified pregnathione reservoir framework implant prepared in Example 8-1 and the pregnathione reservoir framework implant prepared in Comparative Example 1.

[0208] Figure 8 The images show the in vitro release data of the modified paliperidone reservoir-type implants prepared with different amounts of hydroxyapatite in Examples 12-1, 12-2, and 12-3.

[0209] Figure 9 The in vitro release data of the modified paliperidone reservoir implants prepared with methyl vinyl polysiloxanes of different vinyl contents in Examples 12-1 and 13 are shown in the figure.

[0210] Figure 10 The in vitro release data of the modified paliperidone reservoir-type implants prepared using different molar ratios of Si-H in hydrogen-containing silicone oils to vinyl groups in methyl vinyl polysiloxanes in Examples 12-1, 14-1, and 14-2 are shown.

[0211] Figure 11This is a graph showing the in vitro release data of the modified paliperidone reservoir implant prepared in Example 14-1.

[0212] Figure 12 This is a graph showing the in vitro release data of the paliperidone reservoir-type implant prepared in Comparative Example 2.

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

[0214] Figure 14 The graph shows the in vitro release data of the modified estradiol reservoir implants prepared at different vulcanization temperatures in Examples 17-1, 17-2, and 17-3.

[0215] Figure 15 The graph shows the in vitro release data of the modified estradiol reservoir implants with different wall thicknesses prepared in Examples 18-1, 18-2 and 18-3.

[0216] Figure 16 This is a graph showing the in vitro release data of the modified estradiol reservoir implant prepared in Example 17-2.

[0217] Figure 17 This is a graph showing the in vitro release data of the estradiol reservoir-type implant prepared in Comparative Example 3.

[0218] Figure 18 This is a comparison chart showing the long-term in vitro release effects of the modified estradiol reservoir implant from Example 17-2 and the estradiol reservoir implant from Comparative Example 3. Detailed Implementation

[0219] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0220] The sources of each component in the examples and comparative examples are shown in the table below.

[0221] Components Commercial purchase source Methyl vinyl polysiloxane, 100,000-800,000 g / mol Dongjue Organosilicon Group Co., Ltd. Hydrogen-containing silicone oil (Si-H group content is 0.75 mol%) Guangdong Siyue New Materials Technology Co., Ltd. Hydrophilic fumed silica N20 (contact angle 14-90°) Wacker International Group GmbH, Germany Hydrophilic silica TH-a200 (contact angle <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 Siyue New Materials Technology Co., Ltd. 2-Methyl-3-butyn-2-ol Jiuding Chemical Technology Co., Ltd. Paliperidone Shanghai Aladdin Biochemical Technology Co., Ltd. Pregnadienone (98% purity, batch number: 190327) Hebei Mokai Technology Co., Ltd. Estradiol (99% purity, 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. Chromatographic 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 table below:

[0223]

[0224]

[0225] 1. Silicone tubing

[0226] 1.1 Preparation method of silicone tubing

[0227] (1) Dry methyl vinyl polysiloxane raw rubber at 40℃ for 12h for later use; dry hydrophilic fumed silica at 130℃ for 24h for later use;

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

[0229] (3) Mixture A is divided into component A1 and component A2. Component A1 is refining in a two-roll mill with a roller distance parameter of 1 unit, and the prescribed amount of the hydrogen-containing silicone oil and inhibitor 2-methyl-3-butyn-2-ol are added dropwise. After addition, different roller distances are set, and the mixture is triangularly packaged, passed through a thin mill, and then left to stand for 24 hours to obtain component B1 for later use. Component A2 is refining in a two-roll 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, and the mixture is passed through a thin mill. After being left to stand for 24 hours, component B2 is obtained for later use.

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

[0231] (5) The mixture B obtained in step (4) is unloaded from the open mill in sheet form and then cut into strips; a die of appropriate size is installed on the extruder, the screw speed of the extruder is set, and the cut silicone strips are fed into the extruder. The rubber material is continuously extruded into silicone tubes through the die orifice under the push of the rotating screw. The outer diameter of the silicone tube is determined by the screw speed of the extruder, the speed of the conveyor belt in the back drying tunnel, and the size of the die, while the wall thickness is determined by the size of the die.

[0232] (6) The silicone tube obtained in step (5) is subjected to a first vulcanization treatment and a second vulcanization treatment; thus, the finished silicone tube is obtained.

[0233] The first vulcanization process involves the silicone tube extruded from the mold opening undergoing rapid high-temperature vulcanization in a pre-drying tunnel (vertical hot air vulcanization channel). This first vulcanization process quickly transforms the silicone tube from a soft and sticky state to an elastic state, thus initially shaping it.

[0234] The second vulcanization process involves the silicone tube entering the post-drying tunnel (horizontal hot air vulcanization channel) after the first vulcanization. This second vulcanization process ensures a more complete vulcanization reaction and achieves the optimal cross-linking state. The finished silicone tube is then continuously transported out via the conveyor belt in the post-drying tunnel.

[0235] 1.2 Investigation of the Formulation and Process of Silicone Tubes

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

[0237] A. Formulation: The concentration of platinum catalyst was 3000 ppm; the amount of platinum catalyst was 0.0098 PHR; the amount of inhibitor 2-methyl-3-butyn-2-ol was 0.69 PHR; other formulation 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 as follows: the temperature of the first vulcanization treatment is 250℃; the time of the first vulcanization treatment is 3s; the temperature of the second vulcanization treatment is 240℃; the time of the second vulcanization treatment is 4min; the diameter of the die is 3mm; the diameter of the core mold is 2.6mm; the wall thickness of the obtained silicone tube is 0.2mm; and the screw speed is 5r·min. -1 .

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

[0242] A. Formulation: The concentration of platinum catalyst is 3000 ppm; the amount of platinum catalyst is 0.0098 PHR; the amount of inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR; the vinyl content in methyl vinyl polysiloxane is 0.18%; the amount of hydrophilic silica TH-a200 is 30 PHR; the molar ratio of Si-H in the hydrogen-containing 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 vulcanization temperature is set as recorded in Table 2; the first vulcanization time is 3 seconds, the second vulcanization time is 4 minutes; the diameter of the die is 3 mm; the diameter of the core mold is 2.6 mm; the wall thickness of the obtained silicone tube is 0.2 mm; and the screw speed is 5 r / min. -1 .

[0244] Table 2

[0245] serial number First sulfidation temperature / °C Second sulfidation temperature / °C 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. Formulation: The concentration of platinum catalyst is 3000 ppm; the amount of platinum catalyst is 0.0098 PHR; the amount of inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR; the vinyl content in methyl vinyl polysiloxane is 0.18%; the amount of hydrophilic silica TH-a200 is 30 PHR; the molar ratio of Si-H in the hydrogen-containing 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. The temperature of the first vulcanization treatment is 250℃; the time of the first vulcanization treatment is 3s; the temperature of the second vulcanization treatment is 240℃; the time of the second vulcanization treatment is 4min; the mold dimensions and screw speed are shown in Table 3. (Note: Ring width = (inner diameter of die - diameter of core die) / 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 Examples 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 Examples 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 At this time, the rubber material can be continuously and uniformly conveyed. With a constant screw speed, the larger the annular width between the inner diameter of the die orifice and the diameter of the core die, the greater the wall thickness of the silicone tube. The outer diameter of the silicone tube is not directly related to the annular width; it is influenced by the combined effects of the die and core die dimensions, the annular width, and the screw speed.

[0252] When using the same tool, the higher the screw speed, the larger the outer diameter of the silicone tube. This is because a higher screw speed results in a higher extrusion speed of the silicone tube, and a smaller stretching effect of the conveyor belt on the silicone tube, thus leading to a larger outer diameter. Conversely, a lower screw speed results in a lower extrusion speed of the silicone tube, a greater stretching effect of the conveyor belt on the silicone tube, and a smaller outer diameter.

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

[0254] 2. Modified pregnadienone reservoir framework implantation agent

[0255] 2.1 Preparation method of planting agent

[0256] (1) Silicone tube preparation method: Prepare silicone tube according to steps (1)-(6) of the preparation method in 1.1;

[0257] (2) Basic formulation and preparation process of the core: pregnadienone, with a particle size of 2-3 μm, added at 100 PHR; methyl vinyl polysiloxane, with a vinyl content of 0.18% to 0.23%; hydrogen-containing silicone oil, with a Si-H group content of 0.75%, added at 0.3 to 5.0 PHR; platinum catalyst, with a platinum concentration of 10,000 ppm, added at 0.000002 to 0.5 PHR; 2-methyl-3-butyn-2-ol as an inhibitor, added at 0.03 to 2.0 PHR;

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

[0259] (3) Soak the silicone tube in petroleum ether for 1-2 minutes, quickly shake off the petroleum ether residue on the surface of the silicone tube, and immediately insert the cut core into the middle of the silicone tube with tweezers, leaving the same length of space at both ends of the silicone tube for sealing. After assembly, let the implant air dry for 12-24 hours to allow the residual petroleum ether to evaporate completely. Then seal both ends of the air-dried implant with sealing glue and let it sit at room temperature for 12-24 hours to allow the sealing glue to cure, thus obtaining the modified pregnadienone storage skeleton implant.

[0260] 2.2 Influence of manufacturing process or formulation on the performance of silicone tubing

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

[0262] A. Formulation: The concentration of platinum catalyst is 10,000 ppm; the amount of platinum catalyst is 0.01 PHR; the amount of inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR; other formulation parameters are shown in Table 1.

[0263] Table 4

[0264] serial number Vinyl content Dosage of hydrophilic fumed silica A380 Molar ratio of hydrogen-containing 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 described in 2.1, and the specific process parameters are as follows: the temperature of the first sulfidation treatment is 250℃; the time of the first sulfidation treatment is 3s; the temperature of the second sulfidation treatment is 240℃; the time of the second sulfidation treatment is 4min; the diameter of the core is fixed at 0.2cm and the length is 1.5cm; and the outer diameter of the silicone tube is fixed at 2.4mm and the length is 1.9cm.

[0266] 3. Modified paliperidone reservoir-type planting agent

[0267] 3.1 Preparation method of planting agent

[0268] Prepare silicone tubes according to steps (1)-(6) of the preparation method in 1.1, and then prepare paliperidone reservoir-type implants through the following steps (7);

[0269] (7) Preparation of paliperidone reservoir-type implant: One end was sealed with KN-300N adhesive and cured for 24 hours. After curing, the drug was filled through the filling funnel. After filling, the other end was sealed with KN-300N adhesive and cured for 24 hours. After curing, check for drug leakage. After confirming that there was no leakage, wash repeatedly with anhydrous ethanol for 30 seconds. The preparation was completed, and the modified paliperidone reservoir-type implant was obtained.

[0270] 3.2 Effects of hydroxyapatite dosage, vinyl content of methyl vinyl polysiloxane, and dosage of hydrosilicone oil on in vitro drug release.

[0271] A. Formulation: Paliperidone was added at 100 PHR; HB-615 hydrophobic fumed silica was added at 20 PHR; platinum catalyst concentration was 3000 ppm; platinum catalyst dosage was 0.21 PHR; inhibitor 2-methyl-3-butyn-2-ol dosage was 0.98 PHR; other formulation parameters are shown in Table 5.

[0272] Table 5

[0273] serial number Vinyl content Hydroxyapatite Molar ratio of hydrogen-containing 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 Example 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 as follows: the temperature of the first sulfidation treatment is 250℃; the time of the first sulfidation treatment is 5s; the temperature of the second sulfidation treatment is 240℃; the time of the second sulfidation treatment is 2min; the wall thickness of the obtained implanting agent is 0.2mm; the outer diameter is 2.2-2.3mm; and the drug release area is 2.7±0.5cm². 2 .

[0275] 4. Modified estradiol reservoir-type implantation agent

[0276] 4.1 Preparation method of planting agent

[0277] Same as the method for preparing the implantation agent described in 3.1

[0278] 4.2 Effects of vulcanization temperature, silicone tube wall thickness, and drug release area on in vitro release of implanting agent

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

[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 The molar ratio of Si-H groups in hydrogen-containing silicone oil to vinyl groups in methyl vinyl polysiloxane 1.2:1 The Si-H group content of hydrogen-containing 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 5 seconds; the second vulcanization treatment time is 2 minutes; the third vulcanization treatment time is 48 hours; other parameters are shown in the table below:

[0283] Table 7

[0284] serial number First sulfidation temperature / °C Second sulfidation temperature / °C Third sulfidation 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 Drug-containing length / 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: Pregnadienone reservoir skeleton type implantation agent

[0290] A. Formulation: Compared with the formulation of the modified pregnadienone skeleton implant, the difference lies in the fact 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 reservoir-type planting agent

[0293] A. Formulation: Compared with the formulation of the modified paliperidone reservoir-type planting agent, 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 Reservoir Type Planting Agent

[0296] A. Formulation: Compared with the formulation of the modified estradiol reservoir type 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 performance of the embodiments and comparative examples of the present invention were studied.

[0300] I. 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 ensure good mechanical properties so that the shape can be maintained during implantation and removal.

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

[0303] 2. Tensile strength (MPa): The maximum tensile stress a sample experiences during a tensile test, stretched until it breaks.

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

[0305] Specific testing method: Prepare samples approximately 5 cm long, with three copies of each sample prepared in parallel. Use a tensile testing instrument to test the samples, setting the test parameters as follows: clamping distance 50 mm, tensile speed 200 mm / min. -1 Once the sample testing is complete, 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 Examples 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 Examples 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] The effect data from Examples 1-1 and 1-2 show 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 significantly different, all exhibiting good mechanical properties. This indicates that the vinyl content in both methods is within a suitable range, and after the addition reaction, the crosslinked chain segments in the formed network structure are of appropriate length and the crosslinking points are distributed in an orderly manner. Therefore, the prepared silicone tube has good elasticity and certain tensile and tear resistance, meeting the requirements for preparing implants and clinical applications.

[0309] According to the effect data of Examples 2-1 to 2-4, when the amount of hydrophilic silica is in the range of 30-50 PHR, the mechanical properties of the silicone tubes after vulcanization are good.

[0310] Based on the effect data from Examples 2-1, 3-1, and 3-2, it can be seen that when the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in methyl vinyl 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 elongation at break, tensile strength, and tear strength of the vulcanized silicone tube is not significant, and the mechanical properties of the silicone tube are all good. In addition reactions, theoretically, the hydrogen in the hydrogen-containing silicone oil and the vinyl in methyl vinyl polysiloxane participate in the reaction at a molar ratio of 1:1. However, in actual reactions, Si-H is lost due to side reactions. Therefore, a slight excess of hydrogen-containing silicone oil is usually used to ensure the addition reaction proceeds fully, the crosslinking becomes increasingly closer to complete, and the mechanical properties of the silicone tube reach their optimal state.

[0311] According to the effect data of Examples 4-1 to 4-4, as the second vulcanization temperature increases, the elongation at break, tensile strength, and tear strength of the vulcanized silicone tube show a trend of first increasing and then decreasing. When the second vulcanization temperature is 240℃, the values ​​of each index reach the maximum. The second vulcanization treatment is mainly to allow the silicone tube to continue vulcanization and the cross-linking reaction to continue. A suitable temperature can make the cross-linking reaction complete and the mechanical properties better. However, if the temperature is too high, it will cause the silicone tube to be over-vulcanized, and the internal cross-linking bonds will undergo thermal decomposition, resulting in a decrease in performance.

[0312] II. In vitro release effect

[0313] 1. In vitro release characterization of modified pregnadienone reservoir framework 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℃;

[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 employed a horizontal shaking method. One implant was attached to both ends of a 50mL stoppered conical flask using silicone adhesive to secure it to the bottom and wall (to prevent the implant from floating on the surface and causing inaccurate release results). After adhesion, the flask was left to stand for 12 hours to allow the silicone adhesive to fully cure. 50mL of distilled water was precisely measured and injected into the conical flask as the release medium. The flask was then placed in a constant-temperature air shaker at 37℃ and an amplitude of 100 rpm. An equal volume of medium was replaced every 24 hours. The release solution was filtered through a 0.22μm microporous membrane and analyzed under chromatographic conditions, with an injection volume of 20μL.

[0324] 1.2 Results Data

[0325] (1) Data on in vitro release effect after 30 days

[0326] Examples 8-1 to 8-3 show implants with different silicone tube wall thicknesses, and their in vitro release performance data are as follows: Figure 1As shown, the thicker the silicone tube wall, the lower the daily release of the implant. The average daily release of the implant over 30 days is approximately 55 μg for a silicone tube with a wall thickness of 0.2 mm; approximately 48 μg for a tube with a wall thickness of 0.3 mm; and approximately 42 μg for a tube with a wall thickness of 0.4 mm. This means that for every 0.1 mm increase in silicone tube thickness, the average daily release decreases by approximately 5-8 μg. From the above data, it can be seen that when the outer diameter and length of the silicone tube, and the diameter and length of the drug core are fixed, the wall thickness of the silicone tube can slightly affect the in vitro release rate of the implant. However, in the actual preparation process of the implant, when the outer diameter of the silicone tube remains constant, a thicker wall results in a smaller inner diameter, making the assembly of the drug core and the silicone tube more difficult. A silicone tube with a wall thickness of 0.2 mm has a relatively larger inner diameter, resulting in better fit with the drug core.

[0327] Examples 8-1, 9-1, and 9-2 show different amounts of hydrophilic silica, and their in vitro release performance data are as follows: Figure 2 As shown, the amount of hydrophilic silica used has a slight effect on the release of the implanting agent. With increasing hydrophilic silica dosage, the average daily release of the implanting agent over 30 days increases slightly. When the hydrophilic silica dosage is 40 PHR, the daily release is relatively high, approximately 55 μg. Figure 5 It can be seen that the drug release curves in the 1-15 day period are significantly higher than those in the 30PHR and 20PHR. The average daily drug release is not much different between the hydrophilic silica dosages of 30PHR and 20PHR, both around 48μg. Moreover, the fluctuations of the two drug release curves are smaller than those of 40PHR, indicating better drug release stability. Furthermore, the extrusion stability and smoothness are better when the dosage of fumed silica is 30PHR during the silicone tube extrusion process.

[0328] Examples 8-1 and 10 are implants with different vinyl contents, and their in vitro release performance data are as follows: Figure 3 As shown, the vinyl content of the silicone tube has little effect on the release of the implanting agent. The average daily release of both groups of implanting agents is between 47-50 μg over 30 days. The methyl vinyl polysiloxane with a vinyl content of 0.18% is more in line with the requirements of mechanical properties and cost.

[0329] Examples 8-1, 11-1, and 11-2 show the in vitro release performance data of implants with different amounts of hydrogen-containing silicone oil. Figure 4 As shown, when the molar ratio of hydrogen-containing silicone oil is 1.2 and 1.8, the release of the implantation agent in the first 3 days is relatively high, with a sudden release phenomenon in the early stage, and the overall release curve fluctuates greatly. However, the release curve fluctuates relatively less when the molar ratio is 1.5. It can be seen that the release curve when the molar ratio is 1.5 is relatively stable, and previous studies have shown that the mechanical properties of silicone tubes are also better.

[0330] (3) In vitro release experiment

[0331] Long-term in vitro release experiments were conducted on the implants of Examples 8-1 and Comparative Example 1 for 150 days, and 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 graph showing the 150-day in vitro release effect of the modified pregnadienone reservoir framework implant prepared in Example 8-1. Figure 6 This is a graph showing the 150-day in vitro release data of the pregnadienone reservoir skeleton implant prepared in Comparative Example 1. Figure 7 This is a comparison chart of the in vitro release effects of Example 8-1 and Comparative Example 1. Based on the data in the table above and... Figure 5 , Figure 6 and Figure 7 It can be seen that, under the premise of meeting the mechanical properties of the implant, hydrophilic silica increased the release of silicone tubing by 18-23 μg compared to hydrophobic silica, indicating that the drug release of the implant meets the requirements and has good drug release stability, achieving stable drug release for at least 5 months. Furthermore, compared to the pregnardene matrix reservoir implant, the in vitro release of the modified pregnardene matrix reservoir implant can be increased by 192%.

[0338] 2. In vitro release characterization of modified paliperidone reservoir-type 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: 1 mL / min

[0344] Column temperature: 35℃

[0345] Injection volume: 20 μL

[0346] Detection wavelength: 280nm

[0347] (2) In vitro release test method

[0348] Take one vial of the modified paliperidone reservoir implant and fix it in a 20 mL sample bottle using silicone adhesive. Accurately measure an appropriate amount of distilled water into the sample bottle, ensuring the formulation remains submerged below the surface of the release medium. Place the bottle in a constant-temperature shaker with an amplitude of 100 rpm and a temperature of 37°C for release. Sample every 24 hours, changing the release medium each time. Filter the solution through a 0.22 μm filter membrane and retain the sample for analysis.

[0349] 2.2 Results Data

[0350] (1) Data on in vitro release effect after 30 days

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

[0352] Examples 12-1 and 13 investigated the effect of the vinyl content of methyl vinyl polysiloxane on the in vitro release of silicone tubing, and the results are as follows: Figure 9 As shown in the figure, the vinyl content in the silicone tube has little effect on the release of the implanting agent. The daily release of both groups of implanting agents within 30 days is between 20-25 μg, with little difference between them. However, when the raw rubber vinyl content in the silicone tube is 0.18%, the overall release curve of the implanting agent is more stable.

[0353] Examples 12-1, 14-1, and 14-2 investigated the effect of the molar ratio of hydrogen-containing silicone oil on the in vitro release amount from silicone tubes. The results are as follows: Figure 10 As shown, the release curves of the implanting agent are not significantly different when the molar ratio of hydrogen-containing silicone oil is different. This is because, theoretically, during the addition reaction, the hydrogen in the hydrogen-containing silicone oil and the vinyl group in the methyl vinyl polysiloxane react in a 1:1 molar ratio. However, in actual reactions, Si-H is lost due to side reactions. Therefore, a slight excess of hydrogen-containing silicone oil is usually used to ensure the addition reaction proceeds fully and the crosslinking becomes increasingly closer to complete.

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

[0355] At a temperature of 37℃ and a shaking speed of 100 r·min -1 Long-term in vitro release experiments were conducted on Examples 14-1 and Comparative Example 2 under the specified conditions. The long-term in vitro release results of Example X are shown in Table 13 below. 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] Figure 11 This is a graph showing the in vitro release effect of the modified paliperidone reservoir implant prepared in Example 14-1. Figure 12 This is a graph showing the in vitro release effect of paliperidone reservoir-type implant prepared in Comparative Example 2. Figure 13 This is a comparison chart of the in vitro release effects of Example 14-1 and Comparative Example 2. According to the effect data in the table above, the in vitro release study of the modified paliperidone reservoir-type implant obtained from the silicone tube provided by this invention shows that the drug release is stable within 150 days. Compared with the paliperidone reservoir-type implant, the in vitro release amount of the modified paliperidone reservoir-type implant is increased by 260%.

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

[0362] 3.1 Test Method

[0363] (1) Take one modified estradiol reservoir implant, cut open the silicone tube, cut the core into several small fragments, place them in a 100mL volumetric flask, add 10mL of methanol to soak, let stand for 3 hours to swell, dilute to the mark with anhydrous ethanol, shake well and filter. Accurately measure 0.2mL of the filtrate into a 50mL volumetric flask, dilute to the mark with the mobile phase, shake well, inject into HPLC, inject 20μL, and calculate the drug content according to the standard curve. 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℃

[0368] Detection wavelength: 202nm

[0369] Flow rate: 0.8 mL·min⁻¹

[0370] Injection volume: 20 μL

[0371] (2) Method for determining release rate

[0372] Release rate determination was performed using the horizontal shaking method: One tube of modified estradiol reservoir implant was fixed in an alternating manner in a 100 mL stoppered conical flask using adhesive. 100 mL of distilled water was accurately measured as the release medium. The stoppered conical flask was placed in a constant-temperature shaker, and the amplitude was set to 100 r / min. -1 The temperature is 37℃. Ensure that the implantation agent is always below the liquid surface. Take samples every 24 hours and replace them with an equal volume of release medium. After filtering the sample solution through a 0.22μm microporous membrane, inject it according to the content determination method in (1). Calculate the drug release amount based on the standard curve.

[0373] 3.2 Results Data

[0374] 3.2.1 Effect of vulcanization conditions on in vitro release amount

[0375] Table 15

[0376]

[0377]

[0378] Figure 14 In vitro release data of modified estradiol reservoir-type implants prepared at different vulcanization temperatures are shown in the table above. Figure 14 The results showed that changing the vulcanization temperature of the silicone tube had little effect on the average daily release of the implanting agent, with minimal fluctuations. Therefore, silicone tubes with better mechanical properties were selected for the preparation of the implanting agent, with the vulcanization conditions being a first vulcanization treatment at 250℃ and a second vulcanization treatment at 240℃.

[0379] 3.3.2 Silicone tube wall thickness

[0380] Table 16

[0381]

[0382]

[0383] Figure 15 This image shows the in vitro release data of modified estradiol reservoir implants with different wall thicknesses. The results indicate that, keeping factors such as outer diameter and release area constant, the in vitro release of the modified estradiol reservoir implants prepared from silicone tubes of three different wall thicknesses gradually decreases with increasing wall thickness. To ensure adequate drug release, the wall thickness should be minimized. However, in practice, a silicone tube with a wall thickness of 0.2 mm is already the limit; further reducing the wall thickness makes it difficult to ensure smooth extrusion molding. Therefore, a silicone tube with a wall thickness of 0.2 mm is recommended.

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

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

[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 release of the modified estradiol reservoir implant increased with increasing release area. In practical applications, due to significant individual patient differences, different specifications of the modified estradiol reservoir implant can be produced to achieve personalized drug delivery, reduce side effects, and maximize benefits according to different needs.

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

[0390] The estradiol reservoir-type implantation agents prepared in Examples 17-2 and Comparative Example 3 were subjected to a temperature of 37°C and a shaking speed of 100 r·min. -1 Long-term in vitro release experiments were conducted under the specified conditions, and the results are shown in the table and figure below.

[0391] Table 18

[0392]

[0393]

[0394] The above table and Figure 16 The results showed that the implantation agent prepared using hydrophilic silica had a stable daily in vitro drug release rate in the range of 20-35 μg, indicating good stability.

[0395] Table 19

[0396]

[0397] The above table and Figure 17 The results showed that the average daily release of estradiol reservoir-type implants 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. The results are as follows: Figure 18 This indicates that, while meeting the mechanical properties of the implant, the modified estradiol implant increases the in vitro release by 245% compared to hydrophobic silica, and also improves the problem of sudden release of the original estradiol reservoir-type implant.

Claims

1. An implant, characterized in that, It includes a drug core and a silicone tube, wherein the drug core contains the active pharmaceutical ingredient; The method for preparing the silicone tube includes the following steps: The silicone tube is obtained by catalytic addition of the raw material composition in a tubular mold; (1) The raw material composition of the silicone tube comprises the following components in parts by weight: R-vinyl polysiloxane: 100 parts; Reinforcing agent: 10-80 parts; Catalyst: 0.000002-1 part; Hydrogen-containing silicone oil; Wherein, R in the R-vinyl polysiloxane is a substituted or unsubstituted C1-C5 straight-chain alkane or branched-chain alkane, or a substituted or unsubstituted C6-C5 alkane. 20 Aromatic hydrocarbons; The vinyl content in the R-vinyl polysiloxane is 0.1 mol%-0.5 mol%; The reinforcing agent contains hydrophilic groups; the water contact angle of the reinforcing agent is 16-35°, and the reinforcing agent is silica; or, the water contact angle of the reinforcing agent is 0-25°, and the reinforcing agent is hydroxyapatite. The Si-H group content in the hydrogen-containing silicone oil is 0.15-1.6 mol%; The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl polysiloxane is (1.2-1.8):1; Optionally, it also includes an inhibitor, which is a substance capable of inhibiting the addition reaction between the R-vinyl polysiloxane and the hydrogen-containing silicone oil; (2) The catalytic addition step includes sequentially undergoing a first sulfidation treatment and a second sulfidation treatment; The temperature of the first vulcanization treatment is 200℃-340℃; the time of the first vulcanization treatment is 2s-30s; The temperature of the second vulcanization treatment is 220℃-260℃; the time of the second vulcanization treatment is 0.1min-5min.

2. The embedding agent as described in claim 1, characterized in that, The raw material composition of the silicone tube satisfies one or more of the following conditions: a. R in the R-vinyl polysiloxane is a substituted or unsubstituted C1-C5 straight-chain alkane; b. The vinyl content in the R-vinyl polysiloxane is 0.15 mol% - 0.3 mol%; c. The reinforcing agent is present in parts by weight of 20-70 parts; d. The amount of the hydrogen-containing silicone oil used is 0.3-5 parts; e. The Si-H group content in the hydrogen-containing silicone oil is 0.18-1.6 mol%; f. The catalyst is a platinum catalyst; g. The amount of the catalyst used is 0.00001-0.5 parts; h. The inhibitor is an alkynyl alcohol compound, a nitrogen-containing compound, or an organic peroxide; i. The inhibitor is present in parts by weight of 0.03-2.0 parts; and, j. Water is used as a solvent, and the active pharmaceutical ingredient is an active drug with a solubility ≤100 mg / mL.

3. The embedding agent as described in claim 2, characterized in that, The raw material composition of the silicone tube satisfies one or more of the following conditions: a. In the R-vinyl polysiloxane, R is methyl; b. The vinyl content in the R-vinyl polysiloxane is 0.18-0.23 mol%; c. The reinforcing agent is present in parts by weight of 30, 40, 45 or 50; d. The amount of the hydrogen-containing silicone oil used is 0.3-3 parts; e. The amount of the catalyst used is 0.00001 parts, 0.0098 parts, or 0.21 parts; f. The inhibitor is methylbutynol; g. The inhibitor is present in 0.69 parts by weight; and, h. The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.2 mol.

4. The implant of claim 3 wherein, The raw material composition of the silicone tube satisfies one or more of the following conditions: a. The amount of the hydrogen-containing silicone oil used is 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts, or 1.70 parts; b. The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl polysiloxane is 1.2:1, 1.5:1, or 1.8:1; c. The inhibitor is 2-methyl-3-butyn-2-ol; and, d. The content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol.

5. The implant of claim 1 wherein, The silica mentioned is hydrophilic fumed silica.

6. The implant of claim 5 wherein, The hydrophilic fumed silica is hydrophilic fumed silica A380.

7. The implant of claim 1 wherein, The raw material composition of the silicone tube includes the following components: methyl vinyl polysiloxane: 100 parts; the vinyl content in methyl vinyl polysiloxane is 0.18 mol%; hydrophilic silica: 30 parts; hydrogen-containing silicone oil: 1.33 parts; the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in methyl vinyl polysiloxane is 1.5:

1. Platinum catalyst: 0.0098 parts; 2-methyl-3-butyn-2-ol: 0.69 parts; Alternatively, the raw material composition of the silicone tube includes the following components: methyl vinyl polysiloxane: 100 parts; the vinyl content in the methyl vinyl polysiloxane is 0.18 mol%; hydrophilic silica: 30 parts; hydrogen-containing silicone oil: 1.33 parts; the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl polysiloxane is 1.5:

1. Platinum catalyst: 0.01 parts; 2-methyl-3-butyn-2-ol: 0.69 parts.

8. The implant of claim 1 wherein, The method for preparing the silicone tube meets one or more of the following conditions: the first vulcanization treatment has a temperature of 250°C; The first vulcanization treatment is performed in a vertical hot air vulcanization tunnel; The temperature for the second vulcanization treatment is 220°C, 240°C, or 260°C; the second vulcanization treatment is performed in a horizontal hot air vulcanization tunnel; and, The step of catalytic addition further comprises a third sulphidation treatment.

9. The embedding agent as described in claim 8, characterized in that, The temperature for the third vulcanization treatment is 150℃-240℃.

10. The implant of claim 9 wherein, The temperature for the third vulcanization treatment is 180°C.

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