Silicone rubber materials, silicone rubber tubes, implants and methods for manufacturing the same, as well as rod cores, perforated implants and methods for manufacturing the same, and applications.

Abstract

This invention discloses a silicone rubber material, a silicone rubber tube and an implant, as well as a method for manufacturing the same, a rod core, a perforated implant and a method for manufacturing the same, and applications. The silicone rubber material comprises 100 parts R-vinylpolysiloxane, 10 to 80 parts a reinforcing agent, and 0.000002 to 1 part a catalyst. The rod core includes a drug-containing layer, the drug-containing layer contains an active drug and an additive, the additive includes a sustained-release additive, the molecular weight of the sustained-release additive is 1000 to 100 million, and the ratio of drug to additive is 1:(0.01 to 100). The silicone rubber material satisfies mechanical properties and improves the release rate of the drug by increasing the water permeability of the silicone rubber tube, thereby improving the drawback of low in vitro release rates in the prior art. The implant is applicable to most drugs and can achieve long-term drug release.

Description

[Technical Field]

[0001] This application claims priority to Chinese patent applications 2023111805573 and 2023111805569, filed on 2023 / 9 / 13. This application references all of the aforementioned Chinese patent applications.

[0002] This invention relates to silicone rubber materials, silicone rubber tubes, implants and methods for manufacturing the same, as well as rod cores, perforated implants and methods for manufacturing the same, and applications. [Background technology]

[0003] Silicone rubber subcutaneous implants primarily involve filling a silicone rubber tube with a drug, implanting it subcutaneously, and allowing water to permeate the tube to form a drug solution. This solution is then released steadily through the tube, achieving long-term effects. Currently available implants include levonorgestrel implants, which provide long-term contraceptive effects. This formulation significantly improves the bioavailability of the drug by avoiding the first-pass effect in the gastrointestinal tract.

[0004] Conventional silicone rubber subcutaneous implants primarily use methyl vinylpolysiloxane and hydrophobic silica as substrates. While hydrophobic silica offers good reinforcing properties, and the resulting silicone rubber tubes adequately meet the mechanical requirements for implantation, their low water permeability and hydrophobic nature prevent moisture from penetrating the silicone rubber tube and dissolving drugs to form solutions. This results in low drug release from the implant, making it difficult to use drugs that require high doses to be effective, thus limiting its clinical application.

[0005] Subcutaneous implants primarily involve embedding an active drug within a carrier and implanting it subcutaneously. The carrier controls drug release, allowing the drug to be absorbed through local capillaries and enter the bloodstream, resulting in stable release over several years and achieving long-term effects. This formulation significantly improves drug bioavailability by avoiding the first-pass effect in the gastrointestinal tract. Because it needs to be implanted in the body, the selection of the carrier material is particularly important.

[0006] Implants typically consist of a drug core and a silicone rubber tube. Conventional implant drug cores are generally divided into two types: one is a rod core filled with powdered drugs. Filling with powdered drugs has problems such as significant drug loss, difficulty in controlling the uniformity of drug filling, and noticeable burst release during drug release. The other is a silicone rubber skeleton rod core, which requires molding by high-temperature vulcanization during its manufacturing process. This rod core is heat-sensitive and clearly not suitable for drugs that are easily denatured at high temperatures.

[0007] Conventional silicone rubber implants use silicone rubber tubing that is not perforated. The silicone rubber tubing forms pores through its own cross-linked network structure. External moisture enters the silicone rubber tubing through these pores, dissolving drugs to form a solution. The drug solution first diffuses into the silicone rubber tubing wall and is then adsorbed onto the silicone rubber tubing wall. Because the polarity of silicone rubber is very low, only drugs with very low polarity can complete this adsorption process and further diffuse, while drugs with very high polarity cannot diffuse to the outside of the silicone rubber tubing. Furthermore, due to the properties of the silicone rubber itself and the size of the network pores in the silicone rubber tubing, only low molecular weight drugs with low polarity and a molecular weight of less than 800 and water molecules can permeate. However, it has a clear blocking effect on drugs with a molecular weight of more than 800, and is therefore not suitable for high molecular weight drugs.

[0008] Therefore, in order to solve the above problems, there is an urgent need for research and development of implants that can be applied to various types of drugs. [Overview of the project] [Problems that the invention aims to solve]

[0009] The present invention primarily aims to overcome the drawback of conventional silicone rubber materials, which have difficulty achieving both mechanical performance and water permeability simultaneously. It provides a silicone rubber material, a method for manufacturing the same, as well as a silicone rubber tube, an implant, a method for manufacturing the same, and applications. The silicone rubber material according to the present invention satisfies the mechanical properties and increases the water permeability of the silicone rubber tube, thereby improving the amount of drug released and overcoming the drawback of low in vitro release rates in conventional technology. [Means for solving the problem]

[0010] This invention solves the above technical problems by the following technical proposal.

[0011] The present invention provides a raw material composition for a silicone rubber material, based on parts by weight, 100 copies of R-vinylpolysiloxane, 10 to 80 parts of reinforcing agent, Including 0.000002 to 1 part catalyst, Here, R in the R-vinylpolysiloxane is a substituted or unsubstituted C1-C5 linear or branched alkane, or a substituted or unsubstituted C6-C 20 It is an aromatic hydrocarbon, The vinyl group content in the R-vinylpolysiloxane is 0.1 mol% to 0.5 mol%, The components contained in the aforementioned reinforcing agent include hydrophilic groups, The Si-H group content in the hydrogen-containing silicone oil is 0.18 mol% to 1.6 mol%, The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinylpolysiloxane is (0.5~10):1. Optionally, it further comprises an inhibitor, and the inhibitor is a substance capable of suppressing the occurrence of the addition reaction between the R-vinyl polysiloxane and the hydrogen-containing silicone oil.

[0012] In the present invention, R in the R-vinyl polysiloxane may be a substituted or unsubstituted C1-C5 linear alkane, such as a methyl group.

[0013] When R is methyl, the R-vinyl polysiloxane is methyl vinyl polysiloxane.

[0014] In the present invention, the structural formula of the R-vinyl polysiloxane may be as follows. [Chemical Formula] Here, m, n, and p are natural numbers, R1 and R2 may be common substituents in the art, and R and R' may be common capping groups in the art.

[0015] For example, when R1=R2=CH3, it is dimethylpolysiloxane, For example, when R1=CH3 and R2=CH=CH2, it is methyl vinyl polysiloxane, For example, when R1=Ph and R2=CH=CH2, it is methyl phenyl vinyl polysiloxane, For example, when R1=CH3CH2CF3 and R2=CH=CH2, it is fluorine-containing polysiloxane, For example, when R1=CH3CH2CN and R2=CH=CH2, it is nitrile polysiloxane.

[0016] In the present invention, the content of vinyl groups in the R-vinyl polysiloxane is preferably 0.15 mol% to 0.3 mol%, for example 0.18 mol% or 0.23 mol%.

[0017] In the present invention, the vinyl group content in the R-vinylpolysiloxane refers to the molar percentage of vinyl groups in the R-vinylpolysiloxane.

[0018] In the present invention, the polysiloxane may be any one of silicone rubber, silicone oil, and silicone resin, and is preferably silicone rubber.

[0019] In the present invention, the amount of the reinforcing agent may be 20 to 70 parts by weight, for example, 30 parts, 40 parts, 45 parts, or 50 parts.

[0020] In the present invention, the water contact angle of the reinforcing agent may be ≤90°, for example, 14-90°, 16-35°, or ≤25°. The water contact angle in the present invention is the static water contact angle of the material, and its measurement is performed by testing using the principle of optical projection. During use, the volume of the water droplet is set using test software, then a syringe needle drops the set volume of water droplets onto the surface of the test sample, and the image of the droplet is projected onto an automated image analysis system using a screen micrometer under the background of an LED light source for measurement. In the present invention, the hydrophilic group may have an atomic group that is soluble in water or readily compatible with water, which is common in the art. For example, one or more of the following oxygen-containing groups that can form hydrogen bonds with water molecules: hydroxyl group, mercapto group, aldehyde group, ketone group, ether bond, block polyether, carboxylic acid group, carboxylic acid ester group, sulfate group, sulfone group, sulfinic acid group, sulfonic acid group, sulfonamide, sulfonic acid ester, thioether, phosphate group, phosphate amide group, phosphate imide group, phosphate ester group, phosphino group, amino group, imino group, tertiary amino group, quaternary ammonium group, nitrile group, cyanate group, thiocyanate group, amide group, and other oxygen-containing groups that can form hydrogen bonds with water molecules.

[0021] Here, the hydroxyl group may be an alcoholic hydroxyl group or a phenolic hydroxyl group.

[0022] In the present invention, the reinforcing agent may be one or more of the following: silica, hydroxyapatite, diatomaceous earth, quartz powder, silica fine powder, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium oxide, titanium dioxide, titanium dioxide, carbon black, zinc oxide, titanium dioxide, clay, lignin, carbonate, and kaolin. The effect of the reinforcing agent is to increase the water permeability of the silicone rubber material and to guarantee the mechanical performance of the silicone rubber material.

[0023] Here, the silica is preferably hydrophilic silica or a mixture of hydrophilic silica and hydrophobic silica.

[0024] The hydrophilic silica is preferably one or more of the hydrophilic vapor-phase silicas, such as hydrophilic vapor-phase silica N20, hydrophilic silica TH-a200, hydrophilic vapor-phase silica A380, hydrophilic vapor-phase silica A300, T30 hydrophilic vapor-phase silica, T40 hydrophilic vapor-phase silica, and V15 hydrophilic vapor-phase silica.

[0025] As a reinforcing agent for addition-type polysiloxanes, hydrophilic gas-phase silica is a white, fluffy powder with active hydroxyl groups on its surface. These hydroxyl groups readily bond to and adsorb polysiloxanes via hydrogen bonds and van der Waals forces, indirectly increasing the crosslinking density between reacting molecules and thereby providing reinforcement. However, compared to hydrophobic silica, hydrophilic silica is unfavorable in terms of the mechanical performance of silicone rubber tubes. Hydrophilic silica has not undergone silanization, and the silanol groups contained on its surface readily introduce moisture during the manufacturing process, leading to the formation of bubbles in the manufactured silicone rubber tubes, which affects the mechanical properties and release of the silicone rubber tubes. This invention aims to significantly improve the drug release rate of silicone rubber materials while satisfying the mechanical properties of silicone rubber tubes, by modifying the formulation of the silicone rubber material and optimizing the manufacturing process.

[0026] 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.

[0027] In the present invention, the hydrogen-containing silicone oil may be a hydrogen-containing silicone oil that is common in the art. The hydrogen-containing silicone oil in the present invention undergoes a crosslinking reaction with R-vinylpolysiloxane as a crosslinking agent, and the addition reaction between Si-H in the crosslinking agent and -CH=CH2- in R-vinylpolysiloxane allows linear R-vinylpolysiloxane polymers to be linked together and crosslinked to form a three-dimensional network structure.

[0028] In the present invention, the mass of the hydrogen-containing silicone oil is calculated by the following formula (1).

number

[0029] In the present invention, the amount of hydrogen-containing silicone oil used is 0.3 to 5 parts, preferably 0.3 to 3 parts, for example, 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts, or 1.70 parts.

[0030] In the present invention, the Si-H group content in the hydrogen-containing silicone oil may be 0.18 to 1.2 mol%, for example, 0.75 mol%.

[0031] In the present invention, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinylpolysiloxane may be (0.5 to 8):1, preferably (0.8 to 5):1, for example 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, or 3:1.

[0032] In the present invention, the catalyst may be a catalyst that is common in the art and capable of catalyzing the addition reaction between methyl vinylpolysiloxane and hydrogen-containing silicone oil, such as a platinum catalyst.

[0033] Here, the concentration of platinum in the platinum catalyst is 1 × 10⁻⁶ 3 ~1 × 10 5 ppm, for example, 1 × 10⁻¹⁶ 3 ppm, 1 × 10⁻¹⁰ 4 The concentration can also be ppm, where ppm refers to a platinum mass concentration of one part per million in a platinum catalyst.

[0034] In the present invention, the amount of catalyst used is preferably 0.00001 to 0.5 parts, for example, 0.00001 parts, 0.0098 parts, or 0.21 parts.

[0035] In the present invention, the raw material composition of the silicone rubber material may further contain an inhibitor, the action of which the inhibitor is to suppress the addition reaction between R-vinylpolysiloxane and hydrogen-containing silicone oil at room temperature.

[0036] In the present invention, the inhibitor may be an acetylene alcohol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol, or for example, 2-methyl-3-butyne-2-ol.

[0037] In the present invention, the amount of the inhibitor by weight may be 0.03 to 2.0 parts, for example, 0.69 parts or 0.7 parts.

[0038] In the present invention, PHR refers to parts by mass of each specific component corresponding to 100 parts by mass of R-vinylpolysiloxane (e.g., methylvinylpolysiloxane).

[0039] In some specific embodiments, the raw material composition of the silicone rubber material may include the following components, where the Si-H group content of the hydrogen-containing silicone oil is 0.75%. [Table 0-1]

[0040] In some specific embodiments, the raw material composition of the silicone rubber material may include the following components, where the Si-H group content of the hydrogen-containing silicone oil is 0.75%. [Table 0-2]

[0041] In some specific embodiments, the raw material composition of the silicone rubber material may include the following components, where the Si-H group content of the hydrogen-containing silicone oil is 0.75%. [Table 0-3]

[0042] In some preferred embodiments, the raw material composition of the silicone rubber material is 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.18 mol%, 30 parts hydrophilic silica, 1.33 parts of hydrogen-containing silicone oil in which the molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane is 1.5:1, 0.0098 parts of platinum catalyst (concentration of 3000 ppm) and It may also contain 0.69 parts of 2-methyl-3-butynic acid-2-ol.

[0043] In some preferred embodiments, the raw material composition of the silicone rubber material is 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.18 mol%, 30 parts hydrophilic silica, 1.33 parts of hydrogen-containing silicone oil in which the molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane is 1.5:1, 0.01 parts of platinum catalyst (concentration of 3000 ppm) and It may also contain 0.69 parts of 2-methyl-3-butynic acid-2-ol.

[0044] In some preferred embodiments, the raw material composition of the silicone rubber material is 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.18 mol%, 20 parts hydroxyapatite and 20 parts of HB-615 hydrophobic vapor-phase silica, 1.33 parts of hydrogen-containing silicone oil in which the molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane is 1.5:1, 0.21 parts of platinum catalyst (concentration of 3000 ppm) and It may also contain 0.98 parts of 2-methyl-3-butynic acid-2-ol.

[0045] In some specific embodiments, the raw material composition of the silicone rubber material is 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.17 mol%, 20 parts hydrophilic vapor-phase silica N20, 20 parts of hydrophobic vapor-phase silica R106, A hydrogen-containing silicone oil having a Si-H group content of 0.75% and a molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane of 1.2:1, 0.00001 parts of platinum catalyst, It may also contain 0.7 parts of 2-methyl-3-butynic acid-2-ol.

[0046] The present invention further provides a method for manufacturing a silicone rubber material, which uses one of the following methods.

[0047] Method 1: S1. Mix the R-vinylpolysiloxane and the reinforcing agent to obtain mixture A. 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, component A2 is mixed with the catalyst to obtain component B2, and optionally, component B1 further contains an inhibitor. S3. The component B1 and the component B2 are mixed to obtain a mixture B, and an addition reaction is carried out with a catalyst to obtain the silicone rubber material.

[0048] Method 2: The silicone rubber material is obtained by performing a catalytic addition reaction on the raw material composition, the raw material composition comprising R-vinylpolysiloxane, a reinforcing agent, a hydrogen-containing silicone oil, and a catalyst, and optionally further comprising an inhibitor.

[0049] In the present invention, the reinforcing agent may be pretreated by a method common in the art, wherein the pretreatment method is preferably drying at 90 to 220°C (e.g., 130°C) for 1 to 24 hours (e.g., 24 hours) to prepare for use, for example, the pretreatment method is drying at 130°C for 24 hours.

[0050] In the present invention, the R-vinylpolysiloxane may be pretreated by a method common in the art, preferably by drying at 20 to 90°C for 1 to 24 hours to prepare for use, for example, by drying at 40°C for 12 hours.

[0051] In step S1, the mixing step may be a process in which the reinforcing agent is added to the R-vinylpolysiloxane in small amounts multiple times and kneaded, followed by thinning by extrusion.

[0052] In step S2, the method for producing component B1 may involve re-kneading component A1 in an open roll with a roll gap parameter of 1 unit, adding one drop each of the hydrogen-containing silicone oil and the inhibitor, setting different roll gaps after addition, performing triangular folding and thin passing, removing and leaving for 24 hours to prepare for use.

[0053] In step S2, the method for producing component B2 may involve re-kneading component A2 in an open roll with a roll gap parameter of 1 unit, adding the catalyst drop by drop, continuously shortening the roll gap, passing the mixture through a thin layer, removing it, and leaving it for 24 hours to prepare it for use.

[0054] In step S3, the mass ratio of component B1 to component B2 in the mixture B may be 1:1.

[0055] In step S3, the method for producing the mixture B may be to place component B1 and component B2 into an open roll, mix and extrude, and pass through six times.

[0056] In step S3, the step of the addition reaction with the catalyst may be a step of sequentially performing a first vulcanization treatment and a second vulcanization treatment on the mixture B, and preferably further includes a third vulcanization treatment.

[0057] Here, the temperature of the first vulcanization treatment may be 200°C to 340°C, for example, 250°C. The temperature of the first vulcanization treatment is also called the pre-drying tunnel temperature. After the silicone rubber material is extruded from the mold opening of the extruder, it passes through a short pre-drying tunnel (a vertical hot air vulcanization tunnel with a length of 0.8 m). This is the first vulcanization treatment. The inhibitor in the silicone rubber material decomposes at high temperature, turns into gas, and volatilizes. At this time, the catalyst starts working and catalyzes the progress of the addition reaction. At this time, the silicone rubber material is initially vulcanized and molded. The length of the pre-drying tunnel is short, and its main function is to quickly vulcanize and mold the silicone rubber material in a short time, preventing the silicone rubber material from being compressed and deformed by gravity as it is transported on the conveyor belt, which would cause flattening and dimensional errors in the tube.

[0058] Here, the duration of the first vulcanization treatment may be 2s to 30s.

[0059] Here, the first vulcanization treatment may be carried out in a vertical hot air vulcanization tunnel. The first vulcanization treatment allows for preliminary high-temperature molding of the rubber material.

[0060] Here, the temperature of the second vulcanization treatment may be 180°C to 280°C, for example, 220°C, 240°C, 260°C, or 280°C. The temperature of the second vulcanization treatment may also be called the rear drying tunnel temperature. After the silicone rubber material is initially vulcanized and molded in the front drying tunnel, the reaction time is short, resulting in incomplete crosslinking of the silicone rubber material. Therefore, it is subsequently towed by a conveyor belt through a long rear drying tunnel (a horizontal hot air vulcanization tunnel with a length of 2.5 m), which is a second vulcanization treatment that allows the addition reaction to proceed more completely, further vulcanizing the silicone rubber material and achieving good mechanical performance.

[0061] Here, the time for the second vulcanization treatment may be 0.1 min to 5 min.

[0062] Here, the second vulcanization treatment may be carried out in a horizontal hot air vulcanization tunnel. The second vulcanization treatment can sufficiently vulcanize the rubber material.

[0063] Here, the temperature of the third vulcanization treatment may be 150°C to 240°C, for example, 180°C. The vulcanization temperature has a significant effect on the mechanical properties and appearance of the silicone rubber material. If the temperature is too low, vulcanization will be insufficient, the silicone rubber material will become too soft and easily deformable, and its mechanical properties will deteriorate. If the temperature is too high, the silicone rubber material is prone to overvulcanization, becoming brittle, easily fractured, and having poor elasticity.

[0064] In the present invention, the vulcanization principle of the two-component addition-type polysiloxane is as follows. The two-component addition-type room-temperature vulcanizable polysiloxane uses, for example, vinyl dimethicone 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), vinyl groups and hydrogen groups undergo a hydrosilylation reaction to form a crosslinked network structure. This crosslinked structure can control drug release, and the reaction equation is as follows. [ka]

[0065] While raw rubber can react at room temperature after being mixed with a crosslinking agent and catalyst, the kneading and processing of the rubber material requires a certain amount of time. If the reactants harden prematurely during the process, the desired shape and properties cannot be obtained. This is especially true for addition polysiloxanes. Therefore, catalytic reactions are generally required to be largely inactive before vulcanization (mixing at room temperature) and to react rapidly once the vulcanization temperature is reached. The usual method to inhibit the reaction is to add an inhibitor. Inhibitors can form complexes with platinum catalysts in certain forms, and effective inhibitors can be left with the rubber material for a considerable amount of time and cannot be vulcanized unless heated to a certain vulcanization temperature. Widely used inhibitors include well-compatible acetylene alcohol compounds, nitrogen-containing compounds, and organic peroxides.

[0066] The present invention further provides a silicone rubber material which is manufactured by the manufacturing method described above.

[0067] The present invention further provides a method for producing a silicone rubber tube, wherein a tubular shape is formed from the mixture B described above by an extrusion process, and then an addition reaction with a catalyst is performed to obtain the silicone rubber tube. Alternatively, the addition reaction process using the catalyst described above is carried out in a tubular mold to obtain the silicone rubber tube.

[0068] The present invention further provides a silicone rubber tube which is manufactured by the method described above.

[0069] The present invention further provides an implant comprising the silicone rubber tube described above and a drug core, the drug core comprising a drug active ingredient.

[0070] In the present invention, the drug active ingredient may be a sustained-release drug ingredient that is common in the art and requires long-term drug release, and is preferably an active drug with a solubility of ≤100 mg / mL (with water as the solvent).

[0071] In the present invention, the drug-active ingredient may include a drug-active ingredient that acts on the reproductive system, or a drug-active ingredient that acts on the urinary system, or a drug-active ingredient that acts on chronic diseases relating to metabolism and nutrition, or a drug-active ingredient for treating chronic diseases relating to connective tissue and rheumatism, or a drug-active ingredient for treating hyperlipidemia, tumors, neuropsychiatric disorders, chronic dental diseases (dental caries, periodontal disease), simple obesity, chronic lower back pain, or leukemia, or a drug-active ingredient that acts on the circulatory system, or a drug-active ingredient that acts on the respiratory system, or a drug-active ingredient that acts on the digestive system, or a drug-active ingredient that acts on the blood system, or a drug-active ingredient that acts on the endocrine system.

[0072] Here, the drug-active ingredient acting on the reproductive system may include a drug-active ingredient for contraception or a steroid estrogen.

[0073] The aforementioned pharmacoactive ingredient for contraception may be one of the common ones in the art, and preferably includes levonorgestrel, gestodene, or gestrinone.

[0074] The steroid estrogen is preferably estradiol.

[0075] Here, the drug-active ingredient acting on the urinary system preferably includes a drug-active ingredient for the treatment of chronic nephritis, chronic renal failure, or chronic prostatitis.

[0076] The drug active ingredient for the treatment of chronic prostatitis is preferably a nonsteroidal anti-inflammatory drug, and more preferably ibuprofen. Generally, the drugs for the treatment of chronic prostatitis include antibiotics (e.g., fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (e.g., erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracyclines), α-receptor antagonists (e.g., doxazosin, terazosin, etc.), and nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, diclofen). These may include medications such as Nac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib, analgesics (e.g., acetaminophen), opioids (e.g., buprenorphine, fentanyl, nalbufine, pentazocine), neuropathic pain medications (e.g., 5-hydroxytryptamine, duloxetine, venlafaxine), antiepileptic drugs (e.g., pregabalin), and M receptor antagonists (e.g., solifenacin, tolterodine).

[0077] The drugs used to treat chronic nephritis may generally include angiotensin-converting enzyme inhibitors (e.g., benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor antagonists (e.g., irbesartan, valsartan, losartan, etc.), calcium channel antagonists (e.g., amlodipine, felodipine, nifedipine, etc.), β-receptor antagonists (e.g., atenolol, bisoprolol, carvedilol, propranolol, etc.), diuretics (e.g., furosemide, spironolactone, hydrochlorothiazide, bendroflumethiazide, bumetanide, etc.), immunosuppressants (e.g., prednisone, leflunomide, methylprednisolone, cyclophosphamide, dexamethasone, etc.), and statin-type dyslipidemia treatments (e.g., fluvastatin, simvastatin, pravastatin).

[0078] The drugs used to treat chronic renal failure may generally include angiotensin-converting enzyme inhibitors (e.g., benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor antagonists (e.g., irbesartan, valsartan, losartan, etc.), diuretics (e.g., furosemide, spironolactone, hydrochlorothiazide, bendroflumethiazide, bumetanide, etc.), iron preparations (e.g., ferrous fumarate), total amino acids, α-keto acids, and recombinant human erythropoietin.

[0079] Here, the pharmacoactive ingredients that act on chronic diseases relating to metabolism and nutrition preferably include pharmacoactive ingredients for antidiabetes, treatment of nutritional deficiencies, antigout, or anti-osteoporosis.

[0080] The drug-active component for antigout is preferably a gout attack suppressant, such as colchicine, indomethacin, diclofenac, ibuprofen, lofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, p-aminosalicylic acid, salsalate, or benolilate, and more preferably ibuprofen. Generally, the drug for antigout may also be a uric acid excretion agent (e.g., benzbromarone, probenecid) or a uric acid production inhibitor (e.g., allopurinol).

[0081] The aforementioned antidiabetic drugs may generally be type 1 diabetes medications (e.g., insulin) or type 2 diabetes medications. The type 2 diabetes medications may be sulfonylurea drugs (e.g., glimepiride, glikidone), glinide drugs (e.g., repaglinide, nateglinide), metformin drugs (e.g., metformin), α-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).

[0082] The drugs used to treat nutritional deficiencies may generally include drugs for gastrointestinal disorders (e.g., omeprazole, mosapride) or nutritional supplements (e.g., vitamin E).

[0083] The aforementioned drugs for treating osteoporosis may generally include bisphosphonate drugs (e.g., sodium alendronate, sodium ibandronate, sodium pamidronate, aminobisphosphonate, disodium clodronate, sodium zoledronate, sodium risedronate), calcitonin drugs (e.g., calcitonin salmon), estrogen drugs (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) (e.g., raloxifene, benzothiophene), RANKL inhibitors, parathyroid hormone drugs, glutamine monofluorophosphate drugs, strontium salt drugs (e.g., strontium ranerate), active vitamin D and its analogues (e.g., calcitriol, α-calciferol), and vitamin K (e.g., menatetrenone).

[0084] Here, the pharmacoactive ingredients for treating chronic diseases relating to connective tissue and rheumatism preferably include pharmacoactive ingredients for the treatment of rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, vasculitis, idiopathic inflammatory muscle disease, systemic scleroderma, or osteoarthritis.

[0085] The pharmacoactive ingredients for the treatment of rheumatoid arthritis are preferably nonsteroidal anti-inflammatory drugs, such as aspirin, meloxicam, celecoxib, ibuprofen, nimeslide, and nabumetone, and more preferably meloxicam or ibuprofen. Generally, the drugs for the treatment of rheumatoid arthritis may also be glucocorticoids (e.g., hydrocortisone, dexamethasone, prednisone) or slow-acting antirheumatic drugs (e.g., methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide).

[0086] The pharmacoactive ingredient for the treatment of osteoarthritis is preferably an analgesic, such as ibuprofen, diclofenac, meloxicam, celecoxib, loxoprofen sodium, or nimeslide, and more preferably ibuprofen or meloxicam. Generally, the drug for the treatment of osteoarthritis may also be a cartilage-nourishing agent or an opioid (such as oxycodone or tramadol hydrochloride).

[0087] The drugs used to treat systemic lupus erythematosus mentioned above may generally include nonsteroidal anti-inflammatory drugs (e.g., naproxen, fenvid), antimalarial drugs, glucocorticoids (e.g., prednisone acetate, methylprednisolone), immunosuppressants (e.g., methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), and biological agents (e.g., rituximab, belimumab).

[0088] The drugs used to treat ankylosing spondylitis may generally include nonsteroidal anti-steroidal drugs (e.g., diclofenac sodium, etoricoxib, celecoxib, nabumetone, imurecoxib), disease-modifying antirheumatic drugs (e.g., sulfasalazine, methotrexate, hydroxychloroquine), glucocorticoids (e.g., prednisone, prednisolone, diprospan), and biological agents such as TNF-α antagonists (e.g., etanercept).

[0089] The drugs used to treat Sjögren's syndrome may generally include systemic agents (e.g., levamisole, transfer factor coenzyme Q10, thymosine), glucocorticoids (e.g., prednisone), and immunosuppressants (e.g., hydroxychloroquine, azathioprine, iguratimod).

[0090] The drugs used to treat vasculitis may generally include glucocorticoids (e.g., prednisone, methylprednisolone, dexamethasone) and immunosuppressants (e.g., cyclophosphamide, cyclosporine, azathioprine).

[0091] The drugs used to treat the aforementioned idiopathic inflammatory muscle disease may generally be glucocorticoids (e.g., dexamethasone, prednisone, hydrocortisone, methylprednisolone) or immunosuppressants (e.g., cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolate esters).

[0092] The drugs used to treat systemic sclerosis may generally include antifibrotic agents (e.g., colchicine), vasoactive agents (e.g., nifedipine, adalat), and several other commonly used drugs (e.g., naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, tocilizumab).

[0093] Here, the pharmacoactive ingredient for the treatment of neuropsychiatric disorders may generally be a drug for the treatment of schizophrenia, an antidepressant, a drug for the treatment of opioid abuse, or a drug for the treatment of anxiety disorders. Preferably, it is a drug for the treatment of schizophrenia, more preferably a phenothiazine (e.g., chlorpromazine), a thioxanthene (e.g., chlorprothixen), a butyrophenone (e.g., haloperidol), a dibenzodiazepine (e.g., olanzapine, clozapine), a benzoisoxazole (e.g., risperidone, paliperidone), a benzoisothiazole (e.g., ziprasidone), a dibenzothiazepine (e.g., quetiapine), or a quinolone (e.g., aripiprazole), and even more preferably a benzoisoxazole (e.g., paliperidone).

[0094] The aforementioned antidepressants may generally include tricyclic antidepressants (e.g., imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (e.g., moclobemide), selective 5-hydroxytryptamine reuptake inhibitors (e.g., sertraline), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (e.g., venlafaxine), 5-hydroxytryptamine blockade and reuptake inhibitors (e.g., trazodone), norepinephrine and dopamine reuptake inhibitors (e.g., bupropion), norepinephrine inhibitors (e.g., reboxetine), and α2 adrenergic receptor antagonists (e.g., mirtazapine).

[0095] The aforementioned drugs for treating opioid abuse may generally be buprenorphine or methadone.

[0096] The aforementioned medications for treating anxiety disorders may generally include benzodiazepines (e.g., diazepam), 5-HT1A receptor partial agonists (e.g., buspirone), β-adrenergic receptor antagonists (e.g., propranolol), and valproates.

[0097] Here, the drugs used to treat hyperlipidemia may generally include statins (e.g., simvastatin, atorvastatin, pravastatin), fibrates (e.g., fenofibrate, bezafibrate, gemfibrozil), and nicotinic acid derivatives (e.g., nicotinic acid).

[0098] Here, the aforementioned antitumor drugs generally include anti-breast cancer drugs (e.g., azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, adriamycin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol, cetuximab, or leuprorelin), anti-prostate cancer drugs (e.g., degarelix, leuprorelin, histrelin, flutamide, estramustine, cyproterone), anti-ovarian cancer drugs (e.g., carboplatin, topotecan, methotrexate), anti-rectal cancer drugs (e.g., panitumumab), anti-colon cancer drugs (e.g., bevacizumab, oxaliplatin), anti-liver cancer drugs (e.g., sorafenib), anti-lung cancer drugs (e.g., erlotinib, gefitinib, docetaxel), and anti-kidney cancer drugs (e.g., These may include, for example, pazopanib, everolimus, temsirolimus), anti-gastric cancer drugs (e.g., fluorouracil, mitomycin, cisplatin, adriamycin, etoposide), anti-pancreatic cancer drugs (e.g., nimotuzumab), anti-esophageal cancer drugs (e.g., docetaxel, paclitaxel, cisplatin, gemcitabine, tegafur / gimeracil / oteracil potassium, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), anti-cutaneous cancer drugs (e.g., fluorouracil), anti-lymphoma drugs (e.g., vincristine, bexarotene, dacarbazine, etoposide), anti-myeloma drugs (e.g., bortezomib), anti-cervical cancer drugs (e.g., bleomycin), or anti-bladder cancer drugs (e.g., epirubicin, BCG vaccine).

[0099] Here, the drugs used to treat chronic dental diseases (e.g., dental caries, periodontal disease) can generally be divided into nitroimidazole drugs (e.g., metronidazole, tinidazole, ornidazole), penicillin drugs, and other commonly used drugs (minocycline, chlorhexidine acetate).

[0100] Here, the drug for treating simple obesity mentioned above may generally be orlistat.

[0101] Here, the pharmacoactive ingredient for the treatment of chronic lower back pain is preferably a nonsteroidal analgesic, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen / codeine, or diclofenac, and more preferably ibuprofen or meloxicam. The drugs used to treat leukemia generally include drugs that inhibit nucleic acid biosynthesis (e.g., cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect the DNA structure and function of cancer cells (e.g., busulfan, mitomycin, chlorambucil, phenylalanine nitrogen mustard, cyclophosphamide), drugs that inhibit transcription processes and interfere with RNA synthesis (e.g., daunorubicin, doxorubicin, adriamycin, acralubicin), drugs that suppress protein synthesis and function (e.g., vindesine, vincristine, L-asparaginase, homohalingotonin), and other commonly used drugs (e.g., interferon, fludarabine, arsenite, etoposide, carmustine).

[0102] Here, the aforementioned pharmacoactive ingredient acting on the circulatory system preferably includes a pharmacoactive ingredient for the treatment of chronic heart failure, coronary heart disease, congenital heart disease, or chronic infective endocarditis, or chronic pericarditis. The aforementioned pharmacoactive ingredients for the treatment of coronary heart disease generally include drugs that improve the symptoms of angina (e.g., puerarin, isosorbide mononitrate), antiplatelet aggregation agents (e.g., aspirin, clopidogrel sulfate, ticagrelor), lipid-lowering and plaque-stabilizing drugs (e.g., atorvastatin, rosuvastatin, pravastatin), drugs that suppress sympathetic nerve activity (e.g., metoprolol, bisoprolol fumarate), and drugs that improve myocardial remodeling (e.g., angiotensin-converting enzyme inhibitors and It may be an angiotensin II receptor antagonist, preferably a drug that improves the symptoms of angina pectoris, and more preferably puerarin. The pharmacoactive ingredient for the treatment of chronic heart failure may generally be a cardiotonic (e.g., digitalis, digoxin, cedilanide), a vasodilator (e.g., sodium nitroprusside, nitroglycerin), a converting enzyme inhibitor (e.g., enalapril, lisinopril, etc.), or a diuretic (e.g., furosemide, hydrochlorothiazide, spironolactone).

[0103] The pharmacoactive ingredients for the treatment of congenital heart disease mentioned above may generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide, or coenzyme Q10.

[0104] The drug-active components for the treatment of chronic infective endocarditis may generally be antibiotics (e.g., vancomycin, cephalosporins, penicillins, aminoglycosides).

[0105] The pharmacoactive ingredient for the treatment of chronic pericarditis may generally be digitalis.

[0106] Here, the aforementioned pharmacoactive ingredients acting on the respiratory system may generally include pharmacoactive ingredients for the treatment of chronic obstructive pulmonary emphysema, asthma, chronic cor pulmonale, chronic respiratory failure, silicosis, or pulmonary fibrosis.

[0107] The pharmacoactive ingredients for the treatment of chronic obstructive pulmonary emphysema mentioned above may generally include bronchodilators (including β-receptor agonists and anticholinergics), inhaled corticosteroids (e.g., budesonide, fluticasone), theophylline-based asthma medications (e.g., theophylline), and expectorants (e.g., carbocysteine, fudosteine). Glucocorticoids and antibiotics (e.g., penicillins, glycosides, and cephalosporins) may also be used as appropriate, depending on the disease.

[0108] The pharmacoactive ingredients for the treatment of asthma mentioned above may generally include commonly used inhalants (e.g., beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (e.g., salbutamol), sustained-release theophylline, leukotriene modulators (which can be used in combination), anticholinergics (e.g., isopropylscopolamine), and antihistamines (e.g., astemizole, ketotifen).

[0109] The pharmacoactive ingredients for the treatment of chronic cor pulmonale, as mentioned above, may generally include antibiotics (e.g., amoxicillin, ceftizoxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (e.g., selective β2 receptor agonists, theophylline drugs), nonspecific airway deinflammatory agents (e.g., prednisone), inhalants (e.g., Becotide), and respiratory stimulants (e.g., Lobelin, doxapram, Almitrin / Lauvasin, etc.).

[0110] The pharmacoactive ingredients for the treatment of chronic respiratory failure mentioned above may generally be bronchospasmodics and expectorants (e.g., salbutamol, acetylcysteine, etc.).

[0111] The aforementioned drug-active ingredients for the treatment of silicosis may generally include tetrandrin, acetylcysteine, aluminum preparations, polyvinylpyridine-N-oxide, and tandin.

[0112] The drug-active components for the treatment of pulmonary fibrosis mentioned above may generally include pirfenidone, nintedanib, glucocorticoids (e.g., methylprednisolone, prednisone), immunosuppressants (e.g., azathioprine, methotrexate, etc.), colchicine, interferon, ACE inhibitors, or statins.

[0113] Here, the aforementioned drug-active ingredients acting on the digestive system may generally include drug-active ingredients for the treatment of chronic gastritis, peptic ulcers, intestinal tuberculosis, chronic enteritis, chronic diarrhea, chronic hepatitis, cirrhosis, chronic pancreatitis, and chronic cholecystitis.

[0114] The drug-active components for the treatment of chronic gastritis may generally include analgesics (such as atropine and propantheline bromide), PPI proton pump inhibitors (e.g., lansoprazole and omeprazole) that can be used in cases of elevated gastric acid, H2 receptor antagonists (e.g., cimetidine, ranitidine, and aluminum hydroxide) that can be used in cases of mild symptoms, digestive stimulants (pancreatin may be added), and anticholinergics (such as metoclopramide and domperidone, and cholestyramine and sucralfate, which can bind to bile acids).

[0115] The aforementioned pharmacoactive ingredients for the treatment of peptic ulcers may generally be levofloxacin, tinidazole, or omeprazole.

[0116] The aforementioned drug-active ingredient for the treatment of intestinal tuberculosis may generally be rifampicin.

[0117] The pharmacoactive ingredients for the treatment of chronic enteritis may generally be anti-inflammatory analgesics, probiotics, or antispasmodic analgesics (e.g., atropine, propantheline bromide).

[0118] The drug-active ingredients for treating chronic diarrhea mentioned above may generally be antidiarrheal agents (e.g., smectite, diphenoxylate, loperamide), intestinal microbiological preparations (e.g., lactic acid bacteria, bifidobacteria), or antispasmodic analgesics (e.g., pinaverium bromide).

[0119] The drug active ingredients for the treatment of chronic hepatitis may generally include hepatoprotective agents (e.g., silymarin-based preparations, gomisi-based preparations, etc.), antifibrotic agents (e.g., oral herbal medicine preparations), antiviral agents (e.g., conventional interferon and polyethylene glycolated interferon), oral nucleoside antiviral agents (e.g., lamivudine, adefovir dipivoxil, terbivudine, entecavir), and immunosuppressants (azathioprine).

[0120] The drug-active components for the treatment of liver cirrhosis mentioned above may generally include hepatitis B treatments (e.g., nucleoside analogs), autoimmune hepatitis treatments (e.g., glucocorticoids), anti-inflammatory drugs, hepatoprotective drugs, anti-hepatic fibrotic drugs (e.g., reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, etc.), idiopathic bacterial peritonitis treatments (e.g., antibiotics), and portal hypertension treatments (e.g., carvedilol).

[0121] The pharmacoactive ingredients for the treatment of chronic pancreatitis may generally be analgesics (e.g., buprenorphine and fentanyl) or pancreatin-based therapeutic agents (e.g., pancreatin).

[0122] The drug-active ingredients for the treatment of chronic cholecystitis may generally be antibacterial and anti-inflammatory drugs (e.g., levofloxacin, ciprofloxacin, amoxicillin), antispasmodic and analgesic drugs, or cholagogues (e.g., ursodeoxycholic acid).

[0123] Here, the aforementioned drug-active components that act on the blood system may generally include drug-active components for the treatment of chronic anemia, chronic myeloid leukemia, and chronic lymphocytic leukemia.

[0124] The drugs used to treat chronic anemia as described above may generally include trace element drugs (e.g., folic acid, vitamin B12), bone marrow stimulants (e.g., strychnine nitrate, seclinin, hyoscyamine, etc.), cobamamide, glucocorticoids (prednisone, meprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (e.g., ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight dextran iron, carboxymaltose iron, isomaltose iron, glucuronate iron, nano-iron oxide, sorbitol iron, etc.), and erythropoiesis-promoting agents (recombinant human erythropoietin α, darbepoetin α, etc.).

[0125] The aforementioned drugs for the treatment of chronic myeloid leukemia may generally include tyrosine kinase inhibitors (e.g., imatinib, nilotinib, bosutinib, ponatinib, etc.) and homohalingonin.

[0126] The drugs used to treat chronic lymphocytic leukemia as described above may generally include chemotherapy drugs (e.g., nimustine, fludarabine, chlorambucil, bendamustine, etc.), molecularly targeted drugs (e.g., idelalisib, venetoclax, ibrutinib, imatinib, dasatinib, etc.), and monoclonal antibodies (e.g., ofatumumab, rituximab, obinutuzumab, alemtuzumab, etc.).

[0127] Here, the aforementioned drug-active components acting on the endocrine system may generally include drug-active components for the treatment of chronic lymphocytic thyroiditis, hyperthyroidism, and hypothyroidism.

[0128] The drugs used to treat chronic lymphocytic thyroiditis may generally be thyroxine derivatives (e.g., levothyroxine, thyroxine) or glucocorticoids (e.g., prednisone, meprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0129] The drugs used to treat hyperthyroidism may generally include thiouracil-based drugs (e.g., propylthiouracil, methylthiouracil, etc.), imidazole-based drugs (e.g., thiamazole, carbimazole, etc.), iodine and iodides (e.g., Lugol's solution, etc.), radioactive iodine (e.g., iodine 131, etc.), and β-receptor antagonists (e.g., metoprolol, atenolol, bisoprolol, carvedilol, propranolol, etc.).

[0130] The aforementioned drugs for treating hypothyroidism may generally be thyroxine-based (e.g., levothyroxine, levothyroxine sodium, thyroxine, etc.).

[0131] In the present invention, the method for producing the drug core may be to sequentially knead, extrude, and vulcanize the drug active ingredient and the polysiloxane.

[0132] Here, the polysiloxane comprises R-vinylpolysiloxane, hydrogen-containing silicone oil, a catalyst, and an inhibitor.

[0133] Here, the temperature of the vulcanization treatment may be 70°C to 160°C.

[0134] Here, the vulcanization treatment time may be 0.5 to 10 hours.

[0135] Here, the raw material composition for the drug core may include, on a basis of parts by weight, 100 parts of a drug active ingredient, 100 parts of R-vinylpolysiloxane, 0.21 parts of a catalyst, 0.98 parts of an inhibitor, and a hydrogen-containing silicone oil in which the molar ratio of Si-H to vinyl groups in the R-vinylpolysiloxane is 4.5:1.

[0136] The present invention provides a method for manufacturing the implant described above, which includes the steps of filling the silicone rubber tube with the drug core and sealing the ends to obtain the implant.

[0137] In the present invention, the drug core may be a skeletal rod core or a powder-type drug core.

[0138] If the drug core is a skeletal rod core, the length of the silicone rubber tube is 0.4 cm longer than the length of the skeletal rod core. To facilitate the sealing of the implant, 0.2 cm is left at each end of the silicone rubber tube.

[0139] If the drug core is a skeletal rod core, the filling method may preferably involve rapidly inserting the skeletal rod core while the silicone rubber tube is swollen, and the swelling can be achieved by immersing the silicone rubber tube in petroleum ether for 1 to 2 minutes. After the filling is completed, it is preferable to allow it to air dry for a further 12 to 24 hours, the purpose of which air drying is to completely volatilize any remaining petroleum ether.

[0140] If the drug core is a powder-type drug core, the filling method is preferably to seal one end of the silicone rubber tube and then fill it using a filling funnel.

[0141] In the present invention, the seal may be sealed with a sealant, and the sealant is preferably silicone rubber.

[0142] In the present invention, after the sealing is completed, the sealant is preferably left at room temperature for 12 to 24 hours to cure.

[0143] In the present invention, the silicone rubber tube is preferably further pre-treated, the pre-treatment method being to immerse it in 75% ethanol for 15 minutes, wash it several times with 75% ethanol, and then allow it to air dry.

[0144] The present invention further provides the application of the silicone rubber material or silicone rubber tube described above as a release rate regulating medium in sustained-release formulations.

[0145] The technical problem that this invention aims to solve is to overcome the drawback that the scope of application of conventional implants is narrow, and in particular there are almost no implants that can be used with highly soluble drugs, heat-sensitive drugs, or polymer drugs, by providing a rod core, a perforated implant, a manufacturing method, and applications. The implant of this invention is applicable to most drugs and can achieve long-term drug release. In this invention, after many experimental studies, the inventors obtained a rod core by press-molding the active drug and additives using a solid press molding method, solving the problem of drug waste or unstable drug release in powder-type drug cores, as well as solving the problem of drug instability in the manufacturing process of silicone rubber skeleton-type rod cores. After the silicone rubber tube is perforated, the amount of drug released is improved and the scope of application of the implant is expanded.

[0146] This invention solves the above technical problems by the following technical proposal.

[0147] The present invention provides a rod core for a perforated implant, which comprises a drug-containing layer, the drug-containing layer comprising an active drug and an additive. Here, the additive includes a sustained-release additive, and the molecular weight of the sustained-release additive is 1000 to 10 million. The ratio of the drug to the additive is 1:(0.01~100), and this ratio represents the mass ratio of the active drug to the additive in the drug-containing layer. Optionally, the rod core of the perforating implant further includes a push layer compounded on the drug-containing layer.

[0148] In the present invention, the active drug may include one or more drugs common in the art, such as high-molecular-weight drugs with good solubility, low-molecular-weight drugs with good solubility, high-molecular-weight drugs with poor solubility, and low-molecular-weight drugs with poor solubility.

[0149] Here, the highly soluble polymer drug may be an active drug common in this field, having a drug solubility > 10 mg / mL and a drug molecular weight greater than 800 Da, and preferably an active drug having a drug solubility > 30 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of exenatide, semaglutide, Centella asiatica total saponins, and human growth hormone.

[0150] Here, the low molecular weight drug with good solubility may be an active drug common in this field, having a drug solubility > 10 mg / mL and a drug molecular weight of 800 Da or less, and preferably an active drug having a drug solubility > 30 mg / mL and a drug molecular weight of 800 Da or less, such as metformin and / or adriamycin hydrochloride.

[0151] Here, the poorly solubility polymer drug may be an active drug common in this field, having a drug solubility ≤ 10 mg / mL and a drug molecular weight greater than 800 Da, preferably an active drug having a drug solubility ≤ 5 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of bovine insulin, paclitaxel, and levothyroxine sodium.

[0152] Here, the low molecular weight drug with poor solubility may be an active drug common in this field, having a drug solubility of ≤10 mg / mL and a drug molecular weight of 800 Da or less. Preferably, it includes one or more active drugs with a drug solubility of ≤5 mg / mL and a drug molecular weight of 800 Da or less, such as estradiol, gestodene, levonorgestrel, meloxicam, ganciclovir, puerarin, and paliperidone.

[0153] In the present invention, the weight-average molecular weight of the sustained-release additive is preferably 11 to 8 million, for example, 11.71, 10,000, 44,000, 200,000, 300,000, 400,000, or 7 million.

[0154] In the present invention, the sustained-release additive preferably includes a poorly soluble skeletal material and / or a hydrophilic gel material.

[0155] Here, the weight-average molecular weight of the sparingly soluble skeletal material is preferably 20 to 8 million, and preferably 30 to 7 million. Here, the poorly soluble skeletal material preferably includes one or more of the following: calcium alginate, methylcellulose, polyethylene, polyvinyl chloride, methacrylate-methyl acrylate copolymer, and ethylcellulose, for example, ethylcellulose. The methacrylate-methyl acrylate copolymer preferably includes one or more of the following: Eudoragit S100, Eudoragit L100, RL, RS, NE, and FS, for example, Eudoragit S100.

[0156] Here, the weight-average molecular weight of the hydrophilic gel material is 10 to 8 million, preferably 10,000 to 7 million.

[0157] Here, the hydrophilic gel material preferably includes one or more of hypromellose, polyoxyethylene, sodium alginate, chitosan, agar, xanthan gum, carbomer, polyvinyl alcohol, N-vinylamide polymer, polylactic acid-glycolic acid copolymer (PLGA), and polyethylene oxide. The hypromellose is preferably one or more of HPMC K100M, HPMC K15M, and HPMC K4M. The N-vinylamide polymer is preferably PVP K30 and / or PVPK90. The polyethylene oxide is preferably one or more of PEO N80, PEO N-750, PEO WSR N-12K, PEO WSR N-60K, PEO WSR 303, and PEO WSR 1105.

[0158] Here, if the sustained-release additive is a sparingly soluble skeletal material and a hydrophilic hydrogel material, the mass ratio of the sparingly soluble skeletal material to the hydrophilic hydrogel material is preferably 1:(0.01~100), for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, 1:80, or 1:100.

[0159] In one preferred embodiment, the active drug is insulin, and the additives are the sustained-release additive and the drug stabilizer, for example, HPMC K4M and trehalose. The mass ratio of the sustained-release additive to the additive may be 1:4.33.

[0160] In one preferred embodiment, the active drug is semaglutide, and the additives are the sustained-release additive and the fillers, such as HPMC K4M and MCC. The mass ratio of the sustained-release additive to the additive may be 1:4.33.

[0161] In one preferred embodiment, the active drug is metformin, and the additives are the sustained-release additive and the fillers, such as HPMC K4M and MCC. The mass ratio of the sustained-release additive to the additive may be 1:4.33.

[0162] In one preferred embodiment, the active drug is paliperidone, and the additives are the sustained-release additive and the fillers, such as HPMC K4M and MCC. The mass ratio of the sustained-release additive to the additive may be 1:4.33.

[0163] In one preferred embodiment, the active drug is exenatide, the additive is the sustained-release additive, and the sustained-release additive is preferably one or more of Eudragit S100, calcium alginate, ethylcellulose, PLGA, HPMCK 15M, and PEO N80, for example, ethylcellulose, or ethylcellulose and HPMCK 15M.

[0164] In one preferred embodiment, the active drug is metformin, the additive is the sustained-release additive, and the sustained-release additive preferably comprises one or more of ethylcellulose, HPMCK 15M, HPMCK 4M, and PEO N80, for example, HPMCK 15M, HPMCK 4M, or ethylcellulose and HPMCK 15M.

[0165] In one preferred embodiment, the active drug is semaglutide, and the sustained-release additive preferably comprises one or more of Eudragit S100, calcium alginate, ethylcellulose, PLGA, HPMCK 15M, and PEO N80, for example, ethylcellulose, or ethylcellulose and HPMCK 15M.

[0166] In one preferred embodiment, the active drug is levothyroxine sodium, and the additives preferably include the sustained-release additive and the fillers, such as PEO N-750 and MCC.

[0167] In the present invention, the ratio of the drug to the additive is preferably 1:(0.01~99), for example, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, or 1:80.

[0168] In the present invention, the additive preferably further comprises one or more of the following: a drug stabilizer, a filler, and a suspending agent.

[0169] Here, the drug stabilizer is preferably trehalose.

[0170] Here, the filler is preferably one or more of starch, dextrin, microcrystalline cellulose (MCC), and lactose.

[0171] Here, the suspending agent is preferably hydroxypropyl methylcellulose and / or polyethylene oxide.

[0172] Here, the mass ratio of the sustained-release additive to the additive is preferably 1:(0.01~100), for example, 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, 1:80, or 1:100.

[0173] In the present invention, the concentration of the active drug in the drug-containing layer may be set to a stepped concentration gradient. The gradient is preferably 1 to 50 steps, for example, 2, 3, 5, 10, 20, or 40 steps, and the stepped concentration gradient generally means that the concentration of each step is independent.

[0174] Here, if the gradient has three stages, the gradient is preferably set in order to a first-stage drug release module, a second-stage drug release module, and a third-stage drug release module, wherein the concentration of the active drug in the first-stage drug release module is preferably 0.1% to 50%, for example 2%, 5%, or 10%. The concentration of the active drug in the second-stage drug release module is preferably 1% to 80%, for example 10% or 20%. The concentration of the active drug in the third-stage drug release module is preferably 1% to 100%, for example 20% or 30%. The concentration of the active drug generally represents the percentage of the mass of the active drug relative to the mass of the stage drug release module.

[0175] In one preferred embodiment, the concentration of the active drug in the drug-containing layer is set in three stages, with the concentration of the active drug in the first stage drug release module being 2%, the concentration of the active drug in the second stage drug release module being 10%, and the concentration of the active drug in the third stage drug release module being preferably 20%.

[0176] In one preferred embodiment, the concentration of the active drug in the drug-containing layer is set in three stages, with the concentration of the active drug in the first stage drug release module being 2%, the concentration of the active drug in the second stage drug release module being 20%, and the concentration of the active drug in the third stage drug release module being preferably 30%.

[0177] In one preferred embodiment, the concentration of the active drug in the drug-containing layer is set in three stages, with the concentration of the active drug in the first stage drug release module being 10%, the concentration of the active drug in the second stage drug release module being 20%, and the concentration of the active drug in the third stage drug release module being preferably 30%.

[0178] In one preferred embodiment, the concentration of the active drug in the drug-containing layer is set in three stages, with the concentration of the active drug in the first stage drug release module being 5%, the concentration of the active drug in the second stage drug release module being 20%, and the concentration of the active drug in the third stage drug release module being preferably 30%.

[0179] In the present invention, if the rod core further includes a push layer, the raw materials of the push layer preferably include an expanding material and a penetration-promoting substance.

[0180] Here, the expanding material in the push layer may be polyethylene oxide, preferably one or more of the following polyethylene oxides having a weight-average molecular weight of 10 to 7 million: PEO N-80, PEO N-750, PEO WSR 1105, PEO WSR 303, PEO N-12K, and PEO N-60K.

[0181] Here, the permeation-promoting substance in the push layer may be any substance that is common in the art and can improve osmotic pressure, preferably one or more of mannitol, lactose, fructose, glucose, and NaCl, for example, NaCl.

[0182] Here, the mass ratio of the expanding material to the penetration-promoting substance in the push layer is preferably (0.01~100):1, for example 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1, or 100:1.

[0183] In the present invention, if the rod core further includes a push layer, the mass ratio of the drug-containing layer to the push layer may be (0.01 to 100):1, for example 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1, or 100:1.

[0184] In the present invention, if the rod core further includes a push layer, the method for manufacturing the push layer may be a method common in the art, for example, pressing the raw material of the push layer.

[0185] Here, the pressing may be performed by solid press forming. The pressure of the pressing may be 0.01 to 10 MPa.

[0186] In the present invention, if the rod core further includes push layers, the number of push layers may be an integer, preferably an even number, for example, 2. When the number of push layers is even, the push layers are preferably placed at both ends of the drug-containing layer.

[0187] In the present invention, the pressing length of the rod core per press is preferably 1 to 50 mm, for example, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 7 mm, 10 mm, 20 mm, 30 mm, 40 mm, or 50 mm. The total length of the rod core may be selected according to the length of the silicone rubber tube.

[0188] In the present invention, the total length of the rod core is preferably 1 to 100 mm, more preferably 5 to 60 mm, for example 7 mm, 10 mm, 15 mm, 18 mm, 20 mm, 30 mm, 40 mm, 50 mm, or 60 mm.

[0189] In the present invention, the diameter of the rod core is preferably 1 to 10 mm, more preferably 1 to 5 mm, for example 2 mm, 3 mm, or 4 mm.

[0190] The present invention further provides a method for manufacturing a perforated implant rod core as described above, which includes the step of obtaining the drug-containing layer by pressing the active drug and the additive together. The push layer is optionally compounded onto the drug-containing layer.

[0191] In the present invention, the pressure of the press is 0.01 to 10 MPa, for example, 0.1, 0.2, 0.3, 0.5, 1, 2, 5, or 10 MPa.

[0192] In the present invention, the pressing may be performed by solid press molding.

[0193] The present invention further provides a perforated implant comprising a rod core for a perforated implant described above and a silicone rubber tube with a drug release hole covering the outside of the rod core.

[0194] In the present invention, when the silicone rubber tube covers the outside of the rod core, the center point of the rod core and the center point of the silicone rubber tube may overlap.

[0195] In the present invention, the plane on which the rod core is located and the radial plane of the silicone rubber tube may be set perpendicular to each other.

[0196] In the present invention, the size, position, and number of drug release holes in the silicone rubber tube may be adjusted according to the actual drug release requirements.

[0197] In the present invention, in the silicone rubber tube with drug release holes, the ratio of the diameter of the drug release holes to the outer diameter of the silicone rubber tube may be (0.0001~0.5):1, preferably (0.002~0.4):1, for example 0.06:1, 0.14:1, or 0.23:1, and more preferably (0.005~0.2):1.

[0198] In the present invention, the pore diameter of the drug release hole is preferably 1 μm to 1000 μm, more preferably 10 to 600 μm, for example 10, 20, 50, 100, 150, 250, 350, 450 or 550 μm, and preferably 250 to 450 μm.

[0199] In the present invention, in the silicone rubber tube with drug release holes, the total area of ​​the drug release holes may be adjusted according to the actual drug release amount needs. For example, the ratio of the total area of ​​the drug release holes to the outer surface area of ​​the silicone rubber tube may be (0.00001~0.4):1, preferably (0.0001~0.35):1, and more preferably (0.0005~0.3):1, such as 0.0005:1, 0.001:1, 0.005:1, 0.01:1, 0.05:1, 0.1:1, or 0.2:1.

[0200] In the present invention, the number of drug release holes is preferably >1, more preferably 1 to 1,000,000, for example 1, 2, 5, 10, 20, 50, 100, 200, 500, 1,000, 5,000, 1,000, 5,000, 1,000, 5,000, or 1,000,000.

[0201] In the present invention, preferably, the location of the drug release holes satisfies the conditions that the silicone rubber tube includes a first end face and a second end face which are installed opposite to each other, the distance between the first end face and the second end face is the total length of the silicone rubber tube, and a plurality of drug release holes are installed in the silicone rubber tube.

[0202] When the number of drug release holes is 1, the distance from the center point of the drug release hole to the first end face of the silicone rubber tube with the drug release hole may be 0 to 100% of the length of the silicone rubber tube, but not 0 or 100%. Preferably, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release hole is 0.1% to 99.9% of the length of the silicone rubber tube, and more preferably 1% to 99%, for example, 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%.

[0203] If the number of drug release holes is greater than or equal to 2, the distance between the center points of the drug release holes is: If the planes of any two drug release holes are not in the same radial cross-section of the silicone rubber tube, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release holes in the axial cross-sectional direction of the silicone rubber tube may be 0 to 100% of the length of the silicone rubber tube, but not 0 or 100%. Preferably, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release holes is 0.1% to 99.9% of the length of the silicone rubber tube, more preferably 1% to 99%, for example, 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%, and the distance between the center points of adjacent drug release holes may be 0.001 to 80 mm.

[0204] If the number of drug release holes is ≥ 2, the distance to the center point of the drug release hole is further: If the planes of any two drug release holes are in the same radial cross-section of the silicone rubber tube, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release holes in the circumferential direction of the radial cross-section of the silicone rubber tube may be 0 to 100% of the length of the silicone rubber tube, but not 0 or 100%. Preferably, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release holes is 0.1% to 99.9% of the length of the silicone rubber tube, more preferably 1% to 99%, for example, 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%, and the distance in the circumference between the center points of adjacent drug release holes may be (2 to 10)π mm.

[0205] In one preferred embodiment, in a silicone rubber tube with a drug release hole, the diameter of the drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone rubber tube is 0.35 mm:2.4 mm, the number of drug release holes is 1, and the position of the drug release hole satisfies the condition that the distance from the center point of the drug release hole to the first end face of the silicone rubber tube with the drug release hole is 50% of the length of the silicone rubber tube.

[0206] In one preferred embodiment, in a silicone rubber tube with drug release holes, the diameter of the drug release holes is 350 μm, the ratio of the diameter of the drug release holes to the outer diameter of the silicone rubber tube is 0.35 mm:2.4 mm, the number of drug release holes is 2, the positions of the drug release holes satisfy the following conditions: the planes of the two drug release holes are not on the same radial cross-section of the silicone rubber tube, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with drug release holes in the axial cross-sectional direction of the silicone rubber tube is 50% of the length of the silicone rubber tube, and the distance between the center points of the two drug release holes is 0.3 cm.

[0207] In one preferred embodiment, in a silicone rubber tube with a drug release hole, the diameter of the drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone rubber tube is 0.35 mm:2.4 mm, the number of drug release holes is 1, and the position of the drug release hole satisfies the condition that the distance from the center point of the drug release hole to the first end face of the silicone rubber tube with the drug release hole is 7.5% of the length of the silicone rubber tube.

[0208] In the present invention, the drug release hole can be obtained by perforating using a laser perforation method or a mechanical perforation method.

[0209] In the present invention, the raw material composition for the silicone rubber tube is preferably, based on parts by weight, 100 units of R-vinyl silicone rubber, 20-80 parts of reinforcing agent, 0.3 to 3.0 parts of hydrogen-containing silicone oil, Including 0.000002 to 1 part catalyst, Here, R in the R-vinyl silicone rubber is preferably a substituted or unsubstituted C1-C5 linear or branched alkane, a substituted or unsubstituted C6-C20 aromatic hydrocarbon, and more preferably a substituted or unsubstituted C1-C3 linear alkane, such as a methyl group.

[0210] When R is a methyl group, the R-vinyl silicone rubber is methyl vinyl silicone rubber.

[0211] Here, the vinyl group content in the R-vinyl silicone rubber may be 0.10% to 0.50 mol%, for example, 0.18 mol% or 0.23 mol%.

[0212] Here, the reinforcing agent may be one or more of the following common reinforcing agents in the art that can improve the hardness of the R-vinyl silicone rubber: for example, silica, diatomaceous earth, quartz powder, silica powder, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium oxide, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate, and calcium carbonate, for example, silica.

[0213] Here, the amount of the reinforcing agent is preferably 30 to 50 parts by weight, for example, 40 parts.

[0214] Here, the Si-H group content in the hydrogen-containing silicone oil may be 0.18 to 1.6 mol%, preferably 0.5 to 1 mol%, for example, 0.75 mol%.

[0215] Here, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber may be (0.5 to 10):1, for example, 1.2:1 or 2.5:1.

[0216] Here, the catalyst may be a catalyst that is common in this field and capable of catalyzing the addition reaction between R-vinyl silicone rubber and the hydrogen-containing silicone oil, such as a platinum catalyst.

[0217] Here, the amount of the catalyst by weight is preferably 0.000005 to 0.5 parts, for example, 0.00001 parts, 0.0098 parts, or 0.21 parts.

[0218] Here, the raw material composition for the silicone rubber tube with drug release holes may further contain an inhibitor, the action of which is to suppress the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil at room temperature.

[0219] The inhibitor may be an acetylene alcohol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol.

[0220] The amount of the inhibitor by weight may be 0.03 to 2.0 parts, for example, 0.7 parts.

[0221] In one preferred embodiment, the silicone rubber tube can be manufactured by the following method.

[0222] S1. Mix the R-vinyl silicone rubber and the reinforcing agent to obtain mixture A. 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. S3. The component B1 and the component B2 are mixed to obtain a mixture B, and an addition reaction is carried out with a catalyst to obtain the silicone rubber tube.

[0223] In the present invention, the silica may be pretreated by a method common in the art, which preferably involves drying at 130°C for 24 hours to prepare it for use.

[0224] In the present invention, a pretreatment is preferably performed before mixing the R-vinyl silicone rubber and the reinforcing agent. The pretreatment may be drying. The drying operation may be a general procedure in the art, for example, drying the R-vinyl silicone rubber in an oven at 40°C for 12 hours, or drying the reinforcing agent in an oven at 110°C for 12 hours.

[0225] In step S1, the mixing operation may be a common practice in the art, for example, kneading R-vinyl silicone rubber and a reinforcing agent in a vacuum kneader to obtain a rubber material, and then re-kneading the rubber material in an open roll. Preferably, 10 parts of the reinforcing agent are added at a time. The roll gap of the open roll is adjustable and is used to thin the rubber material by passing it through and uniformly disperse the reinforcing agent.

[0226] In step S2, if the silicone rubber tube with drug release holes further contains an inhibitor, the inhibitor, component A1, and the hydrogen-containing silicone oil are mixed to obtain component B1.

[0227] In step S2, the method for producing component B1 may involve re-kneading component A1 in an open roll and adding the hydrogen-containing silicone oil and the inhibitor.

[0228] In step S2, the method for producing component B2 may involve adding the catalyst to component A2 drop by drop, continuously shortening the roll gap, and performing thin-pass filtration.

[0229] In step S3, the mass ratio of component B1 to component B2 in the mixture B may be 1:1.

[0230] In step S3, the method for producing the mixture B may involve mixing component B1 and component B2 in an open roll and then extruding them.

[0231] In step S3, the step of the addition reaction with the catalyst may be a step of sequentially performing a first vulcanization treatment and a second vulcanization treatment on the mixture B.

[0232] Here, the first vulcanization treatment is preferably carried out in a front drying tunnel. The temperature of the first vulcanization treatment may be 300°C. The duration of the first vulcanization treatment may be 5 seconds. The first vulcanization treatment allows for preliminary high-temperature molding of the rubber material.

[0233] Here, the second vulcanization treatment is preferably carried out in a rear drying tunnel. The temperature of the second vulcanization treatment may be 240°C. The duration of the second vulcanization treatment may be 2 minutes. The second vulcanization treatment can sufficiently vulcanize the rubber material.

[0234] In the present invention, the silicone rubber tube with drug release holes can be obtained by perforating the silicone rubber tube using a laser perforation method or a mechanical perforation method.

[0235] In the present invention, when the rod core of the perforating implant consists of a drug-containing layer, the perforating implant is a single-layer implant.

[0236] In this case, if the concentration of the active drug in the drug-containing layer is a single concentration, the perforated implant is a single-layer, single-concentration implant.

[0237] Here, if the concentration of the active drug in the drug-containing layer is a stepped concentration gradient, the perforated implant is a single-layer multi-gradient implant. The gradient is preferably 1 to 50 steps, for example, 2, 3, 5, 10, 20, or 40 steps.

[0238] In one preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release hole in the silicone rubber tube with drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone rubber tube is 0.35 mm:2.4 mm, the number of drug release holes is 1, the position of the drug release hole is such that the distance from the center point of the drug release hole to the first end face of the silicone rubber tube with drug release hole is 50% of the length of the silicone rubber tube, the multi-gradient is 3 stages, set in order as a first-stage drug release module, a second-stage drug release module, and a third-stage drug release module, and the condition that the center point of the first-stage drug release module and the center point of the drug release hole coincide is satisfied.

[0239] In one preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release holes in the silicone rubber tube with drug release holes is 350 μm, the ratio of the diameter of the drug release holes to the outer diameter of the silicone rubber tube is 0.35 mm:2.4 mm, the number of drug release holes is 2, the positions of the drug release holes are such that the two drug release holes are not in the same radial cross-section of the silicone rubber tube, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with drug release holes in the axial cross-sectional direction of the silicone rubber tube is 50% of the length of the silicone rubber tube, the distance between the center points of the two drug release holes is 0.3 cm, the multi-gradient may be 3 stages, set in order as a first-stage drug release module, a second-stage drug release module, and a third-stage drug release module, and the conditions are met such that the center points of the first-stage drug release module and the second-stage drug release module each coincide with the center points of the two drug release holes.

[0240] In one preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release holes in the silicone rubber tube with drug release holes is 350 μm, the ratio of the diameter of the drug release holes to the outer diameter of the silicone rubber tube is 0.35 mm:2.4 mm, the number of drug release holes is 3, the positions of the drug release holes are such that the three drug release holes are not in the same radial cross-section of the silicone rubber tube, and in the axial cross-sectional direction of the silicone rubber tube, from the center point of any one of the drug release holes The distance to the first end face of the silicone rubber tube with drug release holes is 50% of the length of the silicone rubber tube, the distance between the center points of adjacent drug release holes is 0.3 cm, the multi-gradient may be in three stages, set in order as a first-stage drug release module, a second-stage drug release module, and a third-stage drug release module, and the conditions are met such that the center points of the first-stage drug release module, the second-stage drug release module, and the third-stage drug release module each coincide with the center points of the three drug release holes.

[0241] In the present invention, if the rod core of the perforating implant further includes a push layer compounded on the drug-containing layer, the perforating implant is a two-layer implant.

[0242] Preferably, the plane on which the drug-containing layer and the push layer are located and the radial plane of the silicone rubber tube are set perpendicular to each other.

[0243] Here, preferably, when the number of drug release holes is 1, the center point of the drug-containing layer and the center point of the drug release holes coincide.

[0244] Here, preferably, if the number of drug release holes > 1, the positional relationship between the center point of the drug-containing layer and the center point of the drug release holes may be selected according to the needs for the amount of active drug to be released.

[0245] The present invention further provides a method for manufacturing a perforated implant as described above, which includes the step of filling the silicone rubber tube with the drug release hole with the pharmaceutical composition or the rod core.

[0246] The present invention further provides the application of the rod core or the perforated implant as a release rate regulating medium in sustained-release formulations.

[0247] By arbitrarily combining the above preferred conditions while being consistent with common sense in the art, various preferred examples of the present invention can be obtained.

[0248] All reagents and raw materials used in this invention are commercially available.

[0249] The positive effects of this invention are as follows:

[0250] The silicone rubber tube manufactured using the silicone rubber material of this invention exhibits superior mechanical performance and increased water permeability. This allows for easier release of drug solutions from the implant when applied, thereby improving drug release rates. Drug release can be several to tens of times greater than with conventional silicone rubber tubes, thereby expanding the range of selectable drugs and significantly broadening the application range of the implant.

[0251] This invention provides a rod core obtained by press-molding an active drug and additives using a solid press molding method, solving the problem of drug waste or unstable drug release in powder-type drug cores, as well as the problem of drug instability in the manufacturing process of silicone rubber skeleton-type rod cores. After the silicone rubber tube is perforated, the range of drug application is expanded to include common drugs in the art, such as highly soluble high-molecular-weight drugs, highly soluble low-molecular-weight drugs, poorly soluble high-molecular-weight drugs, and poorly soluble low-molecular-weight drugs, and the amount of drug released is improved. [Brief explanation of the drawing]

[0252] [Figure 1] This is an in vitro release diagram of modified goserelin reservoir-skeleton implants with different wall thicknesses prepared in Examples 8-1, 8-2 and 8-3. [Figure 2] This is an in vitro release diagram of modified goserelin reservoir-skeleton implants prepared with different silica dosages in Examples 8-1, 9-1 and 9-2. [Figure 3] This is an in vitro release diagram of modified goserelin reservoir-skeleton implants prepared with methylvinylpolysiloxane having different vinyl group contents in Examples 8-1 and 10. [Figure 4] This is an in vitro release diagram of modified goserelin reservoir-skeleton implants prepared at different molar ratios of Si-H in hydrogen-containing silicone oil to vinyl groups in methylvinylpolysiloxane in Examples 8-1, 11-1 and 11-2. [Figure 5] This is an in vitro release data diagram of modified paliperidone reservoir-type implants prepared with different hydroxyapatite contents in Examples 12-1, 12-2 and 12-3. [Figure 6] This is an in vitro release data diagram of modified paliperidone reservoir-type implants prepared with methylvinylpolysiloxane having different vinyl group contents in Examples 12-1 and 13. [Figure 7] This is an in vitro release data diagram of modified paliperidone reservoir-type implants prepared at different molar ratios of Si-H in hydrogen-containing silicone oil to vinyl groups in methylvinylpolysiloxane in Examples 12-1, 14-1 and 14-2. [Figure 8] This is a manufacturing flowchart of a silicone rubber tube. [Figure 9] This is a schematic diagram of the perforated implants of Examples 30 to 33. [Figure 10] This is a schematic diagram of the perforated implants of Examples 20 to 23. [Figure 11] This is a schematic diagram of the perforated implant of Example 34. [Figure 12] These are schematic diagrams of the perforating implants of Examples 24-1 and 25-1. [Figure 13] These are schematic diagrams of the perforating implants of Examples 24-2 and 25-2. [Figure 14] These are schematic diagrams of the perforating implants of Examples 24-3 and 25-3. [Figure 15] These are schematic diagrams of the perforating implants of Examples 26-2, 27-2, 28-2, and 29-2. [Modes for carrying out the invention]

[0253] The present invention will be further described below with reference to embodiments, but this does not limit the present invention to the scope of the embodiments described above. Specific experimental conditions are not explicitly stated in the embodiments below, but they are selected according to conventional methods and conditions, or according to the product description.

[0254] The origins of each component in the examples and comparative examples are shown in the table below. [Table 0-4]

[0255] The equipment and instruments used in the manufacturing and testing processes are as shown in the table below. [Table 0-5]

[0256] 1. Silicone rubber tube 1.1 Method for manufacturing silicone rubber tubing (1) Dry methyl vinyl polysiloxane raw rubber at 40°C for 12 hours and prepare for use, and dry hydrophilic vapor-phase silica at 130°C for 24 hours and prepare for use, (2) Mix methyl vinyl polysiloxane raw rubber and hydrophilic vapor-phase silica in a prescribed amount to obtain mixture A. (3) Divide mixture A into component A1 and component A2. Re-knead component A1 in an open roll with a roll gap parameter of 1 unit, add the prescribed amount of hydrogen-containing silicone oil and the inhibitor 2-methyl-3-buty-2-ol one drop at a time, set different roll gaps after addition, perform triangular folding and thin passing, remove and leave for 24 hours to obtain component B1, and prepare for use. Re-knead component A2 in an open roll with a roll gap parameter of 1 unit, add the prescribed amount of platinum catalyst one drop at a time, continuously shorten the roll gap, perform thin passing, remove and leave for 24 hours to obtain component B2, and prepare for use. (4) Place B1 and B2 produced in step (3) into an open roll in a 1:1 ratio, mix, extrude, and pass through 4 to 6 times to obtain mixture B. (5) After removing the mixture B produced in step (4) from the open roll in sheet form, it is cut into strips. A mold of the appropriate size is attached to the extruder, the screw rotation speed of the extruder is set, and the cut silicone rubber strips are fed into the extruder. The rubber material is continuously extruded from the mold opening by the thrust of the screw rotation, forming a silicone rubber tube. The outer diameter of the silicone rubber tube is determined jointly by the screw rotation speed of the extruder, the conveyor belt rotation speed of the rear drying tunnel, and the mold dimensions, and the wall thickness is determined by the mold dimensions. (6) The silicone rubber tube manufactured in step (5) is subjected to a first vulcanization treatment and a second vulcanization treatment to obtain a finished silicone rubber tube. In the first vulcanization process, the silicone rubber tube extruded from the mold opening first passes through the front drying tunnel (vertical hot air vulcanization tunnel) and is vulcanized at high speed and high temperature. This is the first vulcanization process, which quickly changes the silicone rubber tube from a sticky, soft state to an elastic state, and forms a preliminary mold. Here, in the second vulcanization treatment, after the first vulcanization, the material enters the rear drying tunnel (horizontal hot air vulcanization tunnel) to continue being vulcanized. This is the second vulcanization treatment, which makes the vulcanization reaction of the silicone rubber tube more sufficient to reach the optimal crosslinking state, and the finished silicone rubber tube product is continuously conveyed out by the conveyor belt of the rear drying tunnel.

[0257] 1.2 Investigation on formulation and process of silicone rubber tube (1) Effects of the vinyl group content in methyl vinyl polysiloxane, the amount of reinforcing agent used, and the molar ratio of Si-H in hydrogen-containing silicone oil to the vinyl group in methyl vinyl polysiloxane on the mechanical properties of silicone rubber tubes A. Formulation: The concentration of the platinum catalyst is all 3000 ppm, the amount of the platinum catalyst used is all 0.0098 PHR, the amount of the inhibitor 2-methyl-3-butyn-2-ol used is all 0.69 PHR, and other formulation parameters are as shown in Table 1.

[0258] [Table 1]

[0259] B. Manufacturing method: The manufacturing method described in 1.1 is adopted, and the specific process parameters are as follows. The temperature of the first vulcanization treatment is 250°C, the time of the first vulcanization treatment is 3 s, the temperature of the second vulcanization treatment is 240°C, the time of the second vulcanization treatment is 4 min, the diameter of the die is 3 mm, the diameter of the mandrel is 2.6 mm, the wall thickness of the manufactured silicone rubber tube is 0.2 mm, and the screw rotation speed is 5 r·min -1 .

[0260] (2) Effect of the temperature of the second vulcanization treatment on the mechanical properties of silicone rubber tubes A. Formulation: The concentration of the platinum catalyst is 3000 ppm in all cases, the amount of platinum catalyst used is 0.0098 PHR in all cases, the amount of the inhibitor 2-methyl-3-butyne-2-ol used is 0.69 PHR in all cases, the vinyl group content in methyl vinylpolysiloxane is 0.18%, the amount of hydrophilic silica TH-a200 used is 30 PHR, and the molar ratio of Si-H in hydrogen-containing silicone oil to vinyl groups in methyl vinylpolysiloxane is 1.5:1.

[0261] B. Manufacturing method: The manufacturing method described in 1.1 was used, with the difference being that the vulcanization temperature was set as shown in Table 2, the time for the first vulcanization was 3 s, the time for the second vulcanization was 4 min, the die diameter was 3 mm, the mandrel diameter was 2.6 mm, the wall thickness of the resulting silicone rubber tube was 0.2 mm, and the screw rotation speed was 5 r·min. -1 That is the case.

[0262] [Table 2]

[0263] (3) Influence of mold dimensions and screw rotation speed on the outer diameter of the silicone rubber tube A. Formulation: The concentration of the platinum catalyst is 3000 ppm in all cases, the amount of platinum catalyst used is 0.0098 PHR in all cases, the amount of the inhibitor 2-methyl-3-butyne-2-ol used is 0.69 PHR in all cases, the vinyl group content in methyl vinylpolysiloxane is 0.18%, the amount of hydrophilic silica TH-a200 used is 30 PHR, and the molar ratio of Si-H in hydrogen-containing silicone oil to vinyl groups in methyl vinylpolysiloxane is 1.5:1.

[0264] B. Manufacturing Process: The manufacturing method described in 1.1 is used, with the first vulcanization temperature being 250°C and the first vulcanization time being 3 seconds. The second vulcanization temperature is 240°C and the second vulcanization time is 4 minutes. Refer to Table 3 for mold dimensions and screw rotation speed. (Note: Ring width = (Die inner diameter - Mandrel diameter) / 2)

[0265] [Table 3]

[0266] According to the results in Table 3, the screw rotation speed was 5 r·min. -1 It was found that when this condition is reached, the rubber material can be transported continuously and uniformly. When the screw rotation speed is constant, the larger the ring width between the inner diameter of the mold die and the diameter of the mandrel, the thicker the wall of the silicone rubber tube becomes. The outer diameter of the silicone rubber tube is not directly related to the ring width, but is affected by the combined effects of the dimensions of the die and mandrel, the ring width size, and the screw rotation speed.

[0267] When using the same mold, a higher screw rotation speed results in a larger outer diameter of the silicone rubber. This is because a higher screw rotation speed increases the extrusion speed of the silicone rubber tube, reducing the tensile force exerted by the conveyor belt on the silicone rubber tube, thus increasing the outer diameter. Conversely, a lower screw rotation speed results in a lower extrusion speed of the silicone rubber tube, increasing the tensile force exerted by the conveyor belt on the silicone rubber tube, and thus decreasing the outer diameter of the silicone rubber tube.

[0268] In summary, the outer diameter of the silicone rubber tube is greatly affected by the screw rotation speed. By using molds of different dimensions and combining them with corresponding screw rotation speeds, it is possible to manufacture silicone rubber tubes with different outer diameters. This lays the foundation for the subsequent manufacture of implants with different specifications and for drug release research.

[0269] 2. Improved guestden reservoir skeletal implant 2.1 Method of manufacturing implants (1) The method for manufacturing a silicone rubber tube is to manufacture a silicone rubber tube according to steps (1) to (6) of the manufacturing method in 1.1, (2) Basic formulation and manufacturing process of the drug core: For gestodene, the particle size is 2-3 μm and the amount added is 100 PHR; for methylvinylpolysiloxane, the vinyl group content range is 0.18%-0.23%; for hydrogen-containing silicone oil, the Si-H group content is 0.75% and the amount added range is 0.3-5.0 PHR; for platinum catalyst, the platinum concentration is 10000 ppm and the amount added range is 0.000002-0.5 PHR; 2-methyl-3-buty-2-ol is the inhibitor and the amount added range is 0.03-2.0 PHR. The vulcanization temperature was 90°C, the vulcanization time was 1 hour, the diameter of the drug core was 0.2 cm, and the length was 1.5 cm. (3) Immerse the silicone rubber tube in petroleum ether for 1-2 minutes, quickly shake it by hand to remove any remaining petroleum ether from the surface of the silicone rubber tube, immediately insert the cut drug core into the center of the silicone rubber tube with tweezers, leaving a space of the same length at both ends of the silicone rubber tube in preparation for sealing, and after the assembly is complete, air dry the implant for 12-24 hours to allow any remaining petroleum ether to completely evaporate, then seal both ends of the air-dried implant with sealant, leave it at room temperature for 12-24 hours to allow the sealant to harden, and obtain the improved guestden reservoir skeletal implant.

[0270] 2.2 Influence of manufacturing process or formulation on the performance of silicone rubber tubing (1) The effect of the vinyl group content in methyl vinylpolysiloxane, the amount of reinforcing agent used, the molar ratio of Si-H in hydrogen-containing silicone oil to vinyl groups in methyl vinylpolysiloxane, and the wall thickness of the silicone rubber tube on the in vitro release of the silicone rubber tube.

[0271] A. Formulation: The concentration of the platinum catalyst was 10,000 ppm in all cases, the amount of platinum catalyst used was 0.01 PHR, and the amount of the inhibitor 2-methyl-3-butyne-2-ol used was 0.69 PHR in all cases. Other formulation parameters are as shown in Table 1.

[0272] [Table 4]

[0273] B. The manufacturing method described in 2.1 is used, and the specific process parameters are as follows: The temperature of the first vulcanization treatment is 250°C, the time of the first vulcanization treatment is 3 s, the temperature of the second vulcanization treatment is 240°C, the time of the second vulcanization treatment is 4 min, the diameter of the specified drug core is 0.2 cm and the length is 1.5 cm, the outer diameter of the specified silicone rubber tube is 2.4 mm and the length is 1.9 cm.

[0274] 3. Improved paliperidone reservoir type implant 3.1 Method of manufacturing implants A silicone rubber tube is manufactured according to steps (1) to (6) of the manufacturing method in 1.1, and a paliperidone reservoir-type implant is manufactured according to step (7) below. (7) Manufacture of paliperidone reservoir-type implant: One end was sealed with KN-300N adhesive and cured for 24 hours, then the drug was filled through a filling funnel. After the filling was completed, the other end was similarly sealed with KN-300N adhesive and cured for 24 hours. After curing was completed, the implant was inspected for drug leakage. After confirming no leakage, it was repeatedly washed with absolute ethanol for 30 seconds, and the manufacture was completed to obtain the improved paliperidone reservoir-type implant.

[0275] 3.2 Effects of the usage amount of hydroxyapatite, the vinyl group content of methyl vinyl polysiloxane, and the usage amount of hydrogen-containing silicone oil on the in vitro drug release A. Formulation: The added amount of paliperidone is 100 PHR, the usage amount of HB-615 hydrophobic fumed silica is all 20 PHR, the concentration of the platinum catalyst is all 3000 ppm, the usage amount of the platinum catalyst is all 0.21 PHR, the usage amount of the inhibitor 2-methyl-3-butyn-2-ol is all 0.98 PHR, and other formulation parameters are as shown in Table 5.

[0276] [Table 5]

[0277] B. Manufacturing method: The manufacturing method described in 2.1 is used, and the specific process parameters are as follows. The temperature of the first vulcanization treatment is 250°C, the time of the first vulcanization treatment is 5 s, the temperature of the second vulcanization treatment is 240°C, the time of the second vulcanization treatment is 2 min, the wall thickness of the obtained implant is 0.2 mm, the outer diameter is 2.2 to 2.3 mm, and the drug release area is 2.7±0.5 cm 2 .

[0278] 4. Improved estradiol reservoir-type implant 4.1 Manufacturing method of the implant The same as the implant manufacturing method described in 3.1 4.2 Effects of vulcanization temperature, silicone rubber tube wall thickness, and drug release area on in vitro release of implants A. Prescription: As shown in the table below.

[0279] [Table 6]

[0280] B. Manufacturing process: The time for the first vulcanization treatment is 5 seconds, the time for the second vulcanization treatment is 2 minutes, and the time for the third vulcanization treatment is 48 hours. Other parameters are as shown in the table below.

[0281] [Table 7]

[0282] [Table 8]

[0283] [Table 9]

[0284] Comparative Example 1: Guestden reservoir skeletal implant A. Formula: The difference from the formula for the improved guest den skeletal implant is that the reinforcing agent is solely HB-615 hydrophobic vapor-phase silica.

[0285] B. Manufacturing process: The manufacturing method is the same as that described in 2.1.

[0286] Comparative Example 2: Paliperidone reservoir type implant A. Formula: Compared to the formula for the improved paliperidone reservoir-type implant, the difference is that the reinforcing agent is only HB-615 hydrophobic vapor-phase silica and does not contain hydroxyapatite.

[0287] B. Manufacturing process: The manufacturing method is the same as that described in 3.1.

[0288] Comparative Example 3: Estradiol Reservoir Type Implant A. Formula: Compared to the formula for the improved estradiol reservoir type implant, the difference is that the reinforcing agent is only hydrophobic vapor-phase silica R106 and does not contain N20 hydrophilic silica.

[0289] B. Manufacturing process: The manufacturing method is the same as that described in 4.1.

[0290] Examples of Effects Mechanical performance and in vitro release performance were studied for embodiments and comparative examples of the present invention.

[0291] 1. Mechanical performance Subcutaneous implants should meet the national standard GB / T528 (ISO37) "Measurement of tensile stress-strain performance of vulcanized rubber or thermoplastic rubber," and must possess good mechanical properties to maintain their shape during implantation and removal.

[0292] 1. The elongation at break (%) is the elongation of the sample at tensile fracture. 2. Tensile strength (MPa) is the maximum tensile stress that a sample experiences when it is pulled to the point of fracture during a tensile test. 3, Tear strength (KN m -1 ) is the strength required when the sample is torn apart.

[0293] Specific testing method: A sample approximately 5 cm in length is prepared, three copies of each sample are prepared in parallel, and the samples are tested using a tensile testing machine with the following test parameters: clamping distance 50 mm, tensile speed 200 mm·min. -1 The settings were configured, and data was recorded after the sample test was completed.

[0294] [Table 10]

[0295] As can be seen from the effect data of Examples 1-1 and 1-2, when the vinyl group content was 0.18% and 0.23%, the elongation at break, tensile strength, and tear strength of the vulcanized silicone rubber tubes did not differ significantly overall, and both showed good mechanical performance. The content of both types of vinyl groups was within an appropriate range, and after the addition reaction, the length of the crosslinking chains in the formed network structure was appropriate, and the distribution of crosslinking points was regular. Therefore, the manufactured silicone rubber tubes had good elasticity, a certain level of tensile and tear resistance, and met the requirements for implant manufacturing and clinical application.

[0296] As can be seen from the effect data of Examples 2-1 to 2-4, the amount of hydrophilic silica used was within the range of 30 to 50 PHR, and the mechanical performance of the silicone rubber tubes after vulcanization was good in all cases.

[0297] As can be seen from the effect data of Examples 2-1, 3-1, and 3-2, when the molar ratio of Si-H in hydrogen-containing silicone oil to vinyl groups in methyl vinylpolysiloxane increased from 1.2:1 to 1.5:1, the tensile strength and tear strength of the silicone rubber tube increased. When the molar ratio increased from 1.5 to 1.8, there was no significant difference overall in the elongation at break, tensile strength, and tear strength of the vulcanized silicone rubber tube, indicating that the mechanical performance of the silicone rubber tube was good in all cases. Theoretically, when an addition reaction occurs, the hydrogen in hydrogen-containing silicone oil and the vinyl groups in methyl vinylpolysiloxane participate in the reaction in a molar ratio of 1:1. However, in actual reactions, Si-H is lost due to side reactions. Therefore, by using a slightly excess of hydrogen-containing silicone oil, the addition reaction can be allowed to proceed sufficiently, crosslinking can be brought closer to complete, and the mechanical performance of the silicone rubber tube can be optimized.

[0298] As can be seen from the effect data of Examples 4-1 to 4-4, with increasing second vulcanization temperature, the elongation at break, tensile strength, and tear strength of the vulcanized silicone rubber tube initially increased, then tended to decrease. When the second vulcanization temperature was 240°C, each index value was maximized. The second vulcanization treatment is mainly for continuing the vulcanization of the silicone rubber tube and continuing the crosslinking reaction. At an appropriate temperature, the crosslinking reaction proceeds completely, resulting in better mechanical indicators. However, if the temperature is too high, the silicone rubber tube becomes overvulcanized, the internal crosslinking bonds undergo thermal decomposition, and the performance deteriorates.

[0299] 2. In vitro release effect 1. Characterization of in vitro release of improved guestden reservoir skeletal implants 1.1 Test Method (1) Chromatography conditions Chromatography column: Diamonsil (R) C18 chromatography column (4.6 mm × 250 mm, 5 μm), Mobile phase: methanol:water (80:20, v / v) Column temperature: 30℃ Detection wavelength: 239nm, Flow rate: 1.0mL min -1 , Sample input volume: 20 μL

[0300] (2) In vitro release experiment method The release experiment was conducted using the horizontal shaking method. One implant was taken and both ends of the implant were fixed to the bottom and wall of a 50 mL stoppered Erlenmeyer flask with silicone rubber adhesive (to prevent the implant from floating on the liquid surface and resulting in inaccurate release results). After bonding, it was left for 12 hours to allow the silicone rubber adhesive to fully cure. 50 mL of distilled water was accurately measured out as the release medium and poured into the Erlenmeyer flask. The Erlenmeyer flask was placed in a constant temperature air shaker and shaken, with the temperature set to 37°C and the amplitude set to 100 r·min. -1The medium was replaced with an equal volume every 24 hours. The release solution was filtered through a 0.22 μm microfiltration membrane and detected according to the chromatography conditions, with a sample input volume of 20 μL.

[0301] 1.2 Effect Data (1) 30-day in vitro release efficacy data Examples 8-1 to 8-3 are implants with different silicone rubber tube wall thicknesses. The in vitro release effect data is shown in Figure 1. As can be seen, the thicker the silicone rubber tube wall, the lower the daily drug release from the implant. The average daily drug release over 30 days for implants with a silicone rubber tube wall thickness of 0.2 mm was approximately 55 μg, for implants with a wall thickness of 0.3 mm it was approximately 48 μg, and for implants with a wall thickness of 0.4 mm it was approximately 42 μg. In other words, for every 0.1 mm increase in the thickness of the silicone rubber tube, the average daily drug release decreased by approximately 5-8 μg. As can be seen from the above data, when the outer diameter and length of the silicone rubber tube and the diameter and length of the drug core are constant, the wall thickness of the silicone rubber tube can have a slight effect on the in vitro release rate of the implant. In the actual implant manufacturing process, if the outer diameter of the silicone rubber tube is constant, the thicker the wall thickness, the smaller the inner diameter becomes, making it difficult to assemble the drug core and the silicone rubber tube. A silicone rubber tube with a wall thickness of 0.2 mm has a relatively large inner diameter and good compatibility with the drug core.

[0302] Examples 8-1, 9-1, and 9-2 showed different amounts of hydrophilic silica used, and the in vitro release effect data is shown in Figure 2. As can be seen from this, the amount of hydrophilic silica used had a slight effect on implant release, and with increasing amounts of hydrophilic silica used, the average daily release of the implant over 30 days increased slightly. When the amount of hydrophilic silica used was 40 PHR, the daily drug release was high at approximately 55 μg, and as can be seen from Figure 2, the drug release curve was clearly higher than that of 30 PHR and 20 PHR during the period from 1 to 15 days. The average daily drug release for both 30 PHR and 20 PHR of hydrophilic silica was approximately 48 μg, with no significant difference, and the fluctuations in the two drug release curves were smaller than in the case of 40 PHR, indicating better drug release stability. Furthermore, the extrusion stability and smoothness were good when 30 PHR of gas-phase silica was used during the extrusion process of the silicone rubber tube.

[0303] Examples 8-1 and 8-10 were implants with different vinyl group content, and their in vitro release effect data is shown in Figure 3. As can be seen from this, the vinyl group content of the silicone rubber tube did not have a significant effect on implant release, and the average daily release amount within 30 days for both groups of implants was between 47 and 50 μg. Methyl vinylpolysiloxane with a vinyl group content of 0.18% was more suitable for the requirements of mechanical properties and cost.

[0304] Examples 8-1, 11-1, and 11-2 are implants using different amounts of hydrogen-containing silicone oil. The in vitro release effect data is shown in Figure 4. As can be seen, when the molar ratio of hydrogen-containing silicone oil used was 1.2 and 1.8, the release amount was high for 3 days after implant administration, an initial burst release phenomenon occurred, and the overall release curve showed large fluctuations. However, when the molar ratio was 1.5, the fluctuations in the drug release curve were relatively small, and the drug release curve was already stable at the molar ratio of 1.5. Furthermore, preliminary studies showed that the mechanical indicators of the silicone rubber tube were also good.

[0305] (3) In vitro release experiment Long-term in vitro release experiments were conducted for 150 days on the implants of Example 8-1 and Comparative Example 1, and the results are shown in Tables 11 and 12, respectively.

[0306] [Table 11]

[0307] [Table 12]

[0308] As can be seen from the data in the table above, assuming the mechanical performance of the implant is met, hydrophilic silica improved the release rate of the silicone rubber tube by 18-23 μg compared to hydrophobic silica, resulting in the drug release rate of the implant meeting the requirements and demonstrating good drug release stability, enabling stable drug release for at least 5 months. Furthermore, the in vitro release rate of the improved guestden skeleton reservoir implant was improved by 192% compared to the guestden skeleton reservoir implant.

[0309] 2. Characterization of in vitro release of improved paliperidone reservoir-type implants 2.1 Test Method (1) Chromatography conditions Chromatography column: InfinityLab Poroshell HPH-C8 (4.6 × 100 mm, 2.7 μm) Mobile phase: methanol:acetonitrile:phosphate 1:4:15 isocratic elution Flow rate: 1mL / min Column temperature: 35℃ Sample input volume: 20 μL Detection wavelength: 280nm

[0310] (2) In vitro release test method Take one improved paliperidone reservoir implant, fix the implant to a 20 mL sample flask using silicone rubber adhesive, accurately measure out the appropriate amount of distilled water and add it to the sample flask, ensuring that the formulation is always below the liquid surface of the release medium, and set the amplitude to 100 r·min. -1 The release was carried out by placing the mixture in a constant temperature shaker at 37°C. Sampling was performed every 24 hours, the release medium was replaced, and the solution was filtered through a 0.22 μm filter membrane before being stored for testing.

[0311] 2.2 Effect Data (1) 30-day in vitro release efficacy data Examples 12-1 to 12-3 are implants manufactured with different amounts of hydroxyapatite used. The in vitro release effect data is shown in Figure 5, and the in vitro release amount of the silicone rubber tube after vulcanization increased with increasing amounts of hydroxyapatite used.

[0312] In Examples 12-1 and 13, the effect of the vinyl group content of methylvinylpolysiloxane on the in vitro release amount of silicone rubber tubing was studied, and the effect data is shown in Figure 6. As can be seen, the effect of the vinyl group content in the silicone rubber tubing on implant release was not significant, and the daily release amount within 30 days for both groups of implants was between 20 and 25 μg, with no significant difference between the two. However, when the vinyl group content of the raw rubber of the silicone rubber tubing was 0.18%, the implant release curve was more stable overall.

[0313] 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 of silicone rubber tubes. The effect data is shown in Figure 7. As can be seen, the difference in the implant release curves is not large when the molar ratio of hydrogen-containing silicone oil is different. This is because, theoretically, when the addition reaction occurs, the hydrogen in the hydrogen-containing silicone oil and the vinyl group in methyl vinylpolysiloxane participate in the reaction in a molar ratio of 1:1. However, in the actual reaction, Si-H is lost due to side reactions, so usually, a slightly excess of hydrogen-containing silicone oil is used to allow the addition reaction to proceed sufficiently and bring the crosslinking closer to complete.

[0314] (2) Long-term in vitro release results data Temperature 37℃, shaker speed 100r min -1 Long-term in vitro release experiments were conducted on Example 14-1 and Comparative Example 2 under the specified conditions. The long-term in vitro release results for Example X are shown in Table 13 below. The long-term in vitro release results for Comparative Example 2 are shown in Table 14.

[0315] [Table 13]

[0316] [Table 14]

[0317] As can be seen from the efficacy data in the table above, in vitro release studies of the improved paliperidone reservoir-type implant manufactured with the silicone rubber tube according to the present invention showed stable drug release within 150 days, and the in vitro release volume of the improved paliperidone reservoir-type implant was 260% higher than that of the paliperidone reservoir-type implant.

[0318] 3. Characterization of in vitro release of improved estradiol reservoir implants 3.1 Test Method (1) One improved estradiol reservoir implant was taken, the silicone rubber tube was cut lengthwise, the drug core was cut into several small segments, placed in a 100 mL volumetric flask, immersed in 10 mL of methanol, allowed to stand for 3 hours to swell, diluted to the mark with anhydrous ethanol, shaken well, filtered, accurately measured 0.2 mL of the filtrate and placed in a 50 mL volumetric flask, diluted to the mark with mobile phase, shaken well, injected HPLC, added 20 μL of sample, and the drug content was calculated based on the standard curve. The chromatography conditions were as follows.

[0319] chromatography conditions Chromatography column: Diamonsil (R) C18 column (250mm x 4mm, 5μm) Mobile phase: Acetonitrile-water (55:45, v / v) Column temperature: 25℃ Detection wavelength: 202nm Flow rate: 0.8mL min -1 Sample input volume: 20 μL (2) Release measurement method The emission level was measured using the horizontal shaking method. One improved estradiol reservoir implant was taken and fixed to a 100 mL stoppered Erlenmeyer flask by alternately crossing the implants with adhesive. 100 mL of distilled water was accurately measured and used as the emission medium. The stoppered Erlenmeyer flask was placed in a constant temperature shaker, and the amplitude was set to 100 r·min. -1 The settings were adjusted to a temperature of 37°C, ensuring that the implant remained below the liquid level at all times. Sampling was performed every 24 hours, an equal volume of release medium was replaced, and the sample solution was filtered through a 0.22 μm microfiltration membrane. After this, the sample was introduced using the (1) content measurement method, and the drug release amount was calculated based on the standard curve.

[0320] 3.2 Effect Data 3.2.1 Effect of vulcanization conditions on in vitro release rate

[0321] [Table 15]

[0322] In Examples 17-1, 17-2, and 17-3, the in vitro release data for improved estradiol reservoir implants manufactured at different vulcanization temperatures is listed in Table 15. According to the data in the table, changing the vulcanization temperature of the silicone rubber tubing did not significantly affect the average daily drug release of the implant, and the fluctuations were not large. Therefore, the implant was manufactured using a silicone rubber tubing with better mechanical performance, specifically, the first vulcanization treatment was performed at a temperature of 250°C and the second vulcanization treatment at a temperature of 240°C.

[0323] 3.3.2 Wall thickness of silicone rubber tube

[0324] [Table 16]

[0325] The in vitro release data for the improved estradiol reservoir implants with different wall thicknesses manufactured in Examples 18-1, 18-2, and 18-3 are listed in Table 16. The results show that, when factors such as outer diameter and release area were kept constant, the in vitro release amount for the improved estradiol reservoir implants manufactured with three different wall thicknesses of silicone rubber tubing gradually decreased with increasing wall thickness. To ensure drug release, it is necessary to reduce the wall thickness as much as possible. However, in actual operation, a silicone rubber tubing with a wall thickness of 0.2 mm is already at its limit, and further reduction in wall thickness makes it difficult to ensure smooth extrusion molding of the silicone rubber tubing. Therefore, the use of silicone rubber tubing with a wall thickness of 0.2 mm is recommended.

[0326] 3.3.3 Examination of the drug release area of ​​silicone rubber tubing The effect of drug core length in silicone rubber tubing on in vitro release is shown in the table below.

[0327] [Table 17]

[0328] The results showed that increasing the release area increased the daily drug release of the improved estradiol reservoir implant. In practical applications, due to the large individual differences among patients, it is possible to manufacture improved estradiol reservoir implants with different specifications during production, enabling individualized administration according to different needs, reducing side effects, and achieving maximum benefit.

[0329] 3.4 Long-term in vitro release experiment of estradiol reservoir-type implants The estradiol reservoir-type implants manufactured in Example 17-2 and Comparative Example 3 were subjected to a shaking machine at a temperature of 37°C and a shaking machine speed of 100 r·min. -1 Long-term in vitro release experiments were conducted under these conditions, and the results are shown in the table and diagram below.

[0330] [Table 18]

[0331] According to the results in the table above, the average daily in vitro drug release of implants manufactured with hydrophilic silica remained stable within the range of 20-35 μg, demonstrating good stability.

[0332] [Table 19]

[0333] According to the results in the table above, the average daily release of estradiol from estradiol reservoir-type implants was approximately 12 μg, indicating that burst release occurred in the initial stages, followed by stable release in the later stages.

[0334] A comparison of in vitro release between an improved estradiol reservoir-type implant and an original estradiol reservoir-type implant showed that, assuming the implant's mechanical performance was met, the in vitro release volume of the improved estradiol implant was 245% higher than that of hydrophobic silica, and the burst release problem of the original estradiol reservoir-type implant was improved.

[0335] The manufacturing flow of the silicone rubber tube in the following example is shown in Figure 8 below.

[0336] The formulations for the silicone rubber tubes with drug release holes for perforated implants in Examples 20-38 and Comparative Examples 4-5 are as follows. [Table 20]

[0337] Here, the water contact angle of silica is the static water contact angle of the material. It was measured using the principle of optical projection. During use, the volume of the water droplet was set using test software, and then a syringe needle dropped the set volume of water droplets onto the surface of the test sample. The droplet image was then projected onto an automated image analysis system using a screen micrometer under the background of an LED light source for measurement.

[0338] The method for manufacturing the silicone rubber tube with drug release holes for perforated implants in Examples 20-38 and Comparative Examples 4-5 is as follows.

[0339] S1. Methyl vinyl silicone rubber was dried in an oven at 40°C for 12 hours, and silica was dried in an oven at 110°C for 12 hours. The methyl vinyl silicone rubber and silica were kneaded in a vacuum kneader to obtain a rubber material, and the rubber material was re-kneaded in an open roll to obtain mixture A. S2. Mixture A is divided into component A1 and component A2. Component A1 is re-kneaded in an open roll, hydrogen-containing silicone oil and methylbutynol are added to obtain component B1. A platinum catalyst is added to component A2 drop by drop, the roll gap is continuously shortened, and thin-pass filtration is performed to obtain component B2. The mass ratio of component B1 to component B2 is 1:1. S3. Component B1 and component B2 are mixed in an open roll and extruded to obtain mixture B. Mixture B is subjected to a first vulcanization treatment and a second vulcanization treatment in sequence to obtain a silicone rubber tube. S4. A silicone rubber tube with a drug release hole was obtained from a silicone rubber tube by laser perforation. The obtained silicone rubber tube had a length of 4 cm and an outer diameter of 2.4 mm.

[0340] The manufacturing methods for the rod cores in Examples 20-38 and Comparative Examples 4-5 are as follows.

[0341] A drug-containing layer is obtained by pressing a pharmaceutical composition at 0.3 MPa using solid press molding. If a push layer is included, the push layer is obtained by pressing the raw material for the push layer at 0.3 MPa using solid press molding, and the push layer is compounded with the drug-containing layer. The manufactured rod core had a length of 7 mm and a diameter of 2 mm, and the plane on which the rod core was located and the radial plane of the silicone rubber tube were perpendicular to each other.

[0342] (1) Examination of the drug release port process in perforated implants I. Examination of the size of the drug release port diameter in perforated implants. Schematic diagrams of the perforating implants in Examples 20-23 are shown in Figure 10.

[0343] Example 20: Insulin-perforating implant [Table 21]

[0344] Example 21: Semaglutide perforated implant [Table 22]

[0345] Example 22: Metformin-perforated implant [Table 23]

[0346] Example 23: Paliperidone perforated implant [Table 24]

[0347] II. Examination of the number of drug release holes in perforating implants Schematic diagrams of the perforating implants of Examples 24-25 are shown in Figures 12-14.

[0348] Example 24, Comparative Example 4: Insulin-perforating implant [Table 25]

[0349] Example 25, Comparative Example 5: Semaglutide-type perforated implant [Table 26]

[0350] III. Examination of the location of drug release ports in perforated implants Schematic diagrams of the perforating implants in Examples 26-29 are shown in Figures 11 and 15, respectively.

[0351] Example 26: Insulin-perforating implant [Table 27]

[0352] Example 27: Semaglutide-type perforated implant [Table 28]

[0353] Example 28: Metformin-perforated implant [Table 29]

[0354] Example 29: Paliperidone perforated implant [Table 30]

[0355] (ii) Examination of rod core formulation for perforating implants I. Single-layer, single-gradient drilling implant The pore parameters of the silicone rubber tubes with drug release holes for the perforated implants in Examples 30, 32, and 34-38 are as follows: [Table 31]

[0356] The pore parameters of the silicone rubber tube with drug release holes for the perforated implants in Examples 31 and 33 are as follows: [Table 32]

[0357] (i) Examination of the types of additives in the drug-containing layer of the rod core of a single-layer, single-gradient drilling type implant. Schematic diagrams of the perforating implants of Examples 30-33 are shown in Figure 9.

[0358] Example 30: Exenatide perforated implant [Table 33]

[0359] Example 31: Metformin-perforated implant [Table 34]

[0360] (ii) Investigation of the ratio of drug to additive in the drug-containing layer of the rod core of a single-layer, single-gradient drilling type implant. Example 32: Exenatide perforated implant [Table 35]

[0361] (iii) Investigation of the ratio of poorly soluble skeletal material to hydrophilic gel material in the sustained-release additive of the drug-containing layer of the rod core of a single-layer single-gradient perforated implant. Example 33: Metformin-perforated implant [Table 36]

[0362] II. Single-layer, multi-gradient perforated implant (i) Investigation of active drug concentrations in each stage drug release module of the rod core of a single-layer multi-gradient perforated implant. A schematic diagram of the perforating implant of Example 34 is shown in Figure 11.

[0363] Example 34: Semaglutide perforated implant [Table 37]

[0364] III. Two-layer perforated implant (i) Examination of the types of additives in the drug-containing layer of the rod core of a two-layer perforated implant.

[0365] Example 35: Levothyroxine sodium perforating implant [Table 38]

[0366] (ii) Investigation of the mass ratio of sustained-release additive to filler in the drug-containing layer of the rod core of a two-layer perforated implant. Example 36: Levothyroxine sodium perforating implant [Table 39]

[0367] (iii) Examination of the type of expansion material in the push layer of the rod core of a two-layer perforated implant. Example 37: Levothyroxine sodium perforating implant [Table 40]

[0368] (iv) Investigation of the amount of expansion material used in the push layer of the rod core of a two-layer perforated implant. Example 38: Levothyroxine sodium perforating implant [Table 41]

[0369] Establishment of a method for measuring the emission level of the effective examples. 1. Detection conditions (1) Chromatographic conditions for exenatide Chromatography column: Diamonsil (R) C18 column (250 mm x 4.60 mm, 5 μm), Mobile phase: Phase A: 0.08% trifluoroacetate acetonitrile solution, Mobile phase: Phase B: 0.08% trifluoroacetic acid aqueous solution, The change in the ratio of mobile phase A over time is 28% to 55% (0 to 25 min). Flow rate: 1.0mL min -1 , Detection wavelength: 214nm, Column temperature: 30℃ Sample input volume: 20 μL.

[0370] (2) Chromatographic conditions for estradiol Chromatography column: Diamonsil (R) C18 column (250mm x 4mm, 5μm), Mobile phase: Acetonitrile-water (55:45, v / v) Column temperature: 25℃, Detection wavelength: 202nm, Flow rate: 0.8mL min -1 ,

[0371] (3) Chromatographic conditions for semaglutide Chromatography column: Diamonsil (R) C18 column (250 mm x 4.60 mm, 5 μm), Mobile phase: 0.2 mol·L-1 sulfate buffer - acetonitrile (60:40, v / v) Column temperature: 30℃ Detection wavelength: 192nm, Flow rate: 1mL min- 1 , Sample input volume: 20 μL.

[0372] (4) Chromatographic conditions for levothyroxine sodium Chromatography column: SinoDetect HCl-C18 column (4.6 × 250 mm, 5 μm) Mobile phase: Acetonitrile-0.1% TFA (50:50, v / v) Column temperature: 30℃ Detection wavelength: 225nm, Flow rate: 1mL min -1 , Sample input volume: 20 μL.

[0373] (5) Chromatographic conditions for metformin Schema column: Agilent (R) C18 chromatography column (4.6 mm × 150 mm, 5 μm), Mobile phase: methanol:water (10:90, v / v) (pH adjusted to 3.5 with phosphoric acid and triethylamine), Column temperature: Room temperature, Detection wavelength: 233nm, Flow rate: 1.0mL min -1 , Sample input volume: 20 μL.

[0374] (6) Chromatography conditions for insulin Chromatography column: Diamonsil (R) C18 column (250 mm x 4.60 mm, 5 μm), Mobile phase: methanol:water (65:35, v / v, 0.1% TFA added to total volume) Column temperature: 40°C, Detection wavelength: 214nm, Flow rate: 1.0mL min -1 , Sample input volume: 20 μL.

[0375] (7) Chromatographic conditions for paliperidone Schema column: Agilent (R) C8 chromatography column (4.6 × 100 mm, 2.7 μm), Mobile phase: methanol:acetonitrile:water (5:25:70, v / v) (pH adjusted to 3 with phosphoric acid and triethylamine) Column temperature: 35℃, Detection wavelength: 270nm, Flow rate: 0.8mL min -1 , Sample input volume: 20 μL.

[0376] 2, emission results (1) Examination of the process of drug release pathways in perforating implants I. Examination of the size of the drug release port diameter in perforated implants. (1) The release results (daily release amount μg) of the insulin monolayer single-gradient perforation implant model are shown in the table below. [Table 42]

[0377] (2) The release results (daily release amount μg) of the semaglutide single-layer single-gradient perforation implant model are shown in the table below. [Table 43]

[0378] (3) The release results (daily release amount μg) of metformin from a single-layer, single-gradient perforation implant model are shown in the table below. [Table 44]

[0379] (4) The release results (daily release amount μg) of the paliperidone single-layer single-gradient perforation implant model are shown in the table below. [Table 45]

[0380] As can be seen from Example 20-4, the implant was applicable to soluble polymer drugs, poorly soluble polymer drugs, poorly soluble polymer drugs, and soluble low molecular weight drugs.

[0381] Further analysis of Example 20-4 revealed that in the initial stages of drug release, when the pore size was larger than 450 μm, a drug burst release phenomenon occurred, resulting in rapid drug release followed by a sharp decrease in the release rate, leading to a lack of power in the later stages and making it difficult to achieve long-term drug release. When the pore size was less than 250 μm (excluding metformin), the release rate was relatively stable throughout the entire release cycle, but the daily release rate of the formulation was lower compared to formulations with larger pore sizes (e.g., greater than 250 μm).

[0382] II. Examination of the number of drug release holes in perforating implants (1) The release results (daily release amount μg) of the insulin monolayer single-gradient perforation implant model are shown in the table below. [Table 46]

[0383] (2) The release results (daily release amount μg) of the semaglutide single-layer single-gradient perforation implant model are shown in the table below. [Table 47]

[0384] In the initial stages of drug release, the daily release rate of the formulation increased with increasing number of drug release holes. In implants with two or three drug release holes, a burst release phenomenon was observed.

[0385] III. Examination of the location of drug release ports in perforated implants (1) The release results (daily release amount μg) of the insulin monolayer single-gradient perforation implant model are shown in the table below. [Table 48]

[0386] (2) The release results (daily release amount μg) of the semaglutide single-layer single-gradient perforation implant model are shown in the table below. [Table 49]

[0387] (3) The release results (daily release amount μg) of metformin from a single-layer, single-gradient perforation implant model are shown in the table below. [Table 50]

[0388] (4) The release results (daily release amount μg) of paliperidone single-layer single-gradient perforated implant model are shown in the table below. [Table 51]

[0389] According to the drug release curve results, changes in the position of the drug release port in a single pathway did not significantly affect drug release, and the release curves were relatively similar with no significant differences.

[0390] (ii) Examination of rod core formulation for perforating implants I. Single-layer, single-gradient drilling implant (i) The results of the investigation into the types of additives in the drug-containing layer of the rod core of a single-layer, single-gradient perforated implant (daily release amount μg) are shown in the table below. [Table 52]

[0391] As can be seen from Example 30, when the sustained-release additive was a poorly soluble skeletal material (Eudoragit S100, calcium alginate, ethylcellulose), the release curve was stable. The difference is that Eudoragit S100 and calcium alginate have poor water solubility, resulting in an overly strong release control ability, which may cause a stagnation of release in the initial stages of drug release. Relatively speaking, ethylcellulose showed a relatively good drug release tendency.

[0392] In drug release curves where hydrophilic gel materials are used as sustained-release additives, PEO N80 exhibits high viscosity, a high degree of hydration, and a stronger release control effect on the drug. As a result, the initial drug release is extremely low. Subsequently, the continuous dissolution of the hydration layer on the drug rod surface exposes the drug locally to the formulation surface, increasing the release rate. However, the majority remains contained within the hydration layer formed from PEO, and the release rate gradually decreases. No significant drug release stagnation was observed with PLGA and HPMC K15M. A clear phenomenon of formulation expansion (which may be called "tube expansion") was observed during the in vitro release process. Considering that the silicone rubber tube needs to maintain a certain level of mechanical properties after implantation in the human body for long-term stable release, the effectiveness of using hydrophilic gel framework materials alone as sustained-release materials is inferior to that of poorly soluble framework materials. [Table 53]

[0393] As can be seen from the release curve in the figure below, when the hydrophilic gel backbone material is HPMC K15M, it interacts with ethylcellulose and was able to achieve an ideal sustained release effect.

[0394] (2) The release results (daily release amount μg) in the study of the ratio of drug to additive in the drug-containing layer of the rod core of a single-layer single-gradient perforated implant are shown in the table below. [Table 54]

[0395] As can be seen from the above, when the ratio of drug to additive is 1:5, drug release is stable, and no clear burst release or stagnation phenomena of the drug were observed.

[0396] (3) The release results (daily release amount μg) in the study of the ratio of poorly soluble skeletal material to hydrophilic gel material in the sustained-release additive of the drug-containing layer of the rod core of a single-layer single-gradient perforated implant are shown in the table below. [Table 55]

[0397] When EC:HPMC K15M = 2:1, the drug release curve was stable, and conversely, the initial drug burst release increased as the HPMC K15M content increased.

[0398] II. Single-layer, multi-gradient perforated implant (1) The drug release results (daily release amount μg) in the study of drug ratios at each stage of single-layer multi-gradient perforation implants are shown in the table below. [Table 56]

[0399] III, Two-layer implant (1) The release results (daily release amount μg) in the investigation of the types of additives in the drug-containing layer of the rod core of the two-layer perforation implant are shown in the table below. [Table 57]

[0400] Both PEO WSR-303 and PEO WSRN-750 showed good and stable release, however, PEO WSR-303 may affect the overall appearance of the implant if the viscosity of the drug-containing layer is high.

[0401] (2) The release results (daily release amount μg) in the study of the mass ratio of the sustained-release additive and the filler in the drug-containing layer of the rod core of a two-layer perforated implant are shown in the table below. [Table 58]

[0402] The results showed that when the amount of PEO WSRN-750 was 20 mg, the drug could not be adequately suspended, resulting in a lack of power in the later stages of drug release. However, as the amount of PEO WSRN-750 used increased, drug release became slower, and when the amount of PEO WSRN-750 was 60 mg, the drug release rate decreased.

[0403] (3) The release results (daily release amount μg) in the investigation of the type of expansion material in the push layer of the rod core of a two-layer perforated implant are shown in the table below. [Table 59]

[0404] The results showed that changes in PEO molecular weight within the selected range did not significantly affect drug release, and that increasing the PEO molecular weight increased viscosity and improved the moldability of the additive powder.

[0405] (4) The release results (daily release amount μg) in the study of the amount of expansion material used in the push layer of the rod core of a two-layer perforated implant are shown in the table below. [Table 60]

[0406] The amount of PEO WSR N60K used within the selected range did not have a significant effect on drug release.

[0407] Although specific embodiments of the present invention have been described above, those skilled in the art will understand that these are merely illustrative examples and that many changes or modifications can be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is limited by the appended claims. [Explanation of Symbols]

[0408] 1- Drug release hole, 2- Silicone rubber tube, 3- Length of silicone rubber tube, 4- Outer diameter of silicone rubber tube, 5- Hole diameter of drug release hole, 6- Distance from the center point of the drug release hole to the end point of the silicone rubber tube, 7- Distance between the center points of adjacent drug release holes, 8- End sealant, 9- Drug-containing layer, 901- First drug release module, 902- Second drug release module, 903- Third drug release module, 10- Drug release direction, 11- Push layer.

Claims

1. A raw material composition for silicone rubber material, based on parts by weight, 100 copies of R-vinylpolysiloxane, 10 to 80 parts of reinforcing agent, A catalyst comprising 0.000002 to 1 part, Here, R in the R-vinylpolysiloxane is a substituted or unsubstituted C. １ -C ５ Linear or branched alkanes, substituted or unsubstituted C ６ -C ２０ It is an aromatic hydrocarbon, The vinyl group content in the R-vinylpolysiloxane is 0.1 mol% to 0.5 mol%, The components contained in the aforementioned reinforcing agent include hydrophilic groups, The Si-H group content in hydrogen-containing silicone oil is 0.18 to 1.6 mol%, The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinylpolysiloxane is (0.5 to 10):

1. A raw material composition for a silicone rubber material, characterized in that it optionally further comprises an inhibitor, the inhibitor being a substance capable of suppressing the occurrence of an addition reaction between the R-vinylpolysiloxane and the hydrogen-containing silicone oil.

2. The raw material composition of the aforementioned silicone rubber material is a. In the R-vinylpolysiloxane, R is either substituted or unsubstituted C. １ -C ５ The linear alkane, for example, the methyl group, b. The content of vinyl groups in the R-vinylpolysiloxane is 0.15 mol% to 0.3 mol%, for example, 0.18 mol% or 0.23 mol%, c. The amount of the reinforcing agent is 20 to 70 parts by weight, for example, 30 parts, 40 parts, 45 parts, or 50 parts. d. The water contact angle of the reinforcing agent is ≤90°, for example, 14 to 90°, 16 to 35°, or ≤25°. e. The hydrophilic group is one or more of the following: a hydroxyl group, a mercapto group, an aldehyde group, a ketone group, an ether bond, a blocked polyether, a carboxylic acid group, a carboxylic acid ester group, a sulfate group, a sulfone group, a sulfinic acid group, a sulfonic acid group, a sulfonamide, a sulfonic acid ester, a thioether, a phosphate group, a phosphate amide group, a phosphate imide group, a phosphate ester group, a phosphino group, an amino group, an imino group, a tertiary amino group, a quaternary ammonium group, a nitrile group, a cyanate group, a thiocyanate group, an amide group, and other oxygen-containing groups that can form hydrogen bonds with water molecules. f. The reinforcing agent is one or more of the following: silica, hydroxyapatite, diatomaceous earth, quartz powder, silica fine powder, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium oxide, titanium dioxide, carbon black, zinc oxide, titanium dioxide, clay, lignin, carbonate, and kaolin, wherein the silica is preferably hydrophilic silica or a mixture of hydrophilic silica and hydrophobic silica, wherein the hydrophilic silica is preferably one or more of the following: hydrophilic vapor-processed silica, for example, hydrophilic vapor-processed silica N20, hydrophilic silica TH-a200, hydrophilic vapor-processed silica A380, hydrophilic vapor-processed silica A300, T30 hydrophilic vapor-processed silica, T40 hydrophilic vapor-processed silica, and V15 hydrophilic vapor-processed silica. g. The amount of hydrogen-containing silicone oil used is 0.3 to 5 parts, preferably 0.3 to 3 parts, for example 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts, or 1.70 parts. h. The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinylpolysiloxane is (0.5 to 8):1, preferably (0.8 to 3):1, for example 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1, or 3:

1. i. The Si-H group content in the hydrogen-containing silicone oil is 0.15 to 1.6 mol%, preferably 0.15 to 1.2 mol%, for example, 0.75 mol%, j. The catalyst is a platinum catalyst, wherein the concentration of platinum in the platinum catalyst is preferably 1×10 ３ to 1×10 ５ ppm, for example 1×10 ３ ppm, 1×10 ４ ppm, wherein ppm refers to that the mass concentration of platinum in the platinum catalyst is one part per million k. The amount of catalyst used is 0.00001 to 0.5 parts, for example, 0.00001 parts, 0.0098 parts, or 0.21 parts. l. The inhibitor is an acetylene alcohol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol or, for example, 2-methyl-3-butyne-2-ol. m. The amount of the inhibitor by weight is 0.03 to 2.0 parts, for example, 0.69 parts. n. The raw material composition for the silicone rubber material may also contain 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.18 mol%, 30 parts of hydrophilic silica, 1.33 parts of hydrogen-containing silicone oil having a molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane of 1.5:1, 0.0098 parts of platinum catalyst (with a concentration of 3000 ppm), and 0.69 parts of 2-methyl-3-butyne-2-ol. Alternatively, the raw material composition for the silicone rubber material may contain 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.18 mol%, 30 parts of hydrophilic silica, 1.33 parts of hydrogen-containing silicone oil having a molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane of 1.5:1, 0.01 parts of platinum catalyst (with a concentration of 3000 ppm), and 0.69 parts of 2-methyl-3-butyne-2-ol. Alternatively, the raw material composition for the silicone rubber material may contain 100 parts methylvinylpolysiloxane having a vinyl group content of 0.18 mol%, 20 parts hydroxyapatite, 20 parts HB-615 hydrophobic vapor-phase silica, 1.33 parts hydrogen-containing silicone oil having a molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane of 1.5:1, 0.21 parts platinum catalyst (at a concentration of 3000 ppm), and 0.98 parts 2-methyl-3-butyne-2-ol. Alternatively, the raw material composition for the silicone rubber material may contain one or more of the following conditions a to n: 100 parts of methylvinylpolysiloxane having a vinyl group content of 0.17 mol%, 20 parts of hydrophilic vapor-processed silica N20, 20 parts of hydrophobic vapor-processed silica R106, a hydrogen-containing silicone oil having a Si-H group content of 0.75% and a molar ratio of Si-H groups to vinyl groups in methylvinylpolysiloxane of 1.2:1, 0.00001 parts of platinum catalyst, and 0.7 parts of 2-methyl-3-butyne-2-ol.

3. A method for manufacturing a silicone rubber material, Step S1 involves mixing R-vinylpolysiloxane with a reinforcing agent to obtain mixture A, Step S2 involves dividing the mixture A into component A1 and component A2, mixing component A1 with hydrogen-containing silicone oil to obtain component B1, mixing component A2 with a catalyst to obtain component B2, and optionally further comprising an inhibitor in component B1. The process includes step S3, which involves mixing component B1 and component B2 to obtain a mixture B, and then carrying out an addition reaction with a catalyst to obtain the silicone rubber material. Here, preferably, the method for manufacturing the silicone rubber material is: (i) The reinforcing agent is pre-treated, and the pre-treatment method is drying at a temperature of 90 to 220°C for 1 to 24 hours, for example, drying at a temperature of 130°C for 24 hours. (ii) The R-vinylpolysiloxane is pretreated, and the pretreatment method is drying at 20 to 90°C for 1 to 24 hours, for example, drying at 40°C for 12 hours, (iii) In step S1, the mixing step is a process in which the reinforcing agent is added to the R-vinylpolysiloxane in small amounts multiple times and kneaded, followed by thinning by extrusion, (iv) In step S2, the method for producing component B1 is to re-knead component A1 in an open roll with a roll gap parameter of 1 unit, add the hydrogen-containing silicone oil and the inhibitor one drop at a time, set different roll gaps after addition, perform triangular folding and thin passing, remove and leave for 24 hours, (v) In step S2, the method for producing component B2 is to re-knead component A2 in an open roll with a roll gap parameter of 1 unit, add the catalyst drop by drop, continuously shorten the roll gap, pass through thinly, remove and leave for 24 hours, (vi) In step S3, the mass ratio of component B1 to component B2 in the mixture B is 1:1, (vii) In step S3, the method for producing the mixture B is to place component B1 and component B2 into an open roll, mix and extrude, and pass through six times, (viii) In step S3, the step of the addition reaction with the catalyst is a step of sequentially performing a first vulcanization treatment and a second vulcanization treatment on the mixture B, preferably further including a third vulcanization treatment, wherein the temperature of the first vulcanization treatment is preferably 200°C to 340°C, for example 250°C, and the time of the first vulcanization treatment is preferably 2s to 30s, wherein the first vulcanization treatment is preferably performed in a vertical hot air vulcanization tunnel, and A method for producing a silicone rubber material, characterized in that the temperature of the second vulcanization treatment is preferably 180°C to 280°C, for example 220°C, 240°C, 260°C, or 280°C; the time of the second vulcanization treatment is preferably 0.1 min to 5 min; the second vulcanization treatment is preferably performed in a horizontal hot air vulcanization tunnel; and the temperature of the third vulcanization treatment is preferably 150°C to 240°C, for example 180°C, satisfying one or more of these conditions.

4. A silicone rubber material characterized by being manufactured by the manufacturing method described in claim 3.

5. A method for manufacturing a silicone rubber tube, wherein a tubular shape is formed from the mixture B described in claim 3 by an extrusion process, and then an addition reaction with a catalyst is performed to obtain the silicone rubber tube, Alternatively, a method for producing a silicone rubber tube, characterized by carrying out the addition reaction process using the catalyst described above in a tubular mold to obtain the silicone rubber tube.

6. A silicone rubber tube characterized by being manufactured by the manufacturing method described in claim 5.

7. An implant comprising a drug core and a silicone rubber tube as described in claim 6, wherein the drug core contains a drug active ingredient.

8. Application of the silicone rubber material according to claim 4 or the silicone rubber tube according to claim 6 as a release rate regulating medium in a sustained-release formulation.

9. A rod core for a perforated implant, comprising a drug-containing layer, wherein the drug-containing layer contains an active drug and an additive. Here, the additive includes a sustained-release additive, and the molecular weight of the sustained-release additive is 1000 to 10 million. The ratio of the drug to the additive is 1:(0.01 to 100), and the ratio of the drug to the additive represents the mass ratio of the active drug to the additive in the drug-containing layer. A rod core for a perforating implant, characterized in that the rod core of the perforating implant optionally further comprises a push layer compounded on the drug-containing layer.

10. The active drug comprises an active drug having a drug solubility > 10 mg / mL and a drug molecular weight greater than 800 Da, preferably an active drug having a drug solubility > 30 mg / mL and a drug molecular weight greater than 800 Da, for example, one or more of exenatide, semaglutide, Centella asiatica total saponins, and human growth hormone. and / or the active drug comprises an active drug having a drug solubility > 10 mg / mL and a drug molecular weight of 800 Da or less, preferably an active drug having a drug solubility > 30 mg / mL and a drug molecular weight of 800 Da or less, such as metformin and / or adriamycin hydrochloride. and / or, the active drug comprises an active drug having a drug solubility ≤ 10 mg / mL and a drug molecular weight greater than 800 Da, preferably an active drug having a drug solubility ≤ 5 mg / mL and a drug molecular weight greater than 800 Da, for example, one or more of bovine insulin, paclitaxel and levothyroxine sodium. and / or, the active drug comprises an active drug having a drug solubility ≤ 10 mg / mL and a drug molecular weight of 800 Da or less, preferably an active drug having a drug solubility ≤ 5 mg / mL and a drug molecular weight of 800 Da or less, for example, one or more of estradiol, gestodene, levonorgestrel, meloxicam, ganciclovir, puerarin, and paliperidone. And / or, the weight-average molecular weight of the sustained-release additive is between 11 million and 8 million, for example, 11.71, 10,000, 44,000, 200,000, 300,000, 400,000, or 7 million. The sustained-release additive preferably comprises a sparingly soluble skeletal material and / or a hydrophilic gel material, wherein the weight-average molecular weight of the sparingly soluble skeletal material is preferably 20 to 8 million, preferably 30 to 7 million, and more preferably one or more of calcium alginate, methylcellulose, polyethylene, polyvinyl chloride, methacrylate-methyl acrylate copolymer and ethylcellulose, for example ethylcellulose, wherein the methacrylate-methyl acrylate copolymer is preferably Eudragit S100, Eudragit S100, Eudragit S100 The hydrophilic gel material is one or more of Git L100, RL, RS, NE, and FS, for example, Eudragit S100, and the weight-average molecular weight of the hydrophilic gel material is preferably 10 to 8 million, and more preferably contains one or more of hypromellose, polyoxyethylene, sodium alginate, chitosan, agar, xanthan gum, carbomer, polyvinyl alcohol, N-vinylamide polymer, polylactic acid-glycolic acid copolymer (PLGA), and polyethylene oxide, and the hypromellose is preferably HPMC The N-vinylamide polymer is preferably one or more of K100M, HPMC K15M, and HPMC K4M, and the polyethylene oxide is preferably one or more of PEO N80, PEO N-750, PEO WSR 303, PEO WSR N-12K, PEO WSR N-60K, and PEO WSR 1105. and / or, the additive further comprises one or more of the drug stabilizers, fillers and suspending agents, and / or, the ratio of the drug to the additive is 1:(0.01 to 99), for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60 or 1:80, and / or, the mass ratio of the sustained-release additive to the additive is 1:(0.01 to 100), for example 1:0.01, 1:0.05, 1:0.1, 1:0.2, 1:0.5, 1:1, 1:1.5, 1:3, 1:4.33, 1:5, 1:7, 1:10, 1:20, 1:40, 1:60, 1:80 or 1:100, and / or, the concentration of the active drug in the drug-containing layer is set to a stepped concentration gradient, the gradient preferably having 1 to 50 steps, for example, 2, 3, 5, 10, 20, or 40 steps, and the stepped concentration gradient generally means that the concentration of each step is independent of each other. and / or, the raw material of the push layer comprises an expanding material and a penetration-promoting substance, and / or, if the rod core further includes a push layer, the mass ratio of the drug-containing layer to the push layer is (0.01 to 100):1, for example 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:1, and / or, if the rod core further includes push layers, the number of push layers is an integer, preferably an even number, for example two, and if the number of push layers is even, the push layers are preferably located at both ends of the drug-containing layer. and / or, the length of the rod core per press is 1 to 50 mm, for example, 1 mm, 2 mm, 3 mm, 4 mm, 5 mm, 7 mm, 10 mm, 20 mm, 30 mm, 40 mm, or 50 mm, and the total length of the rod core may be selected according to the length of the silicone rubber tube. The rod core for a perforated implant according to claim 9, characterized in that the diameter of the rod core is 1 to 10 mm, more preferably 1 to 5 mm, for example 2 mm, 3 mm, or 4 mm.

11. If the gradient has three stages, the gradient is set in order for the first stage drug release module, the second stage drug release module, and the third stage drug release module, wherein the concentration of the active drug in the first stage drug release module is 0.1% to 50%, for example 2%, 5%, or 10%, the concentration of the active drug in the second stage drug release module is 1% to 80%, for example 10%, or 20%, and the concentration of the active drug in the third stage drug release module is 1% to 100%, for example 20%, or 30%, and the concentration of the active drug represents the percentage of the mass of the active drug relative to the mass of the stage drug release module. and / or, the expansion material in the push layer is polyethylene oxide, preferably polyethylene oxide having a weight-average molecular weight of 10 to 7 million, for example, one or more of PEO N-80, PEO N-750, PEO WSR 1105, PEO WSR 303, PEO N-12K, and PEO N-60K. and / or, the penetration-promoting substance in the push layer is one or more of mannitol, lactose, fructose, glucose, and NaCl, for example, NaCl. The perforated implant rod core according to claim 9 or 10, characterized in that the mass ratio of the expanding material to the penetration promoting substance in the push layer is preferably (0.01 to 100):1, for example 0.01:1, 0.02:1, 0.05:1, 0.1:1, 0.2:1, 0.5:1, 1:1, 2:1, 3:1, 4:1, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1, or 100:

1.

12. A method for manufacturing a rod core for a perforated implant according to any one of claims 9 to 11, comprising the step of obtaining the drug-containing layer by pressing the active drug and the additive, The push layer is optionally compounded onto the drug-containing layer. Preferably, the pressure of the press is 0.01 to 10 MPa, for example, 0.1, 0.2, 0.3, 0.5, 1, 2, 5 or 10 MPa, characterized in that the manufacturing method.

13. A perforating implant comprising a rod core for a perforating implant according to any one of claims 9 to 11, and a silicone rubber tube with a drug release hole covering the outside of the rod core, Here, preferably, in the silicone rubber tube with drug release holes, the ratio of the diameter of the drug release holes to the outer diameter of the silicone rubber tube is (0.0001 to 0.5):1, preferably (0.002 to 0.4):1, for example 0.06:1, 0.14:1 or 0.23:1, and more preferably (0.005 to 0.2):

1. and / or, in the silicone rubber tube with drug release holes, the ratio of the total area of ​​the drug release holes to the outer surface area of ​​the silicone rubber tube is (0.00001 to 0.4):1, preferably (0.0001 to 0.35):1, more preferably (0.0005 to 0.3):1, for example 0.0005:1, 0.001:1, 0.005:1, 0.01:1, 0.05:1, 0.1:1, or 0.2:

1. And / or, the pore diameter of the drug release pore is 1 μm to 1000 μm, preferably 10 to 600 μm, for example 10, 20, 50, 100, 150, 250, 350, 450 or 550 μm, and more preferably 250 to 450 μm. And / or, the number of drug release holes is >1, preferably 1 to 1,000,000, for example 1, 2, 5, 10, 20, 50, 100, 200, 500, 1000, 5000, 10000, 50000, 100000, 500000 or 1,000000. and / or, the silicone rubber tube with drug release holes is obtained by perforating the silicone rubber tube using a laser perforation method or a mechanical perforation method. and / or, the location of the drug release holes satisfies the conditions that the silicone rubber tube includes a first end face and a second end face which are installed opposite to each other, the distance between the first end face and the second end face is the total length of the silicone rubber tube, and the silicone rubber tube is provided with a plurality of drug release holes. Here, when the number of drug release holes is 1, the distance from the center point of the drug release hole to the first end face of the silicone rubber tube with the drug release hole is preferably 0 to 100% of the length of the silicone rubber tube, but not 0 or 100%, more preferably the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release hole is 0.1% to 99.9% of the length of the silicone rubber tube, more preferably 1% to 99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%. Here, if the number of drug release holes is ≥ 2, the distance to the center point of the drug release holes is preferably, If the planes of any two drug release holes are not in the same radial cross-section of the silicone rubber tube, the distance from the center point of any one of the drug release holes to the first end face of the silicone rubber tube with the drug release holes in the axial cross-sectional direction of the silicone rubber tube is preferably 0 to 100% of the length of the silicone rubber tube, but not 0 or 100%, and preferably 0.1% to 99.9% of the length of the silicone rubber tube, more preferably 1% to 99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%, and the distance between the center points of adjacent drug release holes is preferably 0.001 to 80 mm. Here, if the number of drug release holes is greater than or equal to 2, the distance to the center point of the drug release hole is further: When the planes of any two drug release holes are in the same radial cross-section of the silicone rubber tube, the distance from the center point of one of the drug release holes to the first end face of the silicone rubber tube with drug release holes in the circumferential direction of the radial cross-section of the silicone rubber tube is preferably 0 to 100% of the length of the silicone rubber tube, but not 0 and 100%, and preferably from the center point of one of the drug release holes to the first end face of the silicone rubber tube with drug release holes. A perforated implant characterized in that the distance to the first end face of the tubing is 0.1% to 99.9% of the length of the silicone rubber tubing, more preferably 1% to 99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98%, or 99%, and the distance on the circumference of the center points of adjacent drug release holes is preferably (2 to 10)π mm.

14. A method for manufacturing a perforated implant according to claim 13, characterized by comprising the step of filling a silicone rubber tube with a drug release hole with the rod core of a perforated implant according to any one of claims 9 to 11.

15. Application of the rod core for perforated implants according to any one of claims 9 to 11 or the perforated implant according to claim 13 as a release rate regulating medium in a sustained-release formulation.

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