Silicone material, silicone tube, implant and preparation method therefor, rod core, perforated implant and preparation method therefor and use thereof

Abstract

Disclosed in the present invention are a silicone material, a silicone tube, an implant and a preparation method therefor, a rod core, a perforated implant and a preparation method therefor and the use thereof. The silicone material comprises the following components: 100 parts of R-vinyl polysiloxane, 10-80 parts of a reinforcing agent and 0.000002-1 part of a catalyst. The rod core comprises a drug-containing layer, wherein the drug-containing layer contains an active drug and an auxiliary material; the auxiliary material comprises a sustained- and controlled-release auxiliary material; the sustained- and controlled-release auxiliary material has a molecular weight of 1000 to 10 million; and the drug-auxiliary material ratio is 1: (0.01-100). With regard to the silicone material, while meeting mechanical properties, the permeability of water to the silicone tube is increased, so that the release amount of drugs is increased and the defect of low in-vitro release in the prior art is ameliorated. The implant can be suitable for most drugs and can achieve long-acting release of a drug.

Description

Silicone material, silicone tube and implant and preparation method thereof, rod core, punched implant and preparation method and application thereof

[0001] This application claims the benefit of Chinese patent applications No. 2023111805573 and No. 2023111805569, filed September 13, 2023. The entire contents of the aforementioned Chinese patent applications are incorporated herein by reference. Technical Field

[0002] The present invention relates to a silica gel material, a silica gel tube and an implant and a preparation method thereof, a rod core, a punched implant and a preparation method and application thereof. Background Art

[0003] Silicone subdermal implants primarily involve filling a silicone tube with a drug and implanting it subcutaneously. Water permeates the tube, forming a drug solution, which is then steadily released through the tube, achieving long-term efficacy. Currently available on the market is the levonorgestrel implant, which offers long-term contraceptive efficacy. This formulation avoids the first-pass effect in the gastrointestinal tract, significantly improving drug bioavailability.

[0004] Existing silicone subcutaneous implants primarily use methylvinyl polysiloxane and hydrophobic silica as their base materials. Hydrophobic silica offers superior reinforcing properties, allowing the resulting silicone tube to meet the mechanical requirements for implantation. However, its low water permeability, as it is hydrophobic, prevents water from effectively penetrating the silicone tube and dissolving the drug to form a solution. Consequently, the implant's drug release is low, making it unsuitable for high-dose medications and limiting its clinical application.

[0005] Subcutaneous implants primarily incorporate active drugs within a carrier and are implanted subcutaneously. The carrier controls the release of the drug, which is absorbed into the bloodstream through local capillaries, resulting in stable release for several years and long-term effects. This formulation avoids the first-pass effect in the gastrointestinal tract, significantly improving drug bioavailability. Because the implant is implanted within the body, the choice of carrier material is particularly important.

[0006] Implants typically consist of a drug core and a silicone tube. Traditional implant drug cores are generally divided into two types: one is a rod core filled with a powdered drug. Powdered drug fillings can lead to high drug loss, difficulty controlling drug filling uniformity, and a pronounced drug release burst. The other is a silicone skeleton rod core, which requires high-temperature vulcanization during its preparation and finalization. This type of rod core is clearly unsuitable for heat-sensitive drugs that are susceptible to high-temperature densification.

[0007] The silicone tube of traditional silicone implants is not perforated. Instead, the tube forms pores through its own cross-linked network structure. Water from the outside enters the tube through these pores, dissolving the drug to form a solution. The drug solution first diffuses into the silicone tube wall and adsorbs onto it. Because silica gel has very low polarity, only drugs with very low polarity can complete this adsorption process and then diffuse. Drugs with high polarity cannot diffuse outside the silicone tube. Secondly, due to the properties of silica gel itself and the size of the silicone tube's network pores, only small-molecule drugs with low polarity and a molecular weight below 800 and water molecules can pass through. It has a significant retention effect on drugs with a molecular weight greater than 800, making it unsuitable for large-molecule drugs.

[0008] Therefore, in order to solve the above problems, it is urgent to develop an implant suitable for various types of drugs.

[0009] Summary of the Invention

[0010] The present invention primarily aims to overcome the drawback of prior art silicone materials, which struggle to achieve both mechanical properties and water permeability. The invention provides a silicone material and its preparation method, a silicone tube, and an implant, as well as their preparation methods and applications. The silicone material provided by the present invention not only meets mechanical properties but also increases water permeability through the silicone tube, thereby increasing drug release and addressing the low in vitro release rate observed in prior art.

[0011] The present invention solves the above technical problems through the following technical solutions.

[0012] The present invention provides a raw material composition of silica gel material, which comprises the following components in parts by weight:

[0013] R-vinyl polysiloxane: 100 parts;

[0014] Reinforcing agent: 10-80 parts;

[0015] Catalyst: 0.000002-1 part;

[0016] Wherein, R in the R-vinyl polysiloxane is a substituted or unsubstituted C1-C5 straight chain alkane or branched chain alkane, a substituted or unsubstituted C6-C 20 aromatic hydrocarbons;

[0017] The content of vinyl groups in the R-vinyl polysiloxane is 0.1 mol% to 0.5 mol%;

[0018] The reinforcing agent contains a hydrophilic group in its ingredients;

[0019] The content of Si-H groups in the hydrogenated silicone oil is 0.18 mol% to 1.6 mol%;

[0020] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl polysiloxane is (0.5-10):1;

[0021] Optionally, an inhibitor is further included, and the inhibitor is a substance that can inhibit the addition reaction between the R-vinyl polysiloxane and the hydrogen-containing silicone oil.

[0022] In the present invention, R in the R-vinyl polysiloxane may be a substituted or unsubstituted C1-C5 straight-chain alkane, such as a methyl group.

[0023] When the R is a methyl group, the R-vinyl polysiloxane is a methyl vinyl polysiloxane.

[0024] In the present invention, the structural formula of the R-vinyl polysiloxane may be as follows:

[0025] Wherein, m, n, and p are natural numbers, R1 and R2 may be conventional substituent groups in the art, and R and R' may be conventional end-capping groups in the art.

[0026] For example, when R1=R2=CH3, it corresponds to dimethyl polysiloxane;

[0027] For example, when R1=CH3, R2=CH=CH2, it corresponds to methyl vinyl polysiloxane;

[0028] For example, when R1=Ph, R2=CH=CH2, it corresponds to methylphenylvinylpolysiloxane;

[0029] For example, when R1=CH3CH2CF3, R2=CH=CH2, it corresponds to fluorosilicone polysiloxane;

[0030] For example, when R1=CH3CH2CN and R2=CH=CH2, it corresponds to nitrile polysiloxane.

[0031] In the present invention, the vinyl content in the R-vinyl polysiloxane is preferably 0.15 mol% to 0.3 mol%, for example, 0.18 mol% or 0.23 mol%.

[0032] In the present invention, the content of vinyl groups in the R-vinyl polysiloxane refers to the molar percentage of vinyl groups in the R-vinyl polysiloxane.

[0033] In the present invention, the polysiloxane may be any one of silicone rubber, silicone oil and silicone resin, preferably silicone rubber.

[0034] In the present invention, the weight proportion of the reinforcing agent may be 20-70 parts, such as 30 parts, 40 parts, 45 parts or 50 parts.

[0035] In the present invention, the water contact angle of the reinforcing agent can be ≤90°, for example, 14-90°, 16-35°, or ≤25°. The water contact angle in the present invention refers to the static water contact angle of the material, measured using the principle of optical projection. The volume of the water droplet is set using the test software, and a syringe needle is used to drop the set volume of water on the surface of the sample to be tested. The image of the droplet is projected onto an automated image analysis system using a screen micrometer under an LED light source for measurement. In the present invention, the hydrophilic group can be any water-soluble or water-affinity atomic group commonly used in the art. For example, one or more of hydroxyl, thiol, aldehyde, ketone, ether bond, block polyether, carboxylic acid, carboxylate, sulfate, sulfone, sulfinic acid, sulfonic acid, sulfonamide, sulfonate, thioether, phosphate, phosphoramide, phosphorimide, phosphate, phosphite, phosphine, amino, imino, tertiary amine, quaternary ammonium, nitrile, cyanate, thiocyanate, amide and other oxygen-containing groups that can form hydrogen bonds with water molecules.

[0036] The hydroxyl group may be an alcoholic hydroxyl group or a phenolic hydroxyl group.

[0037] In the present invention, the reinforcing agent can be one or more of white carbon black, hydroxyapatite, diatomaceous earth, quartz powder, silica powder, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, titanium dioxide, clay, lignin, carbonate, and kaolin. The reinforcing agent increases the water permeability of the silica gel material while maintaining the mechanical properties of the silica gel material.

[0038] The silica is preferably hydrophilic silica or a mixture of hydrophilic silica and hydrophobic silica.

[0039] The hydrophilic silica is preferably hydrophilic fumed silica, such as one or more of hydrophilic fumed silica N20, hydrophilic fumed silica TH-a200, hydrophilic fumed silica A380, hydrophilic fumed silica A300, T30 hydrophilic fumed silica, T40 hydrophilic fumed silica and V15 hydrophilic fumed silica.

[0040] As a reinforcing agent for addition-type polysiloxane, hydrophilic fumed silica is a white fluffy powder with active hydroxyl groups on its surface. The hydroxyl groups on its surface are easily connected and adsorbed with polysiloxane through hydrogen bonds and van der Waals forces, indirectly increasing the cross-linking density between the reaction molecules, thereby achieving a reinforcing effect. However, compared with hydrophobic silica, hydrophilic silica is not conducive to the mechanical properties of silicone tubes. Hydrophilic silica has not undergone a silanization reaction, and the silanol groups on its surface are easily introduced into the silicone tube during the preparation process. The prepared silicone tube will produce bubbles, which will affect the mechanical properties and release of the silicone tube. The present invention greatly improves the drug release amount of the silicone material while meeting the mechanical properties of the silicone tube by changing the prescription of the silicone material and optimizing the preparation process.

[0041] 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.

[0042] In the present invention, the hydrogen-containing silicone oil can be any conventional hydrogen-containing silicone oil in the art, for example. The hydrogen-containing silicone oil in the present invention can be used as a crosslinking agent to undergo a crosslinking reaction with R-vinyl polysiloxane. The addition reaction of Si-H in the crosslinking agent with -CH=CH2- in the R-vinyl polysiloxane causes the linear R-vinyl polysiloxane macromolecules to be bonded and crosslinked to form a three-dimensional network structure.

[0043] In the present invention, the mass of the hydrogenated silicone oil is calculated by the following formula (1):

[0044] In formula (1):

[0045] W: mass of hydrogenated silicone oil;

[0046] A: molar ratio of Si-H in hydrogen silicone oil to vinyl content in R-vinyl polysiloxane;

[0047] ω(Vi): mass percentage of vinyl groups in R-vinyl polysiloxane;

[0048] ω(H): the content of Si-H groups in hydrogenated silicone oil;

[0049] 27: molar mass of vinyl;

[0050] W1: Mass of R-vinyl polysiloxane.

[0051] In the present invention, the amount of the hydrogen-containing silicone oil is 0.3-5 parts, preferably 0.3-3 parts, for example, 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts or 1.70 parts.

[0052] In the present invention, the content of Si-H groups in the hydrogen-containing silicone oil may be 0.18-1.2 mol%, for example, 0.75 mol%.

[0053] In the present invention, the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl polysiloxane may be (0.5-8):1, preferably (0.8-5):1, for example, 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1 or 3:1.

[0054] In the present invention, the catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between methylvinylpolysiloxane and hydrogen-containing silicone oil, such as a platinum catalyst.

[0055] Wherein, the concentration of platinum in the platinum catalyst can be 1×10 3 -1×10 5 ppm, for example 1×10 3 ppm, 1×10 4 ppm, ppm refers to the mass concentration of platinum in the platinum catalyst is one part per million.

[0056] In the present invention, the amount of the catalyst is preferably 0.00001-0.5 parts, for example, 0.00001 parts, 0.0098 parts or 0.21 parts.

[0057] In the present invention, the raw material composition of the silica gel material may further include an inhibitor, and the function of the inhibitor is to inhibit the addition reaction between R-vinyl polysiloxane and hydrogen-containing silicone oil at room temperature.

[0058] In the present invention, the inhibitor may be an alkynol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, or 2-methyl-3-butyn-2-ol.

[0059] In the present invention, the weight portion of the inhibitor may be 0.03-2.0 parts, for example 0.69 parts or 0.7 parts.

[0060] In the present invention, PHR refers to the mass parts of each specific component per 100 mass parts of R-vinyl polysiloxane (such as methyl vinyl polysiloxane).

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

[0062] In some specific embodiments, the raw material composition of the silica gel material may include the following components: wherein the content of Si-H groups in the hydrogenated silicone oil is 0.75%:

[0063] In some specific embodiments, the raw material composition of the silica gel material may include the following components: wherein the content of Si-H groups in the hydrogenated silicone oil is 0.75%:

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

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

[0066] Hydrophilic silica: 30 parts;

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

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

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

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

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

[0072] Hydrophilic silica: 30 parts;

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

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

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

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

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

[0078] Hydroxyapatite: 20 parts;

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

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

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

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

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

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

[0085] Hydrophilic fumed silica N20: 20 parts;

[0086] Hydrophobic fumed silica R106: 20 parts;

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

[0088] Platinum catalyst: 0.00001 parts;

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

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

[0091] Method 1:

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

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

[0094] S3. Mixing the component B1 and the component B2 to obtain a mixture B, and subjecting the mixture to catalytic addition to obtain the silica gel material.

[0095] Method 2:

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

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

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

[0099] In step S1, the mixing step can be performed by adding the reinforcing agent into the R-vinyl polysiloxane in small amounts and multiple times, kneading the mixture, and then thinning the mixture by extrusion.

[0100] In step S2, the preparation method of the component B1 can be as follows: re-refining the component A1 in an open mill with a roller distance parameter of 1 unit, and adding the hydrogenated silicone oil and the inhibitor dropwise, setting different roller distances after the addition, triangular packing, thinning, taking out and parking for 24 hours for standby use.

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

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

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

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

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

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

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

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

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

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

[0111] The temperature of the third vulcanization treatment can be 150°C-240°C, for example, 180°C. The vulcanization temperature has a significant impact on the mechanical properties and appearance of the silicone material. If the temperature is too low, the vulcanization is insufficient, the silicone material becomes too soft and easily deformed, and the mechanical properties are poor. If the temperature is too high, the silicone material is prone to over-vulcanization, becoming brittle and easily broken, and having poor elasticity.

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

[0113] After mixing with the cross-linking agent and catalyst, the raw rubber can react at room temperature. However, the mixing and processing of the rubber material requires a certain amount of time. If the reactants are cured early during the operation, the desired shape and properties cannot be obtained. This is especially true for addition-type polysiloxanes. Therefore, it is generally required that the catalytic reaction has almost no effect before vulcanization (mixing at room temperature), and reacts rapidly when the vulcanization temperature is reached. The method of inhibiting the reaction is usually to add an inhibitor. The inhibitor can form a certain form of complex with the platinum catalyst. An effective inhibitor can be placed with the rubber material for a considerable period of time, and can only be vulcanized when heated to a certain vulcanization temperature. Commonly used are acetylenic alcohol compounds, nitrogen-containing compounds, organic peroxides, etc. with good compatibility.

[0114] The present invention also provides a silica gel material, which is prepared by the above-mentioned preparation method.

[0115] The present invention also provides a method for preparing a silicone tube, comprising extruding the aforementioned mixture B into a tube, and then performing catalytic addition to obtain the silicone tube.

[0116] Alternatively, the aforementioned catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

[0117] The present invention also provides a silicone tube, which is prepared by the above-mentioned preparation method.

[0118] The present invention also provides an implant comprising the aforementioned silicone tube and a drug core, wherein the drug core contains active pharmaceutical ingredients.

[0119] In the present invention, the active pharmaceutical ingredient may be a conventional sustained-release pharmaceutical ingredient in the art that requires long-term drug release, preferably an active pharmaceutical ingredient with a solubility of ≤100 mg / mL (with water as solvent).

[0120] In the present invention, the active pharmaceutical ingredients may include active pharmaceutical ingredients that act on the reproductive system, or active pharmaceutical ingredients that act on the urinary system, or active pharmaceutical ingredients that act on chronic diseases related to metabolism and nutrition, or active pharmaceutical ingredients used to treat chronic diseases related to connective tissue and rheumatism, or active pharmaceutical ingredients used to treat hyperlipidemia, tumors, neuropsychiatric diseases, chronic dental diseases (caries, periodontal disease), simple obesity, chronic low back pain or leukemia, or active pharmaceutical ingredients that act on the circulatory system, or active pharmaceutical ingredients that act on the respiratory system, or active pharmaceutical ingredients that act on the digestive system, or active pharmaceutical ingredients that act on the blood system, or active pharmaceutical ingredients that act on the endocrine system.

[0121] The active pharmaceutical ingredients acting on the reproductive system may include active pharmaceutical ingredients for contraception, or steroidal estrogens.

[0122] The active pharmaceutical ingredient for contraception may be conventional in the art, and preferably includes levonorgestrel, gestodene or gestrinone.

[0123] The steroidal estrogen is preferably estradiol.

[0124] Among them, the active pharmaceutical ingredients acting on the urinary system preferably include active pharmaceutical ingredients for treating chronic nephritis, treating chronic renal failure, or treating chronic prostatitis.

[0125] The active ingredient of the drug for treating chronic prostatitis is preferably a non-steroidal anti-inflammatory drug, more preferably ibuprofen. Generally, the drug for treating chronic prostatitis can be: antibiotics (such as fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracycline), α-receptor blockers (such as doxazosin, terazosin, etc.), non-steroidal anti-inflammatory drugs (such as ibuprofen, diclofenac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib, etc.), analgesics (such as acetaminophen, etc.), opioids (such as morphine, fentanyl, nalbuphine, pentazocine, etc.), anti-neuropathic pain drugs (such as 5-hydroxytryptamine, duloxetine, venlafaxine), anti-epileptics (such as pregabalin, etc.), M receptor blockers (such as solifenacin, tolterodine, etc.).

[0126] The drugs for treating chronic nephritis can generally be: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan, etc.), calcium channel blockers (such as amlodipine, felodipine, nifedipine, etc.), beta-blockers (such as atenolol, bisoprolol, carvedilol, propranolol, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide, etc.), immunosuppressants (such as prednisone, Ainopril, methylprednisolone, cyclophosphamide, dexamethasone, etc.), statins (such as fluvastatin, simvastatin, pravastatin, etc.).

[0127] The drugs for treating chronic renal failure generally include: angiotensin-converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide, etc.), iron preparations (ferrous fumarate, etc.), compound amino acids, α-keto acids, and recombinant human erythropoietin.

[0128] Among them, the active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition preferably include active pharmaceutical ingredients for treating diabetes, nutritional deficiency diseases, gout, or osteoporosis.

[0129] The anti-gout active ingredient is preferably an anti-gout attack drug, such as colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, para-aminosalicylic acid, salsalate, benolate, more preferably ibuprofen. Generally, the anti-gout drug can also be a uricosuric agent drug (such as benzbromarone, probenecid), a uric acid synthesis blocker drug (such as allopurinol).

[0130] The anti-diabetic drug can generally be an anti-type 1 diabetes drug (such as insulin) or an anti-type 2 diabetes drug. The anti-type 2 diabetes drug can be a sulfonylurea drug (such as glimepiride, gliquidone), a glinide drug (such as repaglinide, nateglinide), a metformin drug (such as metformin), an α-glucosidase inhibitor (such as acarbose, voglibose), a DPP-4 inhibitor (such as sitagliptin), a GLP-1 receptor agonist (such as liraglutide, exenatide) or an SGLT-2 inhibitor (such as dapagliflozin, empagliflozin).

[0131] The drugs for treating nutritional deficiency diseases can generally be drugs for gastrointestinal diseases (such as omeprazole, mosapride) or nutritional supplements (such as vitamin E).

[0132] The anti-osteoporosis drugs can generally be bisphosphonates (e.g., alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonates, clodronate disodium, zoledronic acid sodium, risedronate sodium), calcitonin drugs (e.g., salmon calcitonin), estrogen drugs (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) drugs (e.g., raloxifene, benzothiophene), RANKL inhibitor drugs, parathyroid hormone drugs, glutamine monofluorophosphate drugs, strontium salt drugs (e.g., strontium ranelate), active vitamin D and analogs (e.g., calcitriol, α-calciferol), vitamin K (e.g., menatetrenone).

[0133] Among them, the active pharmaceutical ingredients for treating chronic diseases involving connective tissue and rheumatism preferably include active pharmaceutical ingredients for treating rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, vasculitis, idiopathic inflammatory myopathy, systemic sclerosis, or osteoarthritis.

[0134] The active ingredient of the drug for treating rheumatoid arthritis is preferably a non-steroidal anti-inflammatory drug, such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, nabumetone, more preferably meloxicam or ibuprofen. Generally, the drug for treating rheumatoid arthritis can be a glucocorticoid drug (such as hydrocortisone, dexamethasone, prednisone), a slow-acting antirheumatic drug (such as methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide).

[0135] The active ingredient of the drug for treating osteoarthritis is preferably an analgesic, such as ibuprofen, Voltaren, meloxicam, celecoxib, loxoprofen sodium, and nimesulide, more preferably ibuprofen or meloxicam. Generally, the drug for treating osteoarthritis can be a drug for nourishing cartilage, an opioid (such as oxycodone or chimantin).

[0136] The drugs for treating systemic lupus erythematosus can generally be non-steroidal anti-inflammatory drugs (such as naproxen, ibuprofen), antimalarial drugs, glucocorticoid drugs (such as prednisone acetate, methylprednisolone), immunosuppressant drugs (such as methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), and biological drugs (such as rituximab, belimumab).

[0137] The drugs for treating ankylosing spondylitis can generally be non-steroidal drugs (such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, and etoricoxib), disease-modifying anti-rheumatic drugs (such as pyridine, methotrexate, and hydroxychloroquine), glucocorticoid drugs (such as prednisone, prednisolone, and diprospan), and biological TNF-a antagonists (such as etanercept).

[0138] The drugs for treating Sjögren's syndrome can generally be systemic therapeutic drugs (such as levamisole, transfer factor coenzyme Q10, thymosin), glucocorticoid drugs (such as prednisone), and immunosuppressive drugs (such as hydroxychloroquine, azathioprine, and iguratimod).

[0139] The drugs for treating vasculitis can generally be glucocorticoid drugs (such as prednisone, methylprednisolone, dexamethasone) or immunosuppressant drugs (such as cyclophosphamide, cyclosporine, azathioprine).

[0140] The drugs for treating idiopathic inflammatory myopathy can generally be glucocorticoid drugs (such as dexamethasone, prednisone, hydrocortisone, methylprednisolone), immunosuppressant drugs (such as cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolate mofetil).

[0141] The drugs for treating systemic sclerosis can generally be anti-fibrotic drugs (such as colchicine), vasoactive drugs (such as nifedipine, nifedipine) and several other commonly used drugs (such as naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, tocilizumab).

[0142] Among them, the active ingredient of the drug for treating neuropsychiatric disorders can generally be a drug for treating schizophrenia, an antidepressant drug, a drug for treating opioid abuse, or a drug for treating anxiety disorders; preferably, it is a drug for treating schizophrenia, more preferably, phenothiazines (such as chlorpromazine), thioxanthenes (such as chlorprothixene), butyrophenones (such as haloperidol), dibenzodiazepines (such as olanzapine, clozapine), benzisoxazoles (such as risperidone, paliperidone), benzisothiazoles (such as ziprasidone), diphenylthiazepines (such as quetiapine), quinolones (such as aripiprazole), and further preferably, benzisoxazoles (such as paliperidone).

[0143] The antidepressant drugs can generally be tricyclic antidepressants (such as imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (such as moclobemide), selective serotonin reuptake inhibitors (such as sertraline), serotonin and norepinephrine reuptake inhibitors (such as venlafaxine), serotonin blockers and reuptake inhibitors (such as trazodone), norepinephrine and dopamine reuptake inhibitors (such as bupropion), norepinephrine inhibitors (such as reboxetine), and α2 adrenergic receptor blockers (such as mirtazapine).

[0144] The drug for treating opioid abuse may generally be buprenorphine or methadone.

[0145] The anxiety-treating drugs may generally be benzodiazepines (eg, diazepam), 5-HT1A receptor partial agonists (eg, buspirone), β-adrenergic receptor blockers (eg, propranolol), and valproate.

[0146] The hyperlipidemia treatment drugs are generally statins (eg, simvastatin, atorvastatin, pravastatin), fibrates (eg, fenofibrate, bezafibrate, gemfibrozil), and nicotinic acids (eg, niacin).

[0147] Among them, the anti-tumor drug can generally be an anti-breast cancer drug (such as azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol acetate, cetuximab or leuprolide), an anti-prostate cancer drug (such as degarelix, leuprolide, histrelin, flunitronium, estramustine, cyproterone acetate), an anti-ovarian cancer drug (such as carboplatin, topotecan, methotrexate), an anti-rectal cancer drug (such as panitumumab), an anti-colon cancer drug (such as bevacizumab, oxaliplatin), an anti-liver cancer drug (such as sorafenib), an anti-lung cancer drug (such as erlotinib, gefitinib, docetabine) , kidney cancer drugs (e.g., pazopanib, everolimus, temsirolimus), gastric cancer drugs (e.g., fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), pancreatic cancer drugs (e.g., nimotuzumab), esophageal cancer drugs (e.g., docetaxel, paclitaxel, cisplatin, gemcitabine, tegafur, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), skin cancer drugs (e.g., fluorouracil), lymphoma drugs (e.g., vincristine, bexarotene, dacarbazine, etoposide), myeloma drugs (e.g., bortezomib), cervical cancer drugs (e.g., bleomycin), or bladder cancer drugs (e.g., epirubicin, BCG).

[0148] Among them, the drugs for treating chronic dental diseases (such as caries and periodontal disease) can generally be divided into nitroimidazole drugs (such as metronidazole, tinidazole, ornidazole), penicillins, and other commonly used drugs (minocycline, chlorhexidine acetate).

[0149] Wherein, the drug for treating simple obesity can generally be orlistat.

[0150] Wherein, the active ingredient of the drug for treating chronic low back pain is preferably a non-steroidal analgesic drug, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen, voltaren, more preferably ibuprofen or meloxicam;

[0151] The drugs for treating leukemia are generally drugs that interfere with nucleic acid biosynthesis (such as cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect the DNA structure and function of cancer cells (such as busulfan, mitomycin, chlorambucil, phenylalanine mustard, cyclophosphamide), drugs that interfere with the transcription process and prevent RNA synthesis (such as daunorubicin, doxorubicin, adriamycin, aclarubicin), drugs that inhibit protein synthesis and function (such as vindesine, vincristine, L-aspartate aminotransferase, homoharringtonine), and other commonly used drugs (such as interferon, fludarabine, arsenite, etoposide, and carmustine).

[0152] Wherein, the active pharmaceutical ingredients acting on the circulatory system preferably include active pharmaceutical ingredients for treating chronic heart failure, coronary heart disease, congenital heart disease, chronic infective endocarditis, or chronic pericarditis;

[0153] The active ingredients of the drugs for treating coronary heart disease can generally be drugs that improve symptoms of angina pectoris (such as puerarin, isosorbide mononitrate), antiplatelet aggregation drugs (such as aspirin, clopidogrel bisulfate, ticagrelor), lipid-lowering and plaque-stabilizing drugs (such as atorvastatin, rosuvastatin, pravastatin), sympathetic nerve activity inhibition (such as metoprolol, bisoprolol fumarate), and drugs that improve myocardial remodeling (such as angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists); preferably, the drugs are drugs that improve symptoms of angina pectoris, and more preferably, puerarin; the active ingredients of the drugs for treating chronic heart failure can generally be cardiotonic drugs (such as digitalis, digoxin, cedilanid), vasodilator drugs (such as sodium nitroprusside, nitroglycerin, converting enzyme inhibitors (such as enalapril, lenocort, etc.), and diuretics (such as furosemide, hydrochlorothiazide, spironolactone).

[0154] The active ingredient of the drug for treating congenital heart disease can generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide or coenzyme Q10.

[0155] The active ingredient of the drug for treating chronic infective endocarditis can generally be an antibiotic (eg, vancomycin, cephalosporin, penicillin, aminoglycoside).

[0156] The active ingredient of the medicine for treating chronic pericarditis can generally be digitalis.

[0157] Among them, the active pharmaceutical ingredients acting on the respiratory system may generally include active pharmaceutical ingredients for treating chronic obstructive pulmonary emphysema, treating asthma, treating chronic cor pulmonale, treating chronic respiratory failure, treating silicosis or treating pulmonary fibrosis.

[0158] The active ingredients of the drugs for treating chronic obstructive pulmonary emphysema can generally be bronchodilators (including beta-receptor agonists and anticholinergic drugs), inhaled hormones (such as budesonide, fluticasone), theophylline antiasthmatics (such as theophylline), expectorants (such as carbocysteine, fudosteine), and glucocorticoids and antibiotics (such as penicillins, glycosides and cephalosporins) can also be appropriately selected when the condition requires.

[0159] The active ingredients of the asthma treatment drugs can generally be commonly used inhaled drugs (such as beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (such as salbutamol), sustained-release theophylline, leukotriene modifiers (which can be used in combination), anticholinergics (such as isoproscopolamine), and antihistamines (such as astemizole and ketotifen).

[0160] The active ingredients of the drugs for treating chronic cor pulmonale can generally be antibiotics (such as amoxicillin, ceftizoxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (such as selective β2 receptor stimulants, theophylline drugs), drugs that eliminate nonspecific airway inflammation (such as prednisone), inhaled drugs (such as beconazole), respiratory stimulants (such as lobeline, doxapram, duxil, etc.).

[0161] The active ingredient of the drug for treating chronic respiratory failure can generally be a drug for relieving bronchospasm and removing phlegm (such as salbutamol, acetylcysteine, etc.).

[0162] The active ingredients of the medicine for treating silicosis can generally be siping, acetylcysteine, aluminum preparation, closiperazine, and salvia miltiorrhiza.

[0163] The active ingredients of the drug for treating pulmonary fibrosis can generally be pirfenidone, nintedanib, glucocorticoids (such as methylprednisolone, prednisone), immunosuppressants (such as azathioprine, methotrexate, etc.), colchicine, interferon, ACEI or statins, etc.

[0164] Among them, the active pharmaceutical ingredients acting on the digestive system generally include active pharmaceutical ingredients for treating chronic gastritis, treating peptic ulcers, treating intestinal tuberculosis, treating chronic enteritis, treating chronic diarrhea, treating chronic hepatitis, treating cirrhosis, treating chronic pancreatitis, and treating chronic cholecystitis.

[0165] The active ingredients of the drugs for treating chronic gastritis can generally be used to relieve pain (atropine, propantheline, etc. can be used), PPI proton pump inhibitors (such as lansoprazole, omeprazole, etc.) can be used for increased gastric acid, H2 receptor blockers (such as cimetidine, ranitidine, aluminum hydroxide, etc.) can be used for those with mild symptoms, digestive aids (pancreatic enzymes can be added), and bile reflux (metoclopramide and moclobemide, cholestyramine, sucralfate can be used to bind to bile acids).

[0166] The active ingredients of the drug for treating peptic ulcer are generally levofloxacin, tinidazole, and omeprazole.

[0167] The active ingredient of the drug for treating intestinal tuberculosis can generally be rifampicin.

[0168] The active ingredients of the medicine for treating chronic enteritis can generally be anti-inflammatory analgesics, probiotics, antispasmodics and analgesics (such as atropine and propantheline).

[0169] The active ingredients of the medicine for treating chronic diarrhea can generally be antidiarrheal drugs (such as montmorillonite powder, diphenoxylate, loperamide), intestinal microbial preparations (such as lactobacilli, bifidobacteria), and spasmodic analgesics (such as pinaverium bromide).

[0170] The active ingredients of the drugs for treating chronic hepatitis can generally be liver-protecting drugs (such as silymarin preparations, schisandra preparations, etc.), anti-fibrosis drugs (such as oral preparations of traditional Chinese medicines), antivirals (such as conventional interferon and pegylated interferon), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine, entecavir), and immunosuppressants (azathioprine).

[0171] The active ingredients of the drugs for treating cirrhosis can generally be drugs for treating hepatitis B (such as nucleoside analogs), drugs for treating autoimmune hepatitis (such as glucocorticoids), anti-inflammatory drugs, liver-protecting drugs, anti-liver fibrosis drugs (such as reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizate, etc.), drugs for treating spontaneous bacterial peritonitis (such as antibiotics), and drugs for treating portal hypertension (such as carvedilol).

[0172] The active ingredients of the medicine for treating chronic pancreatitis can generally be analgesics (such as buprenorphine and fentanyl) and pancreatic enzyme treatment drugs (such as pancreatic enzymes).

[0173] The active ingredients of the drug for treating chronic cholecystitis can generally be antibacterial and anti-inflammatory drugs (such as levofloxacin, ciprofloxacin, and amoxicillin), antispasmodics and analgesics, and choleretics (such as ursodeoxycholic acid).

[0174] Among them, the active pharmaceutical ingredients acting on the blood system generally include active pharmaceutical ingredients for treating chronic anemia, treating chronic myeloid leukemia, and treating chronic lymphocytic leukemia.

[0175] The drugs for treating chronic anemia generally include: trace elements (such as folic acid, vitamin B12, etc.), bone marrow stimulants (such as strychnine nitrate, hyoscyamine, hyoscyamine, etc.), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight dextran iron, carboxymaltose iron, isomaltosine iron, glucuronic acid iron, nano iron oxide, sorbitol iron, etc.), erythropoiesis-stimulating drugs (recombinant human erythropoietin α, darbepoetin α, etc.).

[0176] The drugs for treating chronic myeloid leukemia generally include: tyrosine kinase inhibitors (such as imatinib, nilotinib, bosutinib, ponatinib, etc.) and homoharringtonine.

[0177] The drugs for treating chronic lymphocytic leukemia generally include: chemotherapy drugs (such as nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted drugs (such as adranib, venetula, ibrutinib, imatinib, dasatinib, etc.), and monoclonal antibodies (such as ofatumumab, rituximab, atuzumab, alemtuzumab, etc.).

[0178] Among them, the active pharmaceutical ingredients acting on the endocrine system generally include active pharmaceutical ingredients for treating chronic lymphocytic thyroiditis, treating hyperthyroidism, and treating hypothyroidism.

[0179] The drugs for treating chronic lymphocytic thyroiditis generally include: thyroxine (such as levothyroxine, thyroxine), glucocorticoids (such as prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0180] The drugs for treating hyperthyroidism generally include: thiouracils (such as propylthiouracil, methylthiouracil, etc.), imidazoles (such as methimazole, carbimazole, etc.), iodine and iodide (such as Lugol's solution, etc.), radioactive iodine (such as 131 iodine, etc.), beta-blockers (such as metoprolol, atenolol, bisoprolol, carvedilol, propranolol, etc.).

[0181] The drugs for treating hypothyroidism generally include: thyroxine (eg, levothyroxine, levothyroxine sodium, thyroxine, etc.).

[0182] In the present invention, the preparation method of the drug core can be to mix the active pharmaceutical ingredient and polysiloxane in sequence, extrude and vulcanize them to obtain the drug core.

[0183] The polysiloxane comprises R-vinyl polysiloxane, hydrogenated silicone oil, a catalyst and an inhibitor.

[0184] Wherein, the temperature of the vulcanization treatment may be 70°C-160°C.

[0185] The vulcanization treatment time may be 0.5-10 hours.

[0186] Among them, the raw material composition of the drug core can be: in parts by weight, 100 parts of the active pharmaceutical ingredient, 100 parts of R-vinyl polysiloxane, 0.21 parts of the catalyst, 0.98 parts of the inhibitor, and the molar ratio of Si-H in the hydrogenated silicone oil to the vinyl group in the R-vinyl polysiloxane is 4.5:1.

[0187] The present invention provides a method for preparing the implant as described above, which comprises the following steps: filling the drug core into the silicone tube, and then sealing the end to obtain the implant.

[0188] In the present invention, the drug core can be a skeleton-type rod core or a powder-type drug core.

[0189] When the drug core is a skeleton rod core, the length of the silicone tube is 0.4 cm longer than the length of the skeleton rod core. 0.2 cm is reserved at each end of the silicone tube to facilitate sealing of the implant.

[0190] When the drug core is a skeleton-type rod core, the filling method is preferably to quickly insert the skeleton-type rod core while the silicone tube is in a swollen state. Swelling can be achieved by soaking the silicone tube in petroleum ether for 1-2 minutes. After filling, it is preferably air-dried for 12-24 hours; air-drying allows any residual petroleum ether to evaporate.

[0191] When the drug core is a powder type drug core, the filling method is preferably to seal one end of the silicone tube first and then fill it through a drug filling funnel.

[0192] In the present invention, the end-capping can be sealed with a sealing glue; the sealing glue is preferably silica gel.

[0193] In the present invention, after the end-capping is completed, it is preferably placed at room temperature for 12-24 hours to allow the sealing glue to solidify.

[0194] In the present invention, the silicone tube is preferably pretreated by soaking it in 75% ethanol for 15 minutes, then repeatedly rinsing it with 75% ethanol for several times and then air-drying it naturally.

[0195] The present invention also provides a use of the aforementioned silica gel material or the aforementioned silica gel tube as a release rate regulating medium in a sustained-release preparation.

[0196] The technical problem to be solved by the present invention is to overcome the defects of the prior art implants having a narrow scope of application, especially the lack of applicability to drugs with high solubility, heat-sensitive drugs or macromolecular drugs, and to provide a rod core, a punched implant and a preparation method and application. The implant of the present invention is applicable to most drugs and can achieve long-term drug release. In the present invention, after a large number of experimental studies, the inventors used a solid column compression molding method to compress the active drug and excipients to produce a rod core. This not only solves the problem of drug waste or unstable drug release in powder-type drug cores, but also solves the problem of drug instability in the preparation process of silicone skeleton-type rod cores. After the silicone tube is punched, the release amount of the drug is increased, expanding the scope of application of the implant.

[0197] The present invention solves the above technical problems through the following technical solutions.

[0198] The present invention provides a rod core for a perforated implant, comprising a drug-containing layer, wherein the drug-containing layer comprises an active drug and excipients;

[0199] Wherein, the excipients include sustained-release excipients; the molecular weight of the sustained-release excipients is 10 million to 10 million;

[0200] The drug-excipient ratio is 1:(0.01-100); the drug-excipient ratio represents the mass ratio of the active drug to the excipient in the drug-containing layer;

[0201] Optionally, the core of the perforated implant further comprises a booster layer composited on the drug-containing layer.

[0202] In the present invention, the active drug may include conventional drugs in the art, for example, one or more of a macromolecular drug with good solubility, a small molecule drug with good solubility, a macromolecular drug with poor solubility, and a small molecule drug with poor solubility.

[0203] Among them, the macromolecular drug with good solubility can be a conventional active drug in the art with a drug solubility of >10 mg / mL and a drug molecular weight greater than 800 Da, preferably including an active drug with a drug solubility of >30 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of exenatide, semaglutide, Centella asiatica total glycosides and human growth hormone.

[0204] Among them, the small molecule drug with good solubility can be a conventional active drug in the art with a drug solubility of >10 mg / mL and a drug molecular weight of less than or equal to 800 Da, preferably including an active drug with a drug solubility of >30 mg / mL and a drug molecular weight of less than or equal to 800 Da, such as metformin and / or doxorubicin hydrochloride.

[0205] Among them, the macromolecular drug with poor solubility can be a conventional active drug in the art with a drug solubility of ≤10 mg / mL and a drug molecular weight greater than 800 Da, preferably including an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of bovine insulin, paclitaxel and levothyroxine sodium.

[0206] Among them, the small molecule drug with poor solubility can be an active drug with a conventional drug solubility of ≤10 mg / mL and a drug molecular weight of less than or equal to 800 Da in the art, preferably including an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight of less than or equal to 800 Da, such as one or more of estradiol, gestodene, levonorgestrel, meloxicam, ganciclovir, puerarin and paliperidone.

[0207] In the present invention, the weight average molecular weight of the sustained-release excipient is preferably 11 million to 8 million, for example, 11.71 million, 10,000, 44,000, 200,000, 300,000, 400,000 or 7 million.

[0208] In the present invention, the sustained-release excipient preferably includes a poorly soluble skeleton material and / or a hydrophilic gel material.

[0209] The weight average molecular weight of the poorly soluble skeleton material is preferably 20 million to 8 million, more preferably 30 million to 7 million;

[0210] The poorly soluble skeleton material preferably includes one or more of calcium alginate, methylcellulose, polyethylene, polyvinyl chloride, methacrylic acid-methyl acrylate copolymer, and ethyl cellulose, such as ethyl cellulose. The methacrylic acid-methyl acrylate copolymer is preferably one or more of Eudragit S100, Eudragit L100, RL, RS, NE, and FS, such as Eudragit S100.

[0211] The weight average molecular weight of the hydrophilic gel material may be 1,000-8,000,000, preferably 10,000-7,000,000.

[0212] The hydrophilic gel material preferably comprises one or more of: hydropropyl methylcellulose, polyethylene oxide, sodium alginate, chitosan, agar, xanthan gum, carbomer, polyvinyl alcohol, N-vinyl amide polymer, polylactic acid-co-glycolic acid copolymer (PLGA), and polyethylene oxide. The hydropropyl methylcellulose is preferably one or more of: HPMC K100M, HPMC K15M, and HPMC K4M. The N-vinyl amide polymer is preferably PVPK30 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.

[0213] Among them, when the sustained-release excipients are a poorly soluble skeleton material and a hydrophilic hydrogel material, the mass ratio of the poorly soluble skeleton material and 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.

[0214] In a preferred embodiment, the active drug is insulin, and the excipients are the sustained-release excipient and the drug stabilizer, such as HPMC K4M and trehalose. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0215] In a preferred embodiment, the active drug is semaglutide, and the excipients are the sustained-release excipient and the filler, such as HPMC K4M and MCC. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0216] In a preferred embodiment, the active drug is metformin, and the excipients are the sustained-release excipient and the filler, such as HPMC K4M and MCC. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0217] In a preferred embodiment, the active drug is paliperidone, and the excipients are the sustained-release excipient and the filler, such as HPMC K4M and MCC. The mass ratio of the sustained-release excipient to the excipient can be 1:4.33.

[0218] In a preferred embodiment, the active drug is exenatide, and the excipient is the sustained-release excipient, which is preferably one or more of Eudragit S100, calcium alginate, ethyl cellulose, PLGA, HPMCK 15M and PEON80, such as ethyl cellulose, or ethyl cellulose and HPMCK 15M.

[0219] In a preferred embodiment, the active drug is metformin, and the excipient is the sustained-release excipient, which preferably includes one or more of ethyl cellulose, HPMCK 15M, HPMCK 4M, and PEO N80, such as HPMCK 15M, HPMCK 4M, or ethyl cellulose and HPMCK 15M.

[0220] In a preferred embodiment, the active drug is semaglutide, and the sustained-release excipient preferably includes one or more of Eudragit S100, calcium alginate, ethyl cellulose, PLGA, HPMCK 15M and PEO N80, such as ethyl cellulose, or ethyl cellulose and HPMCK 15M.

[0221] In a preferred embodiment, the active drug is levodopa sodium, and the excipients preferably include the sustained-release excipient and the filler, such as PEO N-750 and MCC.

[0222] In the present invention, the excipient ratio 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.

[0223] In the present invention, the excipients preferably further include one or more of a drug stabilizer, a filler and a suspending agent.

[0224] Wherein, the drug stabilizer is preferably trehalose.

[0225] The filler is preferably one or more of starch, dextrin, microcrystalline cellulose (MCC) and lactose.

[0226] Wherein, the suspending agent is preferably hydroxypropyl methylcellulose and / or polyethylene oxide.

[0227] Among them, the mass ratio of the sustained-release excipient and the excipient 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.

[0228] In the present invention, the concentration of the active drug in the drug-containing layer can be set as a gradient concentration. The gradient is preferably 1-50 stages, such as 2 stages, 3 stages, 5 stages, 10 stages, 20 stages, or 40 stages. The gradient concentration is generally expressed as the concentration of each gradient being independent.

[0229] Wherein, when the gradient is 3 sections, the gradient is preferably arranged in sequence as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, and the concentration of the active drug in the first gradient drug release module is preferably 0.1%-50%, for example, 2%, 5% or 10%. The concentration of the active drug in the second gradient drug release module is preferably 1%-80%, for example, 10% or 20%. The concentration of the active drug in the third gradient drug release module is preferably 1%-100%, for example, 20% or 30%. The concentration of the active drug generally represents the percentage of the mass of the active drug to the mass of the gradient drug release module.

[0230] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages: the concentration of the active drug in the first gradient drug release module is 2%, the concentration of the active drug in the second gradient drug release module is 10%, and the concentration of the active drug in the third gradient drug release module is preferably 20%.

[0231] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages: the concentration of the active drug in the first gradient drug release module is 2%, the concentration of the active drug in the second gradient drug release module is 20%, and the concentration of the active drug in the third gradient drug release module is preferably 30%.

[0232] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages: the concentration of the active drug in the first gradient drug release module is 10%, the concentration of the active drug in the second gradient drug release module is 20%, and the concentration of the active drug in the third gradient drug release module is preferably 30%.

[0233] In a preferred embodiment, the concentration of the active drug in the drug-containing layer is set to three stages: the concentration of the active drug in the first gradient drug release module is 5%, the concentration of the active drug in the second gradient drug release module is 20%, and the concentration of the active drug in the third gradient drug release module is preferably 30%.

[0234] In the present invention, when the rod core further comprises a boosting layer, the raw materials of the boosting layer preferably include expansion materials and permeation promoters.

[0235] The expansion material in the boosting layer may be polyethylene oxide, preferably polyethylene oxide with a weight average molecular weight of 100,000-7,000,000, such as one or more of PEO N-80, PEO N-750, PEO WSR 1105, PEO WSR 303, PEO N-12K and PEO N-60K.

[0236] The permeation enhancer in the boost layer may be a conventional substance in the art capable of increasing osmotic pressure, preferably one or more of mannitol, lactose, fructose, glucose and NaCl, such as NaCl.

[0237] Wherein, the mass ratio of the expansion material and the permeation promoter in the boost 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.

[0238] In the present invention, when the stick core further includes a boosting layer, the mass ratio of the drug-containing layer to the boosting layer may be (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, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:1.

[0239] In the present invention, when the rod core further includes a boosting layer, the preparation method of the boosting layer can be conventional in the art, for example, the raw material of the boosting layer can be pressed.

[0240] The pressing can be accomplished by solid column molding, and the pressing pressure can be 0.01-10 MPa.

[0241] In the present invention, when the stick core further includes a boosting layer, the number of the boosting layers may be an integer, preferably an even number, such as 2. When the number of the boosting layers is an even number, the boosting layers are preferably respectively disposed at both ends of the drug-containing layer.

[0242] In the present invention, the single pressing length of the rod core is preferably 1-50 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 can be selected according to the length of the silicone tube.

[0243] In the present invention, the total length of the rod core is preferably 1-100 mm, more preferably 5-60 mm, for example 7 mm or 10 mm or 15 mm or 18 mm or 20 mm or 30 mm or 40 mm or 50 mm or 60 mm.

[0244] In the present invention, the diameter of the rod core is preferably 1-10 mm, more preferably 1-5 mm, such as 2 mm, 3 mm or 4 mm.

[0245] The present invention also provides a method for preparing the punched implant core as described above, which comprises the following steps: compressing the active drug and the excipient to obtain the drug-containing layer;

[0246] Optionally, the boosting layer is compounded on the drug-containing layer.

[0247] In the present invention, the pressing pressure is 0.01-10 MPa, such as 0.1, 0.2, 0.3, 0.5, 1, 2, 5 or 10 MPa.

[0248] In the present invention, the pressing can be accomplished by solid column molding.

[0249] The present invention also provides a perforated implant, which comprises the stick core for the perforated implant as described above and a silicone tube containing drug-releasing holes and covering the outer side of the stick core.

[0250] In the present invention, when the silicone tube is wrapped around the outside of the rod core, the center point of the rod core and the center point of the silicone tube may coincide with each other.

[0251] In the present invention, the plane where the rod core is located can be perpendicular to the radial plane of the silicone tube.

[0252] In the present invention, the size, position, number, etc. of the drug release holes of the silicone tube can be adjusted according to the actual demand for drug release.

[0253] In the present invention, in the silicone tube containing drug release holes, the ratio of the pore diameter of the drug release holes to the outer diameter of the silicone tube can 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).

[0254] In the present invention, the diameter of the drug release pore is preferably 1 μm-1000 μm, more preferably 10-600 μm, such as 10, 20, 50, 100, 150, 250, 350, 450 or 550 μm, preferably 250-450 μm.

[0255] In the present invention, in the silicone tube containing drug release holes, the total area of ​​the drug release holes can be adjusted according to the actual drug release amount requirements. For example, the ratio of the total area of ​​the drug release holes to the external surface area of ​​the silicone tube can be (0.00001-0.4):1, preferably (0.0001-0.35):1, and more preferably (0.0005-0.3):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.

[0256] In the present invention, the number of the drug release holes is preferably >1, more preferably 1-1,000,000, for example, 1, 2, 5, 10, 20, 50, 100, 200, 500, 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 or 1,000,000.

[0257] In the present invention, preferably, the position of the drug release hole meets the following conditions: the silicone tube includes a first end face and a second end face arranged opposite to each other, the distance between the first end face and the second end face is the total length of the silicone tube, and the silicone tube is provided with a plurality of drug release holes.

[0258] When the number of the drug release holes is 1, the distance from the center point of the drug release hole to the first end surface of the silicone tube containing the drug release hole may be 0-100% of the length of the silicone tube but not 0 and 100%. Preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release hole is 0.1%-99.9% of the length of the silicone tube, and more preferably 1%-99%, for example, 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%.

[0259] When the number of drug-releasing holes is ≥2, the distance between the center points of the drug-releasing holes may satisfy the following conditions:

[0260] When the planes of any two of the drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes may be 0-100% of the length of the silicone tube but not 0 and 100%. Preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is 0.1%-99.9% of the length of the silicone tube, more preferably 1%-99%, for example, 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%. The distance between the center points of adjacent drug release holes may be 0.001-80 mm.

[0261] When the number of drug-releasing holes is ≥2, the distance between the center points of the drug-releasing holes may also meet the following conditions:

[0262] When the planes of any two of the drug release holes are on the same radial section of the silicone tube, in the circumferential direction of the radial section of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes may be 0-100% of the length of the silicone tube but not 0 and 100%. Preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is 0.1%-99.9% of the length of the silicone tube, more preferably 1%-99%, for example, 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%. The circumferential distance between the center points of adjacent drug release holes may be (2-10)πmm.

[0263] In a preferred embodiment, in the silicone tube containing a drug release hole, the pore diameter of the drug release hole is 350 μm, the ratio of the pore diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release hole is 1, and the position of the drug release hole meets the following conditions: the distance from the center point of the drug release hole to the first end face of the silicone tube containing the drug release hole is 50% of the length of the silicone tube.

[0264] In a preferred embodiment, in the silicone tube containing drug release holes, the pore diameter of the drug release holes is 350 μm, the ratio of the pore diameter of the drug release holes to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 2, and the positions of the drug release holes meet the following conditions: the planes of the two drug release holes are not on the same radial section of the silicone tube, and in the axial section direction of the silicone tube, the distance from the center point of any drug release hole to the first end face of the silicone tube containing the drug release holes is 50% of the length of the silicone tube, and the distance between the center points of the two drug release holes is 0.3 cm.

[0265] In a preferred embodiment, in the silicone tube containing a drug release hole, the pore diameter of the drug release hole is 350 μm, the ratio of the pore diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release hole is 1, and the position of the drug release hole meets the following conditions: the distance from the center point of the drug release hole to the first end face of the silicone tube containing the drug release hole is 7.5% of the length of the silicone tube.

[0266] In the present invention, the drug-releasing holes can be obtained by laser drilling or mechanical drilling.

[0267] In the present invention, the raw material composition of the silicone tube preferably includes the following components in parts by weight:

[0268] R-vinyl silicone rubber: 100 parts;

[0269] Reinforcing agent: 20-80 parts;

[0270] Hydrogenated silicone oil: 0.3-3.0 parts;

[0271] Catalyst: 0.000002-1 part;

[0272] Wherein, R in the R-vinyl silicone rubber is preferably a substituted or unsubstituted C1-C5 straight-chain alkane or branched alkane, a substituted or unsubstituted C6-C20 aromatic hydrocarbon, and more preferably a substituted or unsubstituted C1-C3 straight-chain alkane, such as methyl.

[0273] When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber.

[0274] The vinyl content in the R-vinyl silicone rubber may be 0.10 mol%-0.50 mol%, for example, 0.18 mol% or 0.23 mol%.

[0275] Among them, the reinforcing agent can be a conventional reinforcing agent in the art that can improve the hardness of the R-vinyl silicone rubber, such as one or more of white carbon black, diatomaceous earth, quartz powder, silicon powder, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate and calcium carbonate, such as white carbon black.

[0276] The weight percentage of the reinforcing agent is preferably 30-50 parts, for example 40 parts.

[0277] The content of Si-H groups in the hydrogenated silicone oil may be 0.18-1.6 mol%, preferably 0.5-1 mol%, such as 0.75 mol%.

[0278] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber may be (0.5-10):1, for example, 1.2:1 or 2.5:1.

[0279] The catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil, such as a platinum catalyst.

[0280] The weight portion of the catalyst is preferably 0.000005-0.5 parts, such as 0.00001 parts, 0.0098 parts or 0.21 parts.

[0281] The raw material composition of the silicone tube containing drug-releasing holes may further include an inhibitor, and the function of the inhibitor is to inhibit the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil at room temperature.

[0282] The inhibitor may be an acetylenic alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol.

[0283] The weight portion of the inhibitor may be 0.03-2.0 parts, for example 0.7 parts.

[0284] In a preferred embodiment, the silicone tube can be made by the following method:

[0285] S1. The R- vinyl silicone rubber and the reinforcing agent are mixed to obtain a mixture A;

[0286] S2. The mixture A is divided into component A1 and component A2, the component A1 and the hydrogen-containing silicone oil are mixed to obtain component B1, and the component A2 and the catalyst are mixed to obtain component B2;

[0287] S3. The component B1 and the component B2 are mixed to obtain a mixture B, and subjected to catalytic addition to obtain the silicone tube.

[0288] In the present invention, the white carbon black can be pretreated by conventional methods in the art, and the pretreatment is preferably drying at 130° C. for 24 hours.

[0289] In the present invention, the R-vinyl silicone rubber and the reinforcing agent are preferably pretreated before mixing. The pretreatment may be drying. The drying operation may be conventional in the art, for example, drying the R-vinyl silicone rubber in a 40°C oven for 12 hours, and drying the reinforcing agent in a 110°C oven for 12 hours.

[0290] In step S1, the mixing operation can be conventional in the art, for example, kneading the R-vinyl silicone rubber and the reinforcing agent in a vacuum kneader to obtain a rubber compound, and then re-milling the rubber compound on an open mill. The reinforcing agent is preferably added in 10 parts per batch. The roller spacing of the open mill can be adjusted to thin the rubber compound through continuous mixing to ensure uniform dispersion of the reinforcing agent.

[0291] In step S2, when the silicone tube containing the drug-releasing holes further comprises an inhibitor, the inhibitor, component A1 and the hydrogen-containing silicone oil are mixed to obtain component B1.

[0292] In step S2, the preparation method of the component B1 can be to re-mill the component A1 in an open mill and add the hydrogenated silicone oil and the inhibitor.

[0293] In step S2, the preparation method of the component B2 can be to add the component A2 dropwise to the catalyst, continuously shorten the roller distance, and perform thin passing.

[0294] In step S3, the mass ratio of the component B1 to the component B2 in the mixture B may be 1:1.

[0295] In step S3, the mixture B may be prepared by mixing and extruding component B1 and component B2 in an open mill.

[0296] In step S3, the catalytic addition step may be to subject the mixture B to a first sulfurization treatment and a second sulfurization treatment in sequence.

[0297] The first vulcanization treatment is preferably performed in a pre-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 can initially set the rubber material at high temperature.

[0298] The second vulcanization treatment is preferably performed in a post-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 fully vulcanize the rubber material.

[0299] In the present invention, the silicone tube containing the drug-releasing holes can be obtained by punching holes in the silicone tube using a laser punching method or a mechanical punching method.

[0300] In the present invention, when the core of the perforated implant consists of a drug-containing layer, the perforated implant is a single-layer implant.

[0301] Wherein, when 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.

[0302] Wherein, when the concentration of the active drug in the drug-containing layer is a gradient concentration, the perforated implant is a single-layer multi-gradient implant. The gradient is preferably 1-50 segments, such as 2 segments, 3 segments, 5 segments, 10 segments, 20 segments, or 40 segments.

[0303] In a preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release hole in the silicone tube containing the drug release hole is 350 μm, the ratio of the diameter of the drug release hole to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release hole is 1, and the position of the drug release hole meets the following conditions: the distance from the center point of the drug release hole to the first end face of the silicone tube containing the drug release hole is 50% of the length of the silicone tube, the multi-gradient is a three-section type, which is sequentially arranged as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, and the center point of the first gradient drug release module coincides with the center point of the drug release hole.

[0304] In a preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release holes in the silicone tube containing drug release holes is 350 μm, the ratio of the diameter of the drug release holes to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 2, and the positions of the drug release holes meet the following conditions: the two drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any drug release hole to the first end face of the silicone tube containing drug release holes is 50% of the length of the silicone tube, and the distance between the center points of the two drug release holes is 0.3 cm; the multi-gradient can be a three-segment type, which is sequentially arranged as a first gradient drug release module, a second gradient drug release module, and a third gradient drug release module, and the center points of the first gradient drug release module and the second gradient drug release module respectively coincide with the center points of the two drug release holes.

[0305] In a preferred embodiment, the perforated implant is a single-layer multi-gradient implant, the diameter of the drug release holes in the silicone tube containing drug release holes is 350 μm, the ratio of the diameter of the drug release holes to the outer diameter of the silicone tube is 0.35 mm:2.4 mm, the number of the drug release holes is 3, and the positions of the drug release holes meet the following conditions: the three drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any drug release hole to the first end face of the silicone tube containing drug release holes is 50% of the length of the silicone tube, and the distance between the center points of adjacent drug release holes is 0.3 cm; the multi-gradient can be a three-segment type, which is sequentially arranged as a first gradient drug release module, a second gradient drug release module, and a third gradient drug release module, and the center points of the first gradient drug release module, the second gradient drug release module, and the third gradient drug release module respectively coincide with the center points of the three drug release holes.

[0306] In the present invention, when the core of the perforated implant further includes a booster layer composited on the drug-containing layer, the perforated implant is a double-layer implant.

[0307] Preferably, the planes where the drug-containing layer and the booster layer are located are perpendicular to the radial plane of the silicone tube.

[0308] Preferably, when the number of the drug-releasing hole is 1, the center point of the drug-containing layer coincides with the center point of the drug-releasing hole.

[0309] Preferably, when the number of the drug-releasing holes is greater than 1, the positional relationship between the center point of the drug-containing layer and the center point of the drug-releasing hole can be selected according to the required release amount of the active drug.

[0310] The present invention also provides a method for preparing the aforementioned perforated implant, which comprises the following steps: filling the pharmaceutical composition or the rod core into the silicone tube having the drug-releasing hole.

[0311] The present invention also provides a use of the stick core or the punched implant as a release rate regulating medium in a sustained-release preparation.

[0312] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0313] The reagents and raw materials used in the present invention are commercially available.

[0314] The positive progress effect of the present invention is:

[0315] The silicone tube made from the silicone material of the present invention has excellent mechanical properties and increased water permeability. This allows for easier release of drugs from the implant as a solution, increasing drug release. Drug release can be several to dozens of times greater than with conventional silicone tubes, expanding the range of drugs available and significantly broadening the application of the implant.

[0316] The present invention utilizes a solid-state compression molding method to compress the active drug and excipients into a rod core. This solves both the drug waste and unstable drug release issues associated with powder-based cores and the drug instability issues associated with silicone skeleton-based cores during preparation. The perforated silicone tube expands the drug application range to include conventional drugs in the field, such as high-solubility macromolecules, high-solubility small-molecule drugs, low-solubility macromolecule drugs, and low-solubility small-molecule drugs, thereby increasing drug release. BRIEF DESCRIPTION OF THE DRAWINGS

[0317] FIG1 is an in vitro release diagram of the improved gestodene reservoir matrix implants with different wall thicknesses prepared in Examples 8-1, 8-2 and 8-3.

[0318] FIG2 is an in vitro release diagram of the improved gestodene reservoir skeleton implant prepared by using different amounts of white carbon black in Examples 8-1, 9-1 and 9-2.

[0319] FIG3 is an in vitro release diagram of the improved gestodene reservoir skeleton implant prepared using methylvinyl polysiloxane with different vinyl contents in Examples 8-1 and 10.

[0320] FIG4 is an in vitro release graph of the improved gestodene reservoir skeleton implant prepared in Examples 8-1, 11-1 and 11-2 using different molar ratios of Si—H in hydrogenated silicone oil to vinyl in methylvinylpolysiloxane.

[0321] FIG5 is a graph showing the in vitro release data of the improved paliperidone reservoir implants prepared with different contents of hydroxyapatite in Examples 12-1, 12-2 and 12-3.

[0322] FIG6 is a graph showing the in vitro release data of the improved paliperidone reservoir implants prepared using methylvinyl polysiloxanes with different vinyl contents in Examples 12-1 and 13.

[0323] FIG7 is a graph showing the in vitro release data of the improved paliperidone reservoir implants prepared in Examples 12-1, 14-1 and 14-2 using different molar ratios of Si—H in hydrogenated silicone oil to vinyl in methylvinylpolysiloxane.

[0324] FIG8 is a flow chart of the preparation of silicone tubes.

[0325] FIG9 is a schematic diagram of the perforated implant of Examples 30-33.

[0326] FIG10 is a schematic diagram of the perforated implant of Examples 20-23.

[0327] FIG11 is a schematic diagram of a perforated implant of Example 34.

[0328] FIG12 is a schematic diagram of the perforated implants of Examples 24-1 and 25-1.

[0329] FIG13 is a schematic diagram of the perforated implants of Examples 24-2 and 25-2.

[0330] FIG14 is a schematic diagram of the perforated implants of Examples 24-3 and 25-3.

[0331] FIG15 is a schematic diagram of the perforated implants of Examples 26-2, 27-2, 28-2, and 29-2.

[0332] The following are the descriptions of the reference numerals:

[0333] 1-drug release hole; 2-silicone tube; 3-length of silicone tube; 4-outer diameter of silicone tube; 5-pore diameter of drug release hole; 6-distance from the center point of drug release hole to the end point of silicone tube; 7-distance between the center points of adjacent drug release holes; 8-sealing glue; 9-drug-containing layer; 901-first drug release module; 902-second drug release module; 903-third drug release module; 10-direction of drug release; 11-boosting layer. DETAILED DESCRIPTION

[0334] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0335] The sources of the components in the Examples and Comparative Examples are shown in the following table.

[0336] The equipment and instruments used in the preparation and testing process are shown in the following table:

[0337] 1. Silicone tube

[0338] 1.1 Preparation method of silicone tube

[0339] (1) Drying the methyl vinyl polysiloxane rubber at 40°C for 12 hours; drying the hydrophilic fumed silica at 130°C for 24 hours;

[0340] (2) mixing methyl vinyl polysiloxane rubber and hydrophilic fumed silica according to the prescribed amount to obtain a mixture A;

[0341] (3) Mixture A is divided into component A1 and component A2, component A1 is re-refined in an open mill with a roller distance parameter of 1 unit, and the prescribed amount of the hydrogenated silicone oil and the inhibitor 2-methyl-3-butyn-2-ol are added dropwise. After the addition, different roller distances are set, and the mixture is triangularly packaged, thinned, taken out and left for 24 hours to obtain component B1 for standby use; component A2 is re-refined in an open mill with a roller distance parameter of 1 unit, and the prescribed amount of platinum catalyst is added dropwise, the roller distance is continuously shortened, thinned, taken out and left for 24 hours to obtain component B2 for standby use;

[0342] (4) B1 and B2 prepared in step (3) are placed in an open mill at a ratio of 1:1 for mixed extrusion, and thin-passed 4-6 times to obtain a mixture B;

[0343] (5) Mixture B obtained in step (4) is unloaded from an open mill in the form of a thin sheet and then cut into strips; a mold of suitable size is installed on an extruder, the extruder screw speed is set, and the cut silicone strips are fed into the extruder. The rubber material is continuously extruded through the die mouth into a silicone tube under the push of the rotating screw. The outer diameter of the silicone tube is determined by the extruder screw speed, the speed of the post-drying channel conveyor belt, and the mold size, and the wall thickness is determined by the mold size.

[0344] (6) subjecting the silicone tube obtained in step (5) to a first vulcanization treatment and a second vulcanization treatment, thereby obtaining a finished silicone tube;

[0345] Among them, the first vulcanization treatment: the silicone tube extruded from the mold mouth first passes through a front drying channel (vertical hot air vulcanization channel) for rapid high-temperature vulcanization, which is the first vulcanization treatment, allowing the silicone tube to quickly change from a sticky and soft state to an elastic state and initially shape it.

[0346] Among them, the second vulcanization treatment: after the first vulcanization, it enters the post-drying channel (horizontal hot air vulcanization channel) to continue vulcanization, which is the second vulcanization treatment, so that the vulcanization reaction of the silicone tube is more complete and reaches the optimal cross-linking state, and then the finished silicone tube is continuously transported out through the conveyor belt of the post-drying channel.

[0347] 1.2 Investigation of the prescription and process of silicone tube

[0348] (1) Effects of vinyl content in methyl vinyl polysiloxane, amount of reinforcing agent, and molar ratio of Si-H in hydrogenated silicone oil to vinyl in methyl vinyl polysiloxane on the mechanical properties of silicone tubes

[0349] A. Prescription: The concentration of the platinum catalyst was 3000 ppm; the dosage of the platinum catalyst was 0.0098 PHR; the dosage of the inhibitor 2-methyl-3-butyn-2-ol was 0.69 PHR. Other prescription parameters are shown in Table 1.

[0350] Table 1

[0351] B. Preparation method: The preparation method described in 1.1 was used. The specific process parameters were: the temperature of the first vulcanization treatment was 250°C; the time of the first vulcanization treatment was 3 seconds; the temperature of the second vulcanization treatment was 240°C; the time of the second vulcanization treatment was 4 minutes; the diameter of the die was 3 mm; the diameter of the core die was 2.6 mm; the wall thickness of the silicone tube was 0.2 mm; and the screw speed was 5 rpm. -1 .

[0352] (2) Effect of the temperature of the second vulcanization treatment on the mechanical properties of silicone tubes

[0353] A. Prescription: The concentration of the platinum catalyst is 3000 ppm; the dosage of the platinum catalyst is 0.0098 PHR; the dosage of the inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR; the vinyl content in the methyl vinyl polysiloxane is 0.18%; the dosage of the hydrophilic silica TH-a200 is 30 PHR; the molar ratio of Si-H in the hydrogenated silicone oil to the vinyl content in the methyl vinyl polysiloxane is 1.5:1.

[0354] B. Preparation method: The preparation method described in 1.1 was used, except that the vulcanization temperature was set according to the settings in Table 2; the first vulcanization time was 3 seconds, and the second vulcanization time was 4 minutes; the diameter of the die was 3 mm; the diameter of the core die was 2.6 mm; the wall thickness of the silicone tube was 0.2 mm; and the screw speed was 5 rpm. -1 .

[0355] Table 2

[0356] (3) Influence of mold size and screw speed on the outer diameter of silicone tube

[0357] A. Prescription: The concentration of the platinum catalyst is 3000 ppm; the dosage of the platinum catalyst is 0.0098 PHR; the dosage of the inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR; the vinyl content in the methyl vinyl polysiloxane is 0.18%; the dosage of the hydrophilic silica TH-a200 is 30 PHR; the molar ratio of Si-H in the hydrogenated silicone oil to the vinyl content in the methyl vinyl polysiloxane is 1.5:1.

[0358] B. Preparation Process: The preparation method described in 1.1 was used, with the first vulcanization temperature of 250°C and the duration of the first vulcanization treatment of 3 seconds; the second vulcanization temperature of 240°C and the duration of the second vulcanization treatment of 4 minutes. The mold dimensions and screw speed are shown in Table 3. (Note: Ring width = (die inner diameter - core mold diameter) / 2)

[0359] Table 3

[0360] The results in Table 3 show that when the screw speed reaches 5 r·min -1 When the screw speed is constant, the larger the ring width between the die inner diameter and the core diameter, the thicker the silicone tube wall. The outer diameter of the silicone tube has no direct relationship with the ring width; it is affected by the combined effects of the die and core dimensions, the ring width, and the screw speed.

[0361] When using the same mold, the greater the screw speed, the larger the outer diameter of the silicone. This is because when the screw speed is higher, the silicone tube is extruded faster, and the conveyor belt's stretching effect on the silicone tube is smaller, so the outer diameter is larger. On the other hand, when the screw speed is lower, the silicone tube is extruded slower, the conveyor belt's stretching effect on the silicone tube is greater, and the outer diameter of the silicone tube is smaller.

[0362] In summary, the outer diameter of the silicone tube is greatly affected by the screw speed. By using molds of different sizes and matching the corresponding screw speeds, silicone tubes with different outer diameters can be prepared, laying the foundation for the subsequent preparation of implants of different specifications and their drug release research.

[0363] 2. Improved gestodene reservoir skeleton implant

[0364] 2.1 Preparation method of implant

[0365] (1) Preparation of Silicone Tube: Prepare a silicone tube according to steps (1) to (6) of the preparation method in 1.1.

[0366] (2) Basic formula and preparation process of drug core: gestodene, particle size 2-3 μm, addition amount 100 PHR; methyl vinyl polysiloxane, vinyl content range 0.18% to 0.23%; hydrogenated silicone oil, Si-H content 0.75%, addition amount range 0.3 to 5.0 PHR; platinum catalyst, platinum concentration 10000 ppm, addition amount range 0.000002 to 0.5 PHR; 2-methyl-3-butyn-2-ol as inhibitor, addition amount range 0.03 to 2.0 PHR;

[0367] The vulcanization temperature is 90°C; the vulcanization time is 1 hour; the diameter of the core is 0.2 cm and the length is 1.5 cm.

[0368] (3) Soak the silicone tube in petroleum ether for 1-2 minutes, quickly shake off the petroleum ether remaining on the surface of the silicone tube by hand, and immediately insert the cut core into the middle position of the silicone tube with tweezers, so that the same length of space is reserved at both ends of the silicone tube for sealing. After assembly, let the implant dry naturally for 12-24 hours to evaporate the residual petroleum ether. Then, seal the two ends of the naturally dried implant with sealing glue and leave it at room temperature for 12-24 hours to solidify the sealing glue. This will give the improved gestodene reservoir skeleton implant.

[0369] 2.2 Effect of preparation process or prescription on silicone tube performance

[0370] (1) The effects of the vinyl content in methylvinylpolysiloxane, the amount of reinforcing agent, the molar ratio of Si-H in hydrogenated silicone oil to vinyl in methylvinylpolysiloxane, and the wall thickness of the silicone tube on the in vitro release of the silicone tube.

[0371] A. Prescription: The concentration of the platinum catalyst is 10,000 ppm; the dosage of the platinum catalyst is 0.01 PHR; the dosage of the inhibitor 2-methyl-3-butyn-2-ol is 0.69 PHR. Other prescription parameters are shown in Table 1.

[0372] Table 4

[0373] B. It adopts the preparation method as described in 2.1, and the specific process parameters are: the temperature of the first vulcanization treatment is 250℃; the time of the first vulcanization treatment is 3s; the temperature of the second vulcanization treatment is 240℃; the time of the second vulcanization treatment is 4min; the diameter of the fixed core is 0.2cm and the length is 1.5cm, and the outer diameter of the fixed silicone tube is 2.4mm and the length is 1.9cm.

[0374] 3. Improved paliperidone reservoir implant

[0375] 3.1 Preparation method of implant

[0376] Prepare a silicone tube according to steps (1) to (6) of the preparation method in 1.1, and then prepare a paliperidone reservoir implant through the following step (7);

[0377] (7) Preparation of paliperidone reservoir implant: seal one end with KN-300N adhesive and fill the implant with drug through the drug filling funnel after curing for 24 hours. After filling, seal the other end with KN-300N adhesive and cure for 24 hours. After curing, check for drug leakage. After confirming that there is no leakage, wash repeatedly with anhydrous ethanol for 30 seconds. The preparation is complete and the improved paliperidone reservoir implant is obtained.

[0378] 3.2 Effects of hydroxyapatite dosage, vinyl content of methylvinylpolysiloxane, and hydrogenated silicone oil dosage on drug release in vitro

[0379] A. Prescription: The amount of paliperidone added is 100 PHR; the amount of HB-615 hydrophobic fumed silica is 20 PHR; the concentration of the platinum catalyst is 3000 ppm; the amount of the platinum catalyst is 0.21 PHR; the amount of the inhibitor 2-methyl-3-butyn-2-ol is 0.98 PHR. Other prescription parameters are shown in Table 5.

[0380] Table 5

[0381] B. Preparation Method: The preparation method described in 2.1 was used. Specific process parameters were: first vulcanization temperature of 250°C, first vulcanization duration of 5 seconds, second vulcanization temperature of 240°C, second vulcanization duration of 2 minutes. The resulting implant had a wall thickness of 0.2 mm, an outer diameter of 2.2-2.3 mm, and a drug release area of ​​2.7 ± 0.5 cm. 2 .

[0382] 4. Improved estradiol reservoir implant

[0383] 4.1 Preparation of implants

[0384] Same as the implant preparation method described in 3.1

[0385] 4.2 Effects of curing temperature, silicone tube wall thickness, and drug release area on in vitro release of implants

[0386] A. Prescription: As shown in the following table:

[0387] Table 6

[0388] B. Preparation process: The first vulcanization treatment time is 5s; the second vulcanization treatment time is 2min; the third vulcanization treatment time is 48h; other parameters are shown in the table below:

[0389] Table 7

[0390] Table 8

[0391] Table 9

[0392] Comparative Example 1 Gestodene Depot Skeleton Implant

[0393] A. Prescription: Compared with the prescription of the modified gestodene skeleton implant, the difference is that the reinforcing agent is only HB-615 hydrophobic fumed silica.

[0394] B. Preparation process: The preparation method is the same as described in 2.1.

[0395] Comparative Example 2 Paliperidone Depot Implant

[0396] A. Formulation: Compared with the formulation of the modified paliperidone reservoir implant, the difference is that the reinforcing agent is only HB-615 hydrophobic fumed silica and does not contain hydroxyapatite.

[0397] B. Preparation process: The preparation method is the same as described in 3.1.

[0398] Comparative Example 3 Estradiol Depot Implant

[0399] A. Prescription: Compared with the prescription of the improved estradiol reservoir implant, the difference is that the reinforcing agent is only hydrophobic fumed silica R106, and does not contain N20 hydrophilic silica.

[0400] B. Preparation process: The preparation method is the same as described in 4.1.

[0401] Effect embodiment

[0402] The mechanical properties and in vitro release properties of the examples of the present invention and the comparative examples were studied.

[0403] 1. Mechanical properties

[0404] Subcutaneous implants should meet the national standard GB / T528 (ISO37) "Determination of tensile stress-strain properties of vulcanized rubber or thermoplastic rubber" to ensure that they have good mechanical properties to ensure that their shape remains unchanged during implantation and removal.

[0405] 1. Elongation at break (%): The elongation of the sample at break

[0406] 2. Tensile strength (MPa) refers to the maximum tensile stress to which the sample is subjected when stretched to fracture during the tensile test.

[0407] 3. Tear strength (KN·m -1 ) The strength required for the sample to be torn.

[0408] Specific test method: Prepare samples of about 5 cm in length, prepare three copies of each sample in parallel, use a tensile tester to test the samples, set the test parameters as a clamping distance of 50 mm and a tensile speed of 200 mm min -1 , after the sample test is completed, record the data.

[0409] Table 10

[0410] The performance data from Examples 1-1 and 1-2 show that the overall elongation at break, tensile strength, and tear strength of the vulcanized silicone tubing at vinyl contents of 0.18% and 0.23% are similar, demonstrating excellent mechanical properties. This indicates that both vinyl contents are within the appropriate range. After the addition reaction, the cross-linked chains in the network structure formed are of appropriate length and have an orderly distribution of cross-linking points. Consequently, the prepared silicone tubing exhibits excellent elasticity, moderate tensile and tear resistance, and meets the requirements for implant preparation and clinical application.

[0411] According to the effect data of Examples 2-1 to 2-4, it can be seen that when the amount of hydrophilic silica is within the range of 30-50 PHR, the mechanical properties of the silicone tube after vulcanization are good.

[0412] The performance data from Examples 2-1, 3-1, and 3-2 show that increasing the molar ratio of Si-H in the hydrogenated silicone oil to vinyl in the methylvinyl polysiloxane from 1.2:1 to 1.5:1 increases the tensile and tear strengths of the silicone tubing. Increasing the molar ratio from 1.5 to 1.8 shows little difference in the elongation at break, tensile strength, and tear strength of the vulcanized silicone tubing, demonstrating excellent mechanical properties. Theoretically, the hydrogen in the hydrogenated silicone oil and the vinyl in the methylvinyl polysiloxane react in a 1:1 molar ratio during the addition reaction. However, in practice, Si-H can be lost due to side reactions. Therefore, a slight excess of hydrogenated silicone oil is typically used to ensure the addition reaction proceeds fully, achieving near-complete crosslinking and achieving optimal mechanical properties.

[0413] According to the effect data of Examples 4-1 to 4-4, it can be seen that with the increase of the second vulcanization temperature, the elongation at break, tensile strength and tear strength of the silicone tube after vulcanization show a trend of first increasing and then decreasing. When the second vulcanization temperature is 240°C, the values ​​of various indicators reach the maximum. The second vulcanization treatment is mainly to allow the silicone tube to continue to vulcanize and the cross-linking reaction to continue. The appropriate temperature can make the cross-linking reaction complete and the mechanical indicators better. However, too high a temperature will cause the silicone tube to be over-vulcanized and the internal cross-linking bonds to undergo thermal cracking, resulting in performance degradation.

[0414] 2. In vitro release effect

[0415] 1. In vitro release characterization of the modified gestodene reservoir matrix implant

[0416] 1.1 Test Method

[0417] (1) Chromatographic conditions

[0418] Chromatographic column: Chromatographic column (4.6 mm × 250 mm, 5 μm);

[0419] Mobile phase: methanol: water (80:20, v / v);

[0420] Column temperature: 30°C;

[0421] Detection wavelength: 239nm;

[0422] Flow rate: 1.0 mL min -1 ;

[0423] Injection volume: 20 μL

[0424] (2) In vitro release experimental method

[0425] The release experiment used a horizontal oscillation method. One implant was taken and fixed to the bottom and wall of a 50 mL stoppered conical flask with silicone adhesive (to prevent the implant from floating on the liquid surface, which would cause inaccurate release results). After adhesion, the implant was left for 12 hours to allow the silicone adhesive to completely cure. Accurately measure 50 mL of distilled water as the release medium and inject it into the conical flask. The conical flask was then placed in a constant temperature air shaker and shaken at 37°C and an amplitude of 100 r / min. -1 The medium was replaced with an equal volume every 24 h. The release solution was filtered through a 0.22 μm microporous filter membrane and detected according to chromatographic conditions with an injection volume of 20 μL.

[0426] 1.2 Effect data

[0427] (1) 30-day in vitro release effect data

[0428] Examples 8-1 to 8-3 show implants with different silicone tube wall thicknesses. Their in vitro release data are shown in Figure 1. It can be seen that the thicker the silicone tube wall, the lower the daily drug release rate of the implant. For an implant with a 0.2 mm wall thickness, the average daily drug release over 30 days was approximately 55 μg; for an implant with a 0.3 mm wall thickness, the average daily drug release over 30 days was approximately 48 μg; and for an implant with a 0.4 mm wall thickness, the average daily drug release over 30 days was approximately 42 μg. In other words, for every 0.1 mm increase in silicone tube thickness, the average daily drug release decreased by approximately 5-8 μg. These data indicate that, when the outer diameter and length of the silicone tube, and the diameter and length of the drug core, are fixed, the wall thickness of the silicone tube can slightly affect the in vitro release rate of the implant. In the actual preparation process of the implant, when the outer diameter of the silicone tube remains unchanged, the thicker the wall thickness, the smaller the inner diameter, and the more difficult it is to assemble the drug core and the silicone tube. The inner diameter of the silicone tube with a wall thickness of 0.2 mm is relatively large, and it cooperates better with the drug core.

[0429] Examples 8-1, 9-1 and 9-2 are different dosages of hydrophilic silica, and their in vitro release effect data are shown in Figure 2. It can be seen that the dosage of hydrophilic silica has a slight effect on the release of the implant. With the increase of the dosage of hydrophilic silica, the average daily release of the implant for 30 days increases slightly. When the dosage of hydrophilic silica is 40PHR, the daily drug release is high, about 55μg. It can be seen from Figure 2 that the drug release curve is significantly higher than that of 30PHR and 20PHR in the 1-15d time period. The average daily drug release of hydrophilic silica dosages of 30PHR and 20PHR is not much different, both at about 48μg, and the fluctuation of the two drug release curves is smaller than that of 40PHR, the drug release stability is better, and in the silicone tube extrusion process, the extrusion stability and smoothness are better when the dosage of fumed silica is 30PHR.

[0430] Examples 8-1 and 10 are implants with different vinyl contents. Their in vitro release data are shown in Figure 3. It can be seen that the vinyl content of the silicone tube has little effect on the release of the implant. The average daily release of both groups of implants over 30 days is between 47 and 50 μg. Methyl vinyl polysiloxane with a vinyl content of 0.18% is more in line with the mechanical properties and cost requirements.

[0431] The in vitro release effect data of the implants of Examples 8-1, 11-1, and 11-2 with different hydrogenated silicone oil dosages are shown in FIG4 . It can be seen that when the molar ratio of hydrogenated silicone oil is 1.2 and 1.8, the release amount of the implant is relatively high in the first three days, with an early burst release phenomenon, and the overall release curve fluctuates greatly. However, the release curve when the molar ratio is 1.5 has relatively small fluctuations. It can be seen that the release curve at the molar ratio of 1.5 is already relatively stable, and the mechanical indicators of the silicone tube shown in previous studies are also good.

[0432] (3) In vitro release experiment

[0433] The implants of Example 8-1 and Comparative Example 1 were subjected to a 150-day long-term in vitro release experiment. The results are shown in Tables 11 and 12, respectively.

[0434] Table 11

[0435] Table 12

[0436] The data in the table above demonstrates that, while maintaining the required mechanical properties, hydrophilic silica increases the release rate from the silicone tube by 18-23 μg compared to hydrophobic silica, demonstrating that the implant meets the required release rate and exhibits excellent release stability, achieving stable release for at least five months. Furthermore, the improved gestodene matrix reservoir implant increases in vitro release by 192% compared to the gestodene matrix reservoir implant.

[0437] 2. In vitro release characterization of the modified paliperidone reservoir implant

[0438] 2.1 Test Method

[0439] (1) Chromatographic conditions

[0440] Column: InfinityLab Poroshell HPH-C8 (4.6 × 100 mm, 2.7 μm)

[0441] Mobile phase: methanol: acetonitrile: phosphate 1:4:15 isocratic elution

[0442] Flow rate: 1 mL / min

[0443] Column temperature: 35°C

[0444] Injection volume: 20 μL

[0445] Detection wavelength: 280nm

[0446] (2) In vitro release test method

[0447] Take a modified paliperidone reservoir implant and fix it in a 20 mL sample bottle with silicone adhesive. Accurately measure an appropriate amount of distilled water into the sample bottle so that the preparation is always below the liquid level of the release medium. Place it in a vibrating chamber with an amplitude of 100 r·min. -1 The release was carried out in a thermostatic oscillator at 37°C. Samples were taken every 24 hours to replace the release medium. The solution was filtered through a 0.22 μm filter membrane and a sample was retained for testing.

[0448] 2.2 Effect data

[0449] (1) 30-day in vitro release effect data

[0450] Examples 12-1 to 12-3 are implants prepared with different amounts of hydroxyapatite. The in vitro release effect data are shown in FIG5 . The in vitro release amount of the vulcanized silicone tube increases with the increase in the amount of hydroxyapatite.

[0451] Examples 12-1 and 13 investigated the effect of the vinyl content of methylvinylpolysiloxane on the in vitro release of silicone tubing. The data are shown in Figure 6. It can be seen that the vinyl content of the silicone tubing had little effect on the release of the implant. The daily release of the implants in both groups over 30 days was between 20 and 25 μg, with little difference between the two groups. However, when the vinyl content of the silicone tubing was 0.18%, the overall release curve of the implant was more stable.

[0452] Examples 12-1, 14-1, and 14-2 investigated the effect of the molar ratio of hydrogenated silicone oil on the in vitro release of silicone tubing. The data are shown in Figure 7. It can be seen that the release curves of the implants were similar when the molar ratio of hydrogenated silicone oil varied. This is because, during the addition reaction, the hydrogen in the hydrogenated silicone oil theoretically reacts with the vinyl groups in methylvinylpolysiloxane in a 1:1 molar ratio. However, in practice, Si-H bonds are lost due to side reactions. Therefore, a slight excess of hydrogenated silicone oil is typically used to ensure that the addition reaction proceeds fully and the cross-linking is increasingly complete.

[0453] (2) Long-term in vitro release results data

[0454] At a temperature of 37°C and a shaking speed of 100 r·min -1 Long-term in vitro release experiments were conducted on Example 14-1 and Comparative Example 2 under the following conditions. The long-term in vitro release results of Example X are shown in Table 13. The long-term in vitro release results of Comparative Example 2 are shown in Table 14.

[0455] Table 13

[0456] Table 14

[0457] According to the effect data in the above table, the in vitro release study of the improved paliperidone reservoir implant prepared with the silicone tube provided by the present invention showed stable drug release over 150 days. Compared with the paliperidone reservoir implant, the in vitro release of the improved paliperidone reservoir implant was increased by 260%.

[0458] 3. In vitro release characterization of the modified estradiol reservoir implant

[0459] 3.1 Test Method

[0460] (1) Take one modified estradiol reservoir implant, split the silicone tube, cut the core into several small pieces, place it in a 100 mL volumetric flask, add 10 mL of methanol to soak, let it stand and swell for 3 hours, dilute it to the mark with anhydrous ethanol, shake it well and filter it, accurately measure 0.2 mL of the filtrate and place it in a 50 mL volumetric flask, dilute it to the mark with mobile phase, shake it well, inject it into HPLC, inject 20 μL, and calculate the drug content according to the standard curve. The chromatographic conditions are as follows:

[0461] Chromatographic conditions

[0462] Chromatographic column: Column (250mm×4mm, 5μm)

[0463] Mobile phase: acetonitrile-water (55:45, v / v)

[0464] Column temperature: 25°C

[0465] Detection wavelength: 202nm

[0466] Flow rate: 0.8 mL min -1

[0467] Injection volume: 20 μL

[0468] (2) Release determination method

[0469] The release rate was determined by the horizontal oscillation method: a modified estradiol reservoir implant was taken and fixed in a 100 mL stoppered conical flask with an adhesive. 100 mL of distilled water was accurately measured as the release medium. The stoppered conical flask was placed in a constant temperature oscillator with an amplitude of 100 r·min. -1 The temperature was 37°C, ensuring that the implant was always below the liquid level. Sampling was performed every 24 hours and an equal volume of release medium was replaced. The sample solution was filtered through a 0.22 μm microporous filter membrane and injected according to the content determination method (1). The drug release amount was calculated based on the standard curve.

[0470] 3.2 Effect data

[0471] 3.2.1 Effect of curing conditions on in vitro release

[0472] Table 15

[0473] Table 15 lists the in vitro release data for the improved estradiol reservoir implants prepared using different vulcanization temperatures in Examples 17-1, 17-2, and 17-3. These data indicate that changes in the vulcanization temperature of the silicone tubing have little effect on the average daily release of the implants, with minimal fluctuation. Therefore, silicone tubing with superior mechanical properties was selected for the preparation of the implants. Specifically, the vulcanization conditions were 250°C for the first vulcanization treatment and 240°C for the second vulcanization treatment.

[0474] 3.3.2 Silicone tube wall thickness

[0475] Table 16

[0476] The in vitro release data for the modified estradiol depot implants of different wall thicknesses obtained in Examples 18-1, 18-2, and 18-3 are listed in Table 16. The results show that, while controlling for external diameter and factors such as the release area remain unchanged, the in vitro release of the modified estradiol depot implants prepared from the three silicone tubes of different wall thicknesses gradually decreases as wall thickness increases. To ensure drug release, wall thickness should be reduced as much as possible. However, in actual operation, a silicone tube with a wall thickness of 0.2 mm is already the limit. Further reduction in wall thickness would make it difficult to ensure smooth extrusion of the silicone tube, so a silicone tube with a wall thickness of 0.2 mm is recommended.

[0477] 3.3.3 Investigation of the drug release area of ​​silicone tube

[0478] The effect of the length of the drug core in the silicone tube on the in vitro release is shown in the following table.

[0479] Table 17

[0480] The results showed that the daily release rate of the modified estradiol reservoir implant increased with increasing release area. In practical applications, due to the large individual differences among patients, different specifications of the modified estradiol reservoir implant can be produced during production to achieve personalized drug delivery based on different needs, minimize side effects, and maximize benefits.

[0481] 3.4 Long-term in vitro release of estradiol depot implants

[0482] The estradiol reservoir implant prepared in Example 17-2 and Comparative Example 3 was placed in a shaker at a temperature of 37°C and a speed of 100 r·min. -1 Long-term in vitro release experiments were conducted under the following conditions, and the results are shown in the following table and figure.

[0483] Table 18

[0484] The results in the above table show that the implant prepared by using hydrophilic silica has an average daily in vitro drug release rate that is stable in the range of 20-35 μg and has good stability.

[0485] Table 19

[0486] The results in the above table show that the average daily release of estradiol reservoir implant is about 12 μg, with a burst release in the early stage and a stable release in the later stage.

[0487] The in vitro release of the modified estradiol reservoir implant was compared with that of the estradiol reservoir implant. The results showed that, while meeting the mechanical properties of the implant, the in vitro release of the modified estradiol implant was increased by 245% compared with hydrophobic silica, and the problem of burst release of the original estradiol reservoir implant was improved.

[0488] The preparation process of the silicone tube in the following examples is shown in Figure 8 below.

[0489] The formula of the silicone tube containing the drug release hole of the perforated implant of Examples 20-38 and Comparative Examples 4-5 is as follows:

[0490] Among them, the water contact angle of silica is the static water contact angle of the material. Its measurement uses the principle of optical appearance projection to test. During use, the volume of the water droplet is set using the test software, and the syringe needle drops the water droplet of the set volume on the surface of the sample to be tested. Under the background of LED light source, the screen micrometer is used to project the image of the droplet onto the automatic image analysis system for measurement.

[0491] The preparation method of the silicone tube containing the drug release hole of the perforated implant of Examples 20-38 and Comparative Examples 4-5 is as follows:

[0492] S1. Dry the methyl vinyl silicone rubber in an oven at 40°C for 12 hours and the silica in an oven at 110°C for 12 hours. Mix the methyl vinyl silicone rubber and silica in a vacuum kneader to obtain a rubber compound, which is then re-mixed on an open mill to obtain a mixture A.

[0493] S2. Mixture A is separated into component A1 and component A2. Component A1 is re-milled in an open mill and hydrogenated silicone oil and methylbutynol are added to obtain component B1. Component A2 is dropwise added with a platinum catalyst while continuously reducing the roller distance to produce component B2. The mass ratio of component B1 to component B2 is 1:1.

[0494] S3. Component B1 and component B2 were mixed and extruded in an open mill to obtain a mixture B, and the mixture B was sequentially subjected to a first vulcanization treatment and a second vulcanization treatment to obtain a silicone tube;

[0495] S4. Laser-drill the silicone tube to obtain a silicone tube with drug-releasing holes. The resulting silicone tube has a length of 4 cm and an outer diameter of 2.4 mm.

[0496] The preparation methods of the rod cores of Examples 20-38 and Comparative Examples 4-5 are as follows:

[0497] The drug composition is formed by solid column pressing and compressed at 0.3 MPa to obtain a drug-containing layer;

[0498] When a boosting layer is included, the raw material of the boosting layer is formed by solid column pressing and pressed at 0.3 MPa, and the boosting layer is composited on the drug-containing layer;

[0499] The prepared rod core has a length of 7 mm and a diameter of 2 mm, and the plane where the rod core is located and the radial plane of the silicone tube are perpendicular to each other.

[0500] (1) Process investigation of drug release holes in perforated implants

[0501] I. Investigation of the Diameter of the Drug Release Channel of Perforated Implants

[0502] A schematic diagram of the perforated implant of Examples 20-23 is shown in FIG10 .

[0503] Example 20 Insulin perforated implant

[0504] The formula composition of the stick core:

[0505] Example 21 Semaglutide perforated implant

[0506] The formula composition of the stick core:

[0507] Example 22 Metformin Perforated Implant

[0508] The formula composition of the stick core:

[0509] Example 23 Paliperidone Perforated Implant

[0510] The formula composition of the stick core:

[0511] II. Investigation of the number of drug-releasing holes in perforated implants

[0512] Schematic diagrams of the perforated implants of Examples 24-25 are shown in Figures 12-14.

[0513] Example 24, Comparative Example 4 Insulin Perforated Implant

[0514] The formula composition of the stick core:

[0515] Example 25, Comparative Example 5 Semaglutide Perforated Implant

[0516] The formula composition of the stick core:

[0517] III. Investigation of the Location of the Drug Release Holes in Perforated Implants

[0518] Schematic diagrams of the perforated implants of Examples 26-29 are shown in Figures 11 and 15, respectively.

[0519] Example 26 Insulin perforated implant

[0520] The formula composition of the stick core:

[0521] Example 27 Semaglutide Perforated Implant

[0522] The formula composition of the stick core:

[0523] Example 28 Metformin Perforated Implant

[0524] The formula composition of the stick core:

[0525] Example 29 Paliperidone Perforated Implant

[0526] The formula composition of the stick core:

[0527] (2) Investigation of the core formulation of perforated implants

[0528] I. Single-layer single-gradient perforated implant

[0529] The pore parameters of the silicone tube containing the drug release holes of the perforated implants of Examples 30, 32, 34-38 are as follows:

[0530] The pore parameters of the silicone tube containing the drug release holes of the perforated implants of Examples 31 and 33 are as follows:

[0531] (i) Investigation of excipient types in the drug-containing layer of single-layer single-gradient perforated implant cores

[0532] Schematic diagrams of the perforated implants of Examples 30-33 are shown in FIG9 .

[0533] Example 30 Exenatide perforated implant

[0534] The formula composition of the stick core:

[0535] Example 31 Metformin Perforated Implant

[0536] The formula composition of the stick core:

[0537] (ii) Investigation of drug-excipient ratio of drug-containing layer in single-layer single-gradient perforated implant core

[0538] Example 32 Exenatide perforated implant

[0539] The formula composition of the stick core:

[0540] (iii) Investigation of the ratio of insoluble matrix material to hydrophilic gel material in the drug-containing layer of the sustained-release excipients of the single-layer single-gradient perforated implant rod core

[0541] Example 33 Metformin Perforated Implant

[0542] The formula composition of the stick core:

[0543] II. Single-layer multi-gradient perforated implant

[0544] (i) Investigation of active drug concentration in each gradient drug release module of the single-layer multi-gradient perforated implant core

[0545] A schematic diagram of the perforated implant of Example 34 is shown in FIG11 .

[0546] Example 34 Semaglutide Perforated Implant

[0547] III. Double-layer perforated implant

[0548] (i) Investigation of the types of excipients in the drug-containing layer of the double-layer perforated implant core

[0549] Example 35 Levothyroxine Sodium Perforated Implant

[0550] The formula composition of the stick core:

[0551] (ii) Investigation of the mass ratio of the sustained-release excipients and fillers in the drug-containing layer of the double-layer perforated implant core

[0552] Example 36 Levothyroxine Sodium Perforated Implant

[0553] The formula composition of the stick core:

[0554] (iii) Investigation of the type of expansion material in the core booster layer of the double-layer perforated implant

[0555] Example 37 Levothyroxine Sodium Perforated Implant

[0556] The formula composition of the stick core:

[0557] (iv) Investigation of the amount of expansion material used in the core booster layer of the double-layer perforated implant

[0558] Example 38 Levothyroxine Sodium Perforated Implant

[0559] Prescription composition of the medicine stick:

[0560] Establishment of the release determination method of the embodiment

[0561] 1. Testing conditions

[0562] (1) Chromatographic conditions of exenatide

[0563] Chromatographic column: Column (250 mm × 4.60 mm, 5 μm);

[0564] Mobile phase: Phase A: 0.08% trifluoroacetic acid in acetonitrile;

[0565] Mobile phase: Phase B: 0.08% trifluoroacetic acid in water;

[0566] The change of the proportion of mobile phase A over time was 28% to 55% (0 to 25 min);

[0567] Flow rate: 1.0 mL min -1 ;

[0568] Detection wavelength: 214nm;

[0569] Column temperature: 30°C;

[0570] Injection volume: 20 μL;

[0571] (2) Chromatographic conditions of estradiol

[0572] Chromatographic column: Column (250 mm × 4 mm, 5 μm);

[0573] Mobile phase: acetonitrile-water (55:45, v / v);

[0574] Column temperature: 25°C;

[0575] Detection wavelength: 202nm;

[0576] Flow rate: 0.8 mL min -1 ;

[0577] (3) Chromatographic conditions of semaglutide

[0578] Chromatographic column: Column (250 mm × 4.60 mm, 5 μm);

[0579] Mobile phase: 0.2 mol·L-1 sulfate buffer-acetonitrile (60:40, v / v);

[0580] Column temperature: 30°C;

[0581] Detection wavelength: 192nm;

[0582] Flow rate: 1 mL min -1 ;

[0583] Injection volume: 20 μL;

[0584] (4) Chromatographic conditions of levothyroxine sodium

[0585] Chromatographic column: SinoDetect HCl-C18 column (4.6×250 mm, 5 μm);

[0586] Mobile phase: acetonitrile-0.1% TFA (50:50, v / v);

[0587] Column temperature: 30°C;

[0588] Detection wavelength: 225nm;

[0589] Flow rate: 1 mL min -1 ;

[0590] Injection volume: 20 μL;

[0591] (5) Chromatographic conditions of metformin

[0592] Chromatographic column: Chromatographic column (4.6 mm × 150 mm, 5 μm);

[0593] Mobile phase: methanol: water (10:90, v / v) (adjusted to pH 3.5 with phosphoric acid and triethylamine);

[0594] Column temperature: room temperature;

[0595] Detection wavelength: 233nm;

[0596] Flow rate: 1.0 mL min -1 ;

[0597] Injection volume: 20 μL.

[0598] (6) Chromatographic conditions of insulin

[0599] Chromatographic column: Column (250 mm × 4.60 mm, 5 μm);

[0600] Mobile phase: methanol: water (65:35, v / v, 0.1% TFA added to the total volume);

[0601] Column temperature: 40°C;

[0602] Detection wavelength: 214nm;

[0603] Flow rate: 1.0 mL min -1 ;

[0604] Injection volume: 20 μL;

[0605] (7) Chromatographic conditions of paliperidone

[0606] Chromatographic column: Chromatographic column (4.6 × 100 mm, 2.7 μm);

[0607] Mobile phase: methanol:acetonitrile:water (5:25:70, v / v) (pH adjusted to 3 with phosphoric acid and triethylamine);

[0608] Column temperature: 35°C;

[0609] Detection wavelength: 270nm;

[0610] Flow rate: 0.8 mL min -1 ;

[0611] Injection volume: 20 μL.

[0612] 2. Release results

[0613] (1) Investigation of drug release channel technology of perforated implants

[0614] I. Investigation of the Diameter of the Drug Release Channel of Perforated Implants

[0615] (1) The release results of the insulin monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0616] (2) The release results of the semaglutide monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0617] (3) The release results of metformin monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0618] (4) The release results of the paliperidone monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0619] As can be seen from Example 20-4, the implant is applicable to soluble macromolecular drugs, poorly soluble macromolecular drugs, poorly soluble macromolecular drugs and soluble small molecule drugs.

[0620] Further analysis of Example 20-4 reveals that, in the initial release phase, when the pore diameter is greater than 450 μm, a burst of drug release occurs, resulting in rapid drug release. This is followed by a sharp drop in release, leading to insufficient dynamics in the later stages and difficulty achieving long-term drug release. When the pore diameter is less than 250 μm (except for metformin), the release rate is relatively stable throughout the release cycle, but the daily release rate of the formulation is lower than that of larger pore diameters (e.g., greater than 250 μm).

[0621] II. Investigation of the number of drug-releasing holes in perforated implants

[0622] (1) The release results of the insulin monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0623] (2) The release results of the semaglutide monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0624] In the initial stage of drug release, the daily release amount of the preparation will increase with the increase in the number of drug release holes. Among them, the implants with double and triple drug release holes have a burst release phenomenon.

[0625] III. Investigation of the Location of the Drug Release Holes in Perforated Implants

[0626] (1) The release results of the insulin monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0627] (2) The release results of the semaglutide monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0628] (3) The release results of metformin monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0629] (4) The release results of the paliperidone monolayer single gradient perforated implant model (daily released dose μg) are shown in the following table.

[0630] The results of the drug release curves showed that the position change of the single-channel drug release hole did not have a significant effect on drug release, and the release curves were relatively close with no significant difference.

[0631] (2) Investigation of the core formulation of perforated implants

[0632] I. Single-layer single-gradient perforated implant

[0633] (i) The results of the investigation of the types of excipients in the drug-containing layer of the single-layer single-gradient perforated implant core (daily released dose μg) are shown in the following table.

[0634] As shown in Example 30, when the sustained-release excipient is a poorly soluble matrix material (Eudrat® S100, calcium alginate, and ethyl cellulose), the release curve is relatively stable. However, the difference is that the controlled-release ability is too strong, possibly due to the poor water solubility of Eudrat® S100 and calcium alginate, resulting in a release stagnation phenomenon in the early stage of drug release. In contrast, ethyl cellulose shows a relatively good drug release trend.

[0635] In the release curve of hydrophilic gel materials used as sustained-release excipients, PEON80, due to its higher viscosity and greater degree of hydration, has a stronger sustained-release effect on the drug. Therefore, the initial drug release is extremely low. Later, due to the continuous dissolution of the hydration layer on the surface of the drug stick, the local drug exposure on the surface of the preparation increases, but most of the drug is still wrapped inside the hydration layer formed by PEO, and the release amount gradually decreases. PLGA and HPMC K15M do not show obvious drug release stagnation. During the in vitro release process, the preparation clearly swells, which can also be called "tube expansion phenomenon." Considering that the silicone tube needs to have certain mechanical properties to ensure long-term drug release stability after implantation in the human body, the effect of hydrophilic gel matrix materials as sustained-release materials alone is inferior to that of poorly soluble matrix materials.

[0636] From the release curve in the figure below, we can conclude that when the hydrophilic gel skeleton material is HPMCK15M, it can interact with ethyl fiber to achieve an ideal sustained-release effect.

[0637] (2) The release results (daily released dose μg) of the drug-excipient ratio of the drug-containing layer of the single-layer single-gradient perforated implant rod core are shown in the following table.

[0638] From the above, it can be seen that when the drug-excipient ratio is 1:5, the drug release is stable, and there is no obvious drug release burst or stagnation phenomenon.

[0639] (3) The release results (daily release dose μg) of the ratio of the insoluble skeleton material to the hydrophilic gel material in the drug-containing layer of the single-layer single-gradient perforated implant rod core are shown in the following table.

[0640] When EC:HPMC K15M=2:1, the drug release curve was relatively stable. When the HPMC K15M content increased, the early burst release of the drug increased instead.

[0641] II. Single-layer multi-gradient perforated implant

[0642] (1) The release results (daily released dose μg) of the drug ratio at each stage of the single-layer multi-gradient perforated implant are shown in the following table.

[0643] III. Double-layer implant

[0644] (1) The release results (daily released dose μg) of the drug-containing excipient types of the double-layer perforated implant core are shown in the following table.

[0645] Both PEO WSR-303 and PEO WSRN-750 have a good smooth release, but the higher viscosity of PEO WSR303 in the drug-containing layer may affect the appearance of the entire implant.

[0646] (2) The release results (daily released dose μg) of the double-layer perforated implant core drug-containing layer sustained-release excipients and fillers are shown in the following table.

[0647] The results showed that when the amount of PEO WSRN-750 was 20 mg, the drug could not be fully suspended and the drug release momentum was insufficient in the later stage. However, as the amount of PEO WSRN-750 increased, the drug release slowed down. When the amount of PEO WSRN-750 was 60 mg, the drug release rate decreased.

[0648] (3) Investigation of the type of expansion material in the booster layer of the double-layer perforated implant core The release results (daily released dose μg) are shown in the following table.

[0649] The results showed that changes in PEO molecular weight within the selected range had no significant effect on drug release. In addition, as the PEO molecular weight increased, the viscosity increased and the formability of the excipient powder improved.

[0650] (4) The release results (daily released dose μg) of the expansion material used in the booster layer of the double-layer perforated implant are shown in the following table.

[0651] The dosage of PEO WSR N60K within the selected range had no significant effect on drug release.

[0652] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may 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 defined by the appended claims.

Claims

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

2. The raw material composition of silica gel material according to claim 1, characterized in that: The raw material composition of the silica gel material satisfies one or more of the following conditions: a. R in the R-vinyl polysiloxane is a substituted or unsubstituted C1-C5 straight chain alkane, such as a methyl group; b. The vinyl content of the R-vinyl polysiloxane is 0.15 mol% to 0.3 mol%, for example 0.18 mol% or 0.23 mol%; c. The weight proportion of the reinforcing agent is 20-70 parts, for example 30 parts, 40 parts, 45 parts or 50 parts; d. The water contact angle of the reinforcing agent is ≤90°, for example, 14-90°, 16-35° or ≤25°; e. the hydrophilic group is selected from one or more of hydroxyl, thiol, aldehyde, ketone, ether bond, block polyether, carboxylic acid, carboxylate, sulfate, sulfone, sulfinic acid, sulfonic acid, sulfonamide, sulfonate, thioether, phosphoric acid, phosphoramide, phosphorimide, phosphate, phosphite, phosphine, amino, imino, tertiary amine, quaternary ammonium, nitrile, cyanate, thiocyanate, amide and other oxygen-containing groups capable of forming hydrogen bonds with water molecules; f. The reinforcing agent is one or more of white carbon black, hydroxyapatite, diatomaceous earth, quartz powder, silica powder, aluminum hydroxide, magnesium hydroxide, aluminum oxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, titanium dioxide, clay, lignin, carbonate and kaolin; the white carbon black is preferably hydrophilic white carbon black or a mixture of "hydrophilic white carbon black and hydrophobic white carbon black"; the hydrophilic white carbon black is preferably hydrophilic fumed white carbon black, such as hydrophilic fumed white carbon black N20, hydrophilic fumed white carbon black TH-a200, hydrophilic fumed white carbon black A380, hydrophilic fumed white carbon black A300, T30 hydrophilic fumed white carbon black, T40 hydrophilic fumed white carbon black and V15 hydrophilic fumed white carbon black. g. The amount of the hydrogen-containing silicone oil is 0.3-5 parts, preferably 0.3-3 parts, for example 1.01 parts, 1.07 parts, 1.33 parts, 1.60 parts or 1.70 parts; h. The molar ratio of Si-H groups in the hydrogen silicone oil to vinyl groups in the R-vinyl polysiloxane is (0.5-8):1, preferably (0.8-3):1, for example 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1 or 3:1; i. The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%, preferably 0.15-1.2 mol%, for example 0.75 mol%; j. The catalyst is a platinum catalyst; wherein the concentration of platinum in the platinum catalyst is preferably 1×10 3 -1×10 5 ppm, for example 1×10 3 ppm, 1×10 4 ppm, ppm refers to the mass concentration of platinum in the platinum catalyst as one part per million; k. The amount of the catalyst is 0.00001-0.5 parts, for example 0.00001 parts, 0.0098 parts or 0.21 parts; l. The inhibitor is an alkynol compound, a nitrogen-containing compound or an organic peroxide, such as methyl butynol, and another example is 2-methyl-3-butyn-2-ol; m. The weight proportion of the inhibitor is 0.03-2.0 parts, for example 0.69 parts; n. The raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.18 mol%; 30 parts of hydrophilic white carbon black; 1.33 parts of hydrogenated silicone oil; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.5:1; 0.0098 parts of platinum catalyst (concentration is 3000 ppm); 0.69 parts of 2-methyl-3-butyn-2-ol; Or, the raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.18 mol%; 30 parts of hydrophilic white carbon black; 1.33 parts of hydrogenated silicone oil; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.5:1; 0.01 parts of platinum catalyst (concentration is 3000 ppm); 0.69 parts of 2-methyl-3-butyn-2-ol; Or, the raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.18 mol%; 20 parts of hydroxyapatite; 20 parts of HB-615 hydrophobic fumed silica; 1.33 parts of hydrogenated silicone oil; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.5:1; 0.21 parts of platinum catalyst (concentration is 3000 ppm); 0.98 parts of 2-methyl-3-butyn-2-ol; Alternatively, the raw material composition of the silica gel material may include the following components: 100 parts of methylvinyl polysiloxane; the content of vinyl in methylvinyl polysiloxane is 0.17 mol%; hydrophilic fumed silica N20: 20 parts; hydrophobic fumed silica R106: 20 parts; the Si-H group content of hydrogenated silicone oil is 0.75%; the molar ratio of Si-H group in hydrogenated silicone oil to vinyl in methylvinyl polysiloxane is 1.2:1; platinum catalyst: 0.00001 parts; 2-methyl-3-butyn-2-ol: 0.7 parts.

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

4. A silica gel material, characterized in that: It is prepared by the preparation method as claimed in claim 3.

5. A method for preparing a silicone tube, characterized in that: The mixture B as claimed in claim 3 is formed into a tube by extrusion process, and then catalytic addition is performed to obtain the silicone tube; Alternatively, the aforementioned catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

6. A silicone tube, characterized in that: It is prepared by the preparation method as claimed in claim 5.

7. An implant, characterized in that: It comprises a medicine core and the silicone tube as claimed in claim 6, wherein the medicine core contains active pharmaceutical ingredients.

8. Use of the silica gel material as claimed in claim 4 or the silica gel tube as claimed in claim 6 as a release rate regulating medium in a sustained-release preparation.

9. A rod core for a perforated implant, characterized in that: The method comprises a drug-containing layer, wherein the drug-containing layer comprises an active drug and excipients; Wherein, the excipients include sustained-release excipients; the molecular weight of the sustained-release excipients is 10-10 million; The drug-excipient ratio is 1:(0.01-100); the drug-excipient ratio represents the mass ratio of the active drug to the excipient in the drug-containing layer; Optionally, the rod core of the perforated implant further includes a boosting layer composited on the drug-containing layer.

10. The rod core for perforated implant according to claim 9, characterized in that: The active drug includes an active drug with a drug solubility of >10 mg / mL and a drug molecular weight of greater than 800 Da, preferably an active drug with a drug solubility of >30 mg / mL and a drug molecular weight of greater than 800 Da, such as one or more of exenatide, semaglutide, Centella asiatica glycosides and human growth hormone; And / or, the active drug includes an active drug with a drug solubility of >10 mg / mL and a drug molecular weight of less than or equal to 800 Da, preferably an active drug with a drug solubility of >30 mg / mL and a drug molecular weight of less than or equal to 800 Da, such as metformin and / or Doxorubicin hydrochloride; And / or, the active drug comprises an active drug with a drug solubility of ≤10 mg / mL and a drug molecular weight greater than 800 Da, preferably an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight greater than 800 Da, such as one or more of bovine insulin, paclitaxel and levothyroxine sodium; And / or, the active drug comprises an active drug with a drug solubility of ≤10 mg / mL and a drug molecular weight of 800 Da or less, preferably an active drug with a drug solubility of ≤5 mg / mL and a drug molecular weight of 800 Da or less, such as one or more of estradiol, gestodene, levonorgestrel, meloxicam, ganciclovir, puerarin and paliperidone; and / or, the weight average molecular weight of the sustained-release excipient is 11 million to 8 million, for example, 11.71, 10,000, 44,000, 200,000, 300,000, 400,000 or 7 million; The sustained-release excipient preferably includes a poorly soluble skeleton material and / or a hydrophilic gel material; the poorly soluble skeleton material preferably has a weight average molecular weight of 20-800 million, preferably 30-700 million; more preferably includes one or more of calcium alginate, methyl cellulose, polyethylene, polyvinyl chloride, methacrylic acid-methyl acrylate copolymer and ethyl cellulose, such as ethyl cellulose; the methacrylic acid-methyl acrylate copolymer is preferably one or more of Eudragit S100, Eudragit L100, RL, RS, NE and FS, such as Eudragit S100; the hydrophilic gel material preferably has a weight average molecular weight of 10-800 million, more preferably includes one or more of hydroxypropyl methylcellulose, polyethylene oxide, sodium alginate, chitosan, agar, xanthan gum, carbomer, polyvinyl alcohol, N-vinyl amide polymer, polylactic acid-glycolic acid copolymer (PLGA) and polyethylene oxide; the hydroxypropyl methylcellulose is preferably HPMC The N-vinyl amide polymer is preferably PVP K30 and / or PVP K90; the polyethylene oxide is preferably PEO N80, PEO N-750, PEO WSR 303, PEO WSR N-12K, PEO WSR N-60K and PEO WSR 1105. And / or, the excipients further include one or more of a drug stabilizer, a filler and a suspending agent; and / or, the drug-excipient ratio is 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; and / or, the mass ratio of the sustained-release excipient to the excipient is 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; And / or, the concentration of the active drug in the drug-containing layer is set as a gradient concentration; the gradient is preferably 1-50 segments, such as 2 segments, 3 segments, 5 segments, 10 segments, 20 segments or 40 segments; the gradient concentration is generally expressed as the concentration of each gradient is independent of each other; And / or, the raw materials of the boost layer include expansion materials and permeation promoters; And / or, when the stick core further includes a boosting layer, the mass ratio of the drug-containing layer to the boosting layer is (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, 5:1, 10:1, 20:1, 40:1, 60:1, 80:1 or 100:1; And / or, when the stick core further includes a boosting layer, the number of the boosting layers is an integer, preferably an even number, such as 2; when the number of the boosting layers is an even number, the boosting layers are preferably respectively arranged at both ends of the drug-containing layer; And / or, the single pressing length of the rod core is 1-50 mm, such as 1 mm or 2 mm or 3 mm or 4 mm or 5 mm or 7 mm or 10 mm or 20 mm or 30 mm or 40 mm or 50 mm; the total length of the rod core can be selected according to the length of the silicone tube; And / or, the diameter of the rod core is 1-10 mm, more preferably 1-5 mm, such as 2 mm, 3 mm or 4 mm.

11. The rod core for perforated implant according to claim 9 or 10, characterized in that: When the gradient is 3 sections, the gradient is sequentially arranged as a first gradient drug release module, a second gradient drug release module and a third gradient drug release module, the concentration of the active drug in the first gradient drug release module is 0.1%-50%, such as 2%, 5% or 10%; the concentration of the active drug in the second gradient drug release module is 1%-80%, such as 10% or 20%; the concentration of the active drug in the third gradient drug release module is 1%-100%, such as 20% or 30%; the concentration of the active drug indicates the percentage of the mass of the active drug to the mass of the gradient drug release module; And / or, the expansion material in the boosting layer is polyethylene oxide, preferably polyethylene oxide with a weight average molecular weight of 100,000-700,000, such as 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 permeation enhancer in the boost layer is one or more of mannitol, lactose, fructose, glucose and NaCl, such as NaCl; Among them, the mass ratio of the expansion material and the permeation promoter in the boost 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.

12. A method for preparing a punched implant rod core according to any one of claims 9 to 11, characterized in that: The method comprises the following steps: compressing the active drug and the auxiliary material to obtain the drug-containing layer; Optionally, the boosting layer is composited on the drug-containing layer; Preferably, the pressing pressure is 0.01-10 MPa, such as 0.1, 0.2, 0.3, 0.5, 1, 2, 5 or 10 MPa.

13. A perforated implant, characterized in that: It comprises a rod core for a perforated implant as claimed in any one of claims 9 to 11 and a silicone tube with drug release holes coated on the outside of the rod core; Preferably, in the silicone tube having drug release holes, the ratio of the diameter of the drug release holes to the outer diameter of the silicone tube is (0.0001-0.5):1, preferably (0.002-0.4):1, such as 0.06:1, 0.14:1 or 0.23:1, more preferably (0.005-0.2):1; And / or, in the silicone tube containing drug release holes, the ratio of the total area of ​​the drug release holes to the outer surface area of ​​the silicone tube is (0.00001-0.4):1, preferably (0.0001-0.35):1, more preferably (0.0005-0.3):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 diameter of the drug release hole is 1 μm-1000 μm, preferably 10-600 μm, such as 10, 20, 50, 100, 150, 250, 350, 450 or 550 μm, more preferably 250-450 μm; and / or, the number of the drug release holes is >1, preferably 1-1,000,000, for example, 1, 2, 5, 10, 20, 50, 100, 200, 500, 1,000, 5,000, 10,000, 50,000, 100,000, 500,000 or 1,000,000; And / or, the silicone tube containing the drug-releasing holes is obtained by punching holes in the silicone tube using a laser punching method or a mechanical punching method; And / or, the position of the drug release hole meets the following conditions: the silicone tube comprises a first end face and a second end face which are arranged opposite to each other, the distance between the first end face and the second end face is the total length of the silicone tube, and a plurality of drug release holes are arranged in the silicone tube; Wherein, when the number of the drug release hole is 1, the distance from the center point of the drug release hole to the first end surface of the silicone tube containing the drug release hole is preferably 0-100% of the length of the silicone tube but not 0 and 100%, and more preferably the center point of any of the drug release holes. The distance from the center point to the first end surface of the silicone tube containing the drug release hole is 0.1%-99.9% of the length of the silicone tube, preferably 1%-99%, such as 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%; Wherein, when the number of drug release holes is ≥2, the distance between the center points of the drug release holes preferably satisfies the following conditions: When the planes of any two of the drug release holes are not on the same radial section of the silicone tube, in the axial section direction of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is preferably 0-100% of the length of the silicone tube but not 0 and 100%, preferably 0.1%-99.9% of the length of the silicone tube, more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%; the distance between the center points of adjacent drug release holes is preferably 0.001-80mm; Wherein, when the number of drug release holes is ≥2, the distance between the center points of the drug release holes may also satisfy the following conditions: When the planes of any two of the drug release holes are on the same radial section of the silicone tube, in the circumferential direction of the radial section of the silicone tube, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is preferably 0-100% of the length of the silicone tube but not 0 and 100%, and preferably, the distance from the center point of any of the drug release holes to the first end surface of the silicone tube containing the drug release holes is 0.1%-99.9% of the length of the silicone tube, and more preferably 1%-99%, for example 1%, 2%, 3%, 5%, 7%, 7.5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 98% or 99%; the distance between the center points of adjacent drug release holes on the circumference is preferably (2-10)πmm.

14. A method for preparing a perforated implant as claimed in claim 13, characterized in that: The method comprises the following steps: filling the rod core of the perforated implant according to any one of claims 9 to 11 into a silicone tube having a drug release hole.

15. Use of the rod core of the perforated implant 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 preparation.

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