CN116808314A - A silicone material and its preparation method, a silicone tube, and an implant containing the same - Google Patents

Abstract

The application discloses a silica gel material, a preparation method thereof, a silica gel tube and an implant containing the silica gel tube. The preparation method of the silica gel material comprises the following steps: the mixture of the raw material composition of the silica gel material is molded by a catalytic addition process; wherein: the raw material composition of the silica gel material comprises the following components in parts by weight: r-vinyl silicone rubber, reinforcing agent, hydrogen-containing silicone oil and catalyst; the vinyl content in the R-vinyl silicone rubber is 0.10-0.50mol%; si-H groups in the hydrogen-containing silicone oil are 0.18 to 1.6mol percent; the molar ratio of Si-H group in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-4): 1; the catalytic addition process is sequentially carried out at 250-360 ℃ and 120-280 ℃. The silica gel material has excellent mechanical property and good biocompatibility; the silica gel prepared implant agent has stable drug release curve after being loaded with active drugs.

Description

Silicone material and preparation method thereof, silicone tube, and implant containing same

This application claims the priority of Chinese patent application No. 2022102727087 filed on March 18, 2022. This application cites the entire text of the above Chinese patent application.

Technical Field

The invention relates to a silica gel material and a preparation method thereof, a silica gel tube and an implant containing the silica gel material.

Background Art

Common modern contraceptive methods include non-hormonal contraception (male/female condoms, male/female sterilization, etc.) and hormonal contraception (various oral contraceptives, subcutaneous implants, progestin intrauterine devices, contraceptive injections, etc.). Among them, hormonal contraceptive methods have always shown their reliable contraceptive effects.

Since the concept of "sustained-release preparations" was proposed, sustained-release preparations used for contraception have made great progress, effectively avoiding the harm of surgical contraception and low compliance with oral contraceptives. Sustained-release preparations that can provide long-term contraception, especially subcutaneous contraceptive implants, have very broad prospects in the field of birth control.

Levonorgestrel (LNG), also known as levonorgestrel, levonorgestrel, etc., has been included in the pharmacopoeias of China, the United States, the United Kingdom, Japan, etc. At present, there are many single tablets and combined contraceptives with levonorgestrel as the main drug on the international and domestic markets. It is the earliest and most widely used over-the-counter drug in clinical application.

Gestodene is a third-generation contraceptive that can achieve contraceptive effects with very small clinical dosages. It has no estrogenic activity, has good anti-estrogen activity and slight androgenic activity, and its bioavailability approaches 100%. It is currently the only progestin that can exert its effects without metabolism.

Subcutaneous implants mainly place active drugs in carriers and implant them under the skin. The implants control the release of drugs through the carriers. The drugs are absorbed into the blood circulation through local capillaries and can be released stably for several years to achieve long-term contraceptive effects. This preparation avoids the first-pass effect of the gastrointestinal tract, thereby greatly improving the bioavailability of the drug. Subcutaneous implants are suitable for people who want long-term contraception and are not suitable for IUD placement. After implantation, if there is a desire to become pregnant, the ability to become pregnant can be restored by removing the implant.

Silicone materials are one of the most biocompatible materials among synthetic materials today. Medical textbooks in the 1960s had already identified silicone as an important implant material, and it is widely used in practice. Dow Corning of the United States has provided a large number of literature reports to prove the safety of silicone gel breast implants in humans. With the research on silicone materials, its application in the medical field is becoming more and more extensive. Some researchers have conducted a large number of animal experiments and implanted silicone materials into animals for up to 3 years without any adverse reactions, and its safety in human implants has gradually been proven to be good.

At present, silicone rubber products used in the production of medical products, especially silicone rubber products to be implanted in the human body for a long time, generally use addition-type silicone rubber. Addition-type silicone rubber is mainly used in various occasions of contact with blood and implantation in the body. Existing silicone rubber is generally made by a simple extrusion process, such as the preparation process disclosed in Chinese patent CN 1727409A. The mechanical properties of the silicone rubber tube made by this addition method are poor and it is difficult to meet the requirements of clinical use.

Summary of the invention

The technical problem to be solved by the present invention is to overcome the defect that the silicone rubber tube prepared by the addition method of the prior art has poor mechanical properties and is difficult to meet the requirements of clinical use, and to provide a silicone material and its preparation method, a silicone tube, and an implant containing the same. The silicone tube prepared by the silicone material in the present invention has excellent mechanical properties and good biocompatibility; the implant prepared by using the silicone tube has a stable drug release curve, and when the loaded drug is a contraceptive (such as gestodene, levonorgestrel), the prepared implant can produce a significant contraceptive effect on rats.

The present invention provides a method for preparing a silica gel material, which comprises the following steps: forming a mixture of a raw material composition of the silica gel material by a catalytic addition process; wherein:

(1) The raw material composition of the silica gel material comprises the following components in parts by weight:

R-vinyl silicone rubber: 100 parts;

Reinforcing agent: 20-80 parts;

Hydrogenated silicone oil: 0.3-3.0 parts;

Catalyst: ≥ 0.000002 parts, preferably 0.000002-0.00005 parts;

in:

R in the R-vinyl silicone rubber is a substituted or unsubstituted C ₁ -C ₅ straight-chain alkane or branched-chain alkane, or a substituted or unsubstituted C ₆ -C ₂₀ aromatic hydrocarbon;

The content of vinyl in the R-vinyl silicone rubber is 0.10-0.50 mol%;

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 silicone rubber is (0.5-4):1;

Optionally, an inhibitor is also included, wherein the inhibitor is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil;

(2) The catalytic addition process includes a first heat treatment and a second heat treatment in sequence. The temperature of the first heat treatment is 250-360°C, and the temperature of the second heat treatment is 120-300°C, for example, 120-280°C.

In the present invention, R in the R-vinyl silicone rubber may be a substituted or unsubstituted C ₁ -C ₅ straight-chain alkane, such as a methyl group.

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

The methyl vinyl silicone rubber may be conventional methyl vinyl silicone rubber in the art, for example, methyl vinyl silicone rubber having a relative molecular weight of 100,000-800,000 g/mol.

In the present invention, the vinyl content in the R-vinyl silicone rubber is preferably 0.10-0.23 mol%, such as 0.17 mol% or 0.23 mol%, more preferably 0.17-0.23 mol%.

In the present invention, the reinforcing agent may 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, silica 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.

The white carbon black can be conventional white carbon black in the art, such as fumed white carbon black, precipitated white carbon black, gel white carbon black or surface treated white carbon black, preferably fumed white carbon black. The fumed white carbon black can be fumed white carbon black purchased from Dalian Shengsen Nano Silicon Carbon Materials Co., Ltd.

The calcium carbonate may be conventional calcium carbonate in the art, such as precipitated calcium carbonate.

In the present invention, the amount of the reinforcing agent is preferably 30-80 parts, such as 30 parts, 35 parts, 40 parts, 45 parts, 50 parts or 60 parts.

In the present invention, the hydrogen-containing silicone oil may be conventional hydrogen-containing silicone oil in the art, such as hydrogen-containing silicone oil purchased from Guangdong Guiye New Material Technology Co., Ltd.

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

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

In the present invention, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is preferably (0.8-2):1, for example, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1 or 3.0:1, preferably (1.2-1.8):1 or (1.2-1.5):1.

In the present invention, the inhibitor may be a conventional inhibitor in the art that can inhibit the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil at room temperature, such as acetylenic alcohol compounds, nitrogen-containing compounds or organic peroxides, such as methyl butynol, and also such as 2-methyl-3-butyn-2-ol.

In the present invention, the dosage of the inhibitor is preferably 0.03-2.0 parts, such as 0.3-1.0 parts, and for example 0.3 parts, 0.5 parts, 0.7 parts or 0.9 parts.

In the present invention, the catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil, such as a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst.

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

In the present invention, the amount of the catalyst is preferably 0.000005-0.00005 parts, for example, 0.000005 parts, 0.00001 parts, 0.00002 parts or 0.00003 parts.

In the present invention, the catalytic addition process may be an extrusion process.

In the present invention, the temperature of the first heat treatment may be 250-330°C, such as 270°C, 280°C, 300°C or 330°C.

In the present invention, the time of the first heat treatment is related to the processing length in the catalytic addition process, such as the extrusion length in the extrusion process. For example, when the processing length of the first heat treatment is 0.8m, the time of the first heat treatment may be about 5s.

In the present invention, the temperature of the second heat treatment may be 150-300°C, such as 150-280°C, such as 150°C, 180°C, 210°C, 260°C or 280°C.

In the present invention, the time of the second heat treatment is related to the treatment length in the catalytic addition process, such as the extrusion length in the extrusion process. For example, when the extrusion length of the second heat treatment is 2.5m, the time of the second heat treatment may be about 2min.

In the present invention, a third heat treatment may be performed after the second heat treatment.

The temperature of the third heat treatment may be 100-280°C, for example 180°C.

The time of the third heat treatment is preferably 0-72 h, such as 0 h, 24 h, 48 h or 72 h.

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

In the present invention, the catalytic addition process can be performed by extrusion molding in a tubular mold. When extrusion is performed in a tubular mold, the silicone material is tubular.

In the present invention, the mixture of the raw material composition of the silica gel material can be prepared by the following method:

Method 1: When the raw material composition of the silica gel material does not include an inhibitor, the preparation method of the mixture comprises the following steps:

S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

S2: In the presence of the catalyst, the mixture A and the hydrogen-containing silicone oil are mixed to obtain a mixture B;

Method 2: When the raw material composition of the silica gel material further includes an inhibitor, the preparation method of the silica gel material includes the following steps:

S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

S2: dividing the mixture A into component A1 and component A2, mixing the component A1 with the catalyst to obtain component B1, and mixing the component A2 with the hydrogen-containing silicone oil and the inhibitor to obtain component B2;

S3: Mix the component B1 and the component B2 to obtain a mixture B.

Among them, in the method 1 and the method 2, the reinforcing agent can be pretreated by conventional methods in the art, such as drying at 100-210° C. (such as 180-210° C., and for example 200° C.) for 1-24 h (such as 24 h) for use.

Among them, in the method 1 and the method 2, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, such as drying at 30-60° C. (such as 40° C.) for 1-24 h (such as 24 h) for use.

Among them, in the method 1 and the method 2, the mixing step in S1 can be:

After the R-vinyl silicone rubber is wrapped around the reinforcing agent, it is extruded and thinned by an open mill, and then pressed into sheets.

Wherein, in the method 1 and the method 2, the mixture A can be placed in a desiccator at room temperature for 24-72 hours.

Among them, in the method 1 and the method 2, the mixing step in S1 can be:

The R-vinyl silicone rubber and the reinforcing agent are kneaded in a kneader at 30° C. for 30 minutes, and then taken out; the mixture is triangularly wrapped and rolled 5 times on an open mill with a roller distance of 1-10 mm (e.g., 1 mm) and then left to stand for 24 hours to obtain the mixture A.

Wherein, in the method 1, before the catalytic addition process, the mixture B may be subjected to the following post-treatment: triangularly wrapped and thinned 4 to 6 times in an open mill, and then uniformly cut into sheets.

Among them, in the second method, the step of mixing the component B1 and the component B2 can be: putting the component B1 and the component B2 in a ratio of 1:1 into an open mixing mill, making triangular packages for 4 to 6 times, and then evenly cutting the materials into slices.

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

Since the intermolecular force between polyorganosilane molecules is very small, the mechanical properties of raw rubber after vulcanization alone are poor and have no use value. In order to improve its mechanical properties, fillers are generally used for reinforcement. Silica gel is the most commonly used reinforcing filler, which can greatly improve the hardness of silicone materials. Among them, the fumed silica treated with silazane is easy to disperse in silicone materials due to its hydrophobic surface, and has a better reinforcement effect.

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

In a preferred embodiment of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

Methyl vinyl silicone rubber: 100 parts;

Reinforcing agent: 20-80 parts;

Hydrogenated silicone oil: 0.3-3.0 parts;

Catalyst: 0.000002-0.00005 parts;

Inhibitor: 0.03-2.0 parts;

in:

The vinyl content in the methyl vinyl silicone rubber is 0.10-0.50 mol%;

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 methyl vinyl silicone rubber is (0.5-4):1.

In a preferred embodiment of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

Methyl vinyl silicone rubber: 100 parts;

Reinforcing agent: 30-60 parts;

Hydrogenated silicone oil: 0.4-2.8 parts;

Catalyst: 0.000002-0.00005 parts;

Inhibitor: 0.3-1.0 parts;

in:

The vinyl content in the methyl vinyl silicone rubber is 0.17-0.23 mol%;

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 methyl vinyl silicone rubber is (0.8-2):1.

In a preferred embodiment of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

Methyl vinyl silicone rubber: 100 parts;

Reinforcing agent: 30-45 parts;

Hydrogenated silicone oil: 0.42-2.52 parts;

Catalyst: 0.000002-0.00005 parts;

Inhibitor: 0.3-0.9 parts;

in:

The vinyl content in the methyl vinyl silicone rubber is 0.17-0.23 mol%;

The content of Si-H groups in the hydrogen-containing silicone oil is 0.5-1.0 mol%;

The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is (1.2-1.8):1.

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

In some preferred embodiments of the present invention, the raw material composition of the silica gel material comprises the following components in parts by weight:

The invention also provides a silica gel material, which is prepared by adopting the method.

When the catalytic addition process is performed by extrusion molding in a tubular mold, the silicone material is in a tubular shape.

The present invention also provides a silicone tube, which is prepared by the following method:

Extruding the silicone material into a tube;

Alternatively, in the method for preparing the silicone material as described above, the catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

The present invention also provides an implant, which comprises a medicine core and the silicone tube, wherein the medicine core contains active pharmaceutical ingredients.

Among them, the active pharmaceutical ingredient may be a small molecule drug with low solubility, such as a drug solubility ≤100 mg/mL (with water as solvent) and a drug active ingredient with a drug molecular weight less than 1000 Da; and also one or more of levonorgestrel, gestodene, gestrinone, estradiol, ibuprofen, paliperidone, meloxicam, and puerarin.

The pharmaceutically active ingredient may be a pharmaceutically active ingredient with a solubility of ≤60 mg/mL (with water as solvent) and a drug molecular weight of less than 1000 Da, such as levonorgestrel, gestodene, gestrinone, estradiol, ibuprofen, paliperidone, meloxicam or puerarin.

The pharmaceutically active ingredient may be a pharmaceutically active ingredient with a solubility of ≤50 mg/mL (with water as solvent) and a drug molecular weight of less than 1000 Da, such as levonorgestrel, gestodene, gestrinone, estradiol, paliperidone, meloxicam or puerarin.

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

The pharmaceutically active ingredient may be a pharmaceutically active ingredient with a solubility of ≤5 mg/mL (with water as solvent) and a drug molecular weight of less than 1000 Da, such as meloxicam or puerarin.

In the present invention, the active pharmaceutical ingredients in the raw material medicine 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.

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

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

The steroidal estrogen is preferably estradiol.

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.

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.).

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

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.

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.

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

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

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

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

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.

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).

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

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).

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

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 elamod).

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

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).

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

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

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

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

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

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

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

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

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;

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

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

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

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

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

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

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.

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

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

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

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

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

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.

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.

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

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

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

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).

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

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

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

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).

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

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.

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

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

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

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

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

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

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

In the present invention, the drug core may be a powder type drug core.

Wherein, in the powder-type drug core, the particle size of the active pharmaceutical ingredient may be 2-180 μm.

When the drug core is a powder type drug core, the implant can be prepared by the following method:

The silicone tube is cut into sections, filled with the powder-type medicine core, and both ends are sealed with silicone to obtain the implant.

In the present invention, the drug core may further include poorly soluble auxiliary materials.

Wherein, the particle size of the poorly soluble auxiliary material may be 1-200 μm.

Wherein, the poorly soluble auxiliary material may include silicon material. The pore size of the silicon material may be less than 1 μm; for example, 0 nm, 5 nm, 10 nm, 18 nm, 50 nm or 100 nm. Those skilled in the art will understand that when the pore size of the silicon material is 0 nm, the silicon material is a non-porous silicon material.

In the silicon material, the content of silicon dioxide may be greater than 50%, preferably 80%, 90%, 95%, 99% or 99.8%.

The poorly soluble auxiliary material may include one or more of white carbon black, AL-1FP mesoporous silica, XDP3050 mesoporous silica and XDP3150 mesoporous silica.

The white carbon black is preferably fumed white carbon black, precipitated white carbon black, gel white carbon black or white carbon black obtained by surface treatment method.

Preferably, the poorly soluble auxiliary material is one or more of white carbon black, AL-1FP mesoporous silica, XDP3050 mesoporous silica and XDP3150 mesoporous silica.

More preferably, the poorly soluble auxiliary material is one or more of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica.

In the present invention, the poorly soluble auxiliary material may also include a poorly soluble weak acid and/or a poorly soluble weak base.

The poorly soluble weak acid preferably includes one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, and more preferably includes boric acid and/or fumaric acid.

The sparingly soluble weak base preferably includes one or more of magnesium hydroxide, aluminum hydroxide, zinc hydroxide, ferrous hydroxide and magnesium oxide; more preferably includes one or more of magnesium hydroxide, aluminum hydroxide and zinc hydroxide.

The poorly soluble auxiliary material may also be white carbon black and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, white carbon black and molybdic acid, white carbon black and silicic acid, white carbon black and tungstic acid, or white carbon black and germanic acid.

Alternatively, the poorly soluble auxiliary material may also be white carbon black, ferrous hydroxide and/or magnesium oxide; for example, white carbon black and ferrous hydroxide, or white carbon black and magnesium oxide.

Alternatively, the poorly soluble auxiliary material may also be AL-1FP mesoporous silica and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, AL-1FP mesoporous silica and molybdic acid, AL-1FP mesoporous silica and silicic acid, AL-1FP mesoporous silica and tungstic acid, or AL-1FP mesoporous silica and germanic acid.

Alternatively, the poorly soluble auxiliary material may also be AL-1FP mesoporous silica, ferrous hydroxide and/or magnesium oxide; for example, AL-1FP mesoporous silica and ferrous hydroxide, or AL-1FP mesoporous silica and magnesium oxide.

Alternatively, the poorly soluble auxiliary material may also be XDP3050 mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, XDP3050 mesoporous silicon and molybdic acid, XDP3050 mesoporous silicon and silicic acid, XDP3050 mesoporous silicon and tungstic acid, or XDP3050 mesoporous silicon and germanic acid.

Alternatively, the poorly soluble auxiliary material may also be XDP3050 mesoporous silica, ferrous hydroxide and/or magnesium oxide; for example, XDP3050 mesoporous silica and ferrous hydroxide, or XDP3050 mesoporous silica and magnesium oxide.

Alternatively, the poorly soluble auxiliary material may also be XDP3150 mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, XDP3150 mesoporous silicon and molybdic acid, XDP3150 mesoporous silicon and silicic acid, XDP3150 mesoporous silicon and tungstic acid, or XDP3150 mesoporous silicon and germanic acid.

Alternatively, the poorly soluble auxiliary material may also be XDP3150 mesoporous silica, ferrous hydroxide and/or magnesium oxide; for example, XDP3150 mesoporous silica and ferrous hydroxide, or XDP3150 mesoporous silica and magnesium oxide.

In the present invention, the content of the bulk drug may be 10% to 99.9%, such as 50% to 99.5%, and another example is 95%; the percentage is the mass percentage of the bulk drug in the pharmaceutical composition.

The content of the poorly soluble excipient may be 0.1% to 90%, such as 0.1% to 50%, and another example is 0.5% to 5%; the percentage is the mass percentage of the poorly soluble excipient in the pharmaceutical composition.

In the present invention, when the insoluble auxiliary material is two or three of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica, the mass ratio thereof can be any ratio. For example, when the insoluble auxiliary material is two of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica, the mass ratio thereof is (0.001-1000):1.

For another example, when the poorly soluble auxiliary materials are XDP3150 mesoporous silica and fumaric acid, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

For another example, when the insoluble auxiliary materials are fumed silica and boric acid, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

For another example, when the poorly soluble auxiliary materials are XDP3050 mesoporous silica and magnesium hydroxide, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

For another example, when the poorly soluble auxiliary material is AL-1FP mesoporous silica and zinc hydroxide, the mass ratio thereof can be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

In the present invention, the outer diameter of the silicone tube is preferably 2.0-5.0 mm, such as 2.4 mm or 2.6 mm.

In the present invention, the length of the silicone tube is preferably 1.5-4.5 cm, such as 1.9 cm or 4.4 cm.

In the present invention, the wall thickness of the silicone tube is preferably 0.2-0.5 mm, such as 0.2 mm, 0.3 mm, 0.4 mm or 0.5 mm.

In the present invention, the drug release area of the silicone tube is preferably 0.4-15.0 cm ² , such as 0.69 cm ² , 1.38 cm ² , 2.07 cm ² , 2.76 cm ² or 3.45 cm ² .

In the present invention, the diameter of the drug core is preferably 1.5-4.0 mm, such as 1.6 mm or 2.0 mm.

In the present invention, the length of the drug core is preferably 1.0-5.0 cm, such as 1.0-4.0 cm, such as 1.5 cm or 3.9 cm, and further such as 1 cm, 2 cm, 3 cm, 4 cm, or 5 cm.

In some preferred embodiments of the present invention, the specifications of the implant are shown in the following table, and the active pharmaceutical ingredient in the drug core is preferably levonorgestrel;

In some preferred embodiments of the present invention, the specifications of the implant are shown in the following table, and the active pharmaceutical ingredient in the drug core is preferably gestodene;

In some preferred embodiments of the present invention, the specifications of the implant are shown in the following table, and the active pharmaceutical ingredient in the drug core is preferably estradiol;

serial number Silicone tube outer diameter/mm Silicone tube wall thickness/mm Drug release area/ ^cm2 1 2.2 0.2 0.69 2 2.2 0.2 1.38 3 2.2 0.2 2.07 4 2.2 0.2 2.76 5 2.2 0.2 3.45

.

The preparation process of the implant of the present invention can be as follows: the silicone material is extruded into a tube or the silicone tube is cut into sections and then filled with drugs, both ends are sealed with adhesives, and then packaged and sterilized to obtain the implant of the present invention.

The present invention also provides an application of the silica gel material or the silica gel tube as a release rate regulating medium in a sustained-release preparation.

In the present invention, the vinyl content in the R-vinyl silicone rubber refers to the molar percentage, and the molar percentage of vinyl refers to the number of moles of vinyl in every 100 moles of R-vinyl silicone rubber.

In the present invention, the hydrogen content in the hydrogen-containing silicone oil refers to the mole percentage, and the mole percentage of hydrogen content refers to the number of moles of hydrogen in every 100 moles of the hydrogen-containing silicone oil.

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

In the present invention, the room temperature refers to 25°C + 5°C.

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

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

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

The positive and progressive effects of the present invention are:

The silicone tube made of the silicone material in the present invention has excellent mechanical properties and good biocompatibility; the implant made of the silicone tube has a stable drug release curve after loading active drugs. When the loaded drug is a contraceptive (such as gestodene, levonorgestrel), the prepared implant can produce a significant contraceptive effect on rats.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a flow chart of the silicone tube preparation process.

Figure 2 is a flow chart of the silicone tube extrusion process.

Figure 3 is a picture of the GEST contraceptive implant.

FIG4 shows the relationship between the daily drug release amount and release time of the gestodene implants ZJ001, ZJ002, and ZJ003 in vitro.

Figure 5 shows the relationship between the in vitro daily drug release and release time of Gestodene Implants ZJ001, ZJ002 and ZJ003 (a daily drug release diagram based on Figure 4 with 5 days as a cycle and simplified data).

FIG6 is a pathological image of muscle tissue after implantation of the gestodene implant, wherein A, C, and E are pathological images at 3, 10, and 30 days after implantation, respectively (HE, ×2), and B, D, and F are pathological images at 3, 10, and 30 days after implantation, respectively (HE, ×20).

FIG. 7 is a vaginal smear of the estrus cycle of rats, wherein FIG. A is the proestrus, FIG. B is the estrus, FIG. C is the metestrus, and FIG. D is between the two estrus.

Figure 8 is an image of a vaginal plug in a rat, wherein Figure A is a milky white vaginal plug observed at the vaginal opening of rat No. 1 in the GEST implant experiment dose group I, whose vaginal smear showed a normal estrus cycle, when vaginal secretions were taken 13 days after implantation; Figure B is a vaginal plug observed at the vaginal opening of rat No. 4 in the GEST implant experiment dose group I, whose vaginal smear showed a normal estrus cycle, when vaginal secretions were taken 20 days after implantation.

Figure 9 shows a persulfurized silicone tube produced at a pre-drying temperature of 360°C.

Figure 10 shows tissue sections of SD rats on the 3rd day after implantation of levonorgestrel implant (A, HE, ×2), local fields of view of tissue sections of SD rats on the 3rd day after implantation (B, HE, ×20), tissue sections of SD rats on the 10th day after implantation (C, HE, ×2), and local fields of view of tissue sections of SD rats on the 10th day after implantation (D, HE, ×20).

FIG. 11 shows the daily dose release curves of the LNG implants in the detumescence group and the untreated group.

FIG. 12 is a cumulative dose release curve of the LNG implant in the decompression group and the untreated group.

FIG13 shows the linear relationship between 1/T and ln(K).

Figure 14 Images of rat vaginal suppositories.

FIG. 15 is a vaginal smear of the estrus cycle of rats, wherein FIG. A is the proestrus, FIG. B is the estrus, FIG. C is the metestrus, and FIG. D is between the two estrus periods.

FIG. 16 shows the results of measuring LH in rats in the levonorgestrel I dose group.

FIG. 17 shows the relationship between the drug area of the silicone tube and the amount of estradiol released.

DETAILED DESCRIPTION

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

In the following embodiments and comparative examples:

The vinyl content in methyl vinyl silicone rubber refers to the mole percentage, and the mole percentage of vinyl refers to the number of moles of vinyl in every 100 moles of methyl vinyl silicone rubber.

The hydrogen content in hydrogen-containing silicone oil refers to the mole percentage, and the mole percentage of hydrogen content refers to the number of moles of hydrogen in every 100 moles of hydrogen-containing silicone oil.

I. Gestodene long-acting contraceptive implant

1. Content determination and in vitro release determination method of gestodene contraceptive implant

(1) Chromatographic conditions

Chromatographic column: C18 column (250 mm × 4.60 mm, 5 μm);

Mobile phase: methanol-water (80:20, v/v);

Column temperature: 30°C;

Detection wavelength: 239nm;

Flow rate: 1 mL min ^-1 ;

Injection volume: 20 μL.

(2) In vitro release test method

The filled implant was placed in an ethanol solution and ultrasonicated in an ultrasonic instrument for 30 minutes. After ultrasonication, the implant was blown dry and placed in a stoppered conical bottle containing a release medium. The stoppered conical bottle was placed in a shaker with the temperature set to 37°C and the shaking speed set to 100 r·min ^-1 . After 24 hours, the implant was taken out and blown dry.

Use silicone rubber sealing glue to stick the two ends of the dried gestodene implant to the bottom and wall of the stoppered conical flask, so that the silicone tube filled with gestodene raw material powder is suspended in the stoppered conical flask and cannot touch the wall (to ensure the contact area between the drug-containing section and the release medium is stable during the shaking process). After sticking, leave it for 24 hours to allow the glue to cure completely. After curing, accurately pour the required amount of release medium into the stoppered conical flask, put it in a shaker, set the temperature to 37°C, and the shaking speed to 100r·min ^-1 . Take samples and replace the medium every 24 hours, and keep the samples for testing.

2. Preparation of two-component addition type silicone tube

1. Instruments and reagents

1.1 Instrument

Small kneading machine Laizhou Shenhong Machinery Co., Ltd. Small mixing mill Dongguan Yizong Machinery Equipment Co., Ltd. Φ16 Silicone Rubber Extruder Zhejiang Baina Rubber & Plastic Equipment Co., Ltd. 3020N outer diameter measuring instrument Shanghai Pinzhong Testing Equipment Co., Ltd. Electron microscopy Shenzhen Zhongwei Kechuang Technology Co., Ltd. XPE Analytical Balance Mettler-Toledo Instruments Ltd. SMD200-2 Electronic Analytical Balance Ohaus International Trading Co., Ltd. 101-2AB Electric Blast Drying Oven Tianjin Test Instrument Co., Ltd. Universal Mechanical Tester Dongguan Nanyue Experimental Equipment Co., Ltd. Shaw A Strength Meter Deqing Shengtaixin Electronic Technology Co., Ltd.

1.2 Drug testing

2 Test methods

2.1 Optimization of silicone tube preparation process

2.1.1 Prescription

Note: The mass fraction of this component corresponding to every 100 mass fractions of polymer compound (methyl vinyl silicone rubber) of PHR;

PPM refers to parts per million, which indicates the concentration of platinum in a platinum catalyst. 3000ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million. PHR indicates the proportion of platinum catalyst in the overall silicone tube formula. Taking the above formula as an example, it specifically refers to adding 0.000002-0.00005 parts of platinum catalyst to 100 parts of methyl vinyl silicone rubber, and the concentration of platinum in the platinum catalyst is 3000 parts per million.

2.1.2 Preparation process

(1) Pretreatment of raw rubber: Raw rubber (methyl vinyl silicone rubber) and fumed silica are put into a kneader in a certain proportion so that the fumed silica is fully wrapped by the raw rubber. The raw rubber wrapped with silica is squeezed and passed through an open mill to make the raw rubber and silica fully mixed. The raw rubber and silica are then pressed into sheets. After unloading, the raw rubber is fully wrapped with plastic wrap and sealed in a ziplock bag. The raw rubber is placed in a desiccator at room temperature for 24-72 hours for use.

(2) Preparation of matrix components: Divide the raw rubber with white carbon black into two equal parts by weight, namely component A and component B. Add the prescribed amount of crosslinking agent hydrogen silicone oil and inhibitor methyl butynol to component A, mix thoroughly with an open mill, and place in a desiccator at room temperature for 24h-72h for use.

(3) Preparation of catalytic components: Add the prescribed amount of platinum catalyst to component B, mix thoroughly with an open mill, and place in a desiccator at room temperature for 24 hours to 72 hours for use.

(4) Mix components A and B that have been stored for the same time, and use an open mill to continuously thin the thin slices and leave them for 12 hours.

(5) Keep the cut glue strips aside for later use.

The flowchart of the above steps (1)-(5) can be seen in Figure 1.

After the two-component silicone rubber material is prepared, it is pressed into sheets and extruded to form a silicone tube. In the extrusion process, the silicone rubber material is extruded by a screw, and the silicone tube is extruded through a mold. The silicone tube passes through the high temperature of the front drying channel to quickly vulcanize the extruded silicone tube and initially form it. Then it enters the rear drying channel to continue vulcanization so that the addition reaction of the silicone tube is basically complete. Finally, the silicone tube is placed in an oven at a certain temperature for oven vulcanization to ensure that the addition reaction of the silicone tube is complete.

During the extrusion process, the front drying channel, the rear drying channel, and the oven provide vulcanization conditions for the addition reaction between the raw rubber and the hydrogen-containing silicone oil, so that the silicone material is solidified and formed. The extrusion speed, the mold, and the stretching speed of the rear drying channel (extrusion speed 3.5r·min ^-1 , the stretching speed of the rear drying channel is set to 0.1m·s ^-1 , the outer diameter of the core mold is 2.50mm, and the inner diameter of the die is 3.90mm) are used to adjust the outer diameter and wall thickness of the prepared silicone tube, so as to prepare silicone tubes of different specifications. The extrusion process is shown in Figure 2

2.1.3 Silicone tube performance test

The tensile strength Ts is the maximum tensile force that the silicone tube withstands during the fracture process, which can indicate the maximum limit of the sample's resistance to external damage;

The elongation at break, Eb, is the deformation condition of the impression specimen when it breaks, which can indicate the deformation range that the specimen can accept before breaking.

Tear strength T refers to the strength of the silicone tube when it is torn, which can indicate the ability of the sample to resist tearing;

Hardness H is the ability of the silicone tube to resist external extrusion.

2.1.3.1 Tensile stress-strain performance test

The tensile stress-strain properties are determined according to the method of GB/T 828-2009. The prepared silicone tube samples are placed symmetrically on the upper and lower clamps of the servo system tensile machine so that the tension is evenly distributed on the cross section. The clamp distance is set to 50mm, the elongation test device is prepared, and the tensile machine is started. The tensile rate of the sample is 200mm/min. The maximum tensile stress during the stretching process, the length of the sample when stretched to fracture, and the force required for the sample to tear are recorded. The elongation at break, tensile strength, and tear strength of the sample are calculated according to the following formulas.

Elongation at break (%) E _b = 100 (L _b - L ₀ ) / L ₀

L _b - gauge length of the specimen at fracture, mm, L ₀ - initial gauge length of the specimen, mm.

Tensile strength (Mpa) Ts = Fm/Wt

Fm - maximum force recorded, W - width of the narrow part of the cutter, mm, t - thickness of the length of the specimen.

Tear strength (KN/m) T = F/t

F is the maximum force required to tear the sample, t is the thickness of the sample (mm).

2.1.3.2 Strength test

The hardness test of the product is determined according to GB/T 531.1-2008; after the prepared matrix component polymer and catalytic component polymer are fully mixed, they are cured and formed at room temperature to prepare a sample with a thickness of 6mm, and then cut into a 24×24mm square test sample. Place the test sample on a solid plane, hold the hardness tester, and steadily press the pressure foot on the test sample, keeping the pressure foot in full contact with the test piece, read the data within 1s, measure 3 times at different positions, and take the average value.

The preferred physical and mechanical properties of silicone tube products are shown in the table below.

project index Hardness/Shore A 50-70 Tensile strength/Mpa ≥7.5 Elongation at break/% ≥200 Tear strength/KN·m ^-1 ≥20

2.1.4 Optimization of silicone tube preparation process

This test uses a fixed recipe and uses elongation at break, tensile strength, tear strength and hardness as mechanical indicators to investigate the front oven temperature (first vulcanization temperature), rear oven temperature (second vulcanization temperature) and oven vulcanization time (third vulcanization time) in the extrusion process.

2.1.4.1 Investigation of the front drying temperature (first vulcanization temperature)

After silicone is extruded through a single screw, it passes through a high-temperature oven. The inhibitor in the silicone tube decomposes into gas at high temperature, and then the catalyst begins to work, catalytic addition reaction proceeds, and the silicone tube is quickly fixed and formed. The oven temperature has a great influence on the appearance and mechanical indicators of the extruded silicone tube. If the temperature is too low, the vulcanization is insufficient, the outer wall of the tube is not formed and it is difficult to stretch for subsequent processes. If the temperature is too high, the silicone tube is prone to over-vulcanization and the mechanical indicators deteriorate. The outer diameter of the silicone tube will shrink rapidly when passing through the high-temperature oven, and recover after coming out of the high-temperature oven. This change may affect the outer diameter and wall thickness of the silicone tube.

In this test, the front oven temperature was set at 270℃, 300℃, 330℃, and 360℃, respectively, and the elongation at break, tensile strength, tear strength, and hardness were used as mechanical indicators to examine the high-temperature oven temperature (in the investigation of the front oven temperature, the extrusion time of the front oven was very short, about 5s; the rear oven temperature was 180℃, the reaction time was very short, about 2min; the oven vulcanization temperature was 180℃, the time was 48h; the other process conditions were the same as the preparation process in 2.1.2 of this section; the prescription was the same as the prescription in 2.1.1 of this section). The outer diameter and wall thickness of the prepared silicone tube were measured to examine whether the change in the front oven temperature had an effect on the size of the silicone tube.

serial number Front drying temperature Example 1-1 270℃ Example 1-2 300℃ Examples 1-3 330℃ Examples 1-4 360℃

2.1.4.2 Investigation of post-drying temperature (second vulcanization temperature)

After the silicone tube is extruded, it passes through the front drying channel for rapid vulcanization. After the initial curing and forming, it passes through the 2.5m long rear drying channel for low-temperature vulcanization, so that the silicone tube can be further cured at a certain temperature and time, and the silicone tube is basically formed.

In this test, the post-baking temperature is set at 120℃, 150℃, 180℃, and 210℃, and the post-baking temperature is investigated with elongation at break, tensile strength, tear strength, and hardness as mechanical indicators (in the investigation of the post-baking temperature, the front-baking temperature is 270℃, the extrusion time of the front-baking is very short, about 5s; the reaction time of the post-baking is very short, about 2min; the oven vulcanization temperature is 180℃, the time is 48h; the other process conditions are the same as the preparation process in 2.1.2 of this section; the prescription is the same as the prescription in 2.1.1 of this section). The outer diameter and wall thickness of the prepared silicone tube are measured to investigate whether the change in the post-baking temperature has an effect on the size of the silicone tube.

serial number Post drying temperature Example 2-1 120℃ Example 2-2 150℃ Example 2-3 180℃ Embodiment 2-4 210℃

2.1.4.3 Investigation of oven vulcanization time (third vulcanization time)

In order to ensure that the silicone tube is completely vulcanized, it will be subjected to oven vulcanization (third vulcanization) treatment. If the third vulcanization time is insufficient, the silicone tube will not be completely vulcanized. If the vulcanization time is too long, the silicone tube is prone to over-vulcanization. This experiment sets the third vulcanization time to 0h, 24h, 48h, and 72h, and uses elongation at break, tensile strength, tear strength, and hardness as mechanical indicators to examine the oven vulcanization time. (In the investigation of oven vulcanization time: the temperature of the front oven is 270°C and the time is about 5s; the temperature of the rear oven is 180°C and the time is about 20s; the oven vulcanization temperature is 180°C; the other process conditions are the same as the preparation process in 2.1.2 of this section; the prescription is the same as the prescription in 2.1.1 of this section)

serial number Oven curing time Example 3-1 0h Example 3-2 24h Example 3-3 48h Embodiment 3-4 72h

2.1.5 Investigation of catalyst dosage

In this test, the dosage of raw rubber, hydrogenated silicone oil, inhibitor, and reinforcing agent is fixed at 100 PHR, 1.01 PHR, 0.7 PHR, and 30 PHR respectively. The dosage of catalyst is changed to 0.000005 PHR, 0.00001 PHR, 0.00002 PHR, and 0.00003 PHR respectively, and the mechanical properties of the silicone tube such as elongation at break, tensile strength, tear strength, and hardness are tested under different dosages of catalyst.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

2.1.6 Investigation of inhibitor dosage

The addition reaction between raw rubber and hydrogen-containing silicone oil can be carried out at room temperature under the catalysis of platinum. As the addition reaction proceeds rapidly, the silicone material solidifies rapidly. In order to prevent the silicone rubber from solidifying in the extruder cavity during the extrusion process, the inhibitor methyl butynol can be added to the silicone rubber to prevent the reaction from proceeding at room temperature.

In this test, the dosage of raw rubber, hydrogenated silicone oil, catalyst, and reinforcing agent is fixed at 100 PHR, 1 PHR, 0.00001 PHR, and 30 PHR respectively. The dosage of inhibitor is changed to 0.3 PHR, 0.5 PHR, 0.7 PHR, and 0.9 PHR respectively, and the mechanical properties of the silicone tube such as elongation at break, tensile strength, tear strength, and hardness are tested under different dosages of inhibitor.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

2.1.7 Investigation of Vinyl Content in Raw Rubber

According to the principle of addition reaction between methyl vinyl rubber and hydrogen-containing silicone oil, the vinyl content of the rubber has a great influence on the cross-linking degree of the silicone tube. The rubber and hydrogen-containing silicone oil undergo addition reaction under the catalytic action of platinum catalyst, and vinyl polysiloxane is the cross-linking chain in the formed network structure. The length of its molecular chain determines the cross-linking density after cross-linking and curing.

In this test, the molecular weight of vinyl polysiloxane, hydrogen silicone oil, catalyst, inhibitor, and fumed silica were fixed at 100 PHR, 1 PHR, 0.00001 PHR, 0.7 PHR, and 30 PHR respectively. The vinyl content of vinyl polysiloxane was changed to 0.05%, 0.07%, 0.17%, and 0.23% respectively, and the mechanical properties of silicone tubes such as elongation at break, tensile strength, tear strength, and hardness were tested under different vinyl contents.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

2.1.8 Investigation of the amount of fumed silica

The hardness of raw rubber is too low, which is not conducive to molding and processing. Adding fumed silica to the raw rubber can reinforce the hardness of the prepared silicone tube and improve the hardness of the raw rubber.

In this test, the amount of raw rubber with 0.17% vinyl content, hydrogenated silicone oil, catalyst and inhibitor was fixed at 100 PHR, 1 PHR, 0.00001 PHR and 0.7 PHR respectively. The amount of fumed silica was changed to 20, 30, 40, 45, 50 and 60 PHR respectively, and the mechanical properties of the silicone tube such as elongation at break, tensile strength, tear strength and hardness were tested under different amounts of fumed silica.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

2.1.9 Investigation of hydrogenated silicone oil

Hydrogenated silicone oil is used as a crosslinking agent to react with raw rubber. The amount of hydrogenated silicone oil added can be calculated as follows:

_W /W ₁ =(A×V _i %)/(H%×27)

Where: W _is the amount of crosslinking agent added; A is the molar ratio of Si-H to Si-Vi (preferably 1.0-1.5), that is, when the molar ratio of vinyl to hydrogen in hydrogen-containing silicone oil reaches 1:1, A is 1; _Vi % is the weight percentage of vinyl in the base rubber; H% is the weight percentage of hydrogen in the crosslinking agent; _W1 is the weight of the base rubber. In actual reactions, the optimal hydrogen content and addition amount of hydrogen-containing silicone oil cannot be calculated only by formulas, but should be obtained through experimental comparison.

2.1.9.1 Investigation of hydrogen content in hydrogenated silicone oil

In this experiment, the amount of raw rubber with a vinyl content of 0.17%, catalyst, inhibitor, and fumed silica was fixed at 100 PHR, 0.00001 PHR, 0.7 PHR, and 40 PHR respectively. The molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber was fixed at 1.2:1. The hydrogen contents of 0.18%, 0.36%, 0.5%, 0.75%,

Silicone tubes were prepared with 1.0% and 1.6% hydrogen-containing silicone oils, and the mechanical properties of the silicone tubes, such as elongation at break, tensile strength, tear strength and hardness, were tested at different hydrogen contents.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

2.1.9.2 Investigation of the dosage of hydrogenated silicone oil

In this experiment, the amount of raw rubber with a vinyl content of 0.17%, catalyst, inhibitor, and reinforcing agent was fixed at 100 PHR, 0.00001 PHR, 0.7 PHR, and 40 PHR respectively. Hydrogen-containing silicone oil with a hydrogen content of 0.75% was selected, and the molar ratio of Si-H group in the hydrogen-containing silicone oil to vinyl group in methyl vinyl silicone rubber was 1:1, 1.2:1, 1.5:1, and 1.8:1 respectively. The mechanical properties of the silicone tube such as elongation at break, tensile strength, tear strength, and hardness were tested under different amounts of hydrogen-containing silicone oil.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

3 Results and discussion

3.1 Silicone tube preparation process optimization

3.1.1 Investigation of the temperature of the front drying tunnel

Using the above prescription, the extrusion speed was fixed at 3.5 r·min ^-1 , the stretching speed was 0.1 m·s ^-1 , the front drying temperature was changed to 270℃, 300℃, 330℃, and 360℃, and three different molds were used to prepare silicone tubes. The outer diameter and wall thickness of the silicone tubes were measured. The results are as follows.

The influence of the front drying oven temperature on the outer diameter of the silicone tube is shown in the following table.

Note: Mould size (core mould diameter/die inner diameter): 3 ^# mould (2.01/3.50); 4 ^# mould (2.50/3.90); 5 ^# mould (3.02/4.32).

The mechanical properties of the silicone tube prepared by changing the front drying oven temperature were tested, and the results are shown in the following table.

The measurement results of the outer diameter and wall thickness of the silicone tube show that the outer diameter and wall thickness of the silicone tubes prepared by different molds have almost no change with the increase of the front oven temperature, and the front oven temperature has no effect on the final outer diameter and wall thickness of the silicone tube. The influence of the front oven temperature on the size of the silicone tube can be eliminated in the subsequent preparation of the silicone tube.

The mechanical results show that as the pre-vulcanization temperature increases, the elongation at break, tensile strength, and tear strength of the silicone tube continue to decrease, while the hardness continues to increase. The mechanical indicators of the silicone tubes prepared at 270°C and 300°C meet the requirements, and the mechanical properties of the silicone tubes prepared at 270°C are better overall. In the experiment, it was found that the higher the pre-drying temperature, the easier it is for the silicone tube to have bubbles. Taking all factors into consideration, the pre-drying temperature is preferably 270°C.

After the silicone is extruded through the extruder, it first passes through the front drying tunnel to quickly heat up the inhibitor to decompose into gas, and the catalyst plays a catalytic role, so that the cross-linking reaction proceeds rapidly and the outer wall of the silicone tube is quickly solidified and formed. If the temperature of the front drying tunnel is too low, the cross-linking reaction is slow and incomplete, and the silicone tube cannot be quickly solidified. The silicone is easily pulled and deformed, and the extrusion process cannot be carried out. If the temperature of the front drying tunnel is too high, it is easy to cause partial oversulfurization of the silicone tube, causing the silicone tube to become too hard and brittle, and the mechanical properties are sharply reduced, and the use value is lost.

3.1.2 Investigation of post-drying tunnel temperature

Using the above-mentioned prescription, the extrusion speed was fixed at 3.5r/min, the stretching speed was 0.1m/s, the rear drying oven temperature was changed to 120, 150, 180, and 210°C, and three different molds were used to prepare the silicone tube. The outer diameter and wall thickness of the silicone tube were measured. The results are as follows.

The influence of post-drying oven temperature on the outer diameter of silicone tube is shown in the following table.

Note: Mould size (core mould diameter/die inner diameter): 3# mould (2.01/3.50); 4# mould (2.50/3.90); 5# mould (3.02/4.32).

The mechanical properties of the silicone tube prepared by changing the drying oven temperature were tested, and the results are shown in the following table.

The measurement results of the outer diameter and wall thickness of the silicone tube show that the outer diameter and wall thickness of the silicone tubes prepared by different molds have almost no change with the increase of the post-baking oven temperature. It can be concluded that the post-baking oven temperature has no effect on the final outer diameter and wall thickness of the silicone tube. It can be judged that the temperature change in the preparation process has no effect on the molding size of the silicone tube.

The mechanical results show that with the increase of the post-baking temperature, the elongation at break, tensile strength, tear strength and hardness of the silicone tube all increase. When the post-baking temperature reaches 180°C, its mechanical indicators are similar to those at 210°C, indicating that the post-baking temperature of 180°C can meet the mechanical performance requirements. In addition, there is a conveyor belt in the post-baking channel, and it is not advisable to set too high a temperature, so the post-baking temperature is preferably 180°C.

The post-baking tunnel is mainly to provide conditions for the subsequent addition reaction of silicone rubber, so that the vulcanization reaction can proceed further. Therefore, if the post-baking tunnel temperature is too high, it is easy to over-vulcanize. The appropriate temperature can make the cross-linking reaction complete and the mechanical indicators better.

3.1.3 Investigation of oven vulcanization time

The oven vulcanization temperature was set at 180° C. The mechanical indicators were measured after oven vulcanization for 0 h, 24 h, 48 h, and 72 h.

Mechanical properties Example 3-1 Example 3-2 Example 3-3 Embodiment 3-4 Elongation at break/Eb(%) 900.49 608.81 565.13 603.54 Tensile strength/Ts(Mpa) 8.49 8.58 9.79 8.76 Tear strength/T(KN/m) 44.28 46.57 54.77 43.48 Hardness/H Shore A 58 61 62 62

The results show that after oven vulcanization, the elongation at break of the silicone tube decreased, but all met the requirements, the tensile strength and tear strength increased first and then decreased, and the hardness gradually increased. The tensile strength and tear strength of the silicone tube vulcanized in the oven for 48 hours are the best, and the elongation at break and hardness meet the standards. Finally, the oven vulcanization condition is preferably oven vulcanized at 180℃ for 48 hours.

The mechanical properties of the silicone tube that has been treated with oven vulcanization are better than those of the unvulcanized silicone tube, which proves that the cross-linking reaction of the silicone tube is not complete when it is just extruded from the post-drying tunnel. Although the silicone tube has been basically solidified after coming out of the post-drying tunnel of the extruder, its internal cross-linking reaction has not been completely reacted. In order to ensure that the vulcanization reaction of the silicone tube is complete, the silicone tube needs to be treated with oven vulcanization. Oven vulcanization is the final step to ensure that the silicone tube is completely vulcanized. However, as the oven vulcanization time continues to increase, the silicone tube will be over-vulcanized, which will reduce the toughness of the silicone tube and increase its brittleness. Therefore, the oven vulcanization time should be appropriate, not too short or too long.

3.1.4 Investigation of catalyst dosage

Silicone tubes were prepared by changing the catalyst dosage to 0.000005, 0.00001, 0.00002, and 0.00003 PHR. The mechanical index results are as follows.

Mechanical properties Example 4-1 Example 4-2 Example 4-3 Example 4-4 Elongation at break/Eb(%) 766.80 1045.50 1035.34 1018.65 Tensile strength/Ts(Mpa) 6.74 8.50 8.58 8.09 Tear strength/T(KN/m) 37.31 45.65 45.87 43.01 Hardness/H Shore A 43 46 45 46

It can be seen from the results that when the amount of added catalyst increases from 0.000005 PHR to 0.00001 PHR, the mechanical indexes are improved, but as the amount of catalyst continues to increase, there is no obvious difference in the mechanical indexes. Therefore, the amount of catalyst is preferably 0.00001 PHR.

When the amount of catalyst added is too low, the catalyst is unevenly dispersed in the rubber. Some rubbers lack catalysts and no cross-linking reaction occurs, and the mechanical properties of the silicone tube prepared therefrom are poor. When the amount of catalyst added is excessive, there is no obvious change in its mechanical indexes, and excessive catalyst cannot improve the mechanical properties of the silicone tube. In addition, the catalyst platinum is a precious metal, and waste should be avoided when using it.

3.1.5 Investigation of inhibitor dosage

The prescription composition and dosage were fixed, the process was fixed, and the inhibitor dosage was changed to 0.3PHR, 0.5PHR, 0.7PHR, and 0.9PHR to prepare silicone tubes. The mechanical index results are as follows.

Mechanical properties Example 5-1 Example 5-2 Example 5-3 Example 5-4 Elongation at break/Eb(%) 588.11 868.23 1045.50 918.83 Tensile strength/Ts(Mpa) 6.68 7.22 8.50 8.07 Tear strength/T(KN/m) 37.22 40.82 45.65 43.44 Hardness/H Shore A 51 48 46 46

From the results, it can be seen that with the increase of the inhibitor dosage, the elongation at break, tensile strength and tear strength first increase and then decrease. When the inhibitor dosage is 0.7 PHR, the elongation at break, tensile strength and tear strength are the best. Therefore, the preferred dosage of the inhibitor is 0.7 PHR.

When the inhibitor dosage is too small, part of the vulcanization reaction will occur at room temperature. When the silicone tube is vulcanized again, it may be over-vulcanized, resulting in too low mechanical indicators. Therefore, as the amount of inhibitor added increases, the elongation at break, tensile strength, and tear strength of the silicone tube increase. When the amount of inhibitor increases to 0.9PHR, its mechanical indicators are equivalent to those of the silicone tube with an addition of 0.7PHR, indicating that the inhibitor has the best inhibitory effect at an addition of 0.7PHR, and when it increases to 0.9PHR, the inhibitor is excessive.

3.1.6 Investigation of Vinyl Content of Raw Rubber

The formula composition and dosage were fixed, the process was fixed, and the vinyl content of the raw rubber was changed to 0.05%, 0.07%, 0.17%, and 0.23% to prepare silicone tubes. The mechanical index results are as follows.

Mechanical properties Example 6-1 Example 6-2 Example 6-3 Example 6-4 Elongation at break/Eb(%) 640.38 757.47 1045.50 559.67 Tensile strength/Ts(Mpa) 1.10 2.20 8.50 7.41 Tear strength/T(KN/m) 6.27 10.36 45.65 38.64 Hardness/H Shore A 40 41 46 59

The results show that with the increase of the vinyl content of the raw rubber, the elongation at break, tensile strength and tear strength of the extruded silicone tube first increase and then decrease, and an extreme value appears when the vinyl content of the raw rubber is 0.17%, and the hardness increases with the increase of the vinyl content. The vinyl content of the raw rubber is preferably 0.17%.

The vinyl content of 0.05% and 0.07% is too low, and the crosslinking density is too low. As the vinyl content increases, the crosslinking density continues to increase, and the mechanical indicators are also better. When the vinyl content increases to 0.23%, the crosslinking density is too high, which will cause the silicone tube to become harder but tougher, and the elongation at break will become lower, thereby reducing the tensile strength and tear strength. The silicone tube prepared with too high a vinyl content has a high hardness, and is brittle and easy to tear. Although the hardness of the silicone tube with a vinyl content of 0.23% meets the requirements, its elongation at break, tensile strength, and tear strength are not as good as those of the silicone tube with a vinyl content of 0.17%.

3.1.7 Investigation of the amount of fumed silica

The prescription composition and dosage were fixed, the process was fixed, and the amount of fumed silica added was changed to 20 PHR, 30 PHR, 40 PHR, 45 PHR, and 50 PHR to prepare silicone tubes. When the amount of silica added was 20 PHR (Example 7-1), the silicone tube was too soft, so this dosage was discarded. The results of the other mechanical indicators are as follows.

Mechanical properties Example 7-2 Example 7-3 Example 7-4 Example 7-5 Example 7-6 Fumed silica addition amount 30PHR 40PHR 45PHR 50PHR 60PHR Elongation at break/Eb(%) 1045.50 900.49 874.92 677.36 582.27 Tensile strength/Ts(Mpa) 8.50 8.49 8.49 9.44 8.76 Tear strength/T(KN/m) 45.65 45.02 42.40 43.08 41.26 Hardness/H Shore A 46 58 69 80 80

The results show that with the increase of the amount of fumed silica added, the hardness of the extruded silicone tube increases significantly, the tensile strength and tear strength do not change significantly, and the elongation at break tends to decrease, but they are all within the qualified range. According to the requirements, the hardness of the silicone tube should be between 50-70, and the addition amount of fumed silica is preferably 40PHR.

When the amount of fumed silica added is insufficient, the hardness of the silicone tube is too low, the moldability is poor during extrusion, and the surface is prone to roughness. The greater the amount of fumed silica added, the higher the hardness reinforcement of the silicone tube, and the stronger the silicone tube's ability to resist external extrusion. The purpose of adding fumed silica is to reinforce the hardness of the silicone material, so when other mechanical indicators are relatively good, the hardness data is mainly considered. When the amount of fumed silica is 40PHR, the hardness reaches the standard, and the elongation at break, tensile strength, and tear strength are good. When too much fumed silica is added, the hardness of the silicone material is too high, and the extruder is prone to lack of power during extrusion, resulting in unstable discharge speed. In addition, the hardness is too high, which easily moves the extrusion mold, resulting in uneven wall thickness of the extruded silicone tube.

3.1.8 Investigation of hydrogenated silicone oil

3.1.8.1 Investigation of hydrogen content in hydrogenated silicone oil

The formulation composition and dosage were fixed, the process was fixed, the molar ratio of the silicon hydrogen group of the hydrogen-containing silicone oil to the vinyl group of the base polymer was fixed at 1.2, the hydrogen content of the hydrogen-containing silicone oil was changed to 0.18%, 0.36%, 0.5%, 0.75%, 1%, and 1.6%, and silicone tubes were prepared. The mechanical index results are as follows.

Mechanical properties Example 8-1 Example 8-2 Example 8-3 Example 8-4 Example 8-5 Example 8-6 Hydrogen content of hydrogen silicone oil 0.18mol% 0.36mol% 0.5mol% 0.75mol% 1.0 mol% 1.6 mol% Elongation at break/Eb(%) 293.09 343.43 549.78 899.72 900.49 922.72 Tensile strength/Ts(Mpa) 5.38 6.67 7.50 8.49 8.31 6.65 Tear strength/T(KN/m) 10.97 13.61 15.31 48.64 34.34 36.34 Hardness/H Shore A 54 57 57 58 59 61

The results show that hydrogen-containing silicone oil has a great impact on the mechanical indicators of silicone tubes. As the hydrogen content of hydrogen-containing silicone oil increases, the hardness of the prepared silicone tube increases continuously, and the elongation at break, tensile strength, and tear strength increase first and then decrease. When the hydrogen content of hydrogen-containing silicone oil is 0.75%, a peak value appears, and the hydrogen content of hydrogen-containing silicone oil is preferably 0.75%.

When the molar ratio of Si-H groups in hydrogen-containing silicone oil to vinyl groups in methyl vinyl silicone rubber is fixed, the lower the hydrogen content, the greater the mass of hydrogen-containing silicone oil added. Since hydrogen-containing silicone oil is a transparent oily substance, the more it is added, the stickier the material is, and the strength of the prepared silicone tube is relatively lower. As the hydrogen content in hydrogen-containing silicone oil increases, the amount of hydrogen-containing silicone oil added becomes lower, the silicon hydrogen groups become denser, the local cross-linking reaction occurs rapidly, the cross-linking density continues to increase, and when the silicone rubber is stretched, the cross-linking chain links are too small to be effectively arranged in order, and only a small part of the cross-linking chain links can bear the external force together, thereby reducing the elasticity of the silicone tube, and its tensile strength and tear strength are reduced.

3.1.8.2 Investigation of the dosage of hydrogenated silicone oil

The formula composition and dosage were fixed, the process was fixed, the hydrogen content of the hydrogen-containing silicone oil was fixed at 0.75%, the molar ratio of the silicon hydrogen group to the vinyl group of the base polymer was changed to 1:1, 1.2:1, 1.5:1, and 1.8:1, and silicone tubes were prepared. The mechanical index results are as follows.

It can be seen from the results that when the hydrogen content of hydrogen-containing silicone oil is fixed, as the amount of hydrogen-containing silicone oil increases, its hardness, elongation at break, tensile strength and tear strength show a trend of first increasing and then decreasing, and a peak value appears when the molar ratio is 1.2: 1. The molar ratio of Si-H groups in hydrogen-containing silicone oil to vinyl groups in methyl vinyl silicone rubber is preferably 1.2: 1.

Increasing the amount of hydrogen-containing silicone oil, the addition reaction is more complete, the cross-linking points increase, and the tensile strength increases. However, when the amount of hydrogen-containing silicone oil is too large, the cross-linking density is too high, the toughness decreases, and the prepared silicone tube is hard and brittle. When the molar ratio of the feed increases to 1.8:1, the hydrogen-containing silicone oil is excessive, and the excess hydrogen-containing silicone oil will prevent part of the cross-linking reaction from proceeding, and the cross-linking degree will decrease instead. The mechanical indicators are observed to be reduced.

3.2 Preparation of the best silicone tube

The prescription is shown in the table below.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

The composition of the drug core is as follows: the drug core is 42 mg of micronized gestodene raw material powder with a particle size of 2.81 μm.

The mechanical indicators of silicone tube are shown in the following table.

serial number Eb(%) Ts(Mpa) T(KN·m ^-1 ) H(Shore A) GJ001 595.78 9.81 54.88 61 GJ002 519.94 9.46 53.05 62 GJ003 579.80 10.08 56.38 62

Note: Eb- elongation at break; Ts- tensile strength; T- tear strength; H- hardness.

Three batches of silicone tubes were prepared in parallel according to the optimal prescription and process. Their elongation at break and hardness met the standards. Their tensile strength and tear strength were greatly improved compared with the standards. In addition, the mechanical properties of the three batches of silicone tubes were similar, indicating that the prescription and process had good reproducibility.

3. Preparation and in vitro release study of gestodene implant

Silicone tubes are used as carriers in implants because of their ability to stably control drug release over a long period of time. After examining the process of silicone tubes based on mechanical indicators, it is also necessary to examine the control of drug release by silicone tubes.

1. Instruments and reagents

1.1 Instrument

TS-100B Constant Temperature Shaker Haijiecheng Experimental Instrument Co., Ltd.

High Performance Liquid Chromatography Shimadzu Corporation

KQ-250DE CNC Ultrasonic Cleaner Kunshan Ultrasonic Instrument Co., Ltd.

AG245 Ultra-micro electronic balance Electronic analytical balance Swiss Mettler Toledo

1.2 Drug testing

Gestodene (purity 98%, batch number: 20190327) Hebei Mokai Technology Development Co., Ltd.

KN-300N Silicone Glue Kanglibang Polymer New Materials Co., Ltd.

2 Experimental methods

2.1 Preparation of Gestodene Implant

According to the prescription and process of each of the following examples, a silicone tube was prepared, and the silicone tube was used as a drug release carrier to control drug release. A homemade silicone tube was taken, and it was soaked in 75% ethanol for 30 minutes for disinfection and then blown dry. One end of the silicone tube was sealed with silicone sealing glue and set aside. The drug (42 mg of micronized gestodene raw material powder with a particle size of 2.81 μm) was filled into the drug filling funnel, and the other end was sealed with silicone, and cured for 24 hours to prepare a gestodene implant (here, the silicone tube wall thickness of the gestodene implant was 0.3 mm, and the drug release area was 94.2 mm ² ).

2.2 Selection of release medium

The prepared implant needs to be implanted in the subcutaneous tissue of the upper arm of the human body, where the pH is close to neutral, so the release medium can be selected between water and saline. Prepare the water and saline supersaturation of the Gestodene API before and after crushing, place it in a shaker for 72 hours, take it out, centrifuge it, take the supernatant and filter it, use high performance liquid chromatography to determine the equilibrium solubility of the Gestodene API before and after crushing in water and saline, and select the appropriate release medium based on the results.

2.3 Investigation of in vitro release and influencing factors

2.3.1 Investigation of silicone tubes treated with oven vulcanization

In the experiment of preparing silicone tubes, the mechanical index of silicone tubes treated by oven vulcanization for 48 hours was better, and it can be judged that the silicone tubes treated by oven vulcanization were completely vulcanized. In order to further determine whether the silicone tubes treated by oven vulcanization have an effect on the in vitro release results of the drug, silicone tubes that have not been vulcanized and silicone tubes treated by oven vulcanization (corresponding to the silicone tubes in the above-mentioned Examples 3-1 and 3-3) were filled with implants of the same specifications, the same drug-containing length, and the same drug loading to conduct in vitro release experiments, and examine the effect of oven vulcanization on the in vitro data of the drug.

2.3.2 Investigation of silicone tubes prepared with different vinyl contents

In addition to the amount of hydrogenated silicone oil added, the vinyl content of the raw rubber also has a great influence on the crosslinking degree of the silicone tube. In order to investigate the influence of the vinyl content on the in vitro release of the drug, silicone tubes were prepared with raw rubber with 0.17% and 0.23% vinyl content, and the effects of silicone tubes prepared with different vinyl contents on the in vitro release of gestodene were investigated.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

2.3.3 Investigation of silicone tubes prepared with different molar ratios of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber

The implant is placed in the release medium, and the release medium enters the silicone tube through the pores of the silicone tube to dissolve the drug and release the drug using the concentration difference. Silicone tubes were prepared with raw rubber with 0.17% vinyl content and hydrogen-containing silicone oil with 0.75% hydrogen content at a molar ratio of 1:1.2 and 1:1.5, respectively. Other factors were the same, and the effect of the addition amount of hydrogen-containing silicone oil on the daily drug release of the implant was investigated.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

3 Results and discussion

3.1 Preparation of Gestodene Contraceptive Implant

When preparing implants, special attention should be paid to the static electricity of the API to prevent the API powder from adhering to the outer wall of the silicone tube. In addition, when sealing the implants, care should be taken to prevent the irregular shape of the sealing glue from affecting the drug release area of the drug-containing segment. Finally, implants of different specifications were prepared with good appearance, uniform sealing locations, and uniform drug filling of the drug-containing segment. The GEST (gestodene) contraceptive implant is shown in Figure 3.

3.2 Selection of in vitro release medium

The equilibrium solubility results of GEST in different solvents are shown in the table below.

The results showed that the solubility of gestodene raw materials of two particle sizes in water was greater than that in physiological saline, and the solubility of the raw materials without crushing treatment was greater than that of the raw materials after crushing treatment. Finally, water was selected as the release medium for the in vitro release experiment.

Theoretically, the smaller the particle size of the API, the larger the contact area with the solvent, and the greater the solubility should be. However, experimental data show that the solubility of the API after pulverization becomes smaller. In the experiment, it can be observed that the API has a large static electricity after pulverization and is prone to agglomeration, which may cause the contact area with the medium to be smaller than that of the API with a larger particle size, so the solubility becomes smaller.

3.3 Investigation of factors affecting in vitro release

3.3.1 Investigation of silicone tubes treated with oven vulcanization

The effect of oven vulcanization process on in vitro release is shown in the table below.

Example No. Oven vulcanization process Average release rate (μg/d) RSD(%) Example 3-3 Oven curing 48h 10.57±0.76 7.19 Example 3-1 No oven curing 12.46±0.92 7.38

The effect of oven curing process on in vitro daily dose release is shown in the table below

The results showed that the average daily drug release of implants filled with oven-cured silicone tubes was lower than that of implants filled with uncured silicone tubes, but the difference was small. The release of implants prepared with oven-cured silicone tubes was more stable in vitro than that of uncured silicone tubes. In addition, considering that the mechanical indexes of oven-cured silicone tubes were better, considering the release data and mechanical indexes, it was better to use silicone tubes that were oven-cured at 180℃ for 48h for drug filling.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

3.3.2 Investigation of preparation of silicone tubes with different vinyl contents

The effect of vinyl content on in vitro release is shown in the table below.

Silicone Tube Prescription Vinyl content (%) Average release rate (μg/d) RSD(%) Example 10-1 0.17 10.57±0.76 6.89 Example 10-2 0.23 15.33±1.38 10.23

The effect of vinyl content on in vitro daily dose release is shown in the table below.

The results showed that silicone tubes prepared with raw rubber of different vinyl contents (0.17% and 0.23%) had a great influence on the average in vitro drug release of the implant. The initial burst release of raw rubber with 0.23% vinyl content was greater than that of 0.17%. The in vitro release of silicone tubes prepared with raw rubber with 0.17% vinyl content was more stable. At the same time, based on the comprehensive mechanical indicators, the silicone tube with 0.17% vinyl content had better performance.

3.3.3 Investigation of silicone tubes containing different amounts of hydrogenated silicone oil

The effect of the amount of hydrogenated silicone oil on in vitro release is shown in the table below.

Silicone Tube Prescription Molar Ratio Average release rate (μg/d) RSD(%) Example 11-2 1.5:1 10.57±0.76 7.16 Example 11-1 1.2:1 8.27±0.53 6.37

Note: The molar ratio refers to the molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber.

The effect of the amount of hydrogen silicone oil on the in vitro daily dose release is shown in the table below.

The results show that the daily drug release of the contraceptive implant filled with silicone tubes prepared with a formula of 0.17% vinyl content and 0.75% hydrogen-containing silicone oil, and a molar ratio of 1:1.2 between vinyl groups in methyl vinyl silicone rubber and Si-H groups in hydrogen-containing silicone oil, is slightly lower than that of the contraceptive implant filled with silicone tubes prepared with a molar ratio of 1:1.5 between vinyl groups in methyl vinyl silicone rubber and Si-H groups in hydrogen-containing silicone oil, but the drug release curve is relatively more stable. The implant must first be able to achieve stable release, so it can be seen that the molar ratio of 1:1.2 between vinyl groups in methyl vinyl silicone rubber and Si-H groups in hydrogen-containing silicone oil is better for controlling drug release.

3.4 Long-term in vitro release of gestodene implant

Three batches of gestodene contraceptive implants (the silicone tube wall thickness of the gestodene implants is 0.3 mm, the drug release area is 94.2 mm ² , the gestodene raw material drug is crushed to a particle size of 2-4 μm (e.g. 2.81 μm), and 42 mg of the crushed gestodene raw material drug is filled into a drug filling funnel) are taken, namely ZJ001, ZJ002, and ZJ003, and a long-term in vitro release experiment is carried out at a temperature of 37°C and a shaking speed of 100 r·min ^-1 to investigate the long-term release stability of the preparations and whether they can achieve a long-term controlled release effect. The results are as follows.

The long-term release data of ZJ001, ZJ002 and ZJ003 implants are shown in the following table.

Based on the 80-day in vitro drug release data in the table, a relationship graph between the daily in vitro drug release amount and the release time of three batches of gestodene subcutaneous contraceptive implants of the same specifications was drawn, as shown in FIG4 .

It can be seen from Figure 4 that the three batches of preparations with the same specifications have a small difference in the fluctuation range of drug release, and tend to be consistent as a whole. The observed curves are all large fluctuations in the early stage, and gradually stabilize in the later stage, and the final daily in vitro drug release of the preparations is mostly stable within the range of 17-20μg. By consulting the literature, it is known that the daily release of 10-20μg of gestodene can produce a contraceptive effect on the human body. These three batches of preparations are almost stable at a release of 17-20μg from 11-80d, which is in line with experimental expectations.

The above data were sorted out and simplified with a 5-day cycle to observe the long-term drug release of the three batches of preparations. The relationship between the drug release amount and release time of the implant at each time period.

According to the data in the above table and the curve changes in Figure 5, it can be found that:

(1) The drug release of the implant is unstable and fluctuates greatly in the first ten days. During this stage, there may be some residual drugs on the surface of the silicone tube that are gradually dissolved, resulting in unstable drug release in the early stage and a large amount of drug release.

(2) The subsequent release stability of the implant is better. Overall, the initial release of the implant shows a downward trend, and then there is a small fluctuation and then a relatively stable state. The release amount has been maintained at 17μg-20μg, and the release amount meets the requirements. This result shows that the gestodene contraceptive implant can achieve controlled release for at least 3 months.

(3) The average drug release of the three batches of implants was 19.70, 19.15, and 18.84 μg, respectively. The RSD value was 2.26%. This result showed that the three batches of preparations had good reproducibility and the long-term in vitro release data were basically consistent.

IV. In vivo study of gestodene contraceptive implant in rats

The prepared silicone tube must meet the mechanical index requirements and be able to stably control the drug release. It must also have good in vivo biocompatibility and must not irritate the tissues in the body. This section mainly examines the irritation of silicone tubes to rat skin by injecting silicone tube extract into rats; the tissue irritation of silicone tubes is examined by implanting silicone tubes in rats for a long time and taking tissue sections of the surrounding tissues. By implanting contraceptive implants of different specifications in rats and observing the changing trend of the rats' body weight before and after implantation, whether the contraceptive implant affects the normal growth of rats is investigated; the contraceptive effect is investigated by observing the changes in the estrous cycle of rats through vaginal smears after implantation, observing whether the rats have vaginal plugs, and detecting the level of luteinizing hormone LH in rats after implantation of contraceptive implants.

1. Instruments and reagents

1.1 Instrument

XS105 Electronic Analytical Balance Mettler-Toledo Instruments Co., Ltd.

SMD200-2 Electronic Analytical Balance Ohaus International Trading Co., Ltd.

TG16MW desktop high-speed centrifuge Hunan Hexi Instrument Equipment Co., Ltd.

KQ-250DE CNC Ultrasonic Cleaner Kunshan Ultrasonic Instrument Co., Ltd.

Rat LH Kit Shanghai Tongwei Biotechnology Co., Ltd.

Electron Microscope Shenzhen Zhongwei Kechuang Technology Co., Ltd.

High Pressure Sterilizer Shanghai Shen'an Medical Equipment Factory

1.2 Drug testing

Gestodene (purity 98%, batch number: 20190327) Hebei Mokai Technology Development Co., Ltd.

Crystal violet Tianjin Damao Chemical Reagent Factory

Physiological saline Shandong Yuwang Chemical Reagent Co., Ltd.

4% paraformaldehyde solution Shanghai Yantuo Biotechnology Co., Ltd.

1.3 Experimental animals

Twelve healthy male SD rats, weighing 180-200 g, and 57 healthy female SD rats, weighing 180-200 g, were purchased from Benxi Changsheng Biotechnology, license: SCXK (Liao) 2020-0001.

2 Experimental methods

2.1 Silicone tube local irritation test in rats

Cut the prepared silicone tube (the silicone tube in preparations ZJ001, ZJ002, and ZJ003) into pieces, soak it in 10 mL of sterile, pyrogen-free purified water, heat and extract it at 70°C for 24 hours, and then sterilize the extract by high pressure for use. Select 6 experimental rats and randomly divide them into two groups, one for the experimental group and the other for the normal saline control group. The backs of the rats were depilated and skinned. The experimental group was intradermally injected with 0.2 mL of the extract on one side of the rat's spine, and the control group was intradermally injected with 0.2 mL of normal saline on one side of the rat's spine. Observe the skin reaction at the injection point after 24 hours, 48 hours, and 72 hours.

2.2 Histopathological study of rats after silicone tube implantation

Seal the prepared silicone tube, and after the sealing glue is completely solidified, sterilize it for later use. Experimental rats were selected and randomly divided into 3 groups, 3 rats in each group. Each rat was implanted with a sterilized homemade silicone tube on the back. The rats were killed 3 days, 10 days, and 30 days after implantation. The 2 cm tissue around the implanted silicone tube was removed, and the skin tissue was fixed with 4% paraformaldehyde and kept for tissue section observation. Observe whether the surrounding tissue has inflammatory reactions such as redness and swelling, and perform a tissue section experiment to observe whether there are abnormal subcutaneous and muscle lesions at the implantation site of the silicone tube.

2.3 In vivo efficacy study of gestodene contraceptive implant in rats

Silicone tubes with an outer diameter of 2.38 mm and a wall thickness of 0.3 mm were prepared using the optimal prescription and process (corresponding to the silicone tubes and drug cores of the aforementioned preparations ZJ001, ZJ002, and ZJ003), and 5 specifications of gestodene implants (drug length/drug loading) were prepared for use, with the specifications being: ① 0.2 cm/2.3 mg, ② 0.5 cm/5.4 mg, ③ 1 cm/10.5 mg, ④ 2 cm/20.7 mg ⑤ 4 cm/41.1 mg.

42 female rats were selected and vaginal smears were performed to check whether they had normal estrus cycles. The 42 female SD rats weighing about 180-200g were randomly divided into experimental dose groups I, II, III, IV, and V (corresponding to the following specifications of implants: ① 0.2cm/2.3mg, ② 0.5cm/5.4mg, ③ 1cm/10.5mg, ④ 2cm/20.7mg ⑤ 4cm/41.1mg, respectively), 1 blank group (group K), and 1 levonorgestrel silicone rod positive control group (group Y) (levonorgestrel silicone rod I, purchased from Liaoning Ludan Pharmaceutical Co., Ltd.).

Rats were injected with an appropriate amount of anesthetic intraperitoneally. After the rats entered the anesthesia state, the hair on the back of the neck was removed, and then disinfected with 2% iodine tincture. A small incision of about 0.5 cm was cut with surgical scissors on the local skin on the side of the back of the rats. The implant needle was inserted subcutaneously to the specified scale of the implant needle. The disinfected implant was placed inside the implant needle. Then the implant needle with the implant was pushed into the skin until the implant could be completely placed. The implant needle was withdrawn, the implant was left under the skin, the incision was sutured, and the wound was disinfected with 2% iodine tincture. 24 hours after the implantation of the rats, they were housed with male rats in a 3:1 ratio of female to male.

2.3.1 Observation of rat status

The rats were weighed and recorded before the implantation surgery. The rats were weighed again 30 days after the implantation of the gestodene contraceptive implant to observe whether the rats grew normally after the implant was implanted. The rats' mental state, activity, and urination and defecation were observed daily.

2.3.2 Vaginal smear experiment to observe the estrus cycle of rats

The average estrous cycle of rats is 4-5 days. The estrous cycle of rats is generally divided into 4 phases, namely proestrus, estrus, metaestrus and diestrus. Proestrus and estrus allow mating and ovulation to lead to fertilization. Metaestrus is a period of degeneration and destruction of the reproductive tract, and diestrus is a period of relative stillness and slow growth. The vaginal smear method is usually used to determine the course of the estrous cycle of rats. When the contraceptive implant exerts its contraceptive effect, the rat should not have an estrus.

Vaginal smear method: Take out the rat, grab and fix the animal in the palm of your hand, moisten a fine cotton swab in saline and gently insert it into the female rat's vagina about 0.5 cm, slowly turn it and take it out, evenly smear the vaginal contents on the cotton swab on the slide, number the slide, dry it naturally, and then stain it with crystal violet. After air drying, observe the vaginal smear under an electron microscope to determine the rat's estrus cycle. For rats that have undergone implantation surgery, perform a vaginal smear experiment 3 days after implantation, and collect vaginal secretions before 9:00 am every day. Observe the changes in the estrus cycle of experimental rats through vaginal smears.

2.3.3 Observation of vaginal plug to determine the mating pregnancy of rats

When the implant plays a contraceptive role, female rats should not be in estrus, that is, they will not mate with male rats, so the contraceptive effect can be judged by observing whether the rats have vaginal plugs after being caged together. After mating, the semen will remain in the vaginal opening, forming vaginal plugs. Generally, vaginal plugs are milky white, and some are slightly yellow. Rats usually mate at night, so when taking vaginal secretions and observing vaginal plugs, it must be completed before 9:00 am to more accurately observe the mating of rats. After the implant surgery, observe whether the rats have vaginal plugs before performing the vaginal smear experiment 3 days after implantation.

2.3.4 Enzyme-linked immunosorbent assay to measure luteinizing hormone (LH) levels in rats

Gestodene mainly acts on the hypothalamus and pituitary gland, significantly reducing the levels of FSH (follicle-stimulating hormone) and LH (luteinizing hormone) in the body, causing the ovaries to not ovulate. It has significant anti-estrogen activity, which can thicken cervical mucus and hinder sperm penetration. It shows extremely strong progesterone activity in endometrial transformation, which can make the endometrium thinner, the endometrial epithelial cells low-columnar, and have poor secretory function, which is not conducive to the implantation of pregnant eggs. The LH level of rats after implantation of contraceptive implants should be significantly lower than that of the blank control group, which proves that the contraceptive implants have achieved contraceptive effects.

After the implantation surgery, female mice were caged and blood was collected from their eye sockets every day after the vaginal secretions were collected. The blood was collected in an EP tube moistened with anticoagulant, centrifuged for about 10 minutes (5000r·min ^-1 ), and the supernatant was carefully collected and stored in a -80℃ refrigerator. Enzyme-linked immunosorbent assay was used to detect the LH level in rats to determine the efficacy of the drug.

3 Experimental results and discussion

3.1 Silicone tube tissue irritation experiment in rats

The experimental group received an intradermal injection of 0.2 mL of the extract on one side of the rat's back, and the control group received an intradermal injection of 0.2 mL of normal saline on one side of the rat's back. The skin reaction at the injection point was observed after 24 hours, 48 hours, and 72 hours. The injection points were dissected, and no redness, swelling, necrosis, or other reactions were observed, indicating a negative result.

3.2 Histopathological study of rats after silicone tube implantation

Muscle tissues at the implantation site were obtained on days 3, 10, and 30 after implantation, and their pathological images (HE, ×2 or HE, ×20) were observed, as specifically shown in FIG6 .

The results showed that after 3 days of implantation of the silicone tube (see Figures A and B in Figure 6), an acute inflammatory reaction was observed, with mild thickening of the epidermis, rich collagen fibers in the dermis, and large cystic structures formed in the local subcutaneous tissue, with connective tissue hyperplasia and more lymphocyte infiltration around it. After 10 days of implantation (see Figures C and D in Figure 6), the acute inflammatory reaction gradually disappeared, the epidermis was mildly thickened, the dermis was rich in collagen fibers, and large cystic structures were formed in the local subcutaneous tissue, with connective tissue hyperplasia and diffuse lymphocyte infiltration around it. After 30 days of implantation (see Figures E and F in Figure 6), the epidermis was intact, the squamous epithelial cells were normal in morphology and structure, and were closely arranged. The dermis was rich in collagen fibers, and large cystic structures were formed in the local subcutaneous tissue, with mild connective tissue hyperplasia and diffuse lymphocyte and macrophage infiltration around it.

Large cystic cavities appeared in all the sites after implantation surgery, indicating that the implant will cause certain damage to the subcutaneous tissue to form cystic cavities when implanted. Mild connective tissue hyperplasia will appear around the cystic cavities, that is, at the junction of the silicone tube and the tissue, and gradually form a capsule. When the silicone tube was dissected 3 days after implantation, it was observed that the silicone tube was easy to fall out. When the silicone tube was dissected 10 days after implantation, a capsule was formed around the silicone tube, and the silicone tube was not easy to move. This shows that as the implantation time increases, a capsule is formed around the silicone tube, and the silicone tube is not easy to shift in the body. In addition, the inflammatory reaction is the largest at 3 days after implantation. As the implantation time increases, the inflammation gradually decreases, indicating that the inflammatory reaction caused by the implantation of the silicone tube can gradually recover.

3.3 In vivo efficacy study of gestodene contraceptive implant in rats

3.3.1 Body weight changes of rats before and after implantation

After the implantation surgery, the rats were observed for their eating status and activity. Their bowel movements and urination were normal, and they did not show signs of mental depression.

The body weights of the rats before and after implantation are shown in the following table.

From observing the weight change data of rats for one month, it can be seen that the implantation surgery and silicone tube had no effect on the growth of rats. The weight change trend of rats in the experimental group was close to that in the blank group. Overall, the gestodene implant had no effect on the growth of rats.

3.3.2 Vaginal smear observation of rat estrus cycle

For the blank control group rats, vaginal secretions of female rats were collected at fixed points every 24 hours, and crystal violet staining smears were performed to observe the estrus cycle, and the experiment was compared with the experimental group rats. After taking samples for one month, it was found that the rats were basically in estrus once every 7 days. The vaginal smears of the rat estrus cycle are shown in Figure 7. The vaginal smears of the rats implanted with the commercially available levonorgestrel implant were observed, and no estrus rats were found, and both had a contraceptive effect.

The experimental group was divided into 5 dose groups. According to vaginal smear observations for one month, rats in the four dose groups II, III, IV, and V began to have a lot of mucus in their vaginal secretions 4 days after implantation, and a large number of white blood cells were observed in the vaginal smears, but no keratinized cells, indicating that the rats no longer had a normal estrous cycle. However, rats numbered 1 and 4 in group I were still observed to have complete estrous cycle changes, indicating that these two rats failed to achieve contraception, and this dose may have a relatively poor contraceptive effect on rats, with a low contraceptive rate.

3.3.3 Observation of vaginal plug to determine the mating pregnancy of rats

When observing the vaginal plug, the rat No. 1 in the experimental dose group I had a normal estrus cycle in the vaginal smear. When the vaginal secretions were taken 13 days after implantation, a milky white vaginal plug was observed at the vaginal opening as shown in Figure 8 A. The rat No. 4 was found to have a vaginal plug 20 days after implantation as shown in Figure 8 B. This result shows that the two female rats No. 1 and 4 in the experimental dose group I mated with male rats, indicating that both rats had estrus and contraception failed. No vaginal plugs were found in the rats in the other experimental dose groups and the commercially available positive group, proving that they did not mate with male rats and that the contraceptive effect was achieved.

3.3.4 Enzyme-linked immunosorbent assay for determination of LH concentration in rat plasma

The LH level in rats was detected by enzyme-linked immunosorbent assay. The gestodene contraceptive implant was implanted for 28 days. The results of LH level determination in 6 rats in each group are as follows.

Rat LH levels are shown in the table below.

Note: * means P < 0.01 compared with the blank group.

The results showed that the LH level data of the positive control group and each experimental dose group were significantly different from those of the blank group (P<0.01). Since the above table is the mean of 6 rats in each experimental group, and the results of vaginal smear and vaginal suppository showed that two rats in the experimental dose group I failed to achieve contraception, the LH level data of the 6 rats in the experimental dose group I were listed separately, and the results are as follows.

The LH levels of each rat in experimental dose I group are shown in the following table.

Group 1 2 3 4 5 6 I 77.04±10.96 55.10±1.80* 55.599±7.62* 72.54±12.79 63.53±7.04* 64.06±9.40*

Note: * means P < 0.01 compared with the blank group.

The results showed that there was no significant difference in LH levels between rats 1 and 4 in the experimental I dose group and the blank group, while there were significant differences between the other four rats and the blank group (P<0.01).

Observation of the LH level data in rats showed that the II, III, IV, V experimental dose groups and the positive control group significantly reduced the LH level in rats compared with the blank group. The greater the dose, the lower the LH level, indicating that the hormone inhibition effect was better. Observation of the LH level data in rats No. 1 and 4 in the experimental I dose group showed that their LH levels were higher than those of other rats and fluctuated greatly, indicating that the implants in these two rats were not stable in drug release and did not achieve the contraceptive effect. Since the length of the drug-containing section of the implant in the experimental I dose group was only 0.2 cm, it was difficult to operate during the preparation of the implant, resulting in unstable drug filling, so that the contraceptive failure of the two rats in this dose group, while the remaining four rats achieved the contraceptive effect.

4 Summary of this part

(1) The local irritation experiment of the silicone tube extract on rats verified that the silicone tube was non-irritating to the local skin of rats and was safe; the silicone tube implantation experiment verified that the prepared silicone tube was non-irritating to rat tissues, the silicone tube had good tissue compatibility, and did not cause inflammation or irritation to the surrounding tissues of the rats after implantation.

(2) Through the implantation experiment, the weight change of rats before and after implantation proved that the rats grew normally after implantation; the estrous cycle of rats was observed by vaginal secretion smear staining, the pregnancy and mating of rats was observed by vaginal plugs, and the LH level changes in rats after implantation were used to investigate the contraceptive effect of the gestodene implant. The results showed that the effective dose group had a good contraceptive effect, no rats in estrus were observed in the vaginal smear, no vaginal plugs were observed, and the LH level was significantly lower than that of the normal group.

(3) The rat efficacy experiment showed that the contraceptive effect of the gestodene implant with a drug section of 0.2 cm and a drug loading of 2.3 mg was poor, with a contraceptive rate of less than 70%. However, when the drug section was larger than 0.5 cm and the drug loading was larger than 5.4 mg, the implant had a good contraceptive effect.

II. Levonorgestrel long-acting implant

1. Content determination and in vitro release determination method of levonorgestrel contraceptive implant

(1) Chromatographic conditions

Chromatographic column: _C18 column (4.6 mm × 250 mm, 5 μm);

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

Column temperature: 30°C;

Detection wavelength: 240nm;

Flow rate: 1.0 mL min ^-1 ;

Injection volume: 20 μL.

(2) In vitro release determination method

The release experiment adopts the horizontal shaking method. Take a set of 6 implants and fix them to the wall of a 125mL stoppered conical bottle with an adhesive. There is an appropriate distance between each medicine stick (to prevent the implant from floating on the liquid surface during release, resulting in inaccurate release results). Accurately measure 100mL of distilled water and inject it into the conical bottle. The conical bottle is placed in a constant temperature air shaker at 37℃ and shaken with an amplitude of 100 times/min. The medium is replaced every 24 hours. The sample is filtered with a 0.22μm microporous membrane and tested according to the chromatographic conditions in this part (1). The injection volume is 20μL.

2. Preparation and evaluation of addition-type silicone rubber tube

Methyl vinyl silicone rubber and hydrogen-containing silicone oil undergo a silylation reaction under the catalysis of a platinum catalyst, and the addition-type silicone rubber products obtained by adding a suitable reinforcing agent have excellent physiological inertness, are non-toxic, odorless, have good biocompatibility, are resistant to biological aging, have good air permeability, have no adverse reactions when implanted in the body, and their physical properties change very little when implanted in the body for a long time. They can be used in various occasions where they come into contact with blood and are buried in the body.

This part mainly studies the addition of reinforcing agent (silicon dioxide) to linear polymer methyl vinyl silicone rubber with vinyl end groups, which undergoes addition reaction under the catalytic action of platinum catalyst to crosslink into a network of polymer elastomers, which are then extruded into tubes through an extruder and then vulcanized in an oven to obtain addition-type silicone tubes.

1. Instruments and Materials

1.1 Instrument

1.2 Reagents and Materials

2 Preparation and determination of addition type silicone rubber tube

2.1 Preparation of addition silicone rubber tube by high temperature vulcanization method

The reinforcing agent white carbon black is dried at 180-210°C (for example, 200°C) for 24 hours for use, and the methyl vinyl silicone rubber raw rubber is dried at 40°C for 24 hours for use; the prescribed amount of white carbon black and raw rubber are added to a kneader and kneaded at 30°C for 30 minutes, and then taken out; the triangular wrapping is passed through 5 times on an open mill with a roller distance of 1-10mm (for example, 1mm) to roll the sheet, and then parked for 24 hours to obtain a mixed rubber; the mixed rubber is evenly divided into two components A and B, the prescribed amount of hydrogenated silicone oil and inhibitor are added to the A component and mixed evenly, and the B component is added The prescribed amount of platinum catalyst is mixed; the A and B components are put into an open mill in a ratio of 1:1 and triangularly wrapped for 4 to 6 times, and then the material is evenly cut into sheets; the cut rubber material is put into a silicone rubber extruder and extruded into a tube, and high-temperature vulcanization is performed for finalization; (the front drying oven is 270°C, the vulcanization time is about 5s; the rear drying oven is 180°C, the vulcanization time is about 2min; the oven vulcanization temperature is 180°C, and the time is 48h). The outer diameter of the extruded silicone tube is measured in real time by an infrared diameter gauge, and the appearance is inspected by an electron microscope. After the product appearance is qualified, it is heated in an oven and vulcanized to obtain a finished product.

2.2 Determination of physical and mechanical properties of addition silicone rubber tube

Medical silicone rubber tubes are required to have good biological properties and physical and mechanical properties. Its biological properties and physical and mechanical properties are determined by materials and production processes. The physical and mechanical properties of silicone tubes mainly include tensile strength, elongation at break, tear strength and hardness. Among them, tensile strength (TS) is the maximum tensile stress to which the sample is subjected until it breaks, representing the resistance to the maximum uniform plastic deformation of the material; tear strength (Tear strength, T) refers to the strength required to tear the sample, representing the sample's ability to resist tearing; elongation at break (Eb) refers to the ratio of the elongated part of the sample when it is broken to the original length; represents the deformation range of the sample; hardness (Hardness, H) is a physical measurement of the degree of compression deformation of a material.

The tensile strength, elongation at break, tear strength and hardness were used as the test indicators to screen and optimize the silicone rubber prescription and extrusion vulcanization process to obtain a suitable silicone tube for evaluation. The tensile strength and elongation at break were measured according to GB/T 528-2005; the tear strength was measured according to GB/T 529-2005; and the Shore A hardness was measured according to GB/T 531-2008.

3 Methods and Results

3.1 Investigation of silicone tube prescription

3.1.1 Investigation of vinyl content of polydimethylsiloxane

In order to investigate the effect of raw rubber (polydimethylsiloxane) with different vinyl contents on the physical and mechanical properties of silicone tubes, silicone tube extrusion vulcanization experiments were carried out using the formula shown in the following table.

PHR: The mass fraction of a component per 100 mass fractions of a polymer compound.

The vinyl group at the end of methyl vinyl silicone rubber reacts with the active hydrogen atoms of hydrogen-containing silicone oil to crosslink into a polymer elastomer. Therefore, the vinyl group, as an active group, is the crosslinking point for forming a polymer network. The amount of vinyl content will affect the physical and mechanical properties of medical silicone rubber hoses.

As shown in the mechanical properties in the following table, the hardness of the silicone tube increases with the increase of the vinyl content, but the properties of the silicone tube such as the elongation at break, tensile strength, and tear strength show a peak-like change that first increases and then decreases. When the vinyl content is 0.05%, the crosslinking points formed by the addition reaction are relatively few, the tear strength and tensile strength of the silicone tube are relatively small, and the mechanical properties are too poor to be used subsequently; when the vinyl content is 0.23%, the crosslinking points formed by the reaction are too many, the elongation at break of the silicone tube decreases, and the tensile strength and tear strength also decrease slightly. This is because the crosslinking density is too large, the crosslinking points formed are too many, the crosslinking chain links become shorter, and the rigidity increases. At this time, the hardness of the silicone tube increases, the elongation at break decreases significantly, the internal crosslinking chain links cannot be arranged in an orderly and effective manner, the invalid crosslinking network increases, and the crosslinking chain links that can withstand external forces when resisting external forces are reduced, thereby reducing the tensile strength, tear strength and other mechanical properties of the silicone tube; when the vinyl content of the raw rubber is 0.17%, the internal crosslinking chain links are distributed in an orderly and reasonable manner, and the physical and mechanical properties of the silicone tube are excellent. Therefore, methyl vinyl silicone rubber with a vinyl content of 0.17% is the preferred methyl vinyl silicone rubber.

Mechanical properties Example 12-1 Example 12-2 Example 12-3 Elongation at break/Eb(%) 640.38 1045.50 559.67 Tensile strength/Ts(Mpa) 1.10 8.50 7.41 Tear strength/T(KN/m) 6.27 45.65 38.64 Hardness/H Shore A 40 46 59

3.1.2 Screening of white carbon black ratio

Compared with other rubber raw rubbers, the main chain of methyl vinyl silicone rubber raw rubber is a single chain structure. The Si-O bond length on the molecular chain is longer than that of C-O and C-Cσ bonds, and it contains isolated double bonds and does not contain other large or polar groups. Therefore, its molecular chain has extremely strong flexibility, and its macroscopic performance is poor mechanical properties. In order to enhance the mechanical properties of methyl vinyl silicone rubber, different fillers are generally filled in it according to its different uses. White carbon black has become the inorganic filler with the best compatibility with silicone rubber due to its similar main elements and chemical bonds with silicone rubber. It is a commonly used reinforcing agent in silicone rubber products.

The experiment was conducted using the prescription shown in the following table to examine the effect of the amount of white carbon black on the mechanical properties of silicone tubes.

PHR: The mass fraction of a component per 100 mass fractions of a polymer compound.

The influence of silica dosage on the physical and mechanical properties of silicone tubes is shown in the following table. When the silica dosage is in the range of 30PHR-40PHR, as the silica dosage increases, the hardness of the silicone tube gradually increases, the deformation of the extruded tube decreases, the tube wall thickness is more uniform, and the tensile strength, tear strength, elongation at break and other physical and mechanical properties of the tube are relatively excellent; but when the silica dosage increases to 40PHR, due to the increase in the hardness of the rubber compound, the extrusion power of the extruder is slightly insufficient, and the extrusion rate fluctuates greatly, resulting in an uneven shape of the extruded tube.

White carbon black can improve the mechanical properties of vulcanized rubber because its surface hydroxyl groups can interact with macromolecules and form a spatial network structure between white carbon black and macromolecules, which can make the molecular chain slip and a large amount of physical adsorption absorb the impact of external force when silicone rubber is deformed by external force, buffer the friction or hysteresis deformation caused by external force, and make the stress distribution uniform. Therefore, adding an appropriate amount of white carbon black can enhance the mechanical properties of silicone rubber, but will not reduce the tensile elasticity of silicone rubber too much. Therefore, it is preferred to add 35% white carbon black by mass of raw rubber for the preparation of silicone tube.

Mechanical properties Example 13-1 Example 13-2 Example 13-3 Elongation at break/Eb(%) 1045.50 979.84 900.49 Tensile strength/Ts(Mpa) 8.50 8.49 8.49 Tear strength/T(KN/m) 45.65 45.02 44.28 Hardness/H Shore A 46 50 58

3.1.3 Investigation of the dosage of hydrogenated silicone oil

Hydrogenated silicone oil is generally used as a crosslinking agent in the preparation of addition silicone rubber. The molecular formula of hydrogenated silicone oil is The active hydrogen connected to the silicon atom participates in the addition reaction and forms crosslinking points together with the vinyl in the methyl vinyl silicone rubber. Therefore, the amount of hydrogen-containing silicone oil will also affect the physical and mechanical properties of the silicone tube.

Using raw rubber with a vinyl content of 0.17% and hydrogen-containing silicone oil with a hydrogen content of 0.75%, the amount of hydrogen-containing silicone oil is calculated according to the vinyl content. The calculation formula is as follows:

In the formula, W is the amount of hydrogenated silicone oil added; A is the molar ratio of Si-H/Si-Vi, that is, when the molar ratio of the vinyl and hydrogen of the hydrogenated silicone oil reaches 1:1, the A value is 1; ω(Vi) is the mass percentage of vinyl in the raw rubber; ω(H) is the mass fraction of hydrogen in the hydrogenated silicone oil; 27 is the molar mass of vinyl; W ₁ is the mass of the raw rubber. The A value is used to represent the change in the amount of hydrogenated silicone oil. The experiment was carried out using the prescription shown in the table below to investigate the effect of the amount of hydrogenated silicone oil on the mechanical properties of the silicone tube.

Note: PHR: the mass fraction of the component per 100 mass fractions of polymer compound;

In the above table, the molar percentage of vinyl in the raw rubber is 0.17%, and the molar percentage of hydrogen in the hydrogen-containing silicone oil is 0.75%.

The experimental results are shown in the mechanical properties in the following table. As the amount of hydrogenated silicone oil increases, the physical and mechanical properties of the silicone tube show a peak-shaped change. This is also related to the density of crosslinking points inside the silicone tube. According to the reaction mechanism, the hydrogen and vinyl of hydrogenated silicone oil participate in the reaction in a molar ratio of 1:1. When the A value is less than 1, the number of active hydrogens participating in the addition reaction is insufficient, and the crosslinking points formed by the addition reaction are relatively few; as the A value increases, the tensile strength, tear strength and hardness of the silicone tube gradually increase, and reach a peak value when the A value is 1.2, that is, when the molar ratio of vinyl to hydrogen of hydrogenated silicone oil is 1:1.2, the physical and mechanical properties of the silicone tube are the best. A slightly excessive amount of hydrogenated silicone oil can make the addition reaction fully occur, and the mechanical properties of the extruded tube reach the best state; but when the amount of hydrogenated silicone oil continues to increase, the crosslinking density of the silicone tube becomes larger and the crosslinking points become disordered, and the physical and mechanical properties of the silicone tube begin to decline. Therefore, when calculating the amount of hydrogenated silicone oil when feeding, the preferred A value is 1.2.

3.2 Investigation of silicone tube preparation process

3.2.1 Investigation of vulcanization temperature and time

After being extruded from the extruder, the silicone rubber will pass through a short front drying tunnel (0.8m) for high-temperature vulcanization by the conveyor belt, and then pass through a long rear drying tunnel (2.5m) for vulcanization under the traction of the conveyor belt. This is the first stage of vulcanization, and the main purpose is to shape the silicone tube. The purpose of high-temperature vulcanization in the short drying tunnel is to quickly shape the silicone tube and reduce the deformation of the silicone tube during the subsequent conveyor belt vulcanization. The temperature of the silicone tube should not be too high when it passes through the short drying tunnel, otherwise over-vulcanization will occur (Figure 9) (the temperature of the front drying tunnel corresponding to the over-vulcanization state in Figure 9 is 360℃), the macromolecules inside the silicone tube will break, the silicone tube will crack under the stretching state, and various physical and mechanical properties will drop sharply. Since the vulcanization reaction needs to continue to form the silicone tube, the vulcanization temperature of the rear drying tunnel should not be too low, but because the temperature of the rear drying tunnel is higher than 200℃, it will affect the service life of the conveyor belt. Therefore, the temperature of the silicone tube passing through the rear drying tunnel under the drag of the conveyor belt is 180℃, and the silicone tube is well formed with little deformation and no over-vulcanization.

After the first stage of heating and molding, due to its short reaction time, the cross-linking of the silicone tube was not complete and the cross-linking density was insufficient. Secondary vulcanization was carried out in an oven at 180°C to allow it to further cross-link. Samples were taken at 0h, 12h, 24h, 48h, and 72h to measure its physical and mechanical properties, and the changes in the physical and mechanical properties of the silicone tube after oven vulcanization were observed.

serial number Oven heat treatment time Example 15-1 0h Example 15-2 12h Example 15-3 24h Example 15-4 48h Example 15-5 72h

The time of secondary vulcanization and the changes in the physical and mechanical properties of silicone tubes are shown in the following table. When the secondary vulcanization time is 0-48h, the cross-linking reaction inside the silicone tube continues to occur, the number of cross-linking points increases, the elongation at break of the silicone tube decreases, and the tensile strength and tear strength are significantly enhanced compared with the silicone tube vulcanized once; when the secondary vulcanization time is 48-72h, the cross-linking reaction inside the silicone tube is basically completed, and the tear strength and tensile strength of the silicone tube are slightly enhanced; but as the vulcanization time increases, the silicone tube begins to over-vulcanize, the internal cross-linking bonds and chain segments begin to undergo thermal cracking reactions, and the tensile strength and tear strength of the silicone tube begin to decrease. Comprehensively comparing the physical and mechanical properties of the silicone tube after secondary vulcanization, it is determined that the optimal conditions for secondary vulcanization are 180℃, 48h.

Mechanical properties Example 15-1 Example 15-2 Example 15-3 Example 15-4 Example 15-5 Elongation at break/Eb(%) 900.49 718.40 608.81 565.13 603.54 Tensile strength/Ts(Mpa) 8.49 8.65 8.58 9.79 8.76 Tear strength/T(KN/m) 44.28 49.06 46.57 54.77 43.48 Hardness/H Shore A 40 52 57 63 64

4. Biological performance test of addition type silicone tube

Implant materials implanted in the body need to be safe, reliable and non-toxic in terms of biological performance to ensure the safety of implantation. This material has been subjected to the following biological tests in accordance with GBT16175-2008-Biological Evaluation Experimental Methods for Medical Silicone Materials to examine whether its biocompatibility is good and whether it meets the requirements for in vivo implantation.

4.1 Acute toxicity test

The prepared clean silicone tube (corresponding to the silicone tube in the aforementioned Example 14-4) was cut into 5 cm lengths, immersed in 100 mL of redistilled water, heated and extracted at 70°C for 24 h, and then sterilized in a high pressure sterilizer at 121°C for 30 min for later use.

Ten healthy SD rats weighing about 200g were randomly divided into an experimental group and a control group. One group was injected with the extract at a dose of 5mL/kg through the tail vein, and the other group was injected with the same dose of normal saline through the tail vein. The rats were observed within 24h, 48h, and 72h. No adverse reactions or deaths were observed.

4.2 Hemolysis assay

According to the general rule 1148 of the 2020 edition of the Chinese Pharmacopoeia, a hemolysis test was performed. 1 mL of healthy rabbit blood was taken and placed in a conical flask containing glass beads and shaken for 10 minutes to remove fibrinogen and make it defibrillated blood. About 10 times the amount of 0.9% sodium chloride solution was added, shaken well, and then centrifuged at 1000 rpm for 15 minutes. The supernatant was removed, and the precipitated red blood cells were washed 3 times with 0.9% sodium chloride solution according to the above method until the supernatant was no longer red. The obtained red blood cells were made into a 2% suspension with 0.9% sodium chloride solution for standby use.

Take 5 clean glass test tubes, No. 1 and No. 2 test tubes are test tubes, No. 3 is a negative control tube, No. 4 is a positive control tube, and No. 5 is a test control tube. Add 2% red blood cell suspension, 0.9% sodium chloride solution, purified water and the extract in "4.1 Acute Toxicity Test" in sequence as shown in the table below, mix well, and immediately place in a constant temperature shaker at 37℃±0.5℃ for incubation. Observe hemolysis and agglutination reactions after 3 hours.

The hemolysis test is shown in the table below.

Test tube number 1 2 3 4 5 2% red blood cell suspension (mL) 2.5 2.5 2.5 2.5 / 0.9% sodium chloride solution (mL) 2.5 2.5 2.5 / 4.7 Purified water (mL) / / / 2.5 / Extract(mL) 0.3 0.3 / / 0.3

The experiment found that there was no obvious difference in tubes 1, 2, 3, and 5 by naked eye observation, the supernatant was clear, and hemolysis occurred in the positive control tube No. 4, indicating that the hemolysis test of this material was negative.

4.3 Stimulation test

Ten healthy SD rats weighing about 200 g were selected and randomly divided into an experimental group and a control group. The hair on both sides of the spine of the rats' backs was removed 4 hours before the start of the experiment (an area of about 3×3 cm).

Take an appropriate amount of the extract in "4.1 Acute Toxicity Test" and drop it onto a 2.5×2.5cm absorbent gauze piece. Apply the soaked gauze piece to the depilated skin of the rat and fix it with adhesive tape. The rats in the control group were applied with a saline gauze piece in the same way as above and fixed. Remove the gauze and observe after 4 hours. No skin reaction was observed.

Ten healthy SD rats weighing 200g were randomly divided into an experimental group and a saline control group. The experimental group was injected with 5 points of extract into the skin on one side of the rat's back, 0.2mL at each point, and the opposite side of the back was injected with an equal amount of saline. The saline control group was injected with an equal amount of saline on both sides of the rat's back according to the above operation. The injection sites were observed within 24h, 48h, and 72h after injection, and no redness, swelling, necrosis, etc. were observed. The irritation test results of the material were negative.

4.4 Short-term implantation experiment

Prepare several clean silicone tubes (corresponding to the silicone tubes in the above-mentioned Example 14-4) with an outer diameter of 2.4 mm, an inner diameter of 1.6 mm, and a length of 35 mm, seal the ends with an adhesive, and then rinse with distilled water, sterilize at 121°C for 30 min, and dry the sterilized silicone tubes for later use. Select 12 healthy SD rats weighing about 200 g, anesthetize the rats, implant the sterilized silicone tubes into the skin on the back of the rats with an implantation needle, and then suture the wounds. Thereafter, feed the rats normally, and randomly select 5 SD rats on the 3rd and 10th days after implantation to kill them, and remove the tissues around the silicone tubes to prepare tissue sections for histological observation.

During the implantation of the silicone tube, the rats had a normal diet, daily routine, and normal weight gain. There were no abnormal lesions in the subcutaneous and muscle tissues of the implanted part by naked eye observation. The experimental results of tissue sections are shown in Figure 10. Figure 10 (A) is a full-view image of the tissue section on the third day after implantation, and mild epidermal thickening can be observed; Figure 10 (B) is a local view of the tissue section on the third day after implantation. Connective tissue hyperplasia can be seen around the implanted part (arrow on the far left), accompanied by scattered lymphocyte infiltration (arrow in the middle position), and multinucleated giant cells (arrow on the far right) can be seen. According to the inflammatory cell response grading standard, the degree of tissue inflammatory cell response three days after implantation is grade III. Figure 10 (C) is a full-view image of the tissue section on the tenth day after implantation, in which mild thickening of the epidermis can still be observed; Figure 10 (D) is a local view of the tissue section on the tenth day after implantation, with connective tissue hyperplasia (arrow on the right) and diffuse lymphocytes (arrow on the left) visible around it. According to the inflammatory cell response grading standard, the degree of inflammatory cell response of the tissue ten days after implantation is grade II. During the implantation of the silicone tube, the rats had a normal diet, daily routine, and normal weight gain. No abnormal lesions were observed by naked eye in the subcutaneous and muscle tissues of the implanted part.

As the implantation time increased, the degree of inflammatory response of the implanted part of the rat gradually decreased. The tissue section results showed that the degree of inflammatory cell response of the implanted part of the rat was less than or equal to grade IV in the first week, and less than or equal to grade II in the fourth week, which met the index requirements for the tissue response degree of the implanted experimental part of "GBT16175-2008-Experimental Methods for Biological Evaluation of Medical Silicone Materials". The implantation experimental results of the silicone tube material were qualified.

The grading criteria for inflammatory cell response are shown in the following table.

level Inflammatory cell response Level I No or very few lymphocytes are seen around the specimen Level II A small amount of lymphocytes can be seen around the sample Level III There are a few neutrophils, lymphocyte infiltration and giant cell reaction around the specimen Level IV Inflammatory reaction mainly characterized by neutrophil infiltration was observed around the specimen, and phagocytes were also observed.

The biocompatibility of the silicone tube was evaluated through acute toxicity experiments, hemolysis experiments, stimulation experiments, and implantation experiments. The silicone tube has good biocompatibility, which lays a foundation for the preparation of the subsequent implant.

3. Preparation and evaluation of levonorgestrel long-acting implant

Silicone rubber has good air permeability and biological inertness. Long-acting contraceptive implants with silicone rubber as a carrier can slowly and constantly release the drugs contained therein, maintain a long-term contraceptive effect, and avoid the first-pass effect of the liver.

This part mainly carried out the preparation of levonorgestrel long-acting implant and in vitro release experiment, investigated the influencing factors of levonorgestrel implant in vitro release, compared the homemade preparation and commercially available implant through long-term release experiment, and investigated the conditions of accelerated experiment.

1Instruments and drugs

1.1 Instrument

LC-10ATVP High Performance Liquid Chromatograph Shimadzu Corporation AG245 Ultra-micro electronic balance type electronic analytical balance Mettler Toledo, Switzerland KQ-250DE CNC Ultrasonic Cleaner Kunshan Ultrasonic Instrument Co., Ltd. TS-100B Constant Temperature Shaker Shanghai Jiecheng Experimental Instrument Co., Ltd.

1.2 Drugs and reagents

LNG (batch number 20190327, purity >98%) Hebei Mokai Technology Co., Ltd. Anhydrous ethanol (analytical grade) Shandong Yuwang Chemical Reagent Co., Ltd. Chromatography Methanol Shandong Yuwang Chemical Reagent Co., Ltd. Levonorgestrel Silicone Rod (I) Liaoning Ludan Pharmaceutical Co., Ltd. KN-300N Adhesive Kanglibang Polymer New Materials Co., Ltd.

2 Preparation and in vitro release experiment of levonorgestrel long-acting implant

2.1 Preparation of levonorgestrel long-acting implant

2.1.1 Treatment of silicone rubber tube

Take an addition-type silicone tube (outer diameter 2.4mm, inner diameter 1.6mm) with qualified appearance and various performances, cut it into the same length of 35mm, put it into a 100mL beaker, add appropriate amount of detergent and distilled water, and ultrasonicate for 30 minutes. After the ultrasonication, rinse it with distilled water for 3 times, then clean it with 75% ethanol and air-dry it naturally for use.

The specific process is: front drying channel 270℃, vulcanization time about 5s; rear drying channel 180℃, vulcanization time about 2min; oven vulcanization temperature 180℃, time 48h; other process conditions are the same as the preparation process in 2.1.2 of "2. Preparation of two-component addition-type silicone tube".

Drug core prescription: levonorgestrel powder with a particle size of 2.12 μm after micronization.

2.1.2 Preparation of implants

Fold one end of the silicone tube, and use a tool to accurately feed 36 mg of LNG (levonorgestrel) powder into the tube for filling (core length 30 mm) at the other end. Then seal the two ends of the silicone tube with adhesive. After the adhesive is cured, shake the silicone tube to make the drug evenly distributed in the silicone tube. Then wash off the powder adhering to the surface of the silicone tube, repeat the above steps 6 times, and you will get a set of levonorgestrel implants (the wall thickness of the levonorgestrel implant used here is (2.4-1.6)/2=0.4mm, and the drug release area is calculated based on S=πd×L (where d is the inner diameter of the silicone tube and L is the length of the drug-containing section)).

2.2 In vitro release experiment of levonorgestrel long-acting implant

The in vitro release test method of levonorgestrel long-acting implant was carried out according to the "in vitro release test method" under the first part.

The in vitro release rate of implants is a key indicator of quality control. It determines the contraceptive effectiveness and provides a basis for subsequent clinical medication.

3 Experimental methods and results

3.1 Study on factors affecting the in vitro release of levonorgestrel implant

3.1.1 Effect of silicone tube preparation formula on in vitro release of implants

Silicone tubes, as the functional membrane of implants, are cross-linked by methyl vinyl raw rubber with vinyl end groups and hydrogen-containing silicone oil under the action of additives. Since the drug needs to diffuse outward through the silicone tubes, their own properties will also affect the release of the drug. Clean silicone tubes with qualified physical and mechanical properties were selected to prepare implants of the same specifications. After pretreatment with explosions, they were placed in a shaker for release experiments. Samples were taken continuously for 35 days to investigate the effect of the preparation prescription of the silicone tubes on the in vitro release of the implants.

3.1.1.1 Effect of vinyl content on in vitro release of implants

Silicone tubes were extruded from raw rubber with vinyl content of 0.17% and 0.23%. Implants were prepared in accordance with the preparation of "2.1 Preparation of levonorgestrel long-acting implants" of this part for in vitro release experiments.

Material Name Example 16-1 Example 16-2 Methyl vinyl silicone rubber 100PHR 100PHR Vinyl Content of Vinyl Polysiloxane 0.17mol% 0.23mol% Fumed silica 35PHR 35PHR Hydrogen silicone oil 1.01PHR 1.36PHR Molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber 1.2:1 1.2:1 Hydrogen content of hydrogen silicone oil 0.75mol% 0.75mol% 2-Methyl-3-butyn-2-ol 0.7PHR 0.7PHR Platinum catalyst (3000ppm) 0.00001PHR 0.00001PHR

The daily dose release of the silicone tubes corresponding to Examples 16-1 and 16-2 is shown in the following table.

The experimental results are shown in the table above. Both groups of implants can release stably. The daily release of the implant prepared with raw rubber having a vinyl content of 0.23% is less than that of the implant prepared with raw rubber having a vinyl content of 0.17%.

When the implant is released, the small drug molecules move outward through the silicone tube wall, and the drug dissolved in the membrane diffuses to the interface between the membrane and the release medium, and finally enters the receptor through distribution and dissolution. The density of the cross-linking points inside the silicone tube affects the relaxation process of the macromolecular chain segments and has a controlling effect on the diffusion behavior of the drug through the cross-linking network. That is, the size of the cross-linking network of the macromolecules inside the silicone tube has a "screening effect" on drug diffusion. The greater the cross-linking density, the more cross-linking points, the shorter the molecular chain length, the more difficult the chain segment movement, the lower the ability of the drug to pass through the gap between the chains, the lower the solubility of the drug in the membrane, and the lower the release rate of the drug.

3.1.1.2 Effect of the dosage of hydrogenated silicone oil on the in vitro release of implants

The in vitro release test was conducted on the silicone tubes made by adding different amounts of hydrogenated silicone oil (the A values were 1, 1.2, and 1.5 respectively when hydrogenated silicone oil was added). The prescription is shown in the following table.

The daily dose release of the silicone tubes corresponding to Examples 17-1, 17-2, and 17-3 is shown in the following table.

The amount of hydrogenated silicone oil used has little effect on the release rate of LNG. When the A value is 1.5, the release rate of the implant is slightly lower than when the A value is 1 and 1.2. This is mainly due to the different cross-linking degrees inside the silicone tube, which leads to different diffusion rates of the drug in the silicone tube.

3.1.1.3 Effect of Silica Dosage on the in vitro Release of Implants

The release rate of silicone tubes with different amounts of white carbon black added was investigated, and the prescription is shown in the following table.

The daily dose release of the silicone tubes corresponding to Examples 18-1, 18-2, and 18-3 is shown in the following table.

The amount of white carbon black has a slight effect on the release of the implant. As the amount of white carbon black increases, the release of the implant decreases slightly.

In conclusion, the preparation formula of the silicone tube will have a certain influence on the release of the implant, mainly because the different degrees of cross-linking inside the silicone tube lead to different solubility of drug small molecules in the silicone tube. However, the drug can be stably released in these silicone tubes with different formulas, and the difference in the diffusion rate of the drug in the silicone tube is not very large. There is no situation where the diffusion rate is too low to cause the drug to be released, and there is no situation where the drug release rate is too fast to cause sudden release. Therefore, the silicone tube with the best mechanical properties (formula: 100PHR of raw rubber with a vinyl content of 0.17%, 35PHR of white carbon black, hydrogen-containing silicone oil A value = 1.2, catalyst ^10-5PHR , inhibitor 0.7PHR) is preferred for the preparation of the implant, which can better meet the long-term and stable release of the implant in the body.

3.1.2 Effect of decompression on in vitro release of implants

Two groups of levonorgestrel implants were prepared according to the "2.1 Preparation of levonorgestrel long-acting implant" of this section. One group was directly placed in a shaker for in vitro release test without any treatment, and the other group was added to a stoppered conical bottle and ultrasonicated for 1 minute, repeated three times, and then added with 100mL of distilled water and left overnight. The next day, the leaching solution was discarded and placed in a shaker for in vitro release test. Samples were taken at fixed points every day to replace the release medium, and the in vitro release of the implant was observed for 12 consecutive days. The experimental results are shown in the following table and Figures 11 and 12.

As shown in Figures 11 and 12, the daily release of the implant without pretreatment of burst removal was relatively high in the first 12 days, and the daily release was unstable, showing a very obvious downward trend. The relative burst release of the implant (Day 1 release/Mean release) was expressed by the ratio of the release of the implant on the first day to the average daily release. The experiment found that the relative burst release of the implant after burst removal was close to 1, that is, the daily release of the levonorgestrel implant after burst removal was very slow from the initial release. The cumulative release (Q _C ) of the implant after burst removal was linear with the release time (t) (R ² = 0.996), the release rate conformed to the zero-order release kinetics, and the daily release curve did not fluctuate greatly.

Because the surface of the levonorgestrel implant without burst removal treatment contains powder adsorbed by the silicone tube electrostatically, the release of the implant has a very obvious burst release effect. In order to make its initial release close to the steady-state release, reduce the observation time of the in vitro release, and reduce the risk of drug burst release after the implant is implanted in the body, it needs to be treated accordingly. After burst removal treatment, the initial release of the implant is close to the steady state.

The release data of LNG implants are shown in the following table.

Note: Q _C : Cumulative drug release.

3.2 Comparison of levonorgestrel implant and commercial preparations

The commercially available levonorgestrel silicone rod I contains 6 drug-containing silicone rods, each containing 36 mg of LNG powder, with a total drug loading of 216 mg, a silicone tube outer diameter of 2.4 mm, a tube wall thickness of 0.4 mm, and a drug core length of 30 mm. Combined with the results of the investigation of the influencing factors of the above-mentioned in vitro release experiment, a 2.4 mm × 1.6 mm × 35 mm × 6 silicone tube was selected to prepare 6 levonorgestrel implants with a drug core length of 30 mm and a drug loading of 216 mg. The commercially available preparation (levonorgestrel silicone rod (I), purchased from Liaoning Ludan Pharmaceutical Co., Ltd.) and the levonorgestrel implant were subjected to a 100-day in vitro release experiment after being deburred.

During the 100-day release period, the daily drug release curve of the implant is shown in the following table. The daily drug release of the homemade preparation (silicone tube corresponding to Example 18-2) and the commercially available preparation is very stable, with no obvious burst release or reduced release.

The in vitro release data of LNG homemade preparations and commercially available preparations are shown in the following table.

/ Mean(μg) RSD(%) Q _C /t equation R ² Homemade preparations 49.02 7.19 Q _C =52.54t-5.59 0.997 Commercially available preparations 45.76 6.70 Q _C =42.50t-0.61 0.998

Note: Q _C : Cumulative drug release.

As shown in the table below, the in vitro release of the homemade preparation is not much different from that of the commercially available preparation. During the in vitro release experiment, the RSD value of the daily drug release of the homemade preparation was 7.19%, and the RSD value of the daily drug release of the commercially available preparation was 6.70%, indicating that the drug release stability of the two groups of preparations is also relatively similar, and their release behaviors are consistent with zero-order release.

4 In vitro accelerated test

Levonorgestrel implants need to maintain effective drug concentrations in the body for several years, so once the preparations are rapidly released or accidentally released in the body, they will cause serious adverse reactions. For this long-acting implant, it takes a long period of time to screen prescriptions by real-time release of drugs, which is inconvenient. Therefore, finding an appropriate method for accelerating drug release plays a very important role in the prescription optimization and quality control of preparations. Raising the temperature is widely used in the in vitro accelerated experiment of preparations, but the accelerated experiment requires a more accurate prediction of the reaction and real-time release, so it is also necessary to judge whether the accelerated release and the normal rapid release drugs are correlated.

4.1 Experimental methods

Take a clean silicone tube with an outer diameter of 2.4mm, an inner diameter of 1.6mm, and a length of 35mm (the length of the silicone tube is 35mm, the length of the pure drug core is 30mm, and the extra 5mm is the length of the end-capping glue at both ends) (the silicone tube corresponding to the prescription of Example 18-2, the front drying tunnel is 270℃, the vulcanization time is about 5s; the rear drying tunnel is 180℃, the vulcanization time is about 2min; the oven vulcanization temperature is 180℃, the time is 48h; the drug core prescription: levonorgestrel powder with a particle size of 2.12μm after micronization) to prepare an implant. With reference to the drug release at 37℃, the release of LNG at 45℃ and 55℃ was investigated. Referring to the normal release conditions, 100mL of water was used as the medium, and the release sample was taken every 1-3h and the new medium was replaced. Three parallel experiments were conducted at each temperature.

4.2 Experimental Results

The release data of LNG implant in vitro at different temperatures are shown in the following table.

Release temperature(℃) QC/t equation K R ² 37 QC＝52.54t-5.59 52.54 0.996 45 Q＝221.54t+2.27 221.54 0.997 55 Q＝1271.09t+4.35 1271.09 0.991

Note: Q _C : Cumulative drug release.

The release rate of LNG increases with increasing temperature and is related to the Arrhenius equation, which is shown below:

K＝A×e ^-Ea/RT (Formula 3-1)

Among them, K is the zero-order release rate, A is a constant, Ea is the activation energy, R is the gas constant, and T is the absolute temperature. Taking the natural logarithm of equation 3-1, we get the following formula:

In the formula, K is calculated by the drug release amount at different temperatures, and ln(K) and 1/T are plotted as a straight line, with a slope of -Ea/2.303R. The predicted drug release rate at 37°C is read out by using the Arrhenius equation to draw a straight line based on the multiple temperatures set in the temperature acceleration experiment, and then compared with the drug release rate obtained from the actual 37°C drug release experiment. This is to investigate whether the drug release rate of the temperature acceleration experiment can predict the actual drug release rate. Therefore, ln(K) = -18841.7 + 64.507 (R ² = 0.999), and the linear relationship between ln(K) and 1/T is shown in Figure 13. The predicted 37°C drug release rate K _37°C = 51.94 μg is calculated by this formula, which is close to the actual drug release amount of the implant at 37°C. The drug release in this accelerated experiment has a good correlation with the normal release rate.

From the data in the above table, it can be seen that the release rate of LNG at 45°C is about 4.5 times that at 37°C, and the release rate of LNG at 55°C is about 28 times that at 37°C. That is, the release amount at 37°C for 24 hours is about the release amount at 45°C for 5.2 hours, and the release amount at 37°C for 24 hours is about the release amount at 55°C for 51 minutes, which greatly saves the time of in vitro release experiment. Therefore, the in vitro release amount of LNG can be increased by increasing the release temperature, and the experimental time of in vitro drug release experiment can be reduced.

IV. In vivo pharmacodynamic study of levonorgestrel long-acting implant

This part mainly studies the pharmacodynamics of levonorgestrel implant in rats. The contraceptive effect of levonorgestrel subcutaneous implant was studied by implanting different specifications of subcutaneous implants in rats, observing the changes in the estrus cycle of SD rats after implantation through vaginal smears, measuring the level of LH (luteinizing hormone) in rats by enzyme-linked immunosorbent assay, and monitoring whether rats had mating behavior.

1. Instruments and reagents

1.1 Instrument

KQ-250DE CNC Ultrasonic Cleaner Kunshan Ultrasonic Instrument Co., Ltd. Rat LH Kit Shanghai Tongwei Biotechnology Co., Ltd. Electron microscopy Shenzhen Zhongwei Kechuang Technology Co., Ltd. Levonorgestrel Silicone Rod (I) Liaoning Ludan Pharmaceutical Co., Ltd. Autoclave Shanghai Shen'an Medical Equipment Factory XS105 Electronic Analytical Balance Mettler-Toledo Instruments Ltd. SMD200-2 Electronic Analytical Balance Ohaus International Trading Co., Ltd. TG16MW desktop high speed centrifuge Hunan Hexi Instrument Equipment Co., Ltd.

1.2 Drug testing

LNG (batch number 20190327, purity >98%) Hebei Mokai Technology Development Co., Ltd. Levonorgestrel Silicone Rod (I) Liaoning Ludan Pharmaceutical Co., Ltd. Heparin Sodium Shandong Yuwang Pharmaceutical Co., Ltd. 4% paraformaldehyde solution Shanghai Yantuo Biotechnology Co., Ltd. Normal saline Shandong Yuwang Chemical Reagent Co., Ltd.

1.3 Experimental animals

SD rats (License No.: SCXK(Liao)2020-0001) Liaoning Changsheng Biotechnology Co., Ltd.

2 Experimental methods

2.1 Administration

Five specifications of levonorgestrel implants were prepared using a 2.4 mm × 1.6 mm silicone tube (the corresponding prescription of Example 18-2, the front oven is 270°C, the vulcanization time is about 5 s; the rear oven is 180°C, the vulcanization time is about 20 s; the oven vulcanization temperature is 180°C, and the time is 48 h; the drug core prescription: the levonorgestrel powder with a particle size of 2.12 μm after micronization) (drug core length/drug loading) for use, and the five specifications are: I (3 mm/3.6 mg), II (10 mm/12 mg), III (15 mm/18 mg), IV (20 mm/24 mg), and V (30 mm/36 mg).

The specific prescription is shown in the following table.

14 healthy male SD rats weighing about 200g were randomly divided into 7 groups for standby; 42 healthy female SD rats weighing about 200g were randomly divided into 7 dose groups, namely, a blank tube group (Negative control group), a positive control group (Positive control group) and 5 drug-dosing groups. The positive control group used a levonorgestrel silicone rod I (from Liaoning Ludan Pharmaceutical) with a core length of 30mm. The blank tube also used a silicone tube with an outer diameter of 2.40mm and a wall thickness of 0.5mm, which was cut into 15mm sections and glued at both ends for standby. All preparations and silicone tubes were sterilized in an autoclave (121℃, 30min) for standby.

The female mice in the drug administration group were anesthetized and fixed on the mouse board. The skin near the spine was shaved and disinfected with 2% iodine tincture. The skin on the back of the rat was slightly lifted, and a small incision of about 0.5 cm was cut on the local skin to separate the fibrous connective tissue between the subcutaneous and the muscle. The disposable implant needle was inserted into the small incision at an angle of 30°, and the implant needle was slowly rotated to advance in the direction parallel to the rat spine. When the implant needle was pushed into the rat skin about 1 cm, the sterilized implant was placed in the implant needle tube, and then the implant needle was continued to be pushed forward. After the forward length of the implant needle under the rat skin exceeded the length of the implant, the implant was slightly pressed, and the implant needle was slowly withdrawn, the wound was sutured, and the wound surface was disinfected. 24 hours after the implantation surgery, the blank group and the drug administration group were caged together for male and female, with 6 female mice and 2 male mice in each cage.

2.2 Rat vulva observation and preparation of vaginal smears

To monitor the estrus, mating and pregnancy of rats, the vulva characteristics were observed and recorded at 9:00 am every day for 30 consecutive days after administration, and vaginal smears were made to observe and record the characteristics of vaginal exfoliated epithelial cells.

2.2.1 Method for preparing rat vaginal smear

Weigh 0.1g crystal violet powder and dissolve it in 100mL distilled water to prepare a 0.1% gentian violet solution for later use; take a clean anti-shedding slide and mark it for later use; soak a cotton swab in sterile saline for later use. Take the female mouse out of the cage and place it on the cage cover. Hold the rat's tail with one hand and gently lift it up to expose the rat's vaginal opening. Use a cotton swab to gently wipe the rat's vaginal opening to clean urine, then insert the pre-prepared wet cotton swab into the rat's vagina for about 0.5cm, and gently rotate it 1 to 2 times, and evenly apply the cotton swab on the anti-shedding slide for smearing. After the anti-shedding slide coated with rat vaginal exfoliated cells is air-dried, add 50 μL of anhydrous ethanol to fix it for 10 minutes; drop 50 μL of gentian violet solution on the slide and let it stand for 1 minute; soak the slide in distilled water for 1 minute, then rinse with distilled water for 10 seconds, and wait for the slide to air-dry naturally; after the slide is air-dried, seal it with neutral gum and observe the rat vaginal smear under an electron microscope.

2.2.2 Observation of the estrous cycle of rats by vaginal smear

The estrous cycle of rats is generally divided into 4 phases, namely proestrus, estrus, metestrus and diestrus. Proestrus and estrus are acceptable for mating and ovulation, leading to fertilization. Metestrus is the period of degeneration and destruction of the reproductive tract, and diestrus is a period of relative stillness and slow growth. The average estrous cycle of rats is 4-5 days, and the vaginal smear method can be used to determine the process of the estrous cycle of rats.

The method for identifying the estrous cycle of rats is shown in the following table.

2.3 Enzyme-linked immunosorbent assay for determination of LH concentration in rat plasma

2.3.1 Blood sample collection

Starting from the third day after administration, 100 μL of blood was collected from the eye socket at 9:30 am every day for 28 consecutive days. The blood was placed in an EP tube pretreated with sodium heparin, mixed, and centrifuged in a centrifuge for 10 min at a speed of 5000 r·min ^-1 . The supernatant was transferred to an EP tube and stored at -80°C for testing.

2.3.2 Enzyme-linked immunosorbent assay for determination of LH concentration in rat plasma

After the levonorgestrel implant was implanted in rats, the pharmacodynamic behavior characteristics of the levonorgestrel implant in rats were explored by observing the level of LH in rat plasma. Serum samples were taken and the LH (luteinizing hormone) content in rat serum was detected by the kit in strict accordance with the instructions of the enzyme-linked immunosorbent assay kit.

A standard curve was drawn using the standard concentration and OD value, and then the concentration of LH in the serum sample was calculated based on the standard curve.

2.3.3 Statistical analysis

The data were analyzed using SPSS21.0 analysis software, and the experimental results were expressed as mean ± standard deviation (mean ± SD). One-way ANOVA was used to evaluate the overall variance difference between the means of multiple groups. If the data variance was homogeneous, LSD was used for multiple comparisons. If the variance was unequal, Dunnett T3 was used for multiple comparisons. For comparisons between two groups, unpaired t-tests were used for comparison. P < 0.05 was considered to be significantly different.

3 Results and discussion

3.1 Monitoring results of estrus and mating in rats

By observing the vulva condition and vaginal smear of each group of rats every day, it was determined whether the rats were in estrus and mating. During the experiment, the rats had a normal diet and normal weight gain. The experiment found that after the blank group was caged, a white gelatinous vaginal plug was found in the vagina of the female rats. The vaginal plug was formed by the mixture of male rat semen, female rat vaginal secretions and vaginal epithelial cells, which quickly hardened after encountering air, as shown in Figure 14. This is an important sign of successful mating. In addition, the vaginal smear of each female rat in the blank tube group can be observed to have a complete estrus cycle, as shown in Figure 15; the progesterone level in the blank tube group rats was normal, and the rats had normal estrus and mating behavior.

In the drug administration group, rats in the four dose groups II, III, IV, V and the positive control group were implanted with the preparation. During the one-month test, the rats' vulva examination showed that their vaginal openings were tightly closed, the vulva was dry, without secretions, no redness or swelling, and no vaginal plugs were found. The vaginal smear showed the presence of a large number of white blood cells, which is a typical feature of the estrus period, indicating that the rats have been in the estrus period and no normal estrus period has occurred. However, in the I dose group, female rats numbered 2 and 4 were found to have complete estrous cycles through vulva examination and vaginal smear examination, indicating that the levonorgestrel implant at this dose did not play a contraceptive role after being implanted in these two rats.

3.2 Changes in LH levels in rats

The experimental results are shown in the table below. After the levonorgestrel implant was implanted into the rats, the LH level in the rats was significantly reduced. That is, the LH levels of the rats in the positive control group and the different dose groups were significantly different from those in the blank tube group (P<0.05). The experiment also found that the LH level in the rats was affected by the dose of LNG. The higher the dose of LNG, the lower the LH level in the rats.

In the estrus cycle of rats, the secretion of LH is regulated by GnRH (gonadotropin-releasing hormone), and LH will have an obvious peak in the proestrus of rats. In the drug-treated group and the positive control group, since levonorgestrel mainly acts on the hypothalamus and pituitary gland, it inhibits the release of GnRH through a negative feedback mechanism, thereby reducing the secretion of LH, causing the peak of LH levels to be significantly reduced or disappear, thereby affecting the growth and maturation process of follicles, and the ovaries do not ovulate, achieving a contraceptive effect. This is consistent with the observation results of vaginal smears. After the implant produces drug effects in rats, the rats have been in the estrus period. The LH peak in their proestrus is suppressed by negative feedback regulation and does not appear. The rats do not ovulate, and the male and female rats do not mate, thereby preventing the rats from becoming pregnant. However, the LH level in the blank tube group was not suppressed, and the LH peak before the estrus period still existed, and the rats could still estrus, mate, and conceive normally.

Note: * means P < 0.05 compared with the blank group.

In addition, the dose of the V dose group was consistent with that of the positive control group. The experiment found that the LH levels in the two groups of rats were also close (LH in the V group = 36.61 ± 2.43 IU·L ^-1 , LH in the positive control group = 39.91 ± 4.75 IU·L ^-1 ). Comparison of the LH levels in the two groups of rats revealed that there was no significant difference (P > 0.05), indicating that the implant prepared in this study was equivalent to the commercially available preparation of levonorgestrel silicone rod I in efficacy.

In addition, in the vaginal smear examination of rats in the I dose group, two rats were found to have estrus. The results of the LH measurement of the rats in this group are shown in Figure 16. The experiment found that the LH levels in rats No. 2 and No. 4 were close to the LH levels of rats in the blank group, while the LH levels of the remaining rats were significantly different from the LH levels of rats in the blank group (P<0.05). Combined with the results of the vaginal smear examination, it was shown that the levonorgestrel implants in these two rats did not produce drug effects. The reason is speculated that the implants of this specification (3mm/3.6mg) are too short in length of the core, and some implants have adhesives that infiltrate drug powders during preparation, which makes it difficult to release the drug, and the amount of drug released is insufficient, so the contraceptive effect is not achieved after being implanted in the rats.

4 Chapter Summary

(1) The experiment determined whether the rats were in estrus and had mating behavior by observing the vulva and vaginal smears of rats in different groups; the LH levels in rats in different groups were measured to study whether the levonorgestrel implant had a pharmacological effect in rats. The experiment found that the LH levels in rats in groups I, II, III, IV, V and the positive control group were significantly lower than those in the blank group (P<0.05), and the LH levels in rats decreased with the increase of the implant dose; rats in groups II, III, IV, V and the positive control group did not have estrus or mating behavior after the levonorgestrel implant was implanted.

(2) The experiment found that the LH level in rats with the same dose of implant as the positive control group was also close to that of the positive control group, with no significant difference (P>0.05), indicating that the implant prepared in this study is equivalent to the commercially available levonorgestrel silicone rod in efficacy.

(3) During the experiment, the rats had a normal lifestyle, diet, and weight gain, and the implant had no adverse effects on the rats.

III. Estradiol long-acting implant

1. Content determination and in vitro release determination method of estradiol long-acting implant

(1) Content determination method

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

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

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

Column temperature: 25°C

Detection wavelength: 202nm

Flow rate: 0.8 mL min-1

Injection volume: 20 μL

(2) Release determination method

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

2. Preparation and in vitro release study of estradiol reservoir implants

1. Instruments and reagents

1.1 Instrument

LC-10ATVP High Performance Liquid Chromatograph Shimadzu Corporation SMD200-2 Electronic Analytical Balance Ohaus International Trading Co., Ltd. AG245 Ultra-micro electronic balance type electronic analytical balance MettlerToledo Switzerland KQ-250DE CNC Ultrasonic Cleaner Kunshan Ultrasonic Instrument Co., Ltd. CHA-S Constant Temperature Oscillator Changzhou Guohua Electric Co., Ltd.

1.2 Materials

2 Experimental methods

2.1 Preparation of estradiol reservoir implants

The formula and preparation method of the silicone tube are as follows.

Material Name Dosage Methyl vinyl silicone rubber 100PHR Vinyl Content of Vinyl Polysiloxane 0.17mol% Fumed silica 30PHR Hydrogen silicone oil 1.01PHR Molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber 1.2:1 Hydrogen content of hydrogen silicone oil 0.75mol% 2-Methyl-3-butyn-2-ol 0.7PHR Platinum catalyst (3000ppm) 0.00001PHR

Different types of addition-type controlled-release silicone tubes were prepared by extrusion technology. The mechanical properties such as elongation at break, tensile strength, and tear strength were used as evaluation indicators. The prescription and process factors of the silicone tubes were investigated, and the final prescription of the silicone tubes was determined as follows: 100 PHR of methyl vinyl silicone rubber, 0.17 mol% of vinyl content of vinyl polysiloxane, 30 PHR of fumed silica, 1.01 PHR of hydrogenated silicone oil, a molar ratio of Si-H group in hydrogenated silicone oil to vinyl group in methyl vinyl silicone rubber of 1.2:1, 0.75 mol% of hydrogen in hydrogenated silicone oil, 0.7 PHR of 2-methyl-3-butyn-2-ol, and 0.00001 PHR of platinum catalyst (3000 ppm); the process conditions were: 300°C vulcanization temperature in the front drying oven (vulcanization time of about 5 s), 280°C vulcanization temperature in the rear drying oven (vulcanization time of about 2 min), and 180°C (48 h) of oven temperature. Silicone tubes with wall thickness of 0.2/0.4/0.6 mm were prepared.

The ends were sealed with adhesive and the drug was filled through the drug filling funnel after curing for 24 hours. After the filling was completed, the other end was sealed with KN-300N adhesive and cured for 24 hours. After the curing was completed, check for drug leakage. After confirming that there was no leakage, it was repeatedly cleaned with anhydrous ethanol for 30 seconds. The preparation was completed and a reservoir-type estradiol implant with an estradiol particle size _D50 of 9.5μm, a wall thickness of 0.2mm, an outer diameter of ^2.2-2.3mm , and a release area of 2.7±0.5cm2 was obtained.

2.2 Release conditions

The implantation site of the implant is mostly in the subcutaneous tissue of the human upper arm, where the pH is close to neutral, so pure water is selected as the release medium and a 37°C constant temperature oscillator is used as the release instrument to investigate the release behavior of the estradiol reservoir implant.

2.3 Investigation of in vitro release and influencing factors

2.3.1 Vulcanization temperature

In the process of preparing silicone tubes, the mechanical index of silicone tubes prepared by curing conditions of 300℃ in the front drying channel and 280℃ in the back drying channel is better, and the curing of silicone tubes is more complete. In order to further determine whether the curing conditions have an effect on the release of implant drugs, other conditions remain unchanged, silicone tubes with different curing temperatures are used to prepare implants for in vitro release experiments to examine the effect of curing temperature on the in vitro release behavior of drugs.

serial number Front drying oven temperature (℃) Post drying temperature (℃) Oven curing temperature (℃) Example 15-1 (300-280) 300 280 180 Example 15-2 (300-260) 300 260 180 Example 15-3 (280-280) 280 280 180

2.3.2 Silicone tube wall thickness

The effect of the wall thickness of the silicone tube on the in vitro release behavior of the drug was investigated. Based on the silicone tubes with wall thicknesses of 0.2 mm, 0.4 mm, and 0.6 mm obtained above, implants with the same length and outer diameter were prepared, and their in vitro release data were measured to investigate the effect of the wall thickness of the silicone tube on the in vitro release of the implant.

serial number Silicone tube outer diameter/mm Silicone tube wall thickness/mm Length containing medicine/cm Example 16-1 (0.2) 2.2 0.2 4 Example 16-2 (0.4) 2.2 0.4 4 Example 16-3 (0.6) 2.2 0.6 4

2.3.3 Drug release area

Silicone implants control drug release through a cylindrical silicone tube. The drug release area can be expressed by the following formula:

S＝πd×L

In the formula: d is the inner diameter of the silicone tube, and L is the length of the drug-containing section.

From the formula, we can know that the drug release area can be changed by changing the length of the drug-containing segment and the inner diameter of the silicone tube. Considering that changing the length of the drug-containing segment is more concise and convenient, this experiment fixed the outer diameter of the silicone tube to 2.4mm and the wall thickness to 0.2mm, and tightly filled the estradiol implants with drug-containing lengths of 1, 2, 3, 4, and 5cm for in vitro release, and investigated the change of in vitro drug release with drug-containing length.

serial number Silicone tube outer diameter/mm Silicone tube wall thickness/mm Drug release area/ ^cm2 Example 17-1 2.2 0.2 0.69 Example 17-2 2.2 0.2 1.38 Example 17-3 2.2 0.2 2.07 Example 17-4 2.2 0.2 2.76 Example 17-5 2.2 0.2 3.45

2.4 Long-term in vitro release experiment of estradiol reservoir implant

After determining the wall thickness and formulation of the silicone tube, vulcanization temperature, drug loading, and drug release area in the implant, three batches of optimal preparations were prepared to investigate their long-term stable release and observe the trend of daily release.

The preparation and prescription of the silicone tube are the same as those in 2.1. The other preparation conditions are as follows: the curing conditions are 300°C for the front drying oven (curing time is about 5s), 280°C for the rear drying oven (curing time is about 2min), and the oven temperature is 180°C (time 48h). The prepared silicone tube has a wall thickness of 0.2mm. The particle size D ₅₀ of estradiol is 9.5μm.

3 Results and discussion

3.1 Preparation of estradiol reservoir implants

Reservoir-type implants of different specifications were prepared, with good appearance, uniform sealing positions, and uniform drug filling in drug-containing sections.

3.2 Investigation of factors affecting in vitro release

3.2.1 Vulcanization conditions

The results show that the change of the vulcanization temperature of the silicone tube has no obvious effect on the average daily drug release of the implant and the fluctuation is not large. Therefore, silicone tubes with better mechanical properties are selected for the preparation of implants, that is, silicone tubes prepared under the vulcanization conditions of 300℃ in the front drying channel and 280℃ in the rear drying channel.

3.3.2 Silicone tube wall thickness

The results showed that the in vitro release of estradiol reservoir implants prepared from three silicone tubes with different wall thicknesses gradually decreased with the increase of wall thickness when the outer diameter and release area were controlled. In order to ensure the drug release, the wall thickness should be reduced as much as possible, but in actual operation, the silicone tube with a wall thickness of 0.2 mm is already the limit. If the wall thickness is reduced further, it is difficult to ensure the smooth extrusion of the silicone tube, so the silicone tube with a wall thickness of 0.2 mm was finally used.

3.3.3 Investigation of the drug release area of silicone tube

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

The results showed that the daily drug release of the estradiol reservoir implant increased with the increase of the release area. In order to further determine the relationship between the release area and the drug release of the implant, the drug release and release area of the five groups of preparations were analyzed, and the results shown in Figure 16 were obtained.

According to the fitted equation and graph, the drug release amount is linearly related to the release area, and the drug release amount increases with the increase of the release area. According to this relationship, the drug release amount can be regulated by fixing the outer diameter and wall thickness of the silicone tube and adjusting the release area. In practical applications, due to the large individual differences among patients, different specifications of estradiol reservoir implants can be produced during production to achieve personalized drug delivery, reduce side effects, and achieve maximum benefits according to different needs.

3.4 Long-term in vitro release of estradiol implants

Final Formulation Three batches of reservoir implants were prepared under the same conditions (refer to 2.4 Estradiol Reservoir Implants in this section) and subjected to long-term in vitro release experiments at 37°C and a shaking speed of 100 r·min ^-1 . The results are shown in the following table.

The results showed that although the daily release of the three batches of implants fluctuated in the early stage, it gradually remained stable in the later stage, and the average daily in vitro drug release was stable in the range of 10-15μg, with similar trends and good reproducibility. By consulting the literature, it was learned that the current estradiol supplementation treatment, the commonly used supplementary dose is 20-40μg estradiol per day, and two implants can achieve the therapeutic effect, which is in line with the experimental expectations.

IV. Four membrane-controlled long-acting implants

1. Preparation of membrane-controlled long-acting implants

The membrane-controlled implant is composed of an addition-type silicone tube and a powder-type drug core. The silicone tube is made by adding a reinforcing agent to methyl vinyl silicone rubber, and then adding hydrogen-containing silicone oil, inhibitors, and catalysts as compounding agents to make a mixed rubber, which is then vulcanized at high temperature through an extrusion process. The drug core is made by directly mixing drug powder with auxiliary materials. Finally, the evenly mixed drug powder is filled into the silicone tube, and the silicone tube filled with drug-auxiliary powder is sealed with a sealing glue to prepare a membrane-controlled long-acting implant.

(1) The formula of addition type silicone tube is:

The basic formula of silicone tube is base polymer, reinforcing agent, cross-linking agent, catalyst and inhibitor. The selected base polymer is methyl vinyl polysiloxane, and the vinyl content is 0.18% to 0.23%; the reinforcing agent is fumed silica, and the addition amount is 30 to 50 PHR; the cross-linking agent is hydrogenated silicone oil, and the addition amount is 0.3 to 2.0 PHR; the concentration of platinum catalyst is 3000 ppm, and the addition amount is 0.000002 to 0.5 PHR; the inhibitor is 2-methyl-3-butyn-2-ol, and the addition amount is 0.03 to 2.0 PHR.

The specific formula is as follows.

(2) The preparation process of the addition type silicone tube is:

① Drying pretreatment of the rubber material: Place the reinforcing agent fumed silica in a 130℃ oven and dry it for 12-24 hours for use; dry the methyl vinyl silicone rubber raw rubber at 40℃ for 12-24 hours for use.

② Preparation of rubber mix: Put the prescribed amount of fumed silica and methyl vinyl silicone rubber raw rubber into a kneader, mix the fumed silica and raw rubber evenly, then take out the rubber mix to get the rubber mix, transfer it to an open mixing mill for extrusion and thinning, use the shearing action of the two rollers of the mixing mill to further mix the rubber, then unload the rubber from the mixing mill in the form of a thin sheet, wrap the rubber with plastic wrap and put it into a ziplock bag, put it in a desiccant and leave it for 12-24 hours for use.

③ Preparation of components A and B: The rubber mixture is divided into two components A and B. Add the prescribed amount of hydrogenated silicone oil and inhibitor to component A, mix it in an open mill, and then pass it through several times to unload it in the form of thin slices. Add the prescribed amount of platinum catalyst to component B, mix it in an open mill, and then pass it through several times to unload it in the form of thin slices. Wrap the prepared components A and B with plastic wrap, put them into self-sealing bags, and put them in a desiccator for 12-24 hours for use.

④ Mixing of components A and B: Put the parked components A and B into the mixing mill at a ratio of 1:1, and make a triangular package 4 to 6 times to make the components A and B fully mixed. Unload them in the form of slices on the mixing mill and cut them into strips.

⑤ Extrusion of silicone tube: Install a mold of appropriate size, set the extruder screw speed, put the cut silicone strips into the extruder, and the rubber is continuously extruded into a silicone tube through the mold mouth under the push of the rotating screw.

⑥ 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 (temperature is 300°C, vulcanization time is about 5s), so that the silicone tube quickly changes from a sticky and soft state to an elastic state, and is initially shaped.

⑦ Second vulcanization treatment: After the first vulcanization, it enters the post-drying tunnel (horizontal hot air vulcanization channel) to continue vulcanization, which is the second vulcanization treatment (temperature is 280°C, vulcanization time is about 2 minutes), so that the vulcanization reaction of the silicone tube is more complete and reaches the optimal cross-linking state. The finished silicone tube is continuously transported out through the conveyor belt of the post-drying tunnel; after oven vulcanization at 180°C for 48 hours, a silicone tube with a wall thickness of 0.2 mm is prepared.

(3) The formula of powder type core is as shown in the following table.

Note: The content percentages of raw materials, poorly soluble excipients and poorly soluble pH adjusters in the above table refer to the mass percentage in the drug core; the total mass of the drug core is 80 mg; the particle size D50 of ibuprofen is 80 μm; the particle size D50 of pariperidone is 10 μm; the particle size D50 of meloxicam is 80 μm; and the particle size D50 of puerarin is 80 μm.

(4) Treatment of silicone tubes: Take addition-type silicone tubes (outer diameter 2.4 mm, inner diameter 1.6 mm) with qualified appearance and various performances, cut them into the same length of 44 mm, put them into a 100 mL beaker, add appropriate amount of distilled water and ultrasonicate for 30 min. After ultrasonication, rinse them with distilled water three times, then clean them with 75% ethanol and air-dry them naturally for use.

(5) Preparation of implant: Seal one end of the silicone tube and let it dry. Use a tool to fill 80 mg of the drug composition powder into the silicone tube at the other end, and then seal it with end-sealing glue. After the end-sealing glue is cured, shake the silicone tube to mix the drug excipients in the tube evenly. Finally, clean the powder on the outside of the silicone tube.

2. Content determination and in vitro release determination methods of membrane-controlled long-acting implants

(1) Ibuprofen

Chromatographic conditions

Chromatographic column: C18 column (4.6 mm × 150 mm, 5 μm);

Mobile phase: methanol: 1% sodium acetate buffer (70:30, v/v);

Column temperature: 35°C;

Detection wavelength: 273nm;

Flow rate: 1.0 mL min ^-1 ;

Injection volume: 20 μL.

Release determination method

The release experiment adopts the horizontal oscillation method. Take one implant and fix the two ends of the implant to the bottom and wall of a 20mL vial with a silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it for 12 hours to allow the silicone adhesive to cure completely. Accurately measure 15mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it. The temperature is set to 37℃ and the amplitude is 100r·min ^-1 . Replace the same volume of medium every 24 hours. The release liquid is filtered with a 0.22μm microporous filter membrane and detected according to the above chromatographic conditions. The injection volume is 20μL.

(2) Paliperidone

Chromatographic conditions

Chromatographic column: C8 column (4.6 × 100 mm, 2.7 μm);

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

Column temperature: 35°C;

Detection wavelength: 270nm;

Flow rate: 0.8 mL min ^-1 ;

Injection volume: 20 μL.

Release determination method

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

(3) Meloxicam

Chromatographic conditions

Chromatographic column: C18 column (4.6 mm × 150 mm, 5 μm);

Mobile phase: methanol: 0.5% phosphoric acid aqueous solution (70:30, v/v);

Column temperature: room temperature;

Detection wavelength: 270nm;

Flow rate: 1.0 mL min ^-1 ;

Injection volume: 20 μL.

Release determination method

The release experiment adopts the horizontal oscillation method. Take one implant and fix the two ends of the implant to the bottom and wall of a 20mL vial with a silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it for 12 hours to allow the silicone adhesive to cure completely. Accurately measure 15mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it. The temperature is set to 37℃ and the amplitude is 100r·min ^-1 . Replace the same volume of medium every 24 hours. The release liquid is filtered with a 0.22μm microporous filter membrane and detected according to the above chromatographic conditions. The injection volume is 20μL.

(4) Puerarin

Chromatographic conditions

Chromatographic column: _C18 column (4.6 mm × 250 mm, 5 μm);

Mobile phase: methanol: water (70:30, v/v);

Column temperature: 35°C;

Detection wavelength: 250nm;

Flow rate: 1.0 mL min ^-1 ;

Injection volume: 20 μL.

Release determination method

The release experiment adopts the horizontal oscillation method. Take one implant and fix the two ends of the implant to the bottom and wall of a 20mL vial with a silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it for 12 hours to allow the silicone adhesive to cure completely. Accurately measure 15mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it. The temperature is set to 37℃ and the amplitude is 100r·min ^-1 . Replace the same volume of medium every 24 hours. The release liquid is filtered with a 0.22μm microporous filter membrane and detected according to the above chromatographic conditions. The injection volume is 20μL.

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

(1) Ibuprofen

(2) Meloxicam

(3) Paliperidone

(4) Puerarin

Claims (10)

1. The preparation method of the silica gel material is characterized by comprising the following steps of molding a mixture of raw material compositions of the silica gel material through a catalytic addition process; wherein:

(1) The raw material composition of the silica gel material comprises the following components in parts by weight:

r-vinyl silicone rubber: 100 parts;

reinforcing agent: 20-80 parts of a lubricant;

hydrogen-containing silicone oil: 0.3-3.0 parts;

catalyst: more than or equal to 0.000002 part, preferably 0.000002 to 0.00005 part;

wherein:

r in the R-vinyl silicone rubber is substituted or unsubstituted C ₁ -C ₅ Linear or branched alkanes, substituted or unsubstituted C ₆ -C ₂₀ Aromatic hydrocarbons;

the vinyl content of the R-vinyl silicone rubber is 0.10-0.50mol%;

the content of Si-H groups in the hydrogen-containing silicone oil is 0.18 to 1.6mol percent;

the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-4) 1;

optionally, the adhesive further comprises an inhibitor, wherein the inhibitor is capable of inhibiting the addition reaction of the R-vinyl silicone rubber and the hydrogen-containing silicone oil;

(2) The catalytic addition process sequentially comprises a first heat treatment and a second heat treatment, wherein the temperature of the first heat treatment is 250-360 ℃, and the temperature of the second heat treatment is 120-300 ℃, such as 120-280 ℃.

2. The method for preparing a silica gel material according to claim 1, wherein the raw material composition of the silica gel material satisfies one or more of the following conditions:

(1) The R-vinyl silicone rubber is methyl vinyl silicone rubber; the methyl vinyl silicone rubber can be methyl vinyl silicone rubber with a relative molecular weight of 100000-800000 g/mol;

(2) the vinyl content of the R-vinyl silicone rubber is 0.10 to 0.23mol%, for example 0.17mol% or 0.23mol%, preferably 0.17 to 0.23mol%;

(3) the reinforcing agent is one or more of white carbon black, diatomite, quartz powder, silica fume, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, ferric oxide, titanium dioxide, zirconium silicate and calcium carbonate, such as white carbon black; the white carbon black can be gas phase white carbon black, precipitation white carbon black, gel white carbon black or surface treatment white carbon black;

(4) the reinforcing agent is used in an amount of 30 to 80 parts, for example, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts or 60 parts;

(5) the hydrogen-containing silicone oil is used in an amount of 0.4 to 2.8 parts, for example, 0.42 parts, 0.67 parts, 0.84 parts, 1.01 parts, 1.26 parts, 1.36 parts, 1.51 parts, 1.68 parts, or 2.52 parts;

(6) the content of Si-H groups in the hydrogen-containing silicone oil is 0.36 to 1.6mol%, for example 0.36mol%, 0.5mol%, 0.75mol%, 1.0mol% or 1.6mol%;

(7) the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is (0.8-4): 1, for example 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1, 2:1 or 3:1, preferably (1.2-1.8): 1 or (1.2-1.5): 1;

(8) The inhibitor is an alkynol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, and also such as 2-methyl-3-butyn-2-ol;

(9) the inhibitor is used in an amount of 0.03 to 2.0 parts, for example 0.3 to 1.0 parts, further for example 0.3 parts, 0.5 parts, 0.7 parts or 0.9 parts;

wherein the catalyst is a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst; the concentration of platinum in the platinum catalyst may be 3000ppm,3000ppm referring to the mass concentration of platinum in the platinum catalyst being 3000 parts per million; and the catalyst is used in an amount of 0.000005 to 0.00005 parts, for example 0.000005 parts, 0.00001 parts, 0.00002 parts or 0.00003 parts.

3. The method for preparing the silica gel material according to claim 1, wherein:

(1) The raw material composition of the silica gel material comprises the following components in parts by weight:

methyl vinyl silicone rubber: 100 parts;

reinforcing agent: 20-80 parts of a lubricant;

hydrogen-containing silicone oil: 0.3-3.0 parts;

catalyst: 0.000002-0.00005 parts;

inhibitors: 0.03-2.0 parts;

wherein:

the vinyl content of the methyl vinyl silicone rubber is 0.10-0.50mol%;

the content of Si-H groups in the hydrogen-containing silicone oil is 0.18 to 1.6mol percent;

the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is (0.5-4) 1;

Or,

(2) The raw material composition of the silica gel material comprises the following components in parts by weight:

methyl vinyl silicone rubber: 100 parts;

reinforcing agent: 30-60 parts;

hydrogen-containing silicone oil: 0.4-2.8 parts;

catalyst: 0.000002-0.00005 parts;

inhibitors: 0.3-1.0 parts;

wherein:

the vinyl content of the methyl vinyl silicone rubber is 0.17-0.23mol%;

the content of Si-H groups in the hydrogen-containing silicone oil is 0.18 to 1.6mol percent;

the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is (0.8-2) 1;

or,

(3) The raw material composition of the silica gel material comprises the following components in parts by weight:

methyl vinyl silicone rubber: 100 parts;

reinforcing agent: 30-45 parts;

hydrogen-containing silicone oil: 0.42-2.52 parts;

catalyst: 0.000002-0.00005 parts;

inhibitors: 0.3-0.9 part;

wherein:

the vinyl content of the methyl vinyl silicone rubber is 0.17-0.23mol%;

the content of Si-H groups in the hydrogen-containing silicone oil is 0.5-1.0mol%;

the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is (1.2-1.8): 1.

4. A method of preparing a silica gel material according to any one of claims 1 to 3, wherein the mixture of the raw material composition of the silica gel material is prepared by any one of the following methods:

(1) The method comprises the following steps: a method of preparing a mixture of the raw material composition of the silica gel material as claimed in any one of claims 1 to 3, when the raw material composition of the silica gel material does not include an inhibitor, comprising the steps of:

s1: uniformly mixing the R-vinyl silicone rubber according to any one of claims 1-3 and the reinforcing agent according to any one of claims 1-3 to obtain a mixture A;

s2: mixing said mixture a with a hydrogen-containing silicone oil according to any one of claims 1 to 3 in the presence of a catalyst according to any one of claims 1 to 3 to obtain a mixture B;

(2) The second method is as follows: when the raw material composition of the silica gel material according to any one of claims 1 to 3 further comprises an inhibitor, the preparation method of the mixture of the raw material composition of the silica gel material comprises the steps of:

s1: uniformly mixing the R-vinyl silicone rubber according to any one of claims 1-3 and the reinforcing agent according to any one of claims 1-3 to obtain a mixture A;

s2: dividing the mixture a into a component A1 and a component A2, mixing the component A1 with the catalyst according to any one of claims 1 to 3 to obtain a component B1, mixing the component A2 with the hydrogen-containing silicone oil according to any one of claims 1 to 3 and the inhibitor according to any one of claims 1 to 3 to obtain a component B2;

S3: and mixing the component B1 and the component B2 to obtain a mixture B.

5. The method for preparing a silica gel material according to claim 4, wherein the method for preparing a mixture of raw material compositions of the silica gel material satisfies one or more of the following conditions:

(1) in the first and second methods, the reinforcing agent is pretreated by the following method: drying at 100-210 deg.C for 1-24 hr;

(2) in the first and second methods, the R-vinyl silicone rubber is pretreated by the following method: drying at 30-60deg.C for 1-24 hr;

(3) in the first and second methods, the step of mixing in S1 is as follows: after wrapping the reinforcing agent with the R-vinyl silicone rubber, extruding and thinning the reinforcing agent by an open mill, and tabletting the reinforcing agent;

or in the first and second methods, the step of mixing in S1 is: kneading the R-vinyl silicone rubber and the reinforcing agent in a kneader at 30 ℃ for 30min, and then taking out; rolling the triangular bag thin pass on an open mill for 5 times with a roll gap of 1-10mm, and then placing the triangular bag thin pass for 24 hours to obtain a mixture A;

(4) in the first method, before the catalytic addition, the mixture B is subjected to the following post-treatments: the triangular bag thin pass is made in an open mill for 4 to 6 times, and then the materials are evenly cut and the sheets are discharged; and

(5) In the second method, the step of mixing the component B1 and the component B2 is: and (3) putting the component B1 and the component B2 into an open mill according to a ratio of 1:1, opening the triangular bag for 4-6 times, and then uniformly blanking and blanking.

6. A method of preparing a silica gel material according to any one of claims 1 to 3, wherein the temperature of the first heat treatment is 250 to 330 ℃, such as 270 ℃, 280 ℃, 300 ℃ or 330 ℃;

and/or the temperature of the second heat treatment is 150-300 ℃, such as 150-280 ℃, also such as 150 ℃, 180 ℃, 210 ℃, 260 ℃, or 280 ℃;

and/or, after the second heat treatment, performing a third heat treatment; the temperature of the third heat treatment may be 100-280 ℃, for example 180 ℃; the time of the third heat treatment is preferably 0 to 72 hours, but not 0, for example 24 hours, 48 hours or 72 hours.

7. A silica gel material produced by the production method of the silica gel material according to any one of claims 1 to 6.

8. The silica gel tube is characterized by being prepared by the following method;

forming the silica gel material according to claim 7 into a tube shape through an extrusion process;

alternatively, in the method for preparing a silicone rubber material according to any one of claims 1 to 6, the catalytic addition process is performed in a tubular mold, and the silicone rubber tube is obtained.

9. An implant comprising a drug core and the silicone tube of claim 8, the drug core comprising a pharmaceutically active ingredient therein, wherein:

the pharmaceutically active ingredients may include pharmaceutically active ingredients acting on the reproductive system, which may include pharmaceutically active ingredients for contraception, which may include levonorgestrel, gestodene; the pharmaceutically active ingredient acting on the reproductive system may include steroidal estrogens, such as estradiol;

the medicine active ingredient can be medicine active ingredient with medicine solubility less than or equal to 100mg/mL and medicine molecular weight less than 1000 Da; such as one or more of levonorgestrel, gestodene, estradiol, ibuprofen, paliperidone, meloxicam, puerarin;

the medicine active ingredient can be medicine active ingredient with solubility less than or equal to 60mg/mL and medicine molecular weight less than 1000 Da;

the medicine active ingredient can be medicine active ingredient with solubility less than or equal to 50mg/mL and medicine molecular weight less than 1000 Da;

the medicine active ingredient can be medicine active ingredient with solubility less than or equal to 10mg/mL and medicine molecular weight less than 1000 Da;

The medicine active ingredient can be medicine active ingredient with solubility less than or equal to 5mg/mL and medicine molecular weight less than 1000 Da;

the drug core may be a powder type drug core;

the outer diameter of the silicone tube is preferably 2.0-5.0mm, for example 2.4mm or 2.6mm;

the length of the silicone tube is preferably 1.5-4.5cm, for example 1.9cm or 4.4cm;

the wall thickness of the silicone tube is preferably 0.2-0.5mm, for example 0.3mm, 0.4mm or 0.5mm;

the medicine release area of the silicone tube is preferably 0.4-15.0cm ² For example 0.69cm ² 、1.38cm ² 、2.07cm ² 、2.76cm ² Or 3.45cm ² ；

The diameter of the core is preferably 1.5-4.0mm, for example 1.6mm or 2.0mm;

the length of the core is preferably 1.0-4.0cm, for example 1.5cm or 3.9cm.

10. Use of the silica gel material according to claim 7 or the silica gel tube according to claim 8 as a release rate controlling medium in a sustained and controlled release formulation.