CN116808314A

CN116808314A - Silica gel material, preparation method thereof, silica gel tube and implant containing silica gel tube

Info

Publication number: CN116808314A
Application number: CN202310271569.0A
Authority: CN
Inventors: 杨星钢; 皮琳玲; 于红; 申瑞; 孙远航
Original assignee: Shenyang Xinghua Medical Technology Co ltd; Shenyang Pharmaceutical University
Current assignee: Shenyang Xinghua Medical Technology Co ltd; Shenyang Pharmaceutical University
Priority date: 2022-03-18
Filing date: 2023-03-20
Publication date: 2023-09-29

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

Silica gel material, preparation method thereof, silica gel tube and implant containing silica gel tube

The present application claims priority from China patent application 2022102727087 with the application date 2022/3/18. The present application incorporates the entirety of the above-mentioned chinese patent application.

Technical Field

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

Background

Modern common methods of contraception include non-hormonal contraception (male/female condoms, male/female sterilization, etc.) and hormonal contraception (various oral contraceptives, subcutaneous implants, progestogens intrauterine devices, contraceptive needles, etc.). Among them, hormonal drug contraceptive methods have been shown to have reliable contraceptive effects.

After the concept of 'sustained and controlled release preparation', the sustained and controlled release preparation for contraception has been developed greatly, the problems of injury of operation contraception and low compliance of oral contraceptive are effectively avoided, and the sustained and controlled release preparation capable of long-acting contraception, in particular the subcutaneous contraception implant, has very broad prospect in the field of contraception.

Levonorgestrel (LNG) is also known as Levonorgestrel, and the like, and has been received from national formulary in China, the United states, the United kingdom, japan, and the like. The single tablet and the compound contraceptive taking the levonorgestrel as the main drug which are marketed in the international and domestic markets are a lot, and are the most widely used non-prescription drugs in clinical application.

The gestodene is a third-generation contraceptive, can achieve contraceptive effect in small clinical dosage, has no any estrogen activity, has good antiestrogen activity and slight androgen activity, has the bioavailability of 100 percent, and is the only progestogen which can play a role without metabolism at present.

The subcutaneous implant is mainly prepared by placing active drugs in a carrier, implanting the active drugs under the skin, controlling the release of the drugs by the carrier, and enabling the drugs to enter blood circulation through local capillary absorption, thus realizing stable release for several years and achieving long-acting contraceptive effect. The preparation avoids first pass effect of gastrointestinal tract, thereby greatly improving bioavailability of the medicine. The subcutaneous implant is suitable for people who want to perform long-term contraception and are not suitable for placing IUD, and after implantation, if pregnancy will occur, the gestational ability can be recovered after the implant is taken out.

Organosilicon materials are one of the materials with the best biocompatibility in the synthetic materials nowadays, organosilicon has been confirmed as an important implant material by medical textbooks in the 60 th century, and practical application is very wide, and the american dow corning company has provided a great deal of literature reports to prove the safety of implanting a silicone gel breast into a human body, and along with research on organosilicon materials, the application of the organosilicon materials in the medical field is more and more wide. A large number of animal experiments are carried out by researchers, adverse reactions are not seen for 3 years when the silicon material is implanted into the animal body, and the safety of the implantation of the silicon material into the human body is gradually proved to be good.

At present, the silicone rubber products which are applied to the production of medical products, in particular to the silicone rubber products which are to be embedded in human bodies for a long time, generally adopt addition type silicone rubber, and the addition type silicone rubber is mainly applied to various occasions of contact with blood and embedding in the human bodies. The existing silicone rubber is generally prepared by a simple extrusion process, such as the preparation process disclosed in chinese patent CN 1727409 a. The silicon rubber tube prepared by the addition method has poor mechanical property and is difficult to meet clinical use requirements.

Disclosure of Invention

The invention aims to overcome the defects that the silicon rubber tube prepared by the addition method in the prior art is poor in mechanical property and difficult to meet clinical use requirements, and provides a silicon rubber material, a preparation method thereof, a silicon rubber tube and an implant containing the silicon rubber tube. The silica gel tube prepared by the silica gel material has excellent mechanical property and good biocompatibility; the implantation agent prepared by the silica gel has stable drug release curve, and can produce obvious contraceptive effect on rats when the loaded drug is contraceptive (such as gestodene and levonorgestrel).

The invention provides a preparation method of a silica gel material, which comprises 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 ℃.

In the present invention, the R-vinyl groupR in the silicone rubber may be substituted or unsubstituted C ₁ -C ₅ Straight chain alkanes such as methyl.

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

Wherein the methyl vinyl silicone rubber may be a methyl vinyl silicone rubber conventional in the art, such as a methyl vinyl silicone rubber having a relative molecular weight of 100000 to 800000 g/mol.

In the present invention, the vinyl group content in the R-vinyl silicone rubber is preferably 0.10 to 0.23mol%, for example 0.17mol% or 0.23mol%, more preferably 0.17 to 0.23mol%.

In the present invention, the reinforcing agent may be one or more of reinforcing agents conventional in the art, such as white carbon black, diatomaceous earth, quartz powder, fine silica powder, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium white, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate and calcium carbonate, for example white carbon black, which can improve the hardness of the R-vinyl silicone rubber.

The white carbon black may be a white carbon black conventional in the art, for example, a vapor phase white carbon black, a precipitated white carbon black, a gel white carbon black or a surface-treated white carbon black, and is preferably a vapor phase white carbon black. The fumed silica can be fumed silica purchased from Dalian Cheng Sen nanometer silicon carbon materials company.

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

In the present invention, the reinforcing agent is preferably used in an amount of 30 to 80 parts, for example, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts or 60 parts.

In the present invention, the hydrogen-containing silicone oil may be a hydrogen-containing silicone oil conventional in the art, such as a hydrogen-containing silicone oil available from Guangdong silicon light New Material technology Co.

In the present invention, the hydrogen-containing silicone oil is preferably 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.

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

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 an inhibitor capable of inhibiting the addition reaction of methyl vinyl silicone rubber and hydrogen-containing silicone oil at ordinary temperature, which is conventional in the art, such as an alkynol compound, a nitrogen-containing compound or an organic peroxide, further such as methylbutinol, further such as 2-methyl-3-butyn-2-ol.

In the present invention, the inhibitor is preferably 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.

In the present invention, the catalyst may be a catalyst which is conventional in the art and can catalyze the addition reaction of 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.

Wherein the concentration of platinum in the platinum catalyst may be 3000ppm,3000ppm means that the mass concentration of platinum in the platinum catalyst is 3000 ppm.

In the present invention, the catalyst is preferably 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.

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 to 330 ℃, for example 270 ℃, 280 ℃,300 ℃ or 330 ℃.

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

In the present invention, the temperature of the second heat treatment may be 150 to 300 ℃, such as 150 to 280 ℃, for example 150 ℃, 180 ℃, 210 ℃, 260 ℃, or 280 ℃.

In the present invention, the time of the second heat treatment is related to the treatment length in the catalytic addition process, for example, 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 2 minutes.

In the present invention, the second heat treatment may be followed by a third heat treatment.

Wherein the temperature of the third heat treatment may be 100-280 ℃, for example 180 ℃.

Wherein the time of the third heat treatment is preferably 0 to 72 hours, for example 0 hours, 24 hours, 48 hours or 72 hours.

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

In the invention, the catalytic addition process can be extrusion molded in a tubular mold. The silicone material is tubular when extruded in a tubular die.

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

the method comprises the following steps: when the raw material composition of the silica gel material does not comprise 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: mixing the mixture A and the hydrogen-containing silicone oil in the presence of the catalyst to obtain a mixture B;

the second method is as follows: when the raw material composition of the silica gel material further comprises an inhibitor, the preparation method of the silica gel material comprises the following steps:

s2: dividing the mixture A into a component A1 and a component A2, mixing the component A1 with the catalyst to obtain a component B1, and mixing the component A2 with the hydrogen-containing silicone oil and the inhibitor to obtain a component B2;

s3: and mixing the component B1 and the component B2 to obtain a mixture B.

In the first and second methods, the reinforcing agent may be pretreated by a conventional method in the art, for example, dried at 100-210 ℃ (for example, 180-210 ℃, for example, 200 ℃) for 1-24 hours (for example, 24 hours) for standby.

In the first and second methods, the R-vinyl silicone rubber may be pretreated by a method conventional in the art, for example, oven-dried at 30-60 ℃ (e.g., 40 ℃) for 1-24 hours (e.g., 24 hours) for use.

In the first and second methods, the step of mixing in S1 may be:

And (3) wrapping the reinforcing agent by the R-vinyl silicone rubber, extruding and thinning by an open mill, and tabletting.

In the first method and the second method, the mixture A can be placed into a drier at room temperature and parked for 24-72 hours.

In the first and second methods, the step of mixing in S1 may be:

kneading the R-vinyl silicone rubber and the reinforcing agent in a kneader at 30 ℃ for 30min, and then taking out; and rolling and discharging the sheet on an open mill for 5 times by taking a triangular bag sheet with a roll spacing of 1-10mm (for example, 1 mm), and standing for 24 hours to obtain the mixture A.

Wherein, in the first method, before the catalytic addition process is performed, the mixture B may be subjected to the following post-treatment: and (3) punching a triangular bag thin pass for 4-6 times in an open mill, and then uniformly cutting materials and blanking.

Wherein, in the second method, the step of mixing the component B1 and the component B2 may be: 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.

In the present invention, the vulcanization principle of the two-component addition type silicone rubber: the double-component addition type room temperature vulcanized silicone rubber takes vinyl polydimethylsiloxane as a base polymer, hydrogen-containing silicone oil as a cross-linking agent, and under the catalysis of a catalyst (such as a platinum catalyst), the vinyl and hydrogen groups undergo hydrosilylation reaction to form a cross-linked network structure, the cross-linked structure can control drug release, and the reaction formula is shown below.

Because the acting force among the molecules of the polyorganosilane is small, the raw rubber is poor in mechanical property and has no use value after being vulcanized independently, in order to improve the mechanical property, the raw rubber is generally reinforced by a filler, and the white carbon black is the most commonly used reinforcing filler, so that the hardness of the silica gel material can be greatly improved, wherein the fumed silica subjected to silation treatment is easy to disperse in the silica gel material due to hydrophobic surface, and the reinforcing effect is better.

The raw rubber, the filler, the cross-linking agent and the catalyst can react at room temperature after being mixed, and the mixing and processing of the rubber material need a certain time, and the reactants cannot obtain the required shape and property if being cured in advance in operation. This is especially true for addition type silicone rubber. Thus, it is generally required that the catalytic reaction hardly acts before vulcanization (mixing at room temperature) and reacts rapidly to reach the vulcanization temperature. The reaction is usually inhibited by adding inhibitors. The inhibitor can form a complex with the platinum catalyst, and the effective inhibitor can be placed with the sizing material for a long time, and can be vulcanized only by heating to a certain vulcanization temperature. The use of alkynols, nitrogen compounds, organic peroxides, etc. which are more commonly used and have 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 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 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.

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 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.

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.

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 extrusion molded in a tubular mold, the silica gel material is tubular.

The invention also provides a silicone tube which is prepared by the following method;

extruding the silica gel material into a tube shape;

or in the preparation method of the silica gel material, the catalytic addition process is performed in a tubular mold, and the silica gel tube is obtained.

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

Wherein, the active pharmaceutical ingredient can be a small molecular drug with lower solubility, for example, the solubility of the drug is less than or equal to 100mg/mL (water is taken as solvent), and the molecular weight of the drug is less than 1000 Da; also for example, one or more of levonorgestrel, gestodene, estradiol, ibuprofen, paliperidone, meloxicam, puerarin.

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

The pharmaceutically active ingredient can be a pharmaceutically active ingredient with a solubility less than or equal to 50mg/mL (water is used as a solvent) and a drug molecular weight less than 1000Da, such as levonorgestrel, gestodene, estradiol, paliperidone, meloxicam or puerarin.

The pharmaceutically active ingredient can be a pharmaceutically active ingredient with a solubility less than or equal to 10mg/mL (water is used as a solvent) and a drug molecular weight less than 1000Da, such as levonorgestrel, gestodene, estradiol, meloxicam or puerarin.

The pharmaceutically active ingredient can be a pharmaceutically active ingredient with a solubility less than or equal to 5mg/mL (water is used as a solvent) and a drug molecular weight less than 1000Da, such as meloxicam or puerarin.

In the present invention, the pharmaceutically active ingredient in the bulk drug may include a pharmaceutically active ingredient acting on the reproductive system, or a pharmaceutically active ingredient acting on the urinary system, or a pharmaceutically active ingredient acting on chronic diseases related to metabolism and nutrition, or a pharmaceutically active ingredient for treating chronic diseases related to connective tissue and rheumatism, or a pharmaceutically active ingredient for treating hyperlipidemia, treating tumors, treating neuropsychiatric diseases, treating chronic odontopathy (caries, periodontal disease), treating simple obesity, treating chronic lumbago or treating leukemia, or a pharmaceutically active ingredient acting on the circulatory system, or a pharmaceutically active ingredient acting on the respiratory system, or a pharmaceutically active ingredient acting on the digestive system, or a pharmaceutically active ingredient acting on the blood system, or a pharmaceutically active ingredient acting on the endocrine system.

Wherein the pharmaceutically active ingredient acting on the reproductive system may comprise a pharmaceutically active ingredient for contraception or a steroid estrogen.

The pharmaceutically active ingredient for contraception may be conventional in the art and preferably comprises levonorgestrel, gestodene or gestodene.

The steroid estrogen is preferably estradiol.

Wherein, the medicine active ingredients acting on the urinary system preferably comprise medicine active ingredients for treating chronic nephritis, chronic renal failure or chronic prostatitis.

The active ingredient of the medicine for treating chronic prostatitis is preferably a non-steroidal anti-inflammatory drug, and more preferably ibuprofen. In general, the medicament for treating chronic prostatitis may be: antibiotics (e.g., fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracyclines), alpha-blockers (e.g., doxazosin, terazosin, etc.), non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac, loxoprofen, flurbiprofen ester, ketorolac, celecoxib, etc.), anti-pain drugs (e.g., acetaminophen, etc.), opioids (e.g., morphine, fentanyl, nalbuphine, pentazocine, etc.), anti-neuropathic pain drugs (e.g., 5-hydroxytryptamine, duloxetine, venlafaxine, etc.), anti-epileptics (e.g., pregabalin, etc.), M-receptor blockers (e.g., solifenacin, tolidine, etc.).

The medicines for treating chronic nephritis can be generally: angiotensin converting enzyme inhibitors (e.g., benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin ii receptor blockers (e.g., irbesartan, valsartan, losartan, etc.), calcium channel blockers (e.g., amlodipine, felodipine, nifedipine, etc.), beta receptor blockers (e.g., atenolol, bisoprolol, carvedilol, propranolol, etc.), diuretics (e.g., furosemide, spironolactone, hydrochlorothiazide, benflumethide, bumetanide, etc.), immunosuppressants (e.g., prednisone, nova, methylprednisolone, cyclophosphamide, dexamethasone, etc.), statin lipid-lowering agents (e.g., fluvastatin, simvastatin, pravastatin).

The medicines for treating chronic renal failure can be generally: angiotensin converting enzyme inhibitors (e.g., benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin ii receptor blockers (e.g., irbesartan, valsartan, losartan, etc.), diuretics (e.g., furosemide, spironolactone, hydrochlorothiazide, benflumethide, bumetanide, etc.), iron agents (ferrous fumarate, etc.), compound amino acids, alpha-keto acids, recombinant human erythropoietin.

Wherein the pharmaceutical active ingredients acting on the chronic diseases related to metabolism and nutrition preferably comprise pharmaceutical active ingredients for resisting diabetes, treating nutritional deficiency, resisting gout or resisting osteoporosis.

The anti-gout pharmaceutical active ingredient is preferably an anti-gout agent, such as colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, p-aminosalicylic acid, bissalicylates, benoride, and more preferably ibuprofen. In general, the anti-gout agents may also be uric acid excreting agent agents (e.g., benzbromarone, probenecid), uric acid synthesis blocking agent agents (e.g., allopurinol).

The antidiabetic agent may generally be an antidiabetic agent of type 1 (e.g., insulin), an antidiabetic agent of type 2. The anti-type 2 diabetes drug may be a sulfonylurea drug (e.g., glimepiride, gliquidone), a glinide drug (e.g., repaglinide, nateglinide), a metformin drug (e.g., metformin), an alpha-glucoglycanase inhibitor (e.g., acarbose, voglibose), a DPP-4 inhibitor (e.g., sitagliptin), a GLP-1 receptor agonist (e.g., liraglutide, exenatide), or a SGLT-2 inhibitor (e.g., dapagliflozin, engagliflozin).

The medicament for treating a nutritional deficiency may generally be a medicament for gastrointestinal disorders (e.g. omeprazole, mosapride), a supplemental nutritional medicament (e.g. vitamin E).

The anti-osteoporosis agents may typically be bisphosphonates (e.g., alendronate, ibandronate, pamidronate, aminobisphosphonates, disodium chlorophosphate, zoledronate, risedronate), calcitonin (e.g., salmon calcitonin), estrogens (e.g., estradiol benzoate, estradiol acetate, estradiol valerate), selective Estrogen Receptor Modulator (SERMs) agents (e.g., raloxifene, benzothiophene), RANKL inhibitor agents, parathyroid hormone agents, glutamine monofluorophosphate agents, strontium salt agents (e.g., strontium ranelate), active vitamin D and analogs (e.g., calcitriol, α -calcitol), vitamin K (e.g., menatetrenone).

Wherein the pharmaceutically active ingredient for treating chronic diseases involving connective tissue and rheumatism preferably comprises a pharmaceutically active ingredient for treating rheumatoid arthritis, treating systemic lupus erythematosus, treating ankylosing spondylitis, treating sjogren's syndrome, treating vasculitis, treating idiopathic inflammatory myopathy, treating systemic sclerosis, or treating osteoarthritis.

The pharmaceutically active ingredient for the treatment of rheumatoid arthritis is preferably a non-steroidal anti-inflammatory drug, such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, nabumetone, more preferably meloxicam or ibuprofen. In general, the drug for treating rheumatoid arthritis may be a glucocorticoid drug (e.g., hydrocortisone, dexamethasone, prednisone), a slow acting antirheumatic drug (e.g., methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide).

The pharmaceutically active ingredient for the treatment of osteoarthritis is preferably an analgesic, such as ibuprofen, furtalin, meloxicam, celecoxib, loxoprofen sodium nimesulide, more preferably ibuprofen or meloxicam. In general, the agent for treating osteoarthritis may be a cartilage-nourishing agent, an opioid (e.g., oxycodone, qimandin).

The drug for treating systemic lupus erythematosus can typically be a non-steroidal anti-inflammatory drug (e.g., naproxen, fenpride), an antimalarial drug, a glucocorticoid drug (e.g., prednisone acetate, methylprednisolone), an immunosuppressant drug (e.g., methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, maculol, tacrolimus), a biologic drug (e.g., rituximab, belicuteb).

The drug for treating ankylosing spondylitis may be generally a non-steroidal drug (such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, eremophilone), an anti-rheumatic drug for alleviating a disease (such as Liu Danhuang pyridine, methotrexate, hydroxychloroquine), a glucocorticoid drug (such as prednisone, prednisolone, deboropine), a biologic TNF-a antagonist (such as etanercept).

The drug for treating sjogren's syndrome may generally be systemic therapeutic drug (e.g., levamisole, transfer factor coenzyme Q10, thymosin), glucocorticoid drug (e.g., prednisone), immunosuppressive drug (e.g., hydroxychloroquine, azathioprine, iguratimod).

The drug for treating vasculitis may typically be a glucocorticoid drug (e.g., prednisone, methylprednisolone, dexamethasone), an immunosuppressant drug (e.g., cyclophosphamide, cyclosporine, azathioprine).

The agent for treating idiopathic inflammatory myopathy may typically be a glucocorticoid agent (e.g., dexamethasone, prednisone, hydrocortisone, methylprednisolone), an immunosuppressant agent (e.g., cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil).

The drug for treating systemic sclerosis can be generally anti-fibrosis drugs (such as colchicine,), vasoactive drugs (such as cardialgine and begonine), and other common drugs (such as naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nidanib and tolizumab).

Wherein, the active pharmaceutical ingredient for treating neuropsychiatric diseases can be generally used for treating schizophrenia, antidepressant, opioid abuse or anxiety; preferably, drugs for treating schizophrenia, more preferably phenothiazines (e.g., chlorpromazine), thioxanthenes (e.g., chlorprothixene), butyrylbenzenes (e.g., haloperidol), benzodiazepines (e.g., olanzapine, clozapine), benzisoxazoles (e.g., risperidone, paliperidone), benzisoxazoles (e.g., ziprasidone), benzothioazenes (e.g., quetiapine), quinolones (e.g., aripiprazole), and even more preferably benzisoxazoles (e.g., paliperidone).

The antidepressants may generally be tricyclic antidepressants (e.g., imipramine, chlorpromethazine, amitriptyline), monoamine oxidase inhibitors (e.g., molobetaine), selective 5-hydroxytryptamine reuptake inhibitors (e.g., sertraline), 5-hydroxytryptamine and norepinephrine reuptake inhibitors (e.g., venlafaxine), 5-hydroxytryptamine blocking and reuptake inhibitors (e.g., trazodone), norepinephrine and dopamine reuptake inhibitors (e.g., bupropion), norepinephrine inhibitors (e.g., reboxetine), alpha 2 adrenergic receptor blockers (e.g., mirtazapine).

The drug of abuse for the treatment of opioids may typically be buprenorphine or methadone.

The anxiety-treating drugs may generally be benzodiazepines (e.g. diazepam), 5-HT1A receptor partial agonists (e.g. buspirone), beta adrenergic receptor blockers (e.g. propranolol), valproate.

Wherein the therapeutic agent for treating hyperlipidemia can be generally statin (e.g. simvastatin, atorvastatin, pravastatin), fibrate (e.g. fenofibrate, bezafibrate, gemfibrozil), nicotinic acid (e.g. niacin).

Wherein the antineoplastic agent may typically be an anti-breast cancer agent (e.g., azacytidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol, cetuximab or leuprorelin), an anti-prostate cancer agent (e.g., degarelix, leuprorelin, histrelin, fluzamide, estramustine, cyproterone), an anti-ovarian cancer agent (e.g., carboplatin, topotecan, methotrexate), an anti-rectal cancer agent (e.g., panitumumab), an anti-colon cancer agent (e.g., bevacizumab, oxaliplatin), an anti-liver cancer agent (e.g., sorafenib), an anti-lung cancer agent (e.g., erlotinib, gefitinib), docetaxel, renal cancer agent (e.g., pazopanib, everin, tamarone), an anti-gastric cancer agent (e.g., fluorouracil, mitomycin, cisplatin, adriamycin), an anti-pancreatic cancer agent (e.g., fludarabine), an anti-tumor agent (e.g., 62, such as fludarabine), an anti-tumor agent (e.g., gezocine), an anti-tumor agent (e.g., gezotinib), a drug (e.g., gezotinib), a) such as fluzocine, a.

Wherein, the medicines for treating chronic odontopathy (such as dental caries and periodontal disease) can be generally classified into nitroimidazole medicines (such as metronidazole, tinidazole and ornidazole), penicillin medicines and other common medicines (minocycline and chlorhexidine acetate).

Wherein, the medicine active ingredient for treating chronic lumbago is preferably a non-steroidal analgesic, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, amoxicodeine and furostaurin, more preferably ibuprofen or meloxicam;

the drugs for treating leukemia are typically drugs that interfere with nucleic acid biosynthesis (e.g., cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect cancer cell DNA structure and function (e.g., busulfan, mitomycin, chlorambucil, melphalan, cyclophosphamide), drugs that interfere with the transcription process and prevent RNA synthesis (e.g., daunorubicin, doxorubicin, aclacinomycin), drugs that inhibit protein synthesis and function (e.g., vindesine, vincristine, levo-aspartyl, homoharringtonine), other common drugs (e.g., interferon, fludarabine, arsenite, etoposide, carmustine).

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

the pharmaceutically active ingredient for treating coronary heart disease may be generally a drug for improving angina symptoms, (e.g., puerarin, isosorbide mononitrate), an anti-platelet aggregation drug (e.g., aspirin, clopidogrel bisulfate, ticagrelor), a drug for reducing lipid-stabilizing plaques (e.g., atorvastatin, rosuvastatin, pravastatin), a drug for inhibiting sympathetic nerve activity (e.g., metoprolol, bisoprolol fumarate), a drug for improving myocardial remodeling (e.g., angiotensin converting enzyme inhibitors and angiotensin ii receptor antagonists); preferably a medicament for ameliorating the symptoms of angina pectoris, more preferably puerarin; the pharmaceutically active ingredient for the treatment of chronic heart failure may typically be a cardiotonic drug (e.g. digitalis, digoxin, sitagliptin), a vasodilator drug (e.g. sodium nitroprusside, nitroglycerin, invertase inhibitors (e.g. enalapril, minopril, etc.), a diuretic drug (e.g. tachyuria, hydrochlorothiazide, spironolactone).

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

The pharmaceutically active ingredient for treating chronic infectious endocarditis can be generally antibiotics (such as vancomycin, cephalosporin, penicillin, aminoglycoside).

The pharmaceutically active ingredient for treating chronic pericarditis may be digitalis.

Wherein the pharmaceutical active ingredient acting on respiratory system can generally comprise pharmaceutical active ingredient for treating chronic obstructive emphysema, treating asthma, treating chronic pulmonary heart disease, treating chronic respiratory failure, treating silicosis or treating pulmonary fibrosis.

The pharmaceutical active ingredients for treating chronic obstructive emphysema can be bronchodilators (including beta receptor agonists and anticholinergic drugs), inhaled hormones (such as budesonide and fluticasone), theophylline antiasthmatic drugs (such as theophylline), expectorants (such as carbocisteine and Fudosteine), and glucocorticoids and antibiotics (such as penicillins, glycosides and cephalosporins) as required by the disease.

The pharmaceutically active ingredients for the treatment of asthma may typically be the usual inhaled drugs (e.g. beclomethasone, budesonide, fluticasone, mometasone), beta 2 agonists (e.g. albuterol), slow release theophylline, leukotriene modulators (useful in combination), anticholinergic agents (e.g. scopolamine isopropyl), antihistamines (e.g. astemizole, ketotifen).

The pharmaceutical active ingredient for treating chronic pulmonary heart disease can be antibiotics (such as amoxicillin, ceftizoxime, cefuroxime, levofloxacin), corticosteroids (such as selective beta 2 receptor stimulant, theophylline drugs), airway nonspecific inflammation (such as prednisone), inhalants (such as hydrocodone), respiratory stimulants (such as lobeline, doxepin, and desipramipexole).

The pharmaceutical active ingredient for treating chronic respiratory failure can be generally drugs (such as salbutamol, acetylcysteine and the like) for relieving bronchospasm and eliminating phlegm.

The active ingredients of the medicine for treating silicosis can be tetralin, acetylcysteine, aluminum preparation, kesilicone and red sage root.

The pharmaceutically active ingredient for treating pulmonary fibrosis can be pirfenidone, nidazole, glucocorticoid (e.g. methylprednisolone, prednisone), immunosuppressant (e.g. azathioprine, methotrexate, etc.), colchicine, interferon, ACEI or statin etc.

Wherein the pharmaceutical active ingredients acting on the digestive system can generally comprise pharmaceutical active ingredients for treating chronic gastritis, treating peptic ulcer, treating intestinal tuberculosis, treating chronic enteritis, treating chronic diarrhea, treating chronic hepatitis, treating liver cirrhosis, treating chronic pancreatitis, and treating chronic cholecystitis.

The pharmaceutical active ingredients for treating chronic gastritis generally can relieve pain (such as atropine, prussine, etc.), increase gastric acid, use PPI proton pump inhibitor (such as lansoprazole, omeprazole, etc.), use H2 receptor blocker (such as cimetidine, ranitidine, aluminum hydroxide amine, etc.), aid (such as pancreatin), bile reflux (such as metoclopramide and morpholine, cholestyramine, sucralfate can be combined with bile acid).

The pharmaceutical active ingredient for treating peptic ulcer can be levofloxacin, tinidazole and omeprazole.

The pharmaceutically active ingredient for the treatment of tuberculosis of the intestines may generally be rifampicin.

The pharmaceutical active ingredients for treating chronic enteritis can be generally anti-inflammatory analgesic, probiotic bacteria, spasmolytic analgesic (such as atropine, and pulmonin).

The pharmaceutically active ingredients for the treatment of chronic diarrhea may generally be laxatives (e.g. montmorillonite powder, diphenoxylate, loperamide), intestinal microbial agents (e.g. lactobacillus, bifidobacteria), spasmodic analgesics (e.g. pivoxil bromide).

The active pharmaceutical ingredients for treating chronic hepatitis can be liver protecting drugs (such as silymarin preparations, shizandra preparations and the like), anti-fibrosis drugs (such as Chinese patent medicine oral preparations), antiviral drugs (such as common interferon and pegylated interferon), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine and entecavir), immunosuppressant (azathioprine).

The pharmaceutically active ingredient for treating liver cirrhosis may be generally a drug for treating hepatitis B (e.g., nucleoside analogues), a drug for treating autoimmune hepatitis (e.g., glucocorticoid), an anti-inflammatory drug, a liver protecting drug, an anti-hepatic fibrosis drug (e.g., reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhetate, etc.), a drug for treating spontaneous bacterial peritonitis (e.g., antibiotics), a drug for treating portal hypertension (e.g., carvedilol).

The pharmaceutically active ingredients for the treatment of chronic pancreatitis may generally be analgesic drugs (e.g. buprenorphine and fentanyl), pancreatin therapeutic drugs (e.g. pancreatin).

The pharmaceutical active ingredients for treating chronic cholecystitis can be antibacterial and anti-inflammatory drugs (such as levofloxacin, ciprofloxacin and amoxicillin), spasmolytic analgesic drugs and cholagogues (such as ursodeoxycholic acid).

Wherein, the pharmaceutical active ingredients acting on the blood system can generally comprise pharmaceutical active ingredients for treating chronic anemia, chronic granulocytic leukemia and chronic lymphocytic leukemia.

The medicines for treating chronic anemia can be generally: microelements (such as folic acid, vitamin b12, etc.), bone marrow stimulants (such as strychnine nitrate, sufferer, scopolamine, etc.), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone), ferrites (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight iron dextran, carboxymaltose iron, isomalt iron, glucuronate iron, nano-iron oxide, sorbitol iron, etc.), erythropoietics (recombinant human erythropoietin alpha, dapoxetine alpha, etc.).

The medicament for treating the chronic granulocytic leukemia can be generally: tyrosine kinase inhibitors (e.g., imatinib, nilotinib, bosutinib, platinib, etc.), homoharringtonine.

The medicines for treating chronic lymphocytic leukemia can be generally: chemotherapeutic (e.g., nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted (e.g., ideranib, valneturab, ibrutinib, dasatinib, etc.), monoclonal antibodies (e.g., ofatuzumab, rituximab, atozuab, alemtuzumab, etc.).

Wherein, the medicine active ingredients acting on endocrine system can generally comprise medicine active ingredients for treating chronic lymphocytic thyroiditis, hyperthyroidism and hypothyroidism.

The medicament for treating chronic lymphocytic thyroiditis can be generally: thyroxine (e.g., levothyroxine, thyroxine), glucocorticoids (e.g., prednisone, methylprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

The drug for treating hyperthyroidism can be generally: thiooxipyrims (e.g., propylthiooxipyrim, methylthiooxipyrim, etc.), imidazoles (e.g., methimazole, carbimazole, etc.), iodides (e.g., lu Geye, etc.), radioiodides (e.g., 131 iodides, etc.), beta blockers (e.g., metoprolol, atenolol, bisoprolol, carvetalol, propranolol, etc.).

The therapeutic agent for the first-class of the nail-reduction can be generally: thyroxine (e.g., 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 drug active ingredient can be 2-180 μm.

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

cutting the silica gel tube into sections, filling the powder type medicine core, and sealing two ends by silica gel to obtain the implantation agent.

In the invention, the medicine core can also comprise insoluble auxiliary materials.

Wherein the particle size of the insoluble auxiliary material can be 1-200 μm.

Wherein, the indissoluble auxiliary materials can comprise silicon materials. The pore size of the silicon material may be less than 1 μm; for example 0nm, 5nm, 10nm, 18nm, 50nm or 100nm. It will be appreciated by those skilled in the art that when the pore size of the silicon material is 0nm, the silicon material is a non-porous silicon material.

The silicon material may have a silicon dioxide content of greater than 50%; preferably 80%, 90%, 95%, 99% or 99.8%.

Wherein, the indissolvable auxiliary materials can comprise one or more of white carbon black, AL-1FP mesoporous silicon, XDP3050 mesoporous silicon and XDP3150 mesoporous silicon.

The white carbon black is preferably white carbon black prepared by a gas phase method, a precipitation method, a gel method or a surface treatment method.

Preferably, the insoluble auxiliary materials are one or more of white carbon black, AL-1FP mesoporous silicon, XDP3050 mesoporous silicon and XDP3150 mesoporous silicon.

More preferably, the insoluble auxiliary materials are one or more of white carbon black, AL-1FP mesoporous silicon and XDP3050 mesoporous silicon.

In the invention, the slightly soluble auxiliary materials can also comprise slightly soluble weak acid and/or slightly soluble weak base.

Wherein the poorly soluble weak acid preferably comprises one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, more preferably boric acid and/or fumaric acid.

Wherein the slightly soluble weak base preferably comprises one or more of magnesium hydroxide, aluminum hydroxide, zinc hydroxide, ferrous hydroxide and magnesium oxide; more preferably one or more of magnesium hydroxide, aluminum hydroxide and zinc hydroxide.

Wherein the insoluble auxiliary material can 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.

Or, the insoluble auxiliary material can 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.

Or, the insoluble auxiliary material can be AL-1FP mesoporous silicon, and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, AL-1FP mesoporous silicon and molybdic acid, AL-1FP mesoporous silicon and silicic acid, AL-1FP mesoporous silicon and tungstic acid, or AL-1FP mesoporous silicon and germanic acid.

Or the insoluble auxiliary material can be AL-1FP mesoporous silicon, ferrous hydroxide and/or magnesium oxide; for example, AL-1FP mesoporous silicon and ferrous hydroxide, or AL-1FP mesoporous silicon and magnesium oxide.

Or the insoluble auxiliary material can 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.

Or the insoluble auxiliary material can be XDP3050 mesoporous silicon, ferrous hydroxide and/or magnesium oxide; for example, XDP3050 mesoporous silicon and ferrous hydroxide, or XDP3050 mesoporous silicon and magnesium oxide.

Or the insoluble auxiliary material can 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.

Or the insoluble auxiliary material can be XDP3150 mesoporous silicon, ferrous hydroxide and/or magnesium oxide; for example, XDP3150 mesoporous silicon and ferrous hydroxide, or XDP3150 mesoporous silicon and magnesium oxide.

In the invention, the content of the raw material medicine can be 10% -99.9%, such as 50% -99.5%, and further such as 95%; the percentage is the mass percentage of the bulk drug in the pharmaceutical composition.

The content of the insoluble auxiliary materials can be 0.1-90%, such as 0.1-50%, and further such as 0.5-5%; the percentage is the mass percentage of the indissoluble auxiliary materials in the pharmaceutical composition.

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

for another example, when the poorly soluble excipients are XDP3150 mesoporous silicon and fumaric acid, the mass ratio thereof may be (0.01 to 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 of the insoluble auxiliary materials can be (0.01-100): 1, preferably 9:1, 1.5:1 or 0.43:1.

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

For another example, when the insoluble auxiliary materials are AL-1FP mesoporous silicon and zinc hydroxide, the mass ratio of the insoluble auxiliary materials 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 to 5.0mm, for example, 2.4mm or 2.6mm.

In the present invention, the length of the silicone tube is preferably 1.5 to 4.5cm, for example 1.9cm or 4.4cm.

In the present invention, the wall thickness of the silicone tube is preferably 0.2 to 0.5mm, for example 0.2mm, 0.3mm, 0.4mm or 0.5mm.

In the invention, the medicine release area of the silica gel 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 。

In the present invention, the core preferably has a diameter of 1.5-4.0mm, for example 1.6mm or 2.0mm.

In the present invention, the length of the core is preferably 1.0 to 5.0cm, for example 1.0 to 4.0cm, further for example 1.5cm or 3.9cm, further for example 1cm, 2cm, 3cm, 4cm, or 5cm.

In some preferred embodiments of the invention, the implant is of the following specifications, and the pharmaceutically active ingredient in the core is preferably levonorgestrel;

in some preferred embodiments of the present invention, the implant is of the following specifications, and the pharmaceutically active ingredient in the core is preferably gestodene;

In some preferred embodiments of the present invention, the implant is of the following specification, and the pharmaceutically active ingredient in the core is preferably estradiol;

numbering device	Silicone tube outer diameter/mm	Wall thickness/mm of silicone tube	Area/cm of drug release ²
				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 invention can be that the silica gel material is extruded into a tube shape or the silica gel tube is cut into sections and then filled with medicine, both ends are blocked by adhesive, and then the implant of the invention is prepared by packaging and sterilizing.

The invention also provides an application of the silica gel material or the silica gel tube in a sustained and controlled release preparation as a release speed regulating medium.

In the invention, the vinyl content in the R-vinyl silicone rubber refers to mole percent, and the mole percent of vinyl refers to the mole number of vinyl in each hundred moles of R-vinyl silicone rubber.

In the invention, the hydrogen content in the hydrogen-containing silicone oil refers to mole percent, and the mole percent of the hydrogen content refers to the mole number of hydrogen in each hundred mole of hydrogen-containing silicone oil.

In the present invention, PHR means parts by mass of each specific component corresponding to 100 parts by mass of R-vinyl silicone rubber (e.g., methyl vinyl silicone rubber).

In the present invention, the room temperature is 25 DEG C+5℃。

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

On the basis of conforming to the common knowledge in the field, the above preferred conditions can be arbitrarily combined to obtain the preferred examples of the invention.

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

The invention has the positive progress effects that:

the silica gel tube prepared by the silica gel material has excellent mechanical property and good biocompatibility; the active drug loaded on the implant prepared by the silica gel has stable drug release curve, and when the loaded drug is a contraceptive (such as gestodene and levonorgestrel), the prepared implant can generate remarkable contraceptive effect on rats.

Drawings

FIG. 1 is a flow chart of a silica gel preparation process.

FIG. 2 is a flow chart of a silicone tube extrusion process.

Fig. 3 is a picture of a GEST contraceptive implant.

FIG. 4 is a graph showing the relationship between the daily drug release amount and the release time of the gestodene implant ZJ001, ZJ002, ZJ003 in vitro.

Fig. 5 shows the relationship between the in vitro daily drug release amounts and the release time of the gestodene implants ZJ001, ZJ002, ZJ003 (on the basis of fig. 4, the data were shown as a graph of the daily drug release amounts after a simplification of the data by taking 5 days as a period).

Fig. 6 is a pathological image of muscle tissue after implantation of a gestodene implant, wherein A, C, E is a pathological image (HE, ×2) at 3, 10, and 30 days after implantation, and B, D, F is a pathological image (HE, ×20) at 3, 10, and 30 days after implantation, respectively.

Fig. 7 shows a periodic vaginal smear of a rat in which fig. a shows a pre-estrus, fig. B shows an estrus, fig. C shows a late estrus, and fig. D shows a period between two estruses.

FIG. 8 is an image of a rat vaginal plug, wherein, FIG. A is a milky white vaginal plug observed at the vaginal orifice when vaginal secretions were taken 13 days after implantation for rats numbered 1 with normal estrus cycle of vaginal smears in GEST implant trial I dose group; panel B is the vaginal plug observed at the vaginal orifice when vaginal secretions were taken 20 days post implantation in rats numbered 4 with normal estrus cycle on vaginal smears in GEST implant trial I dose group.

FIG. 9 shows the resulting silicone tube over-sulfide at 360℃in the pre-bake tunnel.

Fig. 10 is a view of the local field of tissue sections (a, HE, ×2) at day 3 after implantation of levonorgestrel implant in SD rats, 3 day after implantation of the tissue sections (B, HE, ×20) at day 10 after implantation of SD rats (C, HE, ×2) and 10 day after implantation of the SD rats (D, HE, ×20).

Fig. 11 is a daily dose release profile for LNG implants in the burst and untreated groups.

Fig. 12 is a graph of cumulative dose release for LNG implants in the burst and untreated groups.

FIG. 13 is a linear relationship of 1/T to ln (K).

Figure 14 image of a rat vaginal suppository.

Fig. 15 shows a periodic vaginal smear for a rat estrus, wherein fig. a shows a pre-estrus, fig. B shows an estrus, fig. C shows a late estrus, and fig. D shows a period between two estruses.

Fig. 16 shows the results of LH assay in levonorgestrel I dosed rats.

FIG. 17 is a graph showing the relationship between the drug area of the silica gel tube and the amount of estradiol released.

Detailed Description

The invention is further illustrated by means of the following examples, which are not intended to limit the scope of the invention. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.

In the following examples and comparative examples:

the vinyl content in the methylvinyl silicone rubber refers to the mole percent, and the mole percent of vinyl refers to the number of moles of vinyl per hundred moles of methylvinyl silicone rubber.

The hydrogen content in the hydrogen-containing silicone oil refers to mole percent, and the mole percent of the hydrogen content refers to the mole number of hydrogen in each hundred moles of the hydrogen-containing silicone oil.

I. Long-acting contraceptive implantation agent of gestodene

1. Content determination and in vitro release determination method for pregnadienone contraceptive implant

(1) Chromatographic conditions

Chromatographic column:c18 column (250 mm. Times.4.60 mm,5 μm);

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

column temperature: 30 ℃;

detection wavelength: 239nm;

flow rate: 1 mL/min ^-1 ；

Sample injection amount: 20. Mu.L.

(2) In vitro release test method

Placing the filled implant in ethanol solution, placing into an ultrasonic instrument, ultrasonic treating for 30min, blow drying the implant after ultrasonic treatment, placing into a conical bottle with plug filled with release medium, placing into a shaking table, setting the temperature at 37deg.C, and shaking at 100 r.min ^-1 And taking out and drying after 24 hours.

The two ends of the blow-dried gestodene implant are respectively adhered to the bottle bottom and the bottle wall of the conical bottle with the plug by using the silicone rubber sealing glue, so that the silica gel tube part filled with the raw material powder of the gestodene is suspended in the conical bottle with the plug and can not collide with the wall (the contact area between the drug containing section and the release medium in the vibration process is ensured to be stable). And standing for 24 hours after the adhesion is finished to solidify the glue completely. Accurately pouring a required amount of release medium into a conical bottle with a stopper after solidification, and placing the conical bottlePlacing into a shaking table, setting the temperature to 37deg.C and the shaking speed to 100deg.C.min ^-1 . Sampling and replacing the medium every 24 hours, and reserving the sample to be tested.

2. Preparation of double-component addition type silicone tube

1 instrument and reagent

1.1 instruments

Small-sized kneader	Shen Hong mechanical Co Ltd in Lyzhou City
		Small open mill	Dongguan city Yizong mechanical equipments Limited company
Phi 16 silicon rubber extruder	ZHEJIANG BAINA RUBBER EQUIPMENT Co.,Ltd.
		3020N outer diameter measuring and controlling instrument	Shanghai quality inspection Co., ltd
Electron microscope	Micro scientific and technological Co.Ltd in Shenzhen City
		XPE analytical balance	Switzerland-tolido instruments Inc
SMD200-2 electronic analytical balance	Oraus International trade Limited
		101-2AB type electrothermal blowing dryingBox (BW)	TIANJIN TAISITE INSTRUMENT Co.,Ltd.
Universal mechanics tester	Southeast Guangdong laboratory equipment Co.Ltd
		Shore A force instrument	Deqing shengtaixin Electronic Technology Co.,Ltd.

1.2 reagents

2 test method

2.1 preparation Process optimization of Silicone tube

2.1.1 prescriptions

Note that: PHR is the mass part of the component corresponding to every 100 mass parts of high molecular compound (methyl vinyl silicone rubber);

ppm means parts per million (ppm) representing the concentration of platinum in the platinum catalyst, 3000ppm means the mass concentration of platinum in the platinum catalyst is 3000ppm, PHR means the ratio of platinum catalyst in the whole silica gel tube prescription, taking the prescription as an example, specifically, 100 parts of methyl vinyl silicone rubber is added with 0.000002-0.00005 parts of platinum catalyst, and the concentration of platinum in the platinum catalyst is 3000 ppm.

2.1.2 preparation Process

(1) Pretreatment of raw rubber: raw rubber (methyl vinyl silicone rubber) and fumed silica are put into a kneader according to a certain proportion, so that the fumed silica is fully wrapped by the raw rubber, the raw rubber wrapped with the fumed silica is extruded and thinned by an open mill, the raw rubber and the fumed silica are fully mixed uniformly, tabletting is carried out, after unloading, the raw rubber and the fumed silica are fully wrapped by a preservative film, then the raw rubber and the fumed silica are put into a self-sealing bag for sealing, and the raw rubber and the fumed silica are put into a dryer at room temperature for standby.

(2) Preparation of matrix components: the parked raw rubber added with the white carbon black is divided into two parts by mass and the two parts are divided into a component A and a component B. Adding prescribed amount of cross-linking agent hydrogen-containing silicone oil and inhibitor methyl butynol into the component A, fully and uniformly mixing by an open mill, putting into a drier at room temperature, and standing for 24-72h for standby.

(3) Preparation of the catalytic component: adding a prescription amount of platinum catalyst into the component B, fully and uniformly mixing by an open mill, putting the mixture into a drier at room temperature, and standing for 24-72 hours for standby.

(4) The A, B components which were parked for the same time were mixed and the sheet was parked for 12 hours after being continuously thinned through with an open mill.

(5) And cutting the thin strips for standby.

The flow chart of the above steps (1) - (5) can be seen in fig. 1.

The preparation method comprises the steps of preparing a double-component silicone rubber material, tabletting, extruding the prepared double-component silicone rubber material to prepare a silicone tube, extruding the silicone tube through a screw in an extrusion process, extruding the silicone tube through a die, enabling the extruded silicone tube to be rapidly vulcanized and preliminarily molded through the high temperature of a pre-drying tunnel, then entering a post-drying tunnel to be continuously vulcanized to enable the addition reaction of the silicone tube to be basically complete, and finally placing the silicone tube into a drying oven with a certain temperature to be vulcanized, so that the completion of the addition reaction of the silicone tube is ensured.

In the extrusion process, the pre-drying channel, the post-drying channel and the baking oven provide vulcanization conditions for the addition reaction of raw rubber and hydrogen-containing silicone oil, so that the silicone rubber material is solidified and formed. Extrusion speed, die, post-bake tunnel draw speed (extrusion speed 3.5 r.min) ^-1 The stretching speed of the post-drying tunnel is set to be 0.1 m.s ^-1 The outer diameter of the core mold is 2.50mm, the inner diameter of the mouth mold is 3.90 mm), the outer diameter and the wall thickness of the prepared silicone tube are regulated, so that the silicone tubes with different specifications are prepared, and the extrusion flow is shown in figure 2

2.1.3 Silicone tube Performance test

The tensile strength Ts is the maximum tensile force born by the silicone tube in the breaking process, and can indicate the maximum limit of the resistance of the sample to external damage;

the elongation at break Eb is the deformation condition of the stamp sample when the sample breaks, and can indicate the deformation range which the sample can accept before breaking;

the tearing strength T refers to the strength when the silicone tube is torn, and can indicate the tearing resistance of the sample;

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

2.1.3.1 tensile stress Strain Performance test

Tensile stress strain properties were determined according to GB/T828-2009 method. And symmetrically placing the prepared silicone tube samples on an upper holder and a lower holder of a servo system tensile machine, uniformly distributing tensile force on the cross section, setting the clamping distance to be 50mm, preparing an elongation sample testing device, starting the tensile machine, and enabling the tensile rate of the sample to be 200mm/min. The maximum tensile stress during stretching, the length of the coupon when stretched to break, and the force required to tear the coupon are recorded. The elongation at break, tensile strength and tear strength of the test pieces were calculated according to the following formulas.

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

L _b Gauge length at break of sample, mm, L ₀ Initial gauge length of the test specimen, mm.

Tensile strength (Mpa) ts=fm/Wt

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

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

F-maximum force required to tear the specimen, t-thickness of specimen (mm).

2.1.3.2 force test

The hardness test of the product is measured according to GB/T531.1-2008; and fully mixing the prepared matrix component polymer with the catalytic component polymer, curing and forming at room temperature to prepare a sample wafer with the thickness of 6mm, and then cutting the sample wafer into square test sample wafers with the thickness of 24 multiplied by 24 mm. The test piece is placed on a firm plane, the hardness tester is held, the pressing foot is stably pressed on the test piece, the pressing foot is kept in complete contact with the test piece, data are read within 1s, the data are measured for 3 times at different positions, and the average value is obtained.

The preferred physical and mechanical properties of the silicone tube product are shown in the following table.

Project	Index number
		hardness/Shore A	50-70
Tensile Strength/Mpa	≥7.5
		Elongation at break/%	≥200
Tear strength/KN.m ^-1	≥20

2.1.4 preparation Process optimization of Silicone tube

The test fixes the prescription, and takes elongation at break, tensile strength, tearing strength and hardness as mechanical indexes to examine the temperature of a pre-drying channel (first vulcanization temperature), the temperature of a post-drying channel (second vulcanization temperature) and the vulcanization time of an oven (third vulcanization time) in the extrusion process.

Investigation of 2.1.4.1 Pre-drying channel temperature (first vulcanization temperature)

The silica gel is extruded by a single screw rod and then passes through a high-temperature oven, the inhibitor in the silica gel tube is decomposed into gas at high temperature, then the catalyst starts to act, the catalytic addition reaction is carried out, and the silica gel tube can be rapidly fixed and molded. The temperature of the oven has great influence on the appearance and mechanical index of the extruded silicone tube, the temperature is too low, vulcanization is insufficient, the outer wall of the tube is not molded and is difficult to stretch for subsequent processes, the silicone tube with too high temperature is easy to be vulcanized, and the mechanical index is poor. The outside diameter of the silicone tube can shrink rapidly when passing through the high temperature oven, and the silicone tube recovers after coming out of the high temperature oven, and the change can affect the outside diameter and the wall thickness of the silicone tube.

The test sets the temperature of the pre-drying tunnel to 270 ℃, 300 ℃, 330 ℃ and 360 ℃ respectively, and examines the temperature of a high-temperature oven by taking elongation at break, tensile strength, tearing strength and hardness as mechanical indexes (in the examination of the temperature of the pre-drying tunnel, the extrusion time of the pre-drying tunnel is short and is about 5s, the temperature of the post-drying tunnel is 180 ℃, the reaction time is short and is about 2min, the vulcanization temperature of the oven is 180 ℃ and the time is 48h, the other process conditions are the same as the preparation process of 2.1.2 in the part, and the prescription is the same as the prescription of 2.1.1 in the part). The prepared silica gel tube is used for measuring the outer diameter and the wall thickness of the silica gel tube, and whether the temperature change of the pre-drying tunnel has an influence on the size of the silica gel tube is inspected.

Numbering device	Temperature of pre-drying tunnel
		Example 1-1	270℃
Examples 1 to 2	300℃
		Examples 1 to 3	330℃
Examples 1 to 4	360℃

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

After the silicone tube is extruded, the silicone tube is rapidly vulcanized through a pre-drying tunnel, and after preliminary curing and molding, the silicone tube is vulcanized at a low temperature through a post-drying tunnel with the length of 2.5m, so that the silicone tube is further cured at a certain temperature and time, and the silicone tube is basically molded.

The test sets the temperature of the post-drying tunnel at 120 ℃, 150 ℃, 180 ℃, 210 ℃, and examines the temperature of the post-drying tunnel by taking the elongation at break, the tensile strength, the tearing strength and the hardness as mechanical indexes (in the examination of the temperature of the post-drying tunnel, the temperature of the pre-drying tunnel is 270 ℃, the extrusion time of the pre-drying tunnel is short and is about 5s, the reaction time of the post-drying tunnel is short and is about 2min, the vulcanization temperature of the oven is 180 ℃ and the time is 48h, the other process conditions are the same as the preparation process of 2.1.2 in the part, and the prescription is the same as the prescription of 2.1.1 in the part). The prepared silica gel tube is used for measuring the outer diameter and the wall thickness of the silica gel tube, and whether the temperature change of the post-baking channel has an influence on the size of the silica gel tube is inspected.

Numbering device	Post-baking channel temperature
		Example 2-1	120℃
Example 2-2	150℃
		Examples 2 to 3	180℃
Examples 2 to 4	210℃

Investigation of 2.1.4.3 oven vulcanization time (third vulcanization time)

To ensure complete vulcanization of the silicone tube, the silicone tube is subjected to an oven vulcanization (third vulcanization) treatment. And if the third vulcanization time is insufficient, the vulcanization of the silica gel tube is incomplete, and if the vulcanization time is too long, the silica gel tube is easy to oversulfide. The test sets the third vulcanization time to 0h, 24h, 48h and 72h, and uses the elongation at break, the tensile strength, the tearing strength and the hardness as mechanical indexes to examine the vulcanization time of the oven. ( In the investigation of the oven cure time: the temperature of the pre-drying tunnel is 270 ℃ and the time is about 5 s; the temperature of the post-baking channel is 180 ℃ and the time is about 20 s; the vulcanization temperature of the oven is 180 ℃; the other process conditions are the same as the preparation process of 2.1.2 in the present section; prescription 2.1.1 prescriptions in the same part of prescriptions )

Numbering device	Curing time in oven
		Example 3-1	0h
Example 3-2	24h
		Examples 3 to 3	48h
Examples 3 to 4	72h

2.1.5 investigation of the catalyst usage

The dosages of the fixed raw rubber, the hydrogen-containing silicone oil, the inhibitor and the reinforcing agent in the test are unchanged, and are respectively 100PHR, 1.01PHR, 0.7PHR and 30PHR. The dosage of the catalyst is changed to be 0.000005PHR, 0.00001PHR, 0.00002PHR and 0.00003PHR respectively, and the mechanical properties such as elongation at break, tensile strength, tearing strength, hardness and the like of the silicone tube under different dosages of the catalyst are tested.

The specific process comprises the following steps: the pre-baking channel is at 270 ℃ and the vulcanizing time is about 5 s; the post-baking channel is at 180 ℃ and the vulcanizing time is about 2 min; oven vulcanization temperature 180 ℃ and time 48h; the other process conditions are the same as the preparation process of 2.1.2 in the preparation of the two-component and two-component addition type silicone tube.

2.1.6 investigation of inhibitor usage

The addition reaction of raw rubber and hydrogen-containing silicone oil can be carried out at room temperature under the catalysis of platinum, and along with the rapid progress of the addition reaction, the silicone material is rapidly cured, so as to prevent the silicone rubber from being cured in the cavity of an extruder when the extrusion process is carried out, and the reaction can be prevented from being carried out at room temperature by adding an inhibitor methyl butynol into the silicone rubber.

The fixed raw rubber, hydrogen-containing silicone oil, catalyst and reinforcing agent are used in the test in constant amounts of 100PHR, 1PHR, 0.00001PHR and 30PHR respectively. The mechanical properties such as elongation at break, tensile strength, tear strength and hardness of the silicone tube under different inhibitor dosages are tested by changing the inhibitor dosages to be 0.3PHR, 0.5PHR, 0.7PHR and 0.9PHR respectively.

2.1.7 investigation of vinyl content of raw rubber

According to the principle of addition reaction of methyl vinyl raw rubber and hydrogen-containing silicone oil, the vinyl content of raw rubber has great influence on the crosslinking degree of the silicone tube. The raw rubber and hydrogen-containing silicone oil undergo addition reaction under the catalysis of a platinum catalyst, and vinyl polysiloxane is a crosslinking chain link in a formed reticular structure, and the molecular chain length determines the crosslinking density after crosslinking and curing.

The fixed vinyl polysiloxane molecular weight, hydrogen silicone oil, catalyst, inhibitor and gas phase white carbon black are used in the test in constant amounts of 100PHR, 1PHR, 0.00001PHR, 0.7PHR and 30PHR. The vinyl content of the vinyl polysiloxane is changed to be 0.05%, 0.07%, 0.17% and 0.23%, and the mechanical properties such as elongation at break, tensile strength, tearing strength and hardness of the silicone tube under different vinyl contents are tested.

Investigation of the amount of white carbon black by 2.1.8 vapor phase method

The hardness of raw rubber is too low, which is not beneficial to molding and process processing, and the addition of the fumed silica into the raw rubber can reinforce the hardness of the prepared silica gel tube and improve the hardness of the raw rubber.

The amount of raw rubber, hydrogen-containing silicone oil, catalyst and inhibitor used in the test for fixing the vinyl content of 0.17% is unchanged, and the amounts are respectively 100PHR, 1PHR, 0.00001PHR and 0.7PHR. The addition amounts of the fumed silica are respectively 20, 30, 40, 45, 50 and 60PHR, and the mechanical properties such as elongation at break, tensile strength, tearing strength and hardness of the silicone tube under different addition amounts of the fumed silica are tested.

Investigation of 2.1.9 Hydrogen-containing Silicone oil

The hydrogen-containing silicone oil is used as a cross-linking agent to carry out cross-linking reaction with raw rubber, and the addition amount of the hydrogen-containing silicone oil can be calculated according to the following formula:

W _{traffic intersection} /W ₁ ＝(A×V _i ％)/(H％×27)

Wherein: w (W) _{Traffic intersection} The addition amount of the cross-linking agent; a is the molar ratio of Si-H to Si-Vi (preferably 1.0-1.5), namely the molar ratio of vinyl to hydrogen of the hydrogen-containing silicone oil reaches 1: a is 1 at 1; the method comprises the steps of carrying out a first treatment on the surface of the V (V) _i % is the weight percent of vinyl groups in the base size; h% is the weight percent of hydrogen in the crosslinker; w (W) ₁ Is the weight of the basic sizing material. The optimal hydrogen content and the addition amount of the hydrogen-containing silicone oil in the actual reaction cannot be calculated by a formula only, and the optimal hydrogen content and the addition amount of the hydrogen-containing silicone oil are obtained through experimental comparison.

Investigation of Hydrogen content of 2.1.9.1 Hydrogen-containing Silicone oil

The raw rubber, catalyst, inhibitor and gas phase white carbon black with the vinyl content of 0.17 percent are fixed in the test, and the dosages of the raw rubber, catalyst, inhibitor and gas phase white carbon black are respectively 100PHR, 0.00001PHR, 0.7PHR and 40PHR. The molar ratio of Si-H groups in the fixed hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is 1.2:1. The hydrogen content is selected to be 0.18%, 0.36%, 0.5%, 0.75% respectively,

1.0% and 1.6% of hydrogen-containing silicone oil is used for preparing a silicone tube, and the mechanical properties such as elongation at break, tensile strength, tearing strength, hardness and the like of the silicone tube under different hydrogen contents are tested.

Investigation of the amount of the Hydrogen-containing Silicone oil 2.1.9.2

The raw rubber, catalyst, inhibitor and reinforcing agent used in this test to fix 0.17% vinyl content were 100PHR, 0.00001PHR, 0.7PHR and 40PHR, respectively. And (3) selecting hydrogen-containing silicone oil with the hydrogen content of 0.75%, and carrying out experiments by using the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber of 1:1, 1.2:1, 1.5:1 and 1.8:1, wherein the mechanical properties such as elongation at break, tensile strength, tear strength and hardness of the silicone tube are tested under the condition of using different hydrogen-containing silicone oils.

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3 results and discussion

3.1 preparation of silica gel tube Process optimization

3.1.1 investigation of the Pre-drying channel temperature

The extrusion speed was fixed at 3.5 r.min using the recipe described above ^-1 Stretching speed is 0.1 m.s ^-1 The pre-baking tunnel temperature was changed to 270 ℃, 300 ℃, 330 ℃, 360 ℃, 3 different molds were used for the preparation of the silicone tube, and the outside diameter and wall thickness of the silicone tube were measured, with the following results.

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

Note that: die size (mandrel diameter/die inner diameter): 3 ^# A mould (2.01/3.50); 4 ^# A die (2.50/3.90); 5 ^# A mold (3.02/4.32).

The mechanical properties of the silica gel tube prepared by changing the temperature of the pre-drying tunnel were tested, and the results are shown in the following table.

The measuring results of the outer diameter and the wall thickness of the silicone tube show that the outer diameter and the wall thickness of the silicone tube prepared by different dies almost have no change along with the increase of the temperature of the pre-drying channel, the temperature of the pre-drying channel has no influence on the final outer diameter and the wall thickness of the silicone tube, and the influence factors of the temperature of the pre-drying channel on the size of the silicone tube can be eliminated when the silicone tube is prepared subsequently.

The mechanical results show that as the pre-vulcanization temperature is increased, the elongation at break, the tensile strength and the tearing strength of the silicone tube are continuously reduced, and the hardness is continuously enhanced. The mechanical indexes of the silica gel tube prepared at 270 ℃ and 300 ℃ meet the requirements, the whole mechanical property of the silica gel tube prepared at 270 ℃ is better, and the experiment shows that the higher the temperature of the pre-drying tunnel is, the more bubbles are easy to appear in the prepared silica gel tube. In combination, the pre-drying tunnel temperature is preferably 270 ℃.

After the silica gel is extruded by an extruder, the inhibitor is decomposed into gas by quick heating through a pre-drying channel, and the catalyst plays a role in catalysis, so that the crosslinking reaction is quickly carried out, and the outer wall of the silica gel tube is quickly solidified and molded. If the temperature of the pre-drying channel is too low, the crosslinking reaction is slower, the reaction is incomplete, the silica gel tube cannot be rapidly solidified, the silica gel is easy to be pulled and deformed, and the extrusion process cannot be performed. If the temperature of the pre-drying tunnel is too high, the silica gel tube is easy to be partially over-vulcanized, so that the silica gel tube becomes too hard and brittle, the mechanical property is rapidly reduced, and the use value is lost.

3.1.2 investigation of the post-drying tunnel temperature

The preparation of the silicone tube was carried out by using the above-mentioned recipe, fixing the extrusion speed to 3.5r/min, the stretching speed to 0.1m/s, changing the post-baking tunnel temperature to 120, 150, 180, 210℃and using 3 different molds, and the outside diameter and wall thickness of the silicone tube were measured, with the following results.

The effect of post-bake tunnel temperature on the outside diameter of the silicone tube is shown in the following table.

Note that: die size (mandrel diameter/die inner diameter): 3# die (2.01/3.50); a No. 4 die (2.50/3.90); 5# die (3.02/4.32).

The mechanical properties of the silica gel tube prepared by changing the temperature of the post-baking channel were tested, and the results are shown in the following table.

The measuring results of the outer diameter and the wall thickness of the silicone tube show that the outer diameter and the wall thickness of the silicone tube prepared by different dies almost have no change along with the increase of the temperature of the post-drying tunnel, and the conclusion that the temperature of the post-drying tunnel has no influence on the final outer diameter and the wall thickness of the silicone tube can be obtained, so that the temperature change in the preparation process has no influence on the molding size of the silicone tube.

The mechanical results show that with the increase of the temperature of the post-drying tunnel, the elongation at break, the tensile strength, the tearing strength and the hardness of the silicone tube are all increased, and when the post-drying tunnel reaches 180 ℃, the mechanical index is similar to 210 ℃, which indicates that the temperature of the post-drying tunnel can meet the mechanical property requirement at 180 ℃, and in addition, a conveyor belt is arranged in the post-drying tunnel, the temperature of the post-drying tunnel is preferably 180 ℃ because of the inadvisable excessively high temperature.

The post-baking channel is mainly used for providing conditions for the subsequent addition reaction of silica gel, so that the vulcanization reaction further occurs. So that the post-baking channel is easy to oversulfide when the temperature is too high, and the proper temperature can lead the crosslinking reaction to be complete, so that the mechanical index is better.

3.1.3 investigation of oven curing time

The oven cure temperature was set at 180 ℃. And (5) respectively carrying out oven vulcanization for 0h, 24h, 48h and 72h, and measuring mechanical indexes.

Mechanical properties	Example 3-1	Example 3-2	Examples 3 to 3	Examples 3 to 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 result shows that after the silica gel tube is vulcanized by the oven, the elongation at break of the silica gel tube is reduced, but the tensile strength and the tearing strength are increased and then reduced, and the hardness is gradually increased. The tensile strength and the tearing strength of the silica gel tube after oven vulcanization for 48 hours are optimal, the elongation at break and the hardness meet the standards, and finally the oven vulcanization condition is preferably that the oven vulcanization is carried out for 48 hours at 180 ℃.

The mechanical property of the silica gel tube after the oven vulcanization treatment is improved compared with that of an unvulcanized silica gel tube, and the fact that the silica gel tube is just extruded from a post-drying tunnel to carry out the crosslinking reaction is not complete is proved. The silicone tube is basically cured after the silicone tube exits from the post-drying tunnel of the extruder, but the internal crosslinking reaction is not complete, so that the silicone tube needs to be subjected to oven vulcanization treatment in order to ensure complete vulcanization reaction of the silicone tube, and the oven vulcanization is the final link for ensuring complete vulcanization of the silicone tube. However, as the vulcanization time of the oven is continuously prolonged, the silica gel tube is vulcanized, so that the toughness of the silica gel tube is reduced and the brittleness is increased. Therefore, the curing time of the oven is suitable, and is not too short or too long.

3.1.4 investigation of the catalyst usage

The silicone tube was prepared by changing the catalyst usage to 0.000005, 0.00001, 0.00002, 0.00003PHR, and the mechanical index results were as follows.

Mechanical properties	Example 4-1	Example 4-2	Examples 4 to 3	Examples 4 to 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

From the results, when the amount of the added catalyst is increased from 0.000005PHR to 0.00001PHR, the mechanical indexes are improved, but as the dosage of the catalyst is continuously increased, the mechanical indexes are not obviously different. The catalyst amount is therefore preferably 0.00001PHR.

When the addition amount of the catalyst is too low, the catalyst is unevenly dispersed in the sizing material, and if some sizing materials lack the catalyst, the crosslinking reaction does not occur, so that the mechanical property of the prepared silica gel tube is poor. When the adding amount of the catalyst is excessive, the mechanical index of the catalyst is not obviously changed, and the mechanical property of the silicone tube cannot be improved by the excessive catalyst. And the platinum catalyst is noble metal, so that waste is avoided during use.

3.1.5 investigation of inhibitor usage

The prescription composition and the dosage are fixed, the technology is fixed, the inhibitor dosage is changed to 0.3PHR, 0.5PHR, 0.7PHR and 0.9PHR to prepare the silicone tube, and the mechanical index results are as follows.

Mechanical properties	Example 5-1	Example 5-2	Examples 5 to 3	Examples 5 to 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

As can be seen from the results, the elongation at break, the tensile strength and the tear strength are all increased and then decreased with the increase of the amount of the inhibitor, and the elongation at break, the tensile strength and the tear strength are the best when the addition amount of the inhibitor is 0.7PHR. The addition amount of the inhibitor is preferably 0.7PHR.

When the inhibitor amount is too small, partial vulcanization reaction occurs at room temperature, and when the silicone tube is vulcanized again, the silicone tube is possibly vulcanized, so that the mechanical index is too low, and the elongation at break, the tensile strength and the tearing strength of the silicone tube are all increased along with the increase of the inhibitor addition amount. When the amount of the inhibitor is increased to 0.9PHR, the mechanical index of the inhibitor is equivalent to that of a silicone tube added with 0.7PHR, which indicates that the inhibitor added with 0.7PHR has the best inhibiting effect, and when the amount is increased to 0.9PHR, the inhibitor is excessive.

3.1.6 investigation of vinyl content of raw rubber

The prescription composition and the dosage are fixed, the fixing process is adopted, the vinyl content of raw rubber is changed to 0.05%, 0.07%, 0.17% and 0.23% to prepare the silicone tube, and the mechanical index results are as follows.

Mechanical properties	Example 6-1	Example 6-2	Examples 6 to 3	Examples 6 to 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 as the vinyl content of the raw rubber increases, the elongation at break, tensile strength and tear strength of the extruded silicone tube increase and decrease, extreme values occur when the vinyl content of the raw rubber is 0.17%, and the hardness increases as the vinyl content increases. The vinyl content of the raw rubber is preferably 0.17%.

The vinyl content of 0.05% and 0.07% is too low, the crosslinking density is continuously increased along with the increase of the vinyl content, the mechanical index is better, when the vinyl content is increased to 0.23%, the hardness of the silicone tube is increased but the toughness is reduced due to the too high crosslinking density, the elongation at break is reduced instead, so that the tensile strength and the tearing strength are reduced, and the silicone tube prepared by the too high vinyl content is high in hardness, and meanwhile, the silicone tube is high in brittleness and easy to tear. Although the hardness of the silicone tube with 0.23% vinyl content meets the requirements, the elongation at break, tensile strength and tear strength of the silicone tube are not as good as those of the silicone tube with 0.17% vinyl content.

3.1.7 investigation of the amount of fumed silica

The prescription composition and the dosage are fixed, the fixing process is changed, the addition amount of the fumed silica is 20PHR, 30PHR, 40PHR, 45PHR and 50PHR, the silica gel tube is prepared, when the addition amount of the fumed silica is 20PHR (example 7-1), the silica gel tube is too soft, so the dosage is discarded, and the rest mechanical index results are as follows.

Mechanical properties	Example 7-2	Examples 7 to 3	Examples 7 to 4	Examples 7 to 5	Examples 7 to 6
						Addition amount of white carbon black by gas phase method	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 result shows that with the increase of the addition amount of the white carbon black by the gas phase method, the hardness of the extruded silicone tube is obviously increased, the tensile strength and the tearing strength are not obviously changed, and the elongation at break has a decreasing trend, but is in a qualified range. The hardness of the silica tube is 50-70 according to requirements, and the addition amount of the fumed silica is preferably 40PHR.

When the addition amount of the white carbon black by the gas phase method is insufficient, the silica gel tube has low hardness, poor formability during extrusion and easily rough surface. The larger the amount of the white carbon black added by the gas phase method is, the higher the hardness reinforcement of the silica gel tube is, and the stronger the capability of the silica gel tube to resist external force extrusion is. The purpose of adding the gas-phase white carbon black is to strengthen the hardness of the silica gel material, so that the hardness data is mainly seen when other mechanical indexes are relatively good, the hardness reaches the standard when the dosage of the gas-phase white carbon black is 40PHR, and the elongation at break, the tensile strength and the tearing strength are good. When the addition amount of the fumed silica is too much, the hardness of the silica gel material is too large, the power of the extruder is insufficient during extrusion, the discharging speed is unstable, the hardness is too large, the extrusion die is easy to move, and the wall thickness of the extruded silica gel tube is uneven.

3.1.8 investigation of Hydrogen-containing Silicone oil

Investigation of Hydrogen content of 3.1.8.1 Hydrogen-containing Silicone oil

The prescription composition and the dosage are fixed, the fixing process, the mol ratio of the hydrosilyl group of the fixed hydrogen-containing silicone oil to the vinyl of the base polymer is 1.2, the hydrogen content of the hydrogen-containing silicone oil is changed to 0.18%, 0.36%, 0.5%, 0.75%, 1% and 1.6%, and the silicone tube is prepared, and the mechanical index results are as follows.

Mechanical properties	Example 8-1	Example 8-2	Examples 8 to 3	Examples 8 to 4	Examples 8 to 5	Examples 8 to 6
							Hydrogen content of hydrogen-containing silicone oil	0.18mol％	0.36mol％	0.5mol％	0.75mol％	1.0mol％	1.6mol％
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 the mechanical index of the silicone tube is greatly changed by the hydrogen-containing silicone oil. With the increase of the hydrogen content of the hydrogen-containing silicone oil, the hardness of the prepared silicone tube is continuously increased, the elongation at break, the tensile strength and the tearing strength are firstly increased and then reduced, the peak value appears when the hydrogen content of the hydrogen-containing silicone oil is 0.75%, and the hydrogen content of the final hydrogen-containing silicone oil is preferably 0.75%.

When the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is fixed, the smaller the hydrogen content, the larger the added mass of the hydrogen-containing silicone oil, and the more the added mass is, the more viscous the material is, so that the prepared silicone tube has relatively lower strength. Along with the increase of the hydrogen content in the hydrogen-containing silicone oil, the addition amount of the hydrogen-containing silicone oil becomes lower, the more dense the silicon hydrogen groups are, the rapid local crosslinking reaction occurs, the crosslinking density becomes higher continuously, when the silicone rubber is stretched, the flexibility of crosslinking chain links is too small to be effectively and orderly arranged, and only a small part of crosslinking chain links can bear external force together, so that the elasticity of the silicone tube is reduced, and the tensile strength and the tearing strength of the silicone tube are reduced.

Investigation of the amount of the Hydrogen-containing Silicone oil 3.1.8.2

The prescription composition and the dosage are fixed, the fixing process is adopted, the hydrogen content of the fixed hydrogen-containing silicone oil is 0.75%, the vinyl molar ratio of the silicon hydrogen group to the base polymer is changed to be 1:1, 1.2:1, 1.5:1 and 1.8:1, and the silicone tube is prepared, and the mechanical index results are as follows.

From the results, the hydrogen content of the fixed hydrogen-containing silicone oil shows a tendency of increasing and decreasing the hardness, elongation at break, tensile strength and tear strength with increasing the feeding amount of the hydrogen-containing silicone oil, and a peak value appears when the molar ratio is 1.2:1. The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is preferably 1.2:1.

The addition reaction is more complete by increasing the feeding amount of the hydrogen-containing silicone oil, the crosslinking points are increased, and the tensile strength is increased, but when the feeding amount of the hydrogen-containing silicone oil is too large, the crosslinking density is too high, the toughness is reduced, and the prepared silica gel tube is hard and brittle. When the feeding molar ratio is increased to 1.8:1, the hydrogen-containing silicone oil is excessive, and the excessive hydrogen-containing silicone oil can prevent part of crosslinking reaction from proceeding, so that the crosslinking degree is reduced, and the mechanical indexes are reduced.

3.2 preparation of optimal Silicone tube

The recipe is shown in the following table.

The composition of the drug core is as follows: the medicine core is 42mg of gestodene raw material medicine powder with the micronization grain diameter of 2.81 mu m.

The mechanical index of the silicone tube is shown in the following table.

Numbering device	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 that: eb-elongation at break; ts-tensile strength; t-tear strength; h-hardness.

The elongation at break and the hardness of the three batches of silicone tubes prepared in parallel according to the optimal prescription and process meet the standard, the tensile strength and the tearing strength of the three batches of silicone tubes are greatly improved compared with the standard, and the mechanical properties of the three batches of silicone tubes are similar, so that the prescription and process reproducibility is good.

3. Preparation of gestodene implant and in vitro release research

Silica gel tubes are used as carriers for implants because of their ability to stably control drug release over a long period of time. After the technology of the silica gel tube is inspected according to the mechanical index, the release condition of the drug controlled by the silica gel tube is also required to be inspected.

1 instrument and reagent

1.1 instruments

TS-100B constant temperature shaking table Shanghai Jielian laboratory apparatus Co., ltd

High performance liquid chromatograph, shimadzu corporation

KQ-250DE type numerical control ultrasonic cleaner Kunshan ultrasonic instruments Co., ltd

AG245 type ultra-micro electronic balance type electronic analytical balance Mettler Toledo company of Switzerland

1.2 reagents

Gestodene (purity 98%, lot number 20190327) Hebeimo technology development Co., ltd

KN-300N silica gel glue Kang Libang Polymer New Material Co.Ltd

2 Experimental methods

2.1 preparation of gestodene implant

Silicone tubes were prepared according to the formulation and process of the examples below, and the release of drug was controlled using the silicone tubes as drug delivery vehicles. Taking a self-made silica gel tube, soaking the silica gel tube in 75% ethanol for 30min for sterilization, drying, and sealing one end of the silica gel tube with silica gel sealing glue for later use. Filling medicine (42 mg of gestodene powder with micronization particle size of 2.81 μm) via filling funnel, sealing the other end with silica gel, and solidifying24h, and preparing into pregnadienone implant (here, the thickness of silica gel tube wall of pregnadienone implant is 0.3mm, and the drug release area is 94.2 mm) ² )。

2.2 selection of Release Medium

The prepared implant should be implanted in subcutaneous tissue of human thigh where pH is near neutral, so the release medium can be selected between water or physiological saline. Preparing supersaturated water and physiological saline of the gestodene raw material before and after crushing, placing in a shaking table, shaking for 72h, taking out, centrifuging, taking supernatant, filtering, measuring equilibrium solubility of the gestodene raw material before and after crushing in water and physiological saline by high performance liquid chromatography, and selecting a proper release medium according to the result.

2.3 in vitro Release and influencing factor investigation

2.3.1 investigation of oven-cured silicone tubes

In the experiment of preparing the silicone tube, the mechanical index of the silicone tube subjected to the oven vulcanization treatment for 48 hours is better, and the silicone tube subjected to the oven vulcanization treatment can be judged to be completely vulcanized. In order to further judge whether the in-vitro release result of the drug is affected by the silicone tube subjected to the oven vulcanization treatment, the silicone tubes (corresponding to the silicone tubes in the previous examples 3-1 and 3-3) which are not subjected to the oven vulcanization treatment are respectively filled with the same specification and the same drug-containing length, and the in-vitro release experiment is carried out by using the implants with the same drug loading amount, so that the influence of the oven vulcanization treatment on the in-vitro data of the drug is examined.

2.3.2 investigation of silicone tubes prepared with different vinyl contents

In addition to the addition of hydrogen-containing silicone oil, the vinyl content of raw rubber also has a great influence on the crosslinking degree of the silicone tube. In order to examine the extent of the effect of vinyl content on the in vitro release of the drug, silicone tubes were prepared with raw gums of 0.17% and 0.23% vinyl content, and the effect of silicone tubes prepared with different vinyl contents on the in vitro release of gestodene was examined.

2.3.3 investigation of the molar ratio of Si-H groups in different Hydrogen-containing Silicone oils to vinyl groups in methyl vinyl Silicone rubber

The implant is placed in a release medium, the release medium enters the inside of the silica gel tube through the pores of the silica gel tube to dissolve the medicine, and then the medicine is released by using the concentration difference. Silicone tubes were prepared from raw rubber having a vinyl content of 0.17% and hydrogen-containing silicone oil having a hydrogen content of 0.75% in a molar ratio of 1:1.2 to 1:1.5, respectively, and the effect of the addition amount of the hydrogen-containing silicone oil on the daily release amount of the implant was examined for the same other factors.

3 results and discussion

3.1 preparation of a contraceptive implant of gestodene

The static electricity of the raw material medicine is particularly paid attention to when the implantation agent is prepared, the raw material medicine powder is prevented from adhering to the outer wall of the silica gel tube, and in addition, the operation is paid attention to when the implantation agent is blocked, so that the influence of the medicine releasing area of a medicine containing section caused by irregular shape of the sealing gum is prevented. Finally, the implants with different specifications are prepared, the appearance is good, the sealing part is even, the medicine containing section is even to fill medicine, and the GEST 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 following table.

The results show that the solubility of the gestodene raw material medicines with two particle sizes in water is larger than that of the raw material medicines in physiological saline, the solubility of the raw material medicines which are not crushed is larger than that of the raw material medicines after crushing, and finally, water is selected as a release medium for in-vitro release experiments.

In theory, the smaller the particle size of the drug substance, the larger the contact area with the solvent, and the greater the solubility should be, but experimental data shows that the solubility of the drug substance after pulverization becomes smaller. In the experiment, the raw material medicine is larger in static electricity after being crushed and easy to generate agglomeration, and the contact area between the raw material medicine and a medium is possibly smaller than that of the raw material medicine with larger particle size, so that dissolution is reduced.

3.3 in vitro Release influencing factor investigation

3.3.1 examination of Silicone tube for oven vulcanization

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

Examples numbering	Oven vulcanization process	Average release rate (μg/d)	RSD(％)
				Examples 3 to 3	Oven vulcanization for 48h	10.57±0.76	7.19
Example 3-1	No oven vulcanization was performed	12.46±0.92	7.38

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

The results show that the average daily release of the implant filled with oven-cured silicone tubing is lower than the implant filled with silicone tubing not oven-cured, but the gap is smaller and the release of the implant prepared with oven-cured silicone tubing is more stable relative to the in vitro release of the uncured silicone tubing. In addition, the mechanical index of the silica gel tube subjected to oven vulcanization treatment is better, the release data and the mechanical index are comprehensively considered, and the silica gel tube subjected to oven vulcanization treatment at 180 ℃ for 48 hours is better in medicine filling.

3.3.2 investigation of preparation of silicone tubes with different vinyl content

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

Prescription of silicone tube	EthyleneRadical 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 following table.

The results show that the silicone tube prepared from raw rubber with different vinyl contents (0.17% and 0.23%) has larger influence on the in-vitro average release amount of the implant, the early-stage burst release of raw rubber with 0.23% vinyl content is larger than that of the silicone tube prepared from raw rubber with 0.17%, the in-vitro release of the silicone tube prepared from raw rubber with 0.17% vinyl content is more stable, and meanwhile, the performance of the silicone tube with 0.17% vinyl content is better according to the comprehensive view of mechanical indexes.

3.3.3 investigation of Hydrogen-containing Silicone tubes with different amounts of Hydrogen-containing Silicone tubes

The effect of the amount of hydrogen-containing silicone oil on in vitro release is shown in the following table.

Prescription of silicone tube	Molar ratio of	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

And (3) injection: the molar ratio refers to the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber.

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

The results show that the daily release rate of the silicone tube filled contraceptive implant prepared with the recipe of 0.17% vinyl content of raw rubber and 0.75% hydrogen containing silicone oil, with a molar ratio of vinyl in the methyl vinyl silicone rubber to Si-H groups in the hydrogen containing silicone oil of 1:1.2 is slightly less than the release rate of the silicone tube filled contraceptive implant prepared with the recipe of 1:1.5 with a molar ratio of vinyl in the methyl vinyl silicone rubber to Si-H groups in the hydrogen containing silicone oil, but the release profile is relatively more stable. The implant can realize stable release, so that the molar ratio of vinyl in the methyl vinyl silicone rubber to Si-H groups in the hydrogen-containing silicone oil is 1:1.2, and the controlled release of the drug is better.

3.4 experiments on the Long-term in vitro Release of gestodene implants

Taking 3 batches of pregnadienone contraceptive implant (here, the thickness of the silica gel tube wall of the pregnadienone implant is 0.3mm, and the drug release area is 94.2 mm) ² Pulverizing gestodene raw material into particles with particle diameter of 2-4 μm (e.g. 2.81 μm), filling pulverized gestodene raw material 42mg into a filling hopper, respectively ZJ001, ZJ002, ZJ003, and shaking at 37deg.C and shaking table speed of 100deg.R min ^-1 And (3) carrying out a long-term in-vitro release experiment under the condition, and examining the long-term release stability condition of the preparation, so as to obtain a long-term controlled release effect, wherein the result is as follows.

Long-term release data for ZJ001, ZJ002, ZJ003 implants are shown in the table below.

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According to the 80-day in vitro drug release data in the table, a graph of the daily in vitro drug release versus release time for 3 batches of the same-specification subcutaneous contraceptive implant of gestodene is plotted as shown in fig. 4.

As can be basically seen from fig. 4, three batches of formulations with the same specification have small differences in the fluctuation range of drug release, and the whole formulations tend to be consistent, and the curves are observed. The early-stage fluctuation is larger, the later stage is gradually and stably, and the daily in-vitro release amount of the final preparation is mostly stabilized within the release range of 17-20 mug. By looking up the literature, it is known that a contraceptive effect can be produced on the human body by releasing 10-20 mug of gestodene per day. The three batches of preparations are almost stable in 17-20 mug release amount from 11-80d, and meet the experimental expectation.

The data are arranged, the data are simplified by taking 5 days as a period, and the long-term drug release condition of three batches of preparations is observed. The implant is implanted in relation to the release amount and release time of the drug in each time period.

From the data in the table above and the curve change in fig. 5, it can be found that:

(1) The implant releases medicine unstably in the first ten days, the fluctuation is larger, and at the stage, some residual medicine possibly exists on the surface of the silica gel tube and is dissolved gradually, so that the early-stage medicine release is unstable, and the medicine release amount is larger.

(2) The subsequent release stability of the implant is better, the early release amount of the implant shows a descending trend in the whole, the implant shows a more stable state after smaller fluctuation, the release amount is always kept between 17 and 20 mu g, the release amount meets the requirement, and the result shows that the gestodene contraceptive implant can realize the controlled release for at least 3 months.

(3) The average drug release amounts of the three implants were 19.70, 19.15 and 18.84. Mu.g, respectively. The RSD value was 2.26%. The results indicate that the reproducibility of the three formulations is good and the long-term in vitro release data is substantially consistent.

4. In vivo experiments of pregnant dienone contraceptive implant in rats

The prepared silica gel tube has qualified mechanical index, can stably control the drug release, has good in vivo biocompatibility, and can not stimulate in vivo tissues. The irritation of the silicone tube to the skin of the rat is mainly examined by injecting the silicone tube extract liquid into the rat; the tissue irritation of the silicone tube was examined by embedding the silicone tube in a rat for a long period of time and taking out the surrounding tissues thereof for tissue section. Observing the change trend of the weight of the rat before and after implantation by implanting contraceptive implants of different specifications into the rat, and observing whether the contraceptive implants influence the normal growth of the rat; the female sex cycle change of the rat is observed through the post-implantation vaginal smear, whether the female plug appears in the rat is observed, and the luteinizing hormone LH level in the rat body is detected and examined after the contraceptive implant is implanted to examine the contraceptive effect.

1 instrument and reagent

1.1 instruments

XS105 type electronic analytical balance Metrele-Tolyduo instruments Inc

SMD200-2 electronic analytical balance Orhaus International trade Limited

TG16MW bench-top high-speed centrifuge Hunan Hexi instruments Co.Ltd

Rat LH kit Shanghai Tongwei biotechnology Co., ltd

Micro-scientific and technological Co.Ltd in Shenzhen City of electron microscope

Autoclave Shanghai Shen An medical equipment factory

1.2 reagents

Gestodene (purity 98%, lot number 20190327) Hebeijersey technology development Co., ltd

Crystal Violet, methacene chemical reagent plant

Normal saline Shandong Limonitum Wang Huaxue reagent Co., ltd

4% paraformaldehyde solution Shanghai research development Biotech Co.Ltd

1.3 laboratory animals

12 healthy male SD rats weighing 180-200g, 57 healthy female SD rats weighing 180-200g purchased from Benxi long organisms, license certificate: SCXK (Liao) 2020-0001.

2 Experimental methods

2.1 in vivo local irritation experiment in Silicone tube rats

The prepared silicone tube (silicone tube in preparations ZJ001, ZJ002 and ZJ 003) is sheared, immersed in 10mL of sterilized and non-heat source purified water, heated and extracted for 24 hours at 70 ℃, and the extract is sterilized under high pressure for standby. The 6 experimental rats were randomly divided into two groups, one group being the experimental group and one group being the physiological saline control group, and the backs of the rats were removed by Mao Bei skin. The experimental group was injected with 0.2mL of the extract solution intradermally on one side of the rat ridge, and the control group was injected with 0.2mL of physiological saline intradermally on one side of the rat ridge. Skin reactions at the injection sites were observed over 24h, 48h, 72 h.

2.2 histopathological experiments after embedding the silicone tube in rats

Sealing the prepared silicone tube, and sterilizing for later use after the sealing glue is completely solidified. Experimental rats were selected and randomly divided into 3 groups of 3 animals each. The self-made silicone tube which is implanted and sterilized at the back in each rat body is used for killing the rat after implantation for 3 days, 10 days and 30 days respectively, the tissue of 2cm around the implanted silicone tube is taken out, and the skin tissue is fixed by 4% paraformaldehyde and is reserved for tissue section observation. And (3) observing whether surrounding tissues have inflammatory reactions such as red swelling and the like, carrying out a slicing experiment on the tissues, and observing whether subcutaneous and muscle abnormal lesions exist at the implantation part of the silicone tube.

2.3 in vivo efficacy experiment of gestodene contraceptive implant in rats

The silicone tube with the outer diameter of 2.38mm and the wall thickness of 0.3mm (corresponding to the silicone tube and the drug core of the preparation ZJ001, ZJ002 and ZJ 003) and the preparation of the 5-specification gestodene implant (drug-containing length/drug-loading rate) are prepared for standby by the optimal prescription and process, wherein the specification is as follows: (1) 0.2cm/2.3mg (2) 0.5cm/5.4mg (3) 1cm/10.5mg (4) 2cm/20.7mg (4 cm/41.1 mg).

42 female rats were selected and checked for normal oestrus by vaginal smear, and 42 female SD rats weighing 180-200g were randomly divided into I, II, III, IV, V experimental dose groups (corresponding to the following specifications of implant (1; 0.2cm/2.3 mg; 0.5cm/5.4 mg; 3; 1cm/10.5 mg; 4; 2cm/20.7 mg; 4cm/41.1 mg; K groups) and 1 blank group (K groups), 1 Levonorgestrel silica gel stick positive control group (Y groups) (Levonorgestrel silica gel stick I, available from Liaoning Lv Dan pharmaceutical Co., ltd.).

Injecting a proper amount of anesthetic into the abdominal cavity of a rat, removing hair from the neck and back of the rat after the rat enters an anesthetic state, disinfecting with 2% iodine tincture, cutting local skin on the side surface of the back of the rat with surgical scissors to form a small opening of about 0.5cm, inserting a special embedded needle for the implant into the position of an appointed scale of the embedded needle, placing the disinfected implant into the embedded needle, stopping pushing the embedded needle with the implant into the skin continuously until the embedded needle can be completely placed into the length of the implant, withdrawing the embedded needle, leaving the embedded needle under the skin, suturing the incision, and disinfecting the wound surface with 2% iodine tincture. After 24h implantation, the rats are bred in cages with male and female rats according to a ratio of 3:1.

2.3.1 rat State observations

The rats are weighed and recorded before the implantation operation, the pregnant dienone contraceptive implant is implanted for 30 days, the rats are weighed again, whether the rats grow normally after the implantation of the implant in vivo is observed, and the mental state, the activity condition and the urination and defecation condition of the rats are observed daily.

2.3.2 vaginal smear experiment to observe the estrus cycle of rats

The estrus cycle of the rat is on average 4-5d, and the estrus cycle of the rat is generally divided into 4 phases, namely estrus, postestrus and estrus. The preestrus and estrus can be fertilized by mating ovulation, the postestrus is the degenerated destructive period of the reproductive tract, and the interestrus is a relatively stationary and slow growth period. Vaginal smear is commonly used to determine the course of the estrus cycle in rats. When the contraceptive implant exerts contraceptive effect, the rat should have no estrus.

Vaginal smear method: taking out the rat, grabbing and fixing the animal at the palm, slightly inserting the animal into the vagina of the female rat by about 0.5cm after the animal is wetted in physiological saline by using a thin cotton swab, slowly rotating the animal for taking out, uniformly coating the vaginal contents on the cotton swab on a glass slide, naturally drying the glass slide after numbering, performing crystal violet staining, and observing the vaginal smear by using an electron microscope after air drying to judge the oestrus cycle of the rat. Rats subjected to the implantation procedure were subjected to vaginal smear experiments 3d later, taking vaginal secretions 9:00 a.m. each day. The experimental rats were observed for estrus cycle changes by vaginal smear.

2.3.3 observing the vaginal embolus to determine the condition of the mating pregnancy of rats

When the implant plays a contraceptive role, female rats cannot mate with male rats in the estrus-free period, so that the contraceptive effect can be judged by observing whether female rats appear in the cage or not. After the rats are mated, semen can be left at the vaginal orifice to form a vaginal suppository, the vaginal suppository is generally milky white, and sometimes slightly yellow, and the rats are mated generally at night, so that the rats can be accurately observed only when vaginal secretion is collected and the vaginal suppository is observed before 9:00 am is ensured. Rats after implantation were observed for the presence of vaginal plugs prior to vaginal smear experiments after 3d implantation.

2.3.4 ELISA for determining luteinizing hormone LH levels in rats

The gestodene mainly acts on hypothalamus and pituitary gland, so that the levels of FSH (follicle stimulating hormone) and LH (luteinizing hormone) in the body are obviously reduced, the ovaries are anovulatory, and the gestodene has obvious antiestrogenic activity, and can thicken cervical mucus and prevent sperm from penetrating. Shows extremely strong progestogen activity on endometrial transformation, can thin the endometrium, has low columnar epithelial cells, has poor secretion function and is unfavorable for implantation of pregnant eggs. The significantly lower LH levels in rats after implantation of the contraceptive implant compared to the blank control group demonstrates that the contraceptive implant achieves contraceptive effect.

Female mice after implantation surgery and cage closure are subjected to orbital blood collection every day after vaginal secretion collection. Blood was collected by an EP tube moistened with an anticoagulant and centrifuged for about 10 minutes after collection (5000 r.min ^-1 ) The supernatant was carefully collected and stored in a-80℃refrigerator. And detecting the LH level in the rat body by adopting an enzyme-linked immunosorbent assay method, and judging the drug effect.

3 experimental results and discussion

3.1 in vivo tissue irritation experiment in Silicone tube rats

The experimental group was injected with 0.2mL of the extract solution intradermally on one side of the rat ridge, and the control group was injected with 0.2mL of physiological saline intradermally on one side of the rat ridge. Skin reactions at the injection sites were observed over 24h, 48h, 72 h. And dissecting each injection point, and not generating red swelling, necrosis and other reactions, and the result is negative.

3.2 histopathological experiments after embedding the silicone tube in rats

The pathological image (HE, ×2 or HE, ×20) of the muscle tissue at the implantation site at 3, 10, or 30 days after implantation was observed, as shown in FIG. 6.

The results show that the silicone tube implantation for 3 days (see graph A, B in fig. 6) showed an acute inflammatory reaction, the epidermis layer was slightly thickened, the dermis layer was rich in collagen fibers, the local subcutaneous tissue was visible as a large luminal structure formation, and the surrounding connective tissue hyperplasia was visible with more lymphocyte infiltration. The acute inflammatory reaction gradually disappeared when the patch was implanted for 10 days (see graph C, D in fig. 6), the epidermis layer was slightly thickened, the collagen fibers content of the dermis layer was rich, the local subcutaneous tissue was visible as a large capsule structure formed, and connective tissue hyperplasia was visible around with diffuse lymphocyte infiltration. The epidermis layer after 30 days of implantation (see fig. E, F of fig. 6) is complete in structure, squamous epithelial cells are normal in morphological structure and compact in arrangement, the dermis layer is rich in collagen fibers, local subcutaneous tissues can form large capsular structures, mild connective tissue hyperplasia is seen around, and diffuse lymphocyte and macrophage infiltration is accompanied.

The large capsule cavity appears at the implantation operation position, which indicates that the implantation of the implantation agent can cause certain damage to subcutaneous tissues to form the capsule cavity, and the mild connective tissue hyperplasia can appear around the capsule cavity, namely the junction of the silicone tube and the tissues to gradually form the envelope. When the silicone tube is dissected after implantation for 3 days, the silicone tube is observed to be easy to deviate from, when the silicone tube is dissected after implantation for 10 days, the periphery of the silicone tube forms a coating, the silicone tube is not easy to move, so that along with the extension of implantation time, the periphery of the silicone tube forms the coating, and the silicone tube is not easy to shift in a body. In addition, the inflammatory reaction is the largest when the silicone tube is implanted for 3 days, and the inflammatory reaction gradually decreases along with the extension of the implantation time, which indicates that the inflammatory reaction caused by the implantation of the silicone tube can be gradually recovered.

3.3 in vivo efficacy experiment of gestodene contraceptive implant in rats

3.3.1 weight changes before and after rat implantation

After the implantation operation, the rats were observed for feeding status and liveness. Normal urination and defecation, and no listlessness.

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

As can be seen from the observation of the weight change data of rats for one month, the implantation operation and the silica gel tube have no influence on the growth of rats, the weight change trend of rats in the experimental group is similar to that of rats in the blank group, and the overall gestodene implantation agent has no influence on the growth of rats.

3.3.2 vaginal smear observation of estrus cycle in rats

The vaginal secretion of female mice is taken at fixed point 24h a day from the rats in the blank control group, and the estrus cycle is observed by crystal violet staining smear, and the vaginal secretion of female mice is compared with the rats in the experimental group. The rats were observed to develop estrus substantially once every 7 days or so for a period of one month, and the rats were estrus cycle vaginal smears, see figure 7. The commercial levonorgestrel implant embedded rats, the vaginal smear of which is observed, are not in oestrus rats, and all have contraceptive effect.

The experimental groups were 5 dose groups. According to one month of vaginal smear observation, rats in the four dose group of experiment II, III, IV, V began to develop a large amount of mucus in the vaginal secretions after 4 days of implantation, and a large amount of leukocytes but no keratinocytes were observed by observing the vaginal smear, indicating that the rats had no normal estrus cycle. However, rats numbered 1 and 4 in experiment I still observed complete estrus cycle changes, indicating that these two rats failed to contraception, and the dose may be relatively poor for contraception in rats with low contraceptive rates.

3.3.3 observation of vaginal embolus to determine rat mating gestation Condition

When vaginal plugs were observed, rats with number 1, which had a normal estrus cycle, were smeared on the vagina in the experimental dose group, and when vaginal secretions were taken 13 days after implantation, milky-white vaginal plugs were observed at the vaginal orifice as shown in fig. 8, panel a, and rats with number 4 were found to have a vaginal plug appearance 20 days after implantation as shown in fig. 8, panel B. This result indicates that the two mice numbered 1 and 4 in the experimental dose I group were mated with male mice, indicating estrus occurrence and contraceptive failure in both mice. The other experimental dose groups and the commercial positive groups have no occurrence of female bolts, and the rats are proved to have no mating with male rats and also have contraceptive effect.

3.3.4 ELISA determination of LH concentration in rat plasma

The in vivo LH level of the rats is detected by an enzyme-linked immunosorbent assay, a pregnadienone contraceptive implant 28d is implanted, and the in vivo LH level of 6 rats in each group is measured as follows.

The rat LH levels are shown in the table below.

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Note that: * Refers to P <0.01 compared to the blank.

The results showed that the positive control group had a significant difference (P < 0.01) from the LH level data of each experimental dose group compared to the blank group, and since the above table is the mean value of 6 rats in each experimental group, and the results showed that contraception failed in two rats in the experimental dose I group based on vaginal smear and vaginal suppository, the LH level data of 6 rats in the experimental dose I group were individually listed, and the results were as follows.

The LH levels for each rat in experimental dose group I are shown in the table below.

Group of	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 that: * Refers to P <0.01 compared to the blank.

The results showed that no significant difference was observed in LH levels between the number 1 and 4 rats in the experimental I dose group and between the blank group, and that there was a significant difference between the remaining 4 rats and the blank group (P < 0.01).

As can be seen from the observation of the in-vivo LH level data of rats, compared with the blank group, both the II, III, IV, V experimental dosage group and the positive control group obviously reduce the in-vivo LH level of rats, and the larger the dosage, the lower the LH level, which indicates that the better the hormone inhibition effect. In vivo LH level data of rats numbered 1 and 4 of experimental I dose group were observed to show that LH levels were higher than those of other numbered rats and were fluctuant, indicating that implantation and release of the implant in both rats was unstable and contraceptive efficacy was not achieved, and since the implant-containing segment of the implant of experimental I dose group was only 0.2cm long, the operation was not easy to perform during implant preparation, resulting in unstable drug loading, and thus contraceptive failure was achieved in both rats of the dose group and contraceptive efficacy was achieved in all four rats.

4 the section of the knot

(1) The local irritation experiment of the leaching solution of the silicone tube on the rat proves that the silicone tube has no irritation on the local skin of the rat and is safe; the implantation experiment of the silicone tube proves that the prepared silicone tube has no irritation to rat tissues, the silicone tube has good tissue compatibility, and the implantation is not inflamed or stimulated to the surrounding tissues of the rats.

(2) Through an implantation experiment, the weight change of the rats before and after implantation proves that the rats grow normally after implantation of the implantation agent; the estrus cycle of the rat is observed through vaginal secretion smear staining, the gestational mating condition of the rat is observed through a vaginal suppository, and the contraceptive effect of the gestodene implant is examined through three experiments of LH level change in the rat body after implantation. The results showed that the effective dose group showed good contraceptive effect, no estrus rats were observed with vaginal smears, and no vaginal embolism was observed, with a significant decrease in LH levels compared to the normal group.

(3) The drug-containing section of 0.2cm is obtained through a rat drug effect experiment, the contraceptive effect of the gestodene implant with the drug loading of 2.3mg specification is poor, and the contraceptive rate is less than 70 percent. And when the medicine-containing section is larger than 0.5cm, the implantation agent with the medicine-carrying quantity being larger than 5.4mg has good contraceptive effect.

II. Levonorgestrel long-acting implant

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

(1) Chromatographic conditions

Chromatographic column:C ₁₈ chromatographic column (4.6 mm. Times.250 mm,5 μm);

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

column temperature: 30 ℃;

detection wavelength: 240nm;

flow rate: 1.0 mL/min ^-1 ；

Sample injection amount: 20. Mu.L.

(2) In vitro release degree determination method

The release experiment adopts a horizontal oscillation method, a set of 6 implants are taken, the implants are fixed on the wall of a 125mL conical flask with a plug by using an adhesive, and a proper distance is reserved between every two drug rods (so as to prevent inaccurate release results caused by floating on the liquid surface when the implants are released). 100mL of distilled water is precisely measured and injected into a conical flask, the conical flask is placed into a constant temperature air shaking table at 37 ℃ for shaking, the amplitude is 100 times/min, and the medium with the same volume is replaced every 24 hours. The sample was filtered through a 0.22 μm microporous filter membrane, and the sample was sampled at 20. Mu.L according to the chromatographic conditions in this section (1).

2. Preparation and evaluation of addition type silicon rubber tube

The methyl vinyl silicone rubber and the hydrogen-containing silicone oil undergo hydrosilylation reaction under the catalysis of a platinum catalyst, and meanwhile, the addition type silicone rubber product prepared by adding a proper reinforcing agent has excellent physiological inertia, no toxicity, no smell, good biocompatibility, biological aging resistance, good air permeability, no adverse reaction after being implanted into a human body, and little change of physical properties after being implanted into the human body for a long time, and can be applied to various occasions of contact with blood and implantation into the human body.

The preparation method mainly comprises the steps of adding a reinforcing agent (silicon dioxide) into linear high polymer methyl vinyl silicone rubber with a terminal group as a vinyl group, then carrying out addition reaction and crosslinking under the catalysis of a platinum catalyst to form a reticular high polymer elastomer, extruding the reticular high polymer elastomer into a tube shape through an extruder, and then carrying out oven vulcanization to obtain the addition type silicone tube.

1 instrument and materials

1.1 instruments

1.2 reagents and materials

Preparation and measurement of 2-addition type silicon rubber tube

2.1 preparation of addition type silicon rubber tube by high temperature vulcanizing method

Drying reinforcing agent white carbon black for 24 hours at 180-210 ℃ (for example, 200 ℃) for standby, and drying methyl vinyl silicone rubber raw rubber for 24 hours at 40 ℃ for standby; adding the white carbon black and the raw rubber with the prescribed amount into a kneader, kneading for 30min at 30 ℃, and then taking out; taking 1-10mm (1 mm for example) as a roll spacing on an open mill, rolling the triangular bag sheet for 5 times, rolling and discharging sheets, and standing for 24 hours to obtain a rubber compound; the rubber compound is divided into A, B components, wherein the component A is added with hydrogen silicone oil with a prescription amount and inhibitor for uniform mixing, and the component B is added with platinum catalyst with a prescription amount for uniform mixing; putting A, B components 1:1 into an open mill, beating triangular bag thin-pass for 4-6 times, and then uniformly cutting materials and blanking; putting the cut sizing material into a silicone rubber extruder to be extruded into a tube shape, and vulcanizing and shaping at high temperature; (the pre-drying tunnel 270 ℃ and the vulcanizing time are about 5s, the post-drying tunnel 180 ℃ and the vulcanizing time is about 2min, and the oven vulcanizing temperature is 180 ℃ and the vulcanizing time is 48 h), measuring the outer diameter of the extruded silicone tube in real time through the diameter measurement of an infrared diameter measuring instrument, carrying out appearance inspection through an electron microscope, and heating and oven vulcanizing in an oven after the appearance of the product is qualified to obtain the finished product.

2.2 determination of the physical and mechanical Properties of the addition-type Silicone rubber tube

Medical silicone rubber tubes are required to have good biological and physical mechanical properties. The biological performance and physical and mechanical performance are determined by the materials and the production process. The physical and mechanical properties of silicone tubes mainly include tensile strength, elongation at break, tear strength and hardness. Wherein, the Tensile Strength (TS) is the maximum Tensile stress of the sample until fracture, and represents the maximum uniform plastic deformation resistance of the material; tear strength (T) refers to the strength required to Tear a sample, representing the ability of the sample to resist tearing; elongation at break (Elongation at break, eb) refers to the ratio of the elongation at break of the sample to the original length; representing the deformation range of the sample; hardness (H) is a physical measure of the degree of deformation of a substance under compression.

And (3) taking tensile strength, elongation at break, tearing strength and hardness as detection indexes to screen and optimize the prescription and extrusion vulcanization process of the silicone rubber to obtain a proper silicone tube for evaluation. Tensile strength and elongation at break were measured according to GB/T528-2005; tear strength was measured according to GB/T529-2005; shore A hardness was measured according to GB/T531-2008.

3 methods and results

3.1 investigation of Silicone tube prescriptions

3.1.1 investigation of the vinyl content of polydimethylsiloxane

To examine 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 performed using the formulations shown in the following table.

PHR: every 100 parts by mass of the polymer compound corresponds to the parts by mass of the component.

The vinyl at the tail end of the methyl vinyl silicone rubber is subjected to addition reaction with the active hydrogen atom of the hydrogen-containing silicone oil to crosslink into a high polymer elastomer, so that the vinyl is used as an active group, which is a crosslinking point for forming a high polymer network, and the physical and mechanical properties of the medical silicone rubber tube are affected by the content of the vinyl.

As shown in the following table, the hardness of the silicone tube increases with the increase of the vinyl content, but the properties such as elongation at break, tensile strength, tear strength and the like of the silicone tube change in a peak manner from high to low. When the vinyl content is 0.05%, the crosslinking points formed by the addition reaction are fewer, the tearing strength and the tensile strength of the silica gel tube are smaller, and the mechanical property is too poor to be used subsequently; when the vinyl content is 0.23%, the crosslinking point formed by the reaction is too much, the elongation at break of the silicone tube is reduced, and the tensile strength and the tearing strength are slightly reduced, because the crosslinking density is too large, the crosslinking point formed by the silicone tube is too much, the crosslinking chain links are shortened, the rigidity is increased, the hardness of the silicone tube is increased, the elongation at break is obviously reduced, the internal crosslinking chain links cannot be orderly and effectively arranged, the invalid crosslinking network is increased, and the crosslinking chain links capable of bearing the external force when resisting the external force are reduced instead, so that the mechanical properties such as the tensile strength, the tearing strength and the like of the silicone tube are reduced; when the vinyl content of raw rubber is 0.17%, the internal crosslinking chain links are orderly and reasonably distributed, and each physical and mechanical property of the silicone tube is excellent, so that the methyl vinyl silicone rubber with the vinyl content of 0.17% is the preferable 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 proportions

Compared with other rubber raw rubber, the main chain of the methyl vinyl silicone rubber raw rubber is of a single-chain structure, si-O on a molecular chain is longer than C-O and C-C sigma bonds, and the main chain contains isolated double bonds and does not contain other large or polar groups, so that the molecular chain has extremely strong flexibility, and macroscopic performance is poorer mechanical property. In order to enhance the mechanical properties of methyl vinyl silicone rubber, different fillers are generally filled in the methyl vinyl silicone rubber according to different purposes, and white carbon black is an inorganic filler with the best compatibility with the silicone rubber because of main elements and chemical bonds similar to the silicone rubber, and is a commonly used reinforcing agent in silicone rubber products.

Experiments are carried out by using a prescription shown in the following table to examine the influence of the white carbon black consumption on the mechanical properties of the silica gel tube.

The influence of the white carbon black consumption on the physical and mechanical properties of the silica gel tube is shown in the following table, in the range of 30PHR-40PHR of the white carbon black consumption, the hardness of the silica gel tube is gradually enhanced along with the increase of the white carbon black consumption, the deformation of an extruded tube is reduced, the tube wall thickness is more uniform, and the tensile strength, the tearing strength, the elongation at break and other physical and mechanical properties of the tube are excellent; however, when the white carbon black dosage is increased to 40PHR, the extrusion power of the extruder is slightly insufficient due to the increase of the hardness of the sizing material, and the extrusion rate fluctuation is large, so that the appearance of the extruded pipe is uneven.

The white carbon black can improve the mechanical property of vulcanized rubber, and the hydroxyl on the surface of the white carbon black can act with macromolecules, and a space network structure is formed between the white carbon black and the macromolecules, so that when the silicon rubber is deformed under the action of external force, the sliding of molecular chains and the mass physical adsorption can absorb the impact of the external force, the impact of friction or hysteresis deformation caused by the external force can be buffered, and the stress distribution is uniform. Therefore, the mechanical property of the silicone rubber can be enhanced by adding a proper amount of white carbon black, but the tensile elasticity of the silicone rubber is not excessively reduced. Therefore, the silica tube is preferably prepared by adding white carbon black accounting for 35 percent of the mass of the raw rubber.

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 Hydrogen silicone oil usage

The preparation of the addition type silicone rubber generally uses hydrogen-containing silicone oil as a cross-linking agent, and the molecular formula of the hydrogen-containing silicone oil is as followsThe active hydrogen attached to the silicon atom participates in the addition reaction to form a crosslinking point together with the vinyl group 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 vinyl content of 0.17%, hydrogen-containing silicone oil with hydrogen content of 0.75%, and calculating the corresponding hydrogen-containing silicone oil according to the vinyl content, wherein the calculation formula is as follows:

Wherein W is the addition amount of hydrogen-containing silicone oil; a is the mole ratio of Si-H/Si-Vi, namely the mole ratio of vinyl to hydrogen of the hydrogen-containing silicone oil reaches 1: the A value is 1 at 1; omega (Vi) is the mass percent of vinyl in the raw rubber; omega (H) is the mass fraction of hydrogen in the hydrogen-containing silicone oil; 27 is the molar mass of vinyl; w (W) ₁ Is the quality of raw rubber. The A value is used for representing the change of the dosage of the hydrogen-containing silicone oil, and experiments are carried out by using the following table to examine the influence of the dosage of the hydrogen-containing silicone oil on the mechanical property of the silicone tube.

Note that: PHR: every 100 parts by mass of the components corresponding to the macromolecular compounds;

the raw rubber in the table above has a vinyl molar percentage of 0.17% and the hydrogen silicone oil has a hydrogen molar percentage of 0.75%.

The experimental results are shown in the following table, and the physical and mechanical properties of the silicone tube change in a mountain peak manner along with the increase of the dosage of the hydrogen-containing silicone oil. This is also related to the density of crosslinking points inside the silicone tube, and from the reaction mechanism, the hydrogen and vinyl groups of the hydrogen-containing silicone oil are in a molar ratio of 1:1 to participate in the reaction. When the A value is smaller than 1, the quantity of active hydrogen participating in the addition reaction is insufficient, and the crosslinking point formed by the addition reaction is less; the tensile strength, tear strength and hardness of the silicone tube gradually increased with increasing a value, and reached a peak value at a value of 1.2, i.e., the molar ratio of vinyl to hydrogen of the hydrogen-containing silicone oil was 1:1.2, the physical and mechanical properties of the silicone tube are best, and a little excessive hydrogen-containing silicone oil can fully cause the addition reaction, so that the mechanical properties of the extrusion tube reach the best state; however, as the amount of the hydrogen-containing silicone oil continues to increase, the crosslinking density of the silicone tube becomes large and the crosslinking points become disordered, and the physical and mechanical properties of the silicone tube begin to decrease. Therefore, the amount of the hydrogen-containing silicone oil to be used is preferably 1.2 as calculated at the time of charging.

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3.2 investigation of the preparation Process of silica gel tube

3.2.1 investigation of the vulcanization temperature and time

The silicone rubber is vulcanized at high temperature through a short pre-drying channel (0.8 m) after being extruded from an extruder and pulled by a conveyor belt, and then vulcanized through a long post-drying channel (2.5 m) under the traction of the conveyor belt, which is the vulcanization of the first stage, and the main purpose is to form a silicone tube. The purpose of the high-temperature vulcanization of the short drying tunnel is to quickly shape the silicone tube, reduce the deformation of the silicone tube when the subsequent conveyor belt conveys vulcanization, prevent the temperature of the silicone tube from being too high when the silicone tube passes through the short drying tunnel, otherwise, the silicone tube is vulcanized (figure 9) (the temperature of the pre-drying tunnel corresponding to the over-vulcanization state in figure 9 is 360 ℃), the macromolecules in the silicone tube are broken, the silicone tube is cracked in the stretching state, and various physical and mechanical properties are rapidly reduced. The vulcanization reaction is carried out continuously to form the silica gel tube, so that the vulcanization temperature of the post-drying channel is not too low, but the service life of the conveyor belt is influenced when the temperature of the post-drying channel is higher than 200 ℃, so that the temperature of the silica gel tube passing through the post-drying channel under the dragging of the conveyor belt is 180 ℃, the silica gel tube is well formed, has small deformation and has no over-vulcanization phenomenon.

After the first stage of heating forming, the silica gel tube is not fully crosslinked and has insufficient crosslinking density due to short reaction time, secondary vulcanization is carried out at 180 ℃ in an oven to further crosslink the silica gel tube, and the physical and mechanical properties of the silica gel tube are measured by sampling at 0h, 12h, 24h, 48h and 72h, so that the change of various physical and mechanical properties of the silica gel tube after the vulcanization treatment in the oven is observed.

Numbering device	Oven heat treatment time
		Example 15-1	0h
Example 15-2	12h
		Example 15-3	24h
Examples 15 to 4	48h
		Examples 15 to 5	72h

The secondary vulcanization time and the change of the physical and mechanical properties of the silicone tube are shown in the following table, when the secondary vulcanization time is 0-48h, the internal crosslinking reaction of the silicone tube continues to occur, the crosslinking points are increased, the elongation at break of the silicone tube is reduced, and the tensile strength and the tearing strength are obviously enhanced compared with those of the silicone tube vulcanized once; when the secondary vulcanization time is 48-72 hours, the internal crosslinking reaction of the silica gel tube is basically finished, and the tearing strength, the tensile strength and the like of the silica gel tube are slightly enhanced; however, as the vulcanization time increases, the silica gel tube starts to be overcured, the internal crosslinking bonds and segments start to undergo thermal cleavage reaction, and the tensile strength, tear strength, etc. of the silica gel tube start to decrease. And comprehensively comparing physical and mechanical properties of the silica gel tube after secondary vulcanization, and determining that the secondary vulcanization condition is preferably 180 ℃ for 48 hours.

Mechanical properties	Example 15-1	Example 15-2	Example 15-3	Examples 15 to 4	Examples 15 to 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

The implant material implanted in the body needs to be safe, reliable and nontoxic in terms of biological performance, and ensures the safety of implantation. The material is subjected to the following biological tests according to GBT 16175-2008-medical organosilicon material biological evaluation experimental method, and whether the biocompatibility is good or not and whether the material meets the requirement of in-vivo implantation is examined.

4.1 acute toxicity test

The prepared clean silicone tube (corresponding to the silicone tube in the previous examples 14-4) was cut into 5cm length, immersed in 100mL of redistilled water, heated and extracted at 70℃for 24 hours, and sterilized by autoclave 121℃for 30min for use.

10 healthy SD rats weighing about 200g are randomly and equally divided into an experimental group and a control group, wherein one group is injected with the extract by tail vein with the dosage of 5mL/kg, the other group is injected with the physiological saline with the same dosage by tail vein, and the conditions of the rats in 24 hours, 48 hours and 72 hours are observed. As a result, adverse reactions and death were not observed.

4.2 hemolysis experiments

According to rule 1148 of Chinese pharmacopoeia 2020, 1mL of healthy rabbit blood is taken and put into an conical flask containing glass beads to shake for 10min to remove fibrinogen, so that defibrinated blood is obtained. Adding 0.9% sodium chloride solution about 10 times, shaking, centrifuging at 1000 rpm for 15min, removing supernatant, and washing the precipitated red blood cells with 0.9% sodium chloride solution for 3 times until the supernatant does not appear red. The resulting red blood cells were made into a 2% suspension with 0.9% sodium chloride solution for use.

Taking 5 clean glass test tubes, wherein test tubes No. 1 and No. 2 are test sample tubes, a tube No. 3 is a negative control tube, a tube No. 4 is a positive control tube, and a tube No. 5 is a test sample control tube. 2% erythrocyte suspension, 0.9% sodium chloride solution, purified water and extract from "4.1 acute toxicity test" were added in this order as shown in the following table, and after mixing, immediately incubated in a constant temperature shaker at 37 ℃ + -0.5 ℃. After 3 hours, hemolysis and coagulation reactions were observed.

The hemolysis test is shown in the following table.

Test tube numbering	1	2	3	4	5
						2% erythrocyte 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 shows that the tubes 1, 2, 3 and 5 have no obvious difference in visual observation, the supernatant is clear, and the positive control tube 4 has hemolysis, so that the material is negative in the hemolysis test.

4.3 stimulation test

10 healthy SD rats weighing about 200g were selected and randomly aliquoted into experimental and control groups, and the hairs on both sides of the back spine of the rats were removed (approximately 3X 3cm area) 4 hours before the start of the test.

The extract from the "4.1 acute toxicity test" was applied dropwise to a 2.5X2.5 cm absorbent gauze, and the soaked gauze was applied to the rat dehaired skin and fixed with tape. Rats in the control group were covered with a saline gauze and fixed in the same manner as described above. After 4h, the gauze was removed for observation without any skin reaction.

10 healthy SD rats weighing 200g were selected and randomly divided into an experimental group and a physiological saline control group. The experimental group injected 5 spots of extract into the skin on one side of the ridge of the rat, each spot being 0.2mL, the opposite side of the ridge was injected with an equal amount of physiological saline. Saline control group was injected with equal amount of saline on both sides of the rat ridge according to the procedure described above. After injection, the conditions of all injection positions are observed within 24 hours, 48 hours and 72 hours, the phenomena of redness, swelling, necrosis and the like are not seen, and the material has negative stimulation experiment results.

4.4 short term implantation experiments

Preparing a plurality of clean silicone tubes (corresponding to the silicone tubes in the previous examples 14-4) with an outer diameter of 2.4mm and an inner diameter of 1.6mm and a length of 35mm, sealing the two ends with an adhesive, rinsing with distilled water, sterilizing at 121deg.C for 30min, and oven drying the sterilized silicone tubes. After selecting 12 healthy SD rats weighing about 200g, the sterilized silicone tube is implanted into the back skin of the rats by an implantation needle after anesthetizing the rats, the wounds are sutured, the rats are normally raised, 5 SD rats are randomly selected for sacrifice on the 3 rd day and the 10 th day after implantation respectively, and tissues around the silicone tube are taken out to prepare tissue slices for histological observation.

Rats had normal diet and life work and normal weight gain during silicone tube implantation. Subcutaneous and muscle tissue of the implanted portion was visually observed for no abnormal lesions. The results of the tissue section experiments are shown in FIG. 10, where (A) in FIG. 10 is a full view of the tissue section at the third day after implantation, and slight epidermal thickening was observed; in fig. 10 (B), a partial view of a tissue section on the third day after implantation is shown, connective tissue hyperplasia is seen around the implanted portion (leftmost arrow), scattered lymphocyte infiltration is accompanied (middle arrow), multinucleated giant cells are seen (rightmost arrow), and the degree of inflammatory cell response of the tissue on the third day after implantation is judged according to the inflammatory cell response classification standard to be class III. Fig. 10 (C) is a full view of a tissue section from the tenth day after implantation, where slight thickening of the epidermis is still observed; in fig. 10 (D), a partial view of a tissue section on the tenth day after implantation is shown, connective tissue hyperplasia is seen around (right arrow), and the degree of inflammatory cell response of the tissue on the tenth day after implantation is judged by the inflammatory cell response classification criteria with diffuse lymphocytes (left arrow). Rats had normal diet and life work and normal weight gain during silicone tube implantation. Subcutaneous and muscle tissue of the implanted portion was visually observed for no abnormal lesions.

With the increase of implantation time, the inflammatory reaction degree of the rat implantation part gradually decreases, the tissue section result shows that the inflammatory cell reaction degree of the rat implantation part in the first week is less than or equal to IV level, the inflammatory cell reaction degree in the fourth week is less than or equal to II level, the index requirement of the tissue reaction degree of the implantation experimental part of GBT 16175-2008-medical organosilicon material biological evaluation experimental method is met, and the silica gel tube material implantation experimental result is qualified.

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

Level of	Inflammatory cell response
		Class I	No or only very small amounts of lymphocytes are visible around the sample
Class II	Small amounts of lymphocytes were visible around the sample
		Class III	The sample has a small amount of neutrophils, lymphocyte infiltration and giant cell reaction
Grade IV	Around the sample, an inflammatory reaction mainly based on neutrophil infiltration was observed, and phagocytes were observed

The biocompatibility of the silicone tube is evaluated through an acute toxicity experiment, a hemolysis experiment, a stimulation experiment, an implantation experiment and the like, and the silicone tube has good biocompatibility, thereby laying a foundation for the preparation of the later-stage implant.

3. Preparation and evaluation of levonorgestrel long-acting implant

The silicon rubber has good air permeability and biological inertia, and the long-acting contraceptive implant taking the silicon rubber as a carrier can slowly and constantly release the contained medicine, can maintain the long-time contraceptive effect and can avoid the first pass effect of the liver.

The preparation and in-vitro release degree experiments of the levonorgestrel long-acting implant are mainly carried out in the preparation method, influence factors of the in-vitro release degree of the levonorgestrel implant are examined, the homemade preparation and the commercial implant are compared through the long-term release experiments, and the conditions of the acceleration experiments are examined.

1 instrument and medicament

1.1 instruments

LC-10ATVP high performance liquid chromatograph	Shimadzu corporation
		AG245 type ultra-micro electronic balance type electronic analytical balance	Mettler Toledo, switzerland
KQ-250DE type numerical control ultrasonic cleaner	KUNSHAN ULTRASONIC INSTRUMENTS Co.,Ltd.
		TS-100B type constant temperature shaking table	Shanghai Jiecheng Lab Instruments Co.,Ltd.

1.2 medicaments and reagents

LNG (lot number 20190327, purity)>98％)	Hebei mer technologies Co.Ltd
		Absolute ethyl alcohol (analytically pure)	Shandong Yu Wang Huaxue reagent Co., ltd
Chromatographic methanol	Shandong Yu Wang Huaxue reagent Co., ltd
		Levonorgestrel silica gel stick (I)	LIAONING LUDAN MEDICINE Co.,Ltd.
KN-300N adhesive	Kang Libang Polymer New Material Co.Ltd

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

2.1 preparation of Levonorgestrel Long-acting implant

2.1.1 treatment of Silicone rubber tube

Cutting an addition type silicone tube (with the outer diameter of 2.4mm and the inner diameter of 1.6 mm) with qualified appearance and all properties into 35mm with the same length, putting the same into a 100mL beaker, adding a proper amount of detergent and distilled water, carrying out ultrasonic treatment for 30min, washing 3 times with distilled water after ultrasonic treatment, and then washing with 75% ethanol, and naturally drying in air for later use.

Drug core prescription: levonorgestrel powder with the grain diameter of 2.12 mu m after micronization.

2.1.2 preparation of the implant

One end of the silicone tube is folded, 36mg of LNG (Levonorgestrel) powder is accurately fed into the tube through a tool at the other end to be filled (the length of a drug core is 30 mm), then two ends of the silicone tube are sealed through an adhesive, and after the adhesive is solidified, the silicone tube is rubbed and vibrated, so that the medicine in the silicone tube is uniformly distributed. And then cleaning the powder adhered to the surface of the silica gel tube, and repeating the steps for 6 times to obtain 1 set of levonorgestrel implant (the wall thickness of the levonorgestrel implant adopted in the process is (2.4-1.6)/2=0.4 mm, and the drug release area is calculated according to S=pi d×L (in the formula, d is the inner diameter of the silica gel tube and L is the length of the drug containing section)).

2.2 in vitro Release experiments of Levonorgestrel Long-acting implants

In vitro Release test method of Levonorgestrel Long-acting implant the test was performed according to the "in vitro Release test method" under the first section.

The in vitro release of the implant is a key index of quality monitoring, determines the effective rate of contraception, and provides basis for subsequent clinical medication.

3 experimental methods and results

3.1 in vitro Release factor study of Levonorgestrel implant

3.1.1 Effect of silica gel preparation formulation on in vitro Release of implants

The silicone tube is used as a functional film of the implant, and is formed by crosslinking methyl vinyl raw rubber with vinyl groups at the end groups and hydrogen-containing silicone oil under the action of an additive, and the property of the silicone tube can influence the release of the drug because the drug needs to diffuse outwards through the silicone tube. Clean silicone tubes with qualified physical and mechanical properties are selected to prepare the implant with the same specification, the implant is put into a shaking table to carry out a release experiment after breaking pretreatment, continuous sampling is carried out for 35 days, and the influence of the preparation prescription of the silicone tubes on the in-vitro release degree of the implant is examined.

3.1.1.1 Effect of vinyl content on in vitro Release of the implant

In vitro release experiments were examined by preparing implants according to the section "preparation of 2.1 Levonorgestrel long-acting implants" in this section using raw rubber extruded silicone tubes with vinyl content of 0.17% and 0.23%.

Material name	Example 16-1	Example 16-2
			Methyl vinyl silicone rubber	100PHR	100PHR
Vinyl content of vinyl polysiloxane	0.17mol％	0.23mol％
			White carbon black by gas phase method	35PHR	35PHR
Hydrogen-containing silicone oil	1.01PHR	1.36PHR
			Molar ratio of Si-H groups in the Hydrogen-containing Silicone oil to vinyl groups in the methyl vinyl Silicone rubber	1.2:1	1.2:1
Hydrogen content of hydrogen-containing silicone oil	0.75mol％	0.75mol％
			2-methyl-3-butyn-2-ol	0.7PHR	0.7PHR
Platinum catalyst (3000 ppm)	0.00001PHR	0.00001PHR

The daily dose release for the silicone tube for examples 16-1, 16-2 is shown in the following table.

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The results of the experiments are shown in the table above, both groups of implants were stable for release. The implants prepared with a raw gum having a vinyl content of 0.23% released less daily than the implants prepared with a raw gum having a vinyl content of 0.17%.

When the implant is released, the drug small molecules move outwards through the wall of the silica gel tube, and the dissolved drug in the membrane diffuses to the interface between the membrane and the release medium and finally is distributed and dissolved into the receptor. The degree of density of crosslinking points inside the silicone tube influences the relaxation process of macromolecular chain segments, and has a control effect on the diffusion behavior of drugs through a crosslinking network, namely, the larger the crosslinking density is, the shorter the molecular chain length is, the more difficult the chain segment movement is, the lower the capability of the drugs to permeate gaps among chains is, the lower the solubility of the drugs in a film is, and the release rate of the drugs is lower.

Effects of the amount of the Hydrogen-containing Silicone oil of 3.1.1.2 on the in vitro Release of the implant

The in vitro release degree experiment was examined for silica gel tubes prepared by adding different parts of hydrogen-containing silicone oil (A values are 1, 1.2 and 1.5 when hydrogen-containing silicone oil is added). The recipe is shown in the following table.

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The daily dose release for the silicone tube corresponding to examples 17-1, 17-2, 17-3 is shown in the following table.

The amount of hydrogen containing silicone oil used does not greatly affect the release rate of LNG, and the release rate of the implant is slightly less at a value of 1.5 than at a values of 1 and 1.2. This is also mainly due to the difference in the diffusion rate of the drug in the silicone tube due to the difference in the degree of crosslinking inside the silicone tube.

3.1.1.3 Effect of white carbon Black usage on in vitro Release of implants

The release degree of silica gel tubes to which various amounts of white carbon black were added was examined, and the formulation is shown in the following table.

The daily dose release for the silicone tube corresponding to examples 18-1, 18-2, 18-3 is shown in the following table.

The amount of the white carbon black has a slight influence on the release of the implant, and the release amount of the implant is slightly reduced along with the increase of the amount of the white carbon black.

In a word, the preparation prescription of the silicone tube can have a certain influence on the release of the implant, mainly because the solubility of small molecules of the drug in the silicone tube is different due to different crosslinking degrees inside the silicone tube. However, the medicine can be stably released in the silica gel tubes with different prescriptions, the diffusion rate difference of the medicine in the silica gel tubes is not very large, and the situation that the medicine is not released due to the too low diffusion rate or the situation that the medicine is released suddenly due to the too fast release rate is avoided, so that the silica gel tube with the best mechanical property (prescriptions: raw rubber 100PHR with 0.17 percent of vinyl content, white carbon black 35PHR, silica gel tube with the best mechanical property, Hydrogen containing silicone oil a value = 1.2, catalyst 10 ^-5 PHR, inhibitor 0.7 PHR) to better meet the long-term stable release of the implant in vivo.

3.1.2 Effect of burst removal on in vitro Release of implants

Two sets of levonorgestrel implants were prepared as under "preparation of 2.1 levonorgestrel long-acting implants" in this section. One group is directly put into a shaking table for in-vitro release degree experiment after any treatment, the other group is put into a conical bottle with a plug, 50mL of absolute ethyl alcohol is added, ultrasonic treatment is carried out for 1min, the ultrasonic treatment is repeated for three times, 100mL of distilled water is added, the mixture is placed overnight, and the immersed liquid is discarded the next day and then put into the shaking table for in-vitro release degree experiment. The release medium was changed by sampling at fixed points daily for 12 consecutive days, and the in vitro release of the implant was observed. The experimental results are shown in the following table and fig. 11 and 12.

As shown in fig. 11 and 12, the daily release amounts of the implant without the burst removal pretreatment were high in the first 12 days, and the daily release amounts were unstable, showing a very remarkable tendency to slip. The relative burst release amount (Day 1release/Mean release) of the implant is expressed by the release amount of the implant on the first Day compared with the average release amount on the last Day, and experiments show that the relative burst release amount of the implant after the burst removal treatment is close to 1, namely the release amount of the levonorgestrel implant after the burst removal treatment is very gentle from the initial release. Cumulative release of implant after burst removal (Q) _C ) Is linear with the drug release time (t) (R ² =0.996), the release rate conforms to zero order release kinetics, without large fluctuations in the daily release profile.

Because the surface of the levonorgestrel implant is not subjected to burst removal treatment, and the surface of the levonorgestrel implant has the medicinal powder subjected to electrostatic adsorption by a silicone tube, the release of the implant has a very obvious burst effect, and in order to enable the initial release amount to be close to the steady release amount, the observation time of the in-vitro release degree is shortened, the risk caused by burst release of the medicament after the implant is implanted into a body is reduced, and the corresponding treatment is needed. After the burst removal treatment, the initial release of the implant is brought into steady state.

The release data for LNG implants are shown in the table below.

Note that: q (Q) _C : cumulative drug release.

3.2 comparison of Levonorgestrel implant with commercially available formulations

The commercial levonorgestrel silica gel rod I contains 6 medicine-containing silica gel rods, each medicine-containing silica gel rod contains 36mg of LNG medicine powder, the total medicine-carrying amount is 216mg, the outer diameter of a silica gel tube is 2.4mm, the wall thickness of the silica gel tube is 0.4mm, and the length of a medicine core is 30mm. And combining the investigation results of the in-vitro release degree experiment influence factors, selecting 2.4mm multiplied by 1.6mm multiplied by 35mm multiplied by 6 silica gel tubes to prepare 6 levonorgestrel implant with drug loading capacity of 216mg, wherein the length of each drug core is 30mm. Both the commercial formulation (levonorgestrel silica gel stick (I), purchased from the company of the medicine industry, green, and the company of the Liaoning) and the levonorgestrel implant were subjected to an in vitro release test for 100 days after the burst removal treatment.

The daily release rate profile of the implant during this 100 day release period is shown in the following table, and the daily release rates of both the self-made formulation (silica gel tube corresponding to example 18-2) and the commercially available formulation are very stable, with no obvious burst release behavior and no release-reducing behavior.

In vitro release data for LNG homemade formulations and commercial formulations are shown in the table below.

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

Note that: q (Q) _C : cumulative drug release.

As shown in the following table, the in vitro release rate of the self-made preparation is not much different from that of the commercial preparation, the RSD value of the daily release amount of the self-made preparation during the in vitro release experiment is 7.19%, and the RSD value of the daily release amount of the commercial preparation is 6.70%, which indicates that the stability of the release of the two groups of preparations is similar, and the release behaviors of the two groups of preparations are consistent with zero-order release.

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4 in vitro acceleration experiments

The levonorgestrel implant needs to maintain an effective drug concentration in the body for several years, so that once the formulation is released rapidly or accidentally in the body, serious adverse effects are caused. For such long-acting implants, screening the prescription by real-time release of the drug requires a long period of time, which is inconvenient. Finding an appropriate drug-accelerated release method is very important for formulation optimization and quality control. The increased temperature is widely applied to in-vitro acceleration experiments of the preparation, but the acceleration experiments need to be capable of predicting real-time release of more definite reaction, so that whether the drug release by adding and the drug release at constant speed have correlation or not needs to be judged.

4.1 Experimental methods

The implant was prepared by taking a clean silicone tube (silica gel tube corresponding to the prescription of example 18-2, pre-bake channel 270 ℃, vulcanization time about 5s, post-bake channel 180 ℃, vulcanization time about 2min, oven vulcanization temperature 180 ℃, time 48h, drug core prescription: levonorgestrel powder with particle size of 2.12 μm after micronization) with an outer diameter of 2.4mm, an inner diameter of 1.6mm, a length of 35mm (silica gel tube length of 35mm, pure drug core length of 30mm, and excess 5mm length of both end-capped glue). Taking the drug release condition at 37 ℃ as a reference, examining the release condition of LNG at 45 ℃ and 55 ℃. With reference to normal release conditions, 100mL of water was used as the medium, release samples were taken every 1-3h and new medium was replaced, and three experiments were performed in parallel at each temperature.

4.2 experimental results

Release data for in vitro release of LNG implants at different temperatures are shown in the table below.

Release temperature (. Degree. C.)	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 that: q (Q) _C : cumulative drug release.

The increase in LNG release rate with increasing temperature is related to the Arrhenius equation, which is shown below:

K＝A×e ^-Ea/RT (3-1)

Where 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 for 3-1 yields the formula:

Wherein K is obtained by calculating the release amounts at different temperatures, ln (K) and 1/T are drawn as a straight line, and the slope of the straight line is-Ea/2.303R. And according to a plurality of temperatures set in the temperature rise acceleration experiment, using straight lines drawn after Arrhenius equation, reading out the predicted drug release rate at 37 ℃, and comparing the predicted drug release rate with the drug release rate obtained by the actual drug release experiment at 37 ℃. Therefore, whether the drug release rate of the temperature rise acceleration experiment can predict the real drug release rate is examined. Thus, getTo ln (K) = -18841.7+64.507 (R) ² =0.999), ln (K) and 1/T are shown in fig. 13, and the predicted drug release rate K at 37 ℃ is calculated from the formula _37℃ 51.94 μg, which is close to the actual drug release amount of the implant at 37 ℃, the correlation between the accelerated experimental drug release and the constant drug release is good.

As can be seen from the data in the above table, the release rate of LNG at 45 ℃ is about 4.5 times that at 37 ℃ and the release rate of LNG at 55 ℃ is about 28 times that at 37 ℃. Namely, the release amount of 24 hours at 37 ℃ is about 5.2 hours at 45 ℃ and the release amount of 24 hours at 37 ℃ is about 51 minutes at 55 ℃, so that the time of in-vitro release degree experiment is greatly saved, the in-vitro release amount of LNG can be increased by increasing the release temperature, and the experiment time of the in-vitro release degree experiment of the medicine is reduced.

4. In vivo pharmacodynamics study of levonorgestrel long-acting implant

The part mainly carries out pharmacodynamics research of the levonorgestrel implant in the rat body. Subcutaneous implants of different specifications are implanted into rats, the variation of estrus cycle of the SD rats after implantation is observed through vaginal smear, LH (luteinizing hormone) level in the rats is measured by an enzyme-linked immunosorbent assay, and the contraceptive effect of the subcutaneous implantation of levonorgestrel is studied by monitoring the presence or absence of mating behaviors of the rats.

1 instrument and reagent

1.1 instruments

KQ-250DE type numerical control ultrasonic cleaner	KUNSHAN ULTRASONIC INSTRUMENTS Co.,Ltd.
		Rat LH kit	Shanghai Tongwei biotechnology Co.Ltd
Electronic displayMicro mirror	Micro scientific and technological Co.Ltd in Shenzhen City
		Levonorgestrel silica gel stick (I)	LIAONING LUDAN MEDICINE Co.,Ltd.
High pressure sterilizing pot	Shanghai Shen'an medical device factory
		XS105 type electronic analytical balance	Mettler-Tolyduo instruments Co., ltd
SMD200-2 electronic analytical balance	Oraus International trade Limited
		TG16MW desk-top high-speed centrifuge	Hunan Hexi Instrument Equipment Co.,Ltd.

1.2 reagents

LNG (lot number 20190327, purity)>98％)	Hebei mer technology development Co.Ltd
		Levonorgestrel silica gel stick (I)	LIAONING LUDAN MEDICINE Co.,Ltd.
Heparin sodium	SHANDONG YUWANG PHARMACEUTICAL Co.,Ltd.
		4% paraformaldehyde solution	Shanghai research development biotechnology Co.Ltd
Physiological saline	Shandong Yu Wang Huaxue reagent Co., ltd

1.3 laboratory animals

SD rat (license number: SCXK 2020-0001 Liaoning Changsheng Biotechnology Co., ltd.)

2 Experimental methods

2.1 methods of administration

Preparation of 5-size levonorgestrel implants (prescriptions corresponding to example 18-2, pre-bake tunnel 270 ℃, about 5s of curing time; post-bake tunnel 180 ℃, about 20s of curing time; oven curing temperature 180 ℃, time 48h; drug core prescriptions: micronized levonorgestrel powder with particle size of 2.12 μm) (drug core length/drug loading) were prepared with 2.4mm x 1.6mm silica gel, 5 sizes of drug core were: i (3 mm/3.6 mg), II (10 mm/12 mg), III (15 mm/18 mg), IV (20 mm/24 mg), V (30 mm/36 mg).

The specific prescription is shown in the following table.

Randomly dividing 14 healthy SD male mice with the weight of about 200g into 7 groups for later use; 42 healthy female SD rats with weight of about 200g are randomly divided into 7 dose groups, namely a blank tube group (Negative control group), a positive control group (Positive control group) and 5 administration groups, wherein the positive control group adopts a levonorgestrel silica gel stick I (from Liaoning Lv Dan medical industry) with a drug core length of 30mm, the blank tube also adopts a silica gel tube with an outer diameter of 2.40mm and a wall thickness of 0.5mm, and after each segment of 15mm is cut, two ends are bonded for standby. All the preparations and the silica gel tube are sterilized by an autoclave (121 ℃ C., 30 min) for standby.

After anesthesia, the female mice of the administration group were fixed on a rat plate, and the skin near one side of the spinal column was shaved and sterilized with 2% iodine tincture. The back skin of the rat is slightly lifted, a small opening of about 0.5cm is cut on the local skin, and fibrous connective tissue between subcutaneous and muscle is separated. The disposable implantation needle is inserted into the small opening at an angle of 30 degrees, the implantation needle is slowly rotated to advance in a direction parallel to the spinal column of the rat, when the implantation needle is pushed into the skin of the rat by about 1cm, the sterilized implantation agent is put into the needle tube of the implantation needle, then the implantation needle is continuously pushed forward, after the advancing length of the implantation needle under the skin of the rat exceeds the length of the implantation agent, the implantation agent is slightly pressed hard, the implantation needle slowly withdraws, the wound is sutured, and the wound surface is disinfected. The blank group and the administration group are both male and female cages after 24 hours of implantation operation, and each cage contains 6 female mice and 2 male mice.

2.2 preparation of rat vulva observations and vaginal smears

To monitor the oestrus, mating and pregnancy of rats, vulva characteristics were observed and recorded at 9:00 am every day for 30 consecutive days after dosing, and vaginal smears of rats were prepared to observe and record characteristics of vaginal cast-off epithelial cells.

2.2.1 method for making rat vaginal smear

Weighing 0.1g crystal violet powder, and dissolving the crystal violet powder in 100mL distilled water to prepare 0.1% gentian violet solution for later use; taking a clean anti-drop slide mark for standby; the cotton swab is soaked in sterile physiological saline for standby. The female mouse is taken out from the mouse cage and placed on the cage cover, the tail of the rat is caught by one hand and lifted slightly, after the vaginal opening of the rat is exposed and cleaned by a cotton swab, the prepared wet cotton swab is inserted into the vagina of the rat by about 0.5cm, and the cotton swab is lightly rotated for 1-2 circles, and is uniformly coated on the anti-drop glass slide for smearing. After the anti-drop glass slide coated with rat vaginal drop cells is air-dried, 50 mu L of absolute ethyl alcohol is dripped into the anti-drop glass slide for fixation for 10min; dropping 50 mu L gentian violet solution on a glass slide and standing for 1min; immersing and washing the glass slide in distilled water for 1min, washing the glass slide with distilled water for 10s, and naturally air-drying the glass slide; after the glass slide is air-dried, the glass slide is sealed by neutral resin, and then the observation of the vaginal smear of the rat can be carried out under an electron microscope.

2.2.2 observation of estrus cycle in rats by vaginal smear

The estrus cycle of rats is generally divided into 4 phases, namely, estrus pre-estrus, estrus post-estrus and estrus interval. The pre-oestrus period and the oestrus period can be fertilized by mating ovulation, the oestrus period is the degenerated destructive period of the reproductive tract, and the oestrus period is the relatively static and slow growth period. The estrus cycle of the rat averages 4-5d, and the process of the estrus cycle of the rat can be determined by adopting a vaginal smear method.

The method for identifying the estrus cycle of the rat is shown in the following table,

2.3 ELISA determination of LH concentration in rat plasma

2.3.1 blood sample collection

Starting from the third day after administration, taking 100 μl of blood from the eye socket at 9:30 am every day for 28 days, placing blood in the EP tube pretreated with heparin sodium, mixing, centrifuging in a centrifuge for 10min at 5000 r.min ^-1 The supernatant was removed from the EP tube and stored at-80℃until assayed.

2.3.2 ELISA determination of LH concentration in rat plasma

After implantation of the levonorgestrel implant in rats, the pharmacodynamic behavior characteristics of the levonorgestrel implant in rats were studied by observing the levels of LH in the rat plasma. Serum samples are taken, the operation is strictly carried out according to the specification steps of an ELISA kit, and the LH (luteinizing hormone) content in the rat serum is detected by the kit.

And drawing a standard curve through the standard substance concentration and the OD value, and then calculating the concentration of LH in the serum sample according to the standard curve.

2.3.3 statistical treatments

The data were analyzed using SPSS21.0 analysis software and the experimental results were expressed as mean.+ -. Standard deviation (mean.+ -. SD). The comparison between sets of mean values uses One-Way ANOVA (One-Way ANOVA) to evaluate overall variance differences, LSD for multiple comparison if the data variance is uniform, dunnett T3 for multiple comparison if the variance is not uniform. For comparison between the two groups, a unpaired t-test was used for comparison. P <0.05 was considered a significant difference.

3 results and discussion

3.1 monitoring results of oestrus and mating conditions in rats

The rats were judged for oestrus mating by observing daily vulva conditions, vaginal smears, etc. of each group of rats. Rats had normal diet and normal weight gain during the experiment. Experiments find that white colloid-shaped vaginal pessaries in the vagina of female mice are detected in blank groups after cage combination, and the vaginal pessaries are formed by quickly hardening a mixture of semen of male mice, vaginal secretion of female mice and vaginal epithelial cells after the mixture is exposed to air, and are important marks of successful mating as shown in figure 14. In addition, the vaginal smear of each female mouse of the blank tube group was observed to have a complete estrus cycle, as shown in fig. 15; the progestogen level in the rats of the blank tube group is normal, and the rats have normal estrus and mating behaviors.

In the administration group, after the preparation is implanted into rats of four dose groups such as II, III, IV, V and positive control groups, in the detection of one month, the vulva examination of the rats finds that the vaginal orifice is tightly closed, the vulva is dry, has no secretion and has no red swelling, and the vaginal plug is not found; the vaginal smear is observed to see the existence of a large number of white blood cells, which is a typical estrus interval characteristic, and indicates that rats are always in estrus interval and have no normal estrus. However, in the I dose group, female rats numbered 2 and 4 were found to have a complete estrus cycle by vulvar examination and vaginal smear examination, indicating that the dose of levonorgestrel implant did not play a contraceptive role after being implanted into both rats.

3.2 changes in LH levels in rats

The experimental results are shown in the following table, after the levonorgestrel implant is implanted into the rat body, the level of LH in the rat body is obviously reduced, namely, the level of LH in a positive control group and rats in different dosing groups is obviously different from that in a blank tube group (P < 0.05), and the experiment shows that the level of LH in the rat body is influenced by the dosage of LNG, and the higher the dosage of LNG, the lower the level of LH in the rat body.

In the oestrus cycle of rats, LH secretion is regulated by GnRH (gonadotrophin releasing hormone), which has a distinct peak in the pre-oestrus period of rats. In the administration group and the positive control group, since the levonorgestrel mainly acts on hypothalamus and pituitary gland, release of GnRH is inhibited through a negative feedback mechanism, thereby reducing secretion of LH, obviously reducing or eliminating peak of LH level, affecting growth and maturation process of follicles, preventing ovaries from ovulation and realizing contraceptive effect. This is consistent with the observation of vaginal smear, and after the drug effect of the implant in the rat body, the rat is always in estrus interval, the LH peak in the estrus prophase is not inhibited by negative feedback regulation, the rat does not ovulate, and the male and female rats do not mate, thus preventing the pregnancy of the rat. The LH level in the blank tube group is not inhibited, the LH peak before the estrus still exists, and the rats can still normally estrus and mating and conception.

And (3) injection: * Refers to P <0.05 compared to the blank.

In addition, the dose of the V dose group is consistent with that of the positive control group, and experiments show that LH levels in two groups of rats are also relatively close (Vgroup LH= 36.61 + -2.43 IU.L) ^-1 Positive control group lh=39.91±4.75iu·l ^-1 ) The LH levels in the two groups of rats were compared and found to be absent significant differences (P > 0.05), indicating that the implants prepared in this study were equivalent in efficacy to the commercial formulation levonorgestrel silica gel stick I.

In addition, in the vaginal smear examination of the group of rats of I dose, two rats were found to have estrus, and the results of the measurement of LH in the group of rats are shown in FIG. 16, and it was found that the LH levels in the two rats of No. 2 and No. 4 were close to that in the rats of the blank group, and that the LH levels in the remaining rats were significantly different from that in the rats of the blank group (P < 0.05). The results of the vaginal smear examination combined show that the levonorgestrel implant in both rats did not produce efficacy. The reason is presumed that the implant (3 mm/3.6 mg) of this specification is insufficient in release amount because the drug core length is too short and the presence of the adhesive agent partially wets the drug powder during the preparation, resulting in difficulty in drug release, and thus the contraceptive effect is not achieved after implantation into rats.

4 Chapter knots

(1) The experiment judges whether the rats have estrus or not through vulva observation and vaginal smear observation of rats in different groups, and performs mating behaviors; the presence or absence of pharmacodynamic effects of levonorgestrel implants in rats was studied by measuring LH levels in rats of different groups. Experiments show that the LH level in the I, II, III, IV, V group rats and the positive control group rats is obviously reduced (P < 0.05) compared with that in the blank group rats, and the LH level in the rats is reduced along with the increase of the dosage of the implant; II. Rats in group III, IV and V and positive control group had no oestrus and mating behavior after the levonorgestrel implant was implanted in vivo.

(2) Experiments show that the LH level in rats of the implant with the same dosage as that of the positive control group is similar to that of the positive control group, and no significant difference (P is more than 0.05) exists, so that the effect of the implant prepared in the study is equivalent to that of a commercially available preparation of the levonorgestrel silica gel stick.

(3) During the experiment, rats live in a normal diet and have normal weight growth, and the implant has no adverse effect on the rats.

III, estradiol long-acting implant

1. Method for measuring content and in vitro release of estradiol long-acting implant

(1) Content determination method

Taking 1 estradiol implant, cutting a silicone tube, cutting a medicine core into a plurality of small fragments, placing the fragments in a 100mL volumetric flask, adding 10mL of methanol for soaking, standing for swelling for 3 hours, diluting to a scale with absolute ethanol, shaking up and filtering, precisely measuring 0.2mL of continuous filtrate, placing the filtrate in a 50mL volumetric flask, diluting to the scale with a mobile phase, shaking up, injecting into HPLC, injecting 20 mu L of sample, and calculating according to a standard curve to obtain the medicine content. The chromatographic conditions were as follows:

chromatographic column:c18 column (250 mm. Times.4mm, 5 μm)

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

Column temperature: 25 DEG C

Detection wavelength: 202nm

Flow rate: 0.8mL min-1

Sample injection amount: 20 mu L

(2) Release degree measuring method

The release degree is measured by adopting a horizontal oscillation method: taking one estradiol implant, mutually staggering and fixing the estradiol implant in a 100mL conical flask with a plug by using an adhesive, precisely measuring 100mL distilled water as a release medium, placing the conical flask with the plug in a constant temperature oscillator, and setting the amplitude to be 100 r.min ^-1 The temperature is 37 ℃, the implant agent is ensured to be always below the liquid level, sampling is carried out every 24 hours, an equal volume of release medium is replaced, sample solution is filtered by a microporous filter membrane with the thickness of 0.22 mu m, and then sample injection is carried out according to the content measuring method (1), and the drug release amount is calculated according to a standard curve.

2. Preparation of estradiol depot implants and in vitro release studies

1 instrument and reagent

1.1 instruments

LC-10ATVP high performance liquid chromatograph	Shimadzu corporation
		SMD200-2 electronic analytical balance	Oraus International trade Limited
AG245 type ultra-micro electronic balance type electronic analytical balance	Mettler Toledo, switzerland
		KQ-250DE type numerical control ultrasonic cleaner	KUNSHAN ULTRASONIC INSTRUMENTS Co.,Ltd.
CHA-S constant temperature oscillator	CHANGZHOU GUOHUA ELECTRIC APPLIANCE Co.,Ltd.

1.2 materials

2 Experimental methods

2.1 preparation of estradiol depot implants

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

Material name	Dosage of
		Methyl vinyl silicone rubber	100PHR
Vinyl content of vinyl polysiloxane	0.17mol％
		White carbon black by gas phase method	30PHR
Hydrogen-containing silicone oil	1.01PHR
		Molar ratio of Si-H groups in the Hydrogen-containing Silicone oil to vinyl groups in the methyl vinyl Silicone rubber	1.2:1
Hydrogen content of hydrogen-containing silicone oil	0.75mol％
		2-methyl-3-butyn-2-ol	0.7PHR
Platinum catalyst (3000 ppm)	0.00001PHR

The method comprises the steps of preparing addition controlled release silicone tubes of different types by adopting an extrusion technology, taking mechanical properties such as elongation at break, tensile strength, tear strength and the like as evaluation indexes, examining prescription and process factors of the silicone tube, and finally determining that the prescription of the silicone tube is as follows: 100PHR of methyl vinyl silicone rubber, 0.17mol% of vinyl content of vinyl polysiloxane, 30PHR of gas phase white carbon black, 1.01PHR of hydrogen-containing silicone oil, 1.2:1 of mole ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber, 0.75mol% of hydrogen content of the hydrogen-containing silicone oil, 0.7PHR of 2-methyl-3-butyn-2 alcohol and 0.00001PHR of platinum catalyst (3000 ppm); the process conditions are as follows: the pre-drying tunnel vulcanizing temperature is 300 ℃ (vulcanizing time is about 5 s), the post-drying tunnel vulcanizing temperature is 280 ℃ (vulcanizing time is about 2 min), and the oven temperature is 180 ℃ (vulcanizing time is 48 h). A silicone tube with a wall thickness of 0.2/0.4/0.6mm was prepared.

Sealing the adhesive, filling the medicine through a medicine filling funnel after curing for 24 hours, sealing and curing the other end with KN-300N adhesive for 24 hours after filling, checking whether the medicine leaks after curing, repeatedly cleaning with absolute ethyl alcohol for 30 seconds after determining whether the medicine leaks, and obtaining the grain diameter D of the estradiol after preparation ₅₀ 9.5 μm, wall thickness of 0.2mm, outer diameter of 2.2-2.3mm, release area of 2.7+ -0.5 cm ² Is a depot estradiol implant.

2.2 Release conditions

The implantation site of the implant is mostly at subcutaneous tissue of a large arm of a human body, the pH value of the implantation site is close to neutrality, so purified water is selected as a release medium, a constant-temperature oscillation oscillator at 37 ℃ is used as a release instrument, and the release behavior of the estradiol reservoir type implant is examined.

2.3 in vitro Release and influencing factor investigation

2.3.1 vulcanization temperature

In the process of preparing the silicone tube, the vulcanization condition is that the pre-drying tunnel is 300 ℃, the mechanical index of the silicone tube prepared by the post-drying tunnel is 280 ℃ better, and the vulcanization of the silicone tube is more complete. In order to further judge whether the vulcanization conditions have influence on the release of the drug of the implant or not, other conditions are unchanged, silica gel tubes with different vulcanization temperatures are respectively prepared into the implant for in-vitro release experiments, and the influence of the vulcanization temperature on the in-vitro release behavior of the drug is examined.

Numbering device	Front drying tunnel temperature (DEG C)	Post-baking channel temperature (DEG C)	Oven vulcanization temperature (. Degree. C.)
				Example 15-1 (300-280)	300	280	180
Example 15-2 (300-260)	300	260	180
				Examples 15 to 3 (280 to 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 examined. According to the obtained silicone tubes with wall thicknesses of 0.2mm, 0.4mm and 0.6mm, preparing the implant with consistent length and outer diameter, measuring in-vitro release data, and examining the influence of the wall thickness of the silicone tube on the in-vitro release of the implant.

Numbering device	Silicone tube outer diameter/mm	Wall thickness/mm of silicone tube	Medicine containing lengthDegree/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 area of drug delivery

The silica gel implant controls the drug release through a cylindrical silica gel tube, and the drug release area of the drug 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 segment.

As can be seen from the formula, the medicine release area can be changed by changing the length of the medicine containing section and the inner diameter of the silica gel tube. Considering that the length of the drug-containing section is more concise and convenient to change, the outer diameter of the experimental fixed silicone tube is 2.4mm, the wall thickness is 0.2mm, the estradiol implantation agents with the drug-containing length of 1, 2, 3, 4 and 5cm are respectively and tightly filled for in-vitro release, and the change rule of the in-vitro release amount along with the drug-containing length is examined.

Numbering device	Silicone tube outer diameter/mm	Wall thickness/mm of silicone tube	Area/cm of drug release ²
				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
Examples 17 to 4	2.2	0.2	2.76
				Examples 17 to 5	2.2	0.2	3.45

2.4 Long-term in vitro Release experiments of estradiol depot implants

After the wall thickness of the silicone tube in the implant and the prescription, the vulcanization temperature, the drug loading and the drug release area are determined, three batches of optimal preparations are prepared, the long-term stable release condition is inspected, and the daily release quantity change trend is observed.

The preparation and prescription of the silicone tube are 2.1, and other preparation conditions are as follows: the vulcanization condition is 300 ℃ of a pre-drying channel (about 5s of vulcanization time), 280 ℃ of a post-drying channel (about 2min of vulcanization time), 180 ℃ of an oven (about 48h of vulcanization time), and the prepared silicone tube; 0.2mm wall thickness. Particle diameter D of estradiol ₅₀ 9.5 μm.

3 results and discussion

3.1 preparation of estradiol depot implants

The prepared storage type implant with different specifications has good appearance, uniform sealing parts and uniform filling of the medicine containing sections.

3.2 in vitro Release influencing factor investigation

3.2.1 vulcanization conditions

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The result shows that the change of the vulcanization temperature of the silica gel tube has no obvious influence on the average daily drug release amount of the implant, and the fluctuation is small, so that the silica gel tube with better mechanical property is selected for preparing the implant, namely the silica gel tube prepared by the vulcanization condition of 300 ℃ in the pre-drying tunnel and 280 ℃ in the post-drying tunnel.

3.3.2 Silicone tube wall thickness

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The results show that the external diameter, the release area and other factors are unchanged, the in-vitro release amount of the estradiol reservoir type implant prepared by the silica gel with three different wall thicknesses is gradually reduced along with the increase of the wall thickness. In order to ensure the drug release amount, the wall thickness should be reduced as much as possible, but in the practical operation process, the silica gel tube with the wall thickness of 0.2mm is limited, and the smooth extrusion molding of the silica gel tube is difficult to ensure when the wall thickness is reduced, so that the silica gel tube with the wall thickness of 0.2mm is finally adopted.

3.3.3 investigation of the drug delivery area of the silicone tube

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

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The results show that as the release area increases, the daily amount of estradiol released from the depot implant increases. To further determine the relationship between the release area and the release amount of the implant drug, data analysis was performed on the release amounts and release areas of the five formulations, to obtain the results shown in fig. 16.

According to the fitted equation and the image, the release amount and the release area are in a linear relation, and the release amount is increased along with the increase of the release area. According to the relation, the release amount can be regulated and controlled by fixing the outer diameter and the wall thickness of the silicone tube and adjusting the release area. In practical application, because of large individual difference of patients, estradiol reservoir type implants with different specifications can be produced during production, personalized administration is realized according to different requirements, side effects are reduced, and maximum benefit is realized.

3.4 Long-term in vitro Release experiments of estradiol implants

Under the same conditions as the final prescription (see 2.4 estradiol depot implants described in this section) Preparing three batches of storage type implants at 37 ℃ and shaking table speed of 100 r.min ^-1 Long-term in vitro release experiments were performed under conditions and the results are shown in the following table.

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The results show that: although the daily release amount of the three batches of implants fluctuates in the early stage, the later stage is gradually kept stable, the daily in-vitro release amount is stable within the range of 10-15 mu g, the trend is similar, and the reproducibility is good. The current estradiol supplementation treatment is known through reference documents, the common supplementation dose is 20-40 mug of estradiol per day, and the curative effect can be achieved by embedding two estradiol supplementation doses, so that the method meets the experimental expectation.

IV, four film-controlled long-acting implants

1. Preparation of film-controlled long-acting implant

The membrane controlled implant consists of an addition type silicone tube and a powder type drug core. The silicone tube is prepared by adding a reinforcing agent into raw methyl vinyl silicone rubber, adding hydrogen-containing silicone oil, an inhibitor and a catalyst as compounding agents to prepare a mixed rubber, vulcanizing at high temperature by an extrusion process, wherein a drug core is prepared by directly mixing drug powder with auxiliary materials, finally filling the uniformly mixed drug powder into the silicone tube, and sealing the end of the silicone tube filled with the drug auxiliary powder by using a sealing rubber to prepare the film-forming controlled-release long-acting implant.

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

the basic formula of the silicone tube is a base polymer, a reinforcing agent, a cross-linking agent, a catalyst and an inhibitor. The selected base polymer is methyl vinyl polysiloxane, and the vinyl content is 0.18-0.23%; the reinforcing agent is gas phase white carbon black, and the addition amount is 30-50 PHR; the cross-linking agent is hydrogen-containing silicone oil, and the addition amount is 0.3-2.0 PHR; the concentration of the platinum catalyst is 3000ppm, and the addition amount is 0.000002-0.5 PHR; the inhibitor is 2-methyl-3-butine-2-alcohol, and the addition amount is 0.03-2.0 PHR.

The specific formulation is as follows.

(2) The preparation process of the addition type silicone tube comprises the following steps:

(1) drying pretreatment of sizing materials: and (3) placing the reinforcing agent gas-phase white carbon black in a baking oven at 130 ℃, drying for 12-24 hours for standby, and drying the raw methyl vinyl silicone rubber at 40 ℃ for 12-24 hours for standby.

(2) Preparation of the rubber compound: putting the gas-phase white carbon black and the raw methyl vinyl silicone rubber with the prescribed amount into a kneader, uniformly mixing the gas-phase white carbon black and the raw rubber, taking out to obtain a mixed rubber, transferring into an open mill, extruding and thinning, further uniformly mixing the rubber by utilizing the shearing action of two rollers of the open mill, discharging the rubber from the open mill in a sheet form, wrapping the rubber by a preservative film, putting into a self-sealing bag, and placing into a dryer for standing for 12-24 hours for standby.

(3) Preparation of A, B component: the mixed rubber is divided into A, B components, the component A is added with hydrogen silicone oil and inhibitor with the prescribed amount, and the mixture is evenly mixed in an open mill and then discharged in a sheet form for a plurality of times. Adding a prescription amount of platinum catalyst into the component B, uniformly mixing in an open mill, and discharging the mixture in a thin sheet form for a plurality of times. The prepared A, B components are respectively wrapped by preservative films and put into self-sealing bags, and are put into a dryer for standing for 12-24 hours for standby.

(4) A, B components are mixed: placing the parked A, B components into an open mill according to a ratio of 1:1, opening a triangular bag for 4-6 times to fully and uniformly mix the A, B components, discharging the components on the open mill in a sheet form, and cutting the components into strips.

(5) Extrusion of silicone tube: and (3) installing a die with a proper size, setting the rotating speed of a screw of an extruder, putting the cut silica gel strip into the extruder, and continuously extruding the rubber material into a silica gel tube through a die opening under the pushing of the rotation of the screw.

(6) First vulcanization treatment: the silicone tube extruded from the die opening is subjected to quick high-temperature vulcanization through a pre-drying channel (vertical hot air vulcanization channel) to be subjected to first vulcanization treatment (the temperature is 300 ℃ and the vulcanization time is about 5 s), so that the silicone tube is quickly changed from a viscous state to an elastic state and is subjected to preliminary shaping.

(7) And (3) second vulcanization treatment: after the first vulcanization, the mixture enters a post-drying channel (horizontal hot air vulcanization channel) for continuous vulcanization, and the second vulcanization treatment (the temperature is 280 ℃ and the vulcanization time is about 2 min) is carried out, so that the vulcanization reaction of the silica gel tube is more complete, the best crosslinking state is achieved, and the finished silica gel tube product is continuously transported out through a conveyor belt of the post-drying channel; and (3) vulcanizing at 180 ℃ for 48 hours by an oven to prepare the silica gel tube with the wall thickness of 0.2 mm.

(3) The formulation of the powder core is shown in the following table.

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Note that: the content ratio of the raw material, the insoluble auxiliary material and the insoluble pH regulator in the above table refers to the mass percentage in the drug core; the total mass of the medicine core is 80mg; the particle diameter D50 of the ibuprofen is 80 mu m; the particle diameter D50 of the paliperidone is 10 μm; the particle diameter D50 of meloxicam is 80 mu m; the particle diameter D50 of puerarin is 80 μm.

(4) Treatment of a silicone tube: cutting an addition type silicone tube (with the outer diameter of 2.4mm and the inner diameter of 1.6 mm) with qualified appearance and all properties into pieces with the same length of 44mm, putting the pieces into a 100mL beaker, adding a proper amount of distilled water, carrying out ultrasonic treatment for 30min, washing the pieces with distilled water for three times after ultrasonic treatment, and then washing the pieces with 75% ethanol, and naturally air-drying the pieces for later use.

(5) Preparation of the implant: one end of the silicone tube was sealed and air-dried, and the other end was filled with 80mg of the pharmaceutical composition powder into the silicone tube with a tool, and then capped with a capping gel. After the end-capped glue is solidified, the silica gel tube is kneaded and vibrated to uniformly mix the medicinal auxiliary materials in the tube. And finally, cleaning the powder outside the silica gel tube.

2. Method for measuring content and in vitro release of membrane-controlled long-acting implant

(1) Ibuprofen

Chromatographic conditions

Chromatographic column:c18 column (4.6mm.times.150mm, 5 μm);

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

column temperature: 35 ℃;

detection wavelength: 273nm;

flow rate: 1.0 mL/min ^-1 ；

Sample injection amount: 20. Mu.L.

Release degree measuring method

The release experiment adopts a horizontal oscillation method, 1 implant is taken, the two ends of the implant are fixed on the bottle bottom and the bottle wall of a 20mL penicillin bottle by using a silica gel adhesive (the release result is inaccurate because the implant floats on the liquid surface is prevented), and the silica gel adhesive is completely cured after the implant is well adhered and parked for 12 hours. Precisely measuring 15mL distilled water as release medium, injecting into a conical flask, placing the conical flask into a constant temperature air shaking table, shaking at 37deg.C with amplitude of 100deg.C.min ^-1 The medium was replaced with equal volumes every 24 hours. The released solution was filtered through a 0.22 μm microporous filter membrane, and the sample loading was 20. Mu.L as measured by the above chromatographic conditions.

(2) Paliperidone

Chromatographic conditions

Chromatographic column:c8 column (4.6X100 mm,2.7 μm);

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

column temperature: 35 ℃;

detection wavelength: 270nm;

Flow rate: 0.8mL min ^-1 ；

Sample injection amount: 20. Mu.L.

Release degree measuring method

The release experiment adopts a horizontal oscillation method, 1 implant is taken, the two ends of the implant are fixed on the bottle bottom and the bottle wall of a 100mL conical bottle with a plug by using a silica gel adhesive (the release result is inaccurate because the implant floats on the liquid surface is prevented), and the silica gel adhesive is completely cured after the implant is well adhered for 12 hours. Precisely measuring 100mL distilled water as release medium, injecting into a conical flask, placing the conical flask into a constant temperature air shaking table, shaking at 37deg.C with amplitude of 100deg.C.min ^-1 The medium was replaced with equal volumes every 24 hours. The released solution was filtered through a 0.22 μm microporous filter membrane, and the sample loading was 20. Mu.L as measured by the above chromatographic conditions.

(3) Meloxicam preparation

Chromatographic conditions

Chromatographic column:c18 column (4.6mm.times.150mm, 5 μm);

mobile phase: methanol: 0.5% phosphoric acid in water (70:30, v/v);

column temperature: room temperature;

detection wavelength: 270nm;

flow rate: 1.0 mL/min ^-1 ；

Sample injection amount: 20. Mu.L.

Release degree measuring method

The release experiment adopts a horizontal oscillation method, 1 implant is taken, and the two ends of the implant are fixed at the bottle bottom and the bottle wall of a 20mL penicillin bottle by using a silica gel adhesivePrevent the implant from floating on the liquid surface to cause inaccurate release result, and the silica gel adhesive is completely cured after the implant is placed for 12 hours after the implant is adhered. Precisely measuring 15mL distilled water as release medium, injecting into a conical flask, placing the conical flask into a constant temperature air shaking table, shaking at 37deg.C with amplitude of 100deg.C.min ^-1 The medium was replaced with equal volumes every 24 hours. The released solution was filtered through a 0.22 μm microporous filter membrane, and the sample loading was 20. Mu.L as measured by the above chromatographic conditions.

(4) Puerarin

Chromatographic conditions

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

column temperature: 35 ℃;

detection wavelength: 250nm;

flow rate: 1.0 mL/min ^-1 ；

Sample injection amount: 20. Mu.L.

Release degree measuring method

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

(1) Ibuprofen

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(2) Meloxicam preparation

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(3) Paliperidone

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(4) Puerarin

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Claims

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:

r-vinyl silicone rubber: 100 parts;

reinforcing agent: 20-80 parts of a lubricant;

hydrogen-containing silicone oil: 0.3-3.0 parts;

wherein:

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

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:

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 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 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%;

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:

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.