Pharmaceutical composition, rod core, implant and preparation method and application thereof

Abstract

The invention provides a pharmaceutical composition, a rod core, an implant and a preparation method and application thereof. The pharmaceutical composition comprises the following components in parts by weight: 1-1000 parts of active pharmaceutical ingredients; 100 parts of R-vinyl silicone rubber; hydrogen-containing silicone oil; 0.000002 to 1 part of a catalyst; r in the R-vinyl silicone rubber is substituted or unsubstituted C1-C5 straight-chain alkane or branched alkane, and substituted or unsubstituted C6-C20 aromatic hydrocarbon; the content of vinyl in the R-vinyl silicone rubber is 0.10 to 0.50 mol%; the content of Si-H groups in the hydrogen-containing silicone oil is 0.15 to 1.6 mol percent; the molar ratio of Si-H group in the hydrogen-containing silicone oil to vinyl in the R-vinyl silicone rubber is (0.5-20): 1. The implant provided by the invention can reduce drug loss and sudden release phenomenon, the drug release is more stable, and the production speed is greatly increased.

Description

Technical Field

[0001] The invention relates to a medicine composition, a stick core and an implant, and a preparation method and application thereof. Background Art

[0002] Implantable drug delivery system (IDDS) is a drug delivery system that can stably release drugs to specific sites of action. The main advantage is that it delivers drugs in a targeted manner at a continuous and stable rate, requiring less drugs in the treatment of diseases, thus greatly reducing drug toxicity and side effects to achieve better therapeutic effects. Implantable drug delivery systems can reduce the frequency of drug administration from once or several times a day to several months, once a year, or once every three to five years, reducing the side effects of frequent drug administration and avoiding problems such as first-pass and peak-valley of oral administration.

[0003] According to the differences in the form of the drug in the preparation and the way it is used, IDDS can be mainly divided into solid drug-loaded implants, injectable implants, and implant pump preparations. Solid drug-loaded implants refer to drugs dispersed in carrier materials, which are surgically implanted in the form of columns, rods, pills, tablets, etc. They can be implanted subcutaneously or in specific target areas and are currently the most widely used IDDS.

[0004] Solid drug-loaded implants have the advantages of simple and convenient use, safe and stable carrier materials, and low price. At the same time, compared with solid drug-loaded implants implanted in specific target areas, subcutaneous solid drug-loaded implants are more mature in technology development. Subcutaneous implants such as Norplant and Implanon have been used in the field of contraception for decades, and their safety and effectiveness have been fully proven.

[0005] Implantable drug delivery has a wide range of applications. In addition to being used in the well-known field of contraception, clinical experimental research is gradually being carried out in other long-term drug use fields. For example, in tumor treatment, the development of local implant technology has enabled many traditional anti-tumor drugs to play new roles; in the prevention and treatment of AIDS, long-term implantation can replace daily oral administration to avoid missed doses that affect drug effects. In addition, implantable drug delivery systems are also used in the treatment of long-term drug use fields such as diabetes, mental system diseases, withdrawal addiction, and cardiovascular diseases, and their application prospects are promising in the future.

[0006] Traditional solid drug-loaded implants are mainly prepared by filling drug powder into silicone tubes. The drug powder filling process is slow, and a large amount of drug powder will be adsorbed on the silicone tube wall, resulting in drug waste and slow filling speed. There are also a series of disadvantages in actual use, such as severe burst release, poor drug release stability, and low production efficiency. Therefore, it is urgent to study a new type of solid drug-loaded implant. Summary of the invention

[0007] The technical problem solved by the present invention is to overcome the defects of the solid drug-loaded implant in the prior art, such as serious drug waste, serious burst release, poor drug release stability, and slow production speed of the implant, and provide a drug composition, a rod core, and an implant, and a preparation method and application thereof. The implant provided by the present invention can reduce drug loss, reduce burst release, release drugs more smoothly, and greatly improve production speed.

[0008] The present invention solves the above technical problems through the following technical solutions:

[0009] The present invention provides a pharmaceutical composition, which comprises the following raw material components in parts by weight:

[0010] Active pharmaceutical ingredient: 1-1000 parts;

[0011] R-vinyl silicone rubber: 100 parts;

[0012] Hydrogenated silicone oil;

[0013] Catalyst: 0.000002-1 part;

[0014] in:

[0015] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0016] The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0017] The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%;

[0018] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1.

[0019] In the present invention, the structural formula of the R-vinyl silicone rubber may be as follows:

[0020]

[0021] Among them, m, n, p are natural numbers, R 1 , R 2 It can be a conventional substituent group in the art, and R and R' can be a conventional end-capping group in the art.

[0022] For example, when R 1 =R 2 =CH 3When , it corresponds to dimethyl silicone rubber;

[0023] For example, when R 1 =CH 3 , R 2 =CH=CH 2 When , it corresponds to methyl vinyl silicone rubber;

[0024] For example, when R 1 =Ph, R 2 =CH=CH 2 When , it corresponds to methyl phenyl vinyl silicone rubber;

[0025] For example, when R 1 =CH 3 CH 2 CF 3 , R 2 =CH=CH 2 When , it corresponds to fluorosilicone rubber;

[0026] For example, when R 1 =CH 3 CH 2 CN, R 2 =CH=CH 2 When , its corresponding is nitrile silicone rubber.

[0027] In the present invention, the active pharmaceutical ingredient may be a conventional sustained-release pharmaceutical ingredient in the art that requires long-term drug release, preferably an active drug with a solubility of ≤100 mg / mL (with water as the solvent), and more preferably includes an active pharmaceutical ingredient that acts on the reproductive system, or an active pharmaceutical ingredient that acts on the urinary system, or an active pharmaceutical ingredient that acts on chronic diseases related to metabolism and nutrition, or an active pharmaceutical ingredient used to treat chronic diseases related to connective tissue and rheumatism, or an active pharmaceutical ingredient used to treat hyperlipidemia, tumors, neuropsychiatric diseases, chronic dental diseases, simple obesity, chronic low back pain or leukemia, or an active pharmaceutical ingredient that acts on the circulatory system, or an active pharmaceutical ingredient that acts on the respiratory system, or an active pharmaceutical ingredient that acts on the digestive system, or an active pharmaceutical ingredient that acts on the blood system, or an active pharmaceutical ingredient that acts on the endocrine system.

[0028] The active pharmaceutical ingredients acting on the reproductive system may include active pharmaceutical ingredients for contraception.

[0029] The active ingredients of the contraceptive drugs may be conventional ones in the art, and preferably include levonorgestrel, gestodene, gestrinone or steroidal estrogen.

[0030] The steroidal estrogen is preferably estradiol.

[0031] The active pharmaceutical ingredients acting on the urinary system preferably include active pharmaceutical ingredients for treating chronic nephritis, chronic renal failure, or chronic prostatitis.

[0032] The active ingredients of the drug for treating chronic nephritis can generally be: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril or enalapril), angiotensin II receptor blockers (such as irbesartan, valsartan or losartan), calcium channel blockers (such as amlodipine, felodipine or nifedipine), beta-receptor blockers (such as atenolol, bisoprolol, carvedilol or propranolol), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide or bumetanide), immunosuppressants (such as prednisone, Enova, methylprednisolone, cyclophosphamide or dexamethasone), or statins (such as fluvastatin, simvastatin or pravastatin).

[0033] The active ingredients of the drug for treating chronic renal failure can generally be: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide), or iron agents (such as ferrous fumarate), compound amino acids, α-keto acids, and recombinant human erythropoietin.

[0034] The drug for treating chronic prostatitis can be: antibiotics (e.g., fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin), tetracyclines (tetracycline), α receptor blockers (e.g., doxazosin, terazosin), non-steroidal anti-inflammatory drugs (e.g., ibuprofen, diclofenac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib), analgesics (e.g., acetaminophen), opioids (e.g., morphine, fentanyl, nalbuphine, pentazocine), anti-neuropathic pain drugs (e.g., 5-hydroxytryptamine, duloxetine, venlafaxine), anti-epileptics (e.g., pregabalin), or M receptor blockers (e.g., solifenacin, tolterodine), preferably non-steroidal anti-inflammatory drugs, more preferably, ibuprofen.

[0035] The active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition preferably include active pharmaceutical ingredients for treating diabetes, nutritional deficiency, gout, or osteoporosis.

[0036] The anti-diabetic drug active ingredient can generally be an anti-type 1 diabetes drug (e.g., insulin) or an anti-type 2 diabetes drug. The anti-type 2 diabetes drug can be a sulfonylurea drug (e.g., glimepiride, gliquidone), a glinide drug (e.g., repaglinide, nateglinide), a metformin drug (e.g., metformin), an α-glucosidase 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, empagliflozin).

[0037] The active ingredient of the drug for treating nutritional deficiency diseases can generally be a drug for gastrointestinal diseases (such as omeprazole, mosapride), or a nutritional supplement drug (such as vitamin E).

[0038] The anti-gout active ingredient can be an anti-gout attack drug (e.g., colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, para-aminosalicylic acid, salsalate, benolate), a uricosuric acid excretion agent (e.g., benzbromarone, probenecid), or a uric acid synthesis blocker (e.g., allopurinol), preferably an anti-gout attack drug, more preferably ibuprofen.

[0039] The active ingredients of the anti-osteoporosis drugs can generally be bisphosphonates (e.g., alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonates, clodronate disodium, zoledronate sodium, risedronate sodium), calcitonin drugs (e.g., salmon calcitonin), estrogen drugs (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) drugs (e.g., raloxifene, benzothiophene), RANKL inhibitor drugs, parathyroid hormone drugs, monofluoroglutamine drugs, strontium salt drugs (e.g., strontium ranelate), active vitamin D and analogs (e.g., calcitriol, α-calciferol), or vitamin K (e.g., menatetrenone).

[0040] Among them, the active pharmaceutical ingredients for treating chronic diseases involving connective tissue and rheumatism preferably include active pharmaceutical ingredients for treating rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, vasculitis, idiopathic inflammatory myopathy, systemic sclerosis, or osteoarthritis.

[0041] The active ingredient of the drug for treating rheumatoid arthritis can be a glucocorticoid drug (such as hydrocortisone, dexamethasone, prednisone), a slow-acting antirheumatic drug (such as methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide), or a non-steroidal anti-inflammatory drug (such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, nabumetone), preferably a non-steroidal anti-inflammatory drug, more preferably meloxicam or ibuprofen.

[0042] The active ingredient of the drug for treating osteoarthritis can be a cartilage nourishing drug, an opioid (such as oxycodone, chimantin), or an analgesic (such as ibuprofen, voltaren, meloxicam, celecoxib, loxoprofen sodium, nimesulide), preferably an analgesic, more preferably ibuprofen or meloxicam.

[0043] The active ingredients of the drug for treating systemic lupus erythematosus can generally be non-steroidal anti-inflammatory drugs (such as naproxen, ibuprofen), antimalarial drugs, glucocorticoid drugs (such as prednisone acetate, methylprednisolone), immunosuppressant drugs (such as methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), or biological drugs (such as rituximab, belimumab).

[0044] The active ingredients of the drug for treating ankylosing spondylitis can generally be non-steroidal drugs (such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, and ericoxib), disease-modifying antirheumatic drugs (such as pyridine sulfamethoxazole, methotrexate, and hydroxychloroquine), glucocorticoid drugs (such as prednisone, prednisolone, and diprosone), or biological TNF-a antagonists (such as etanercept).

[0045] The active ingredient of the drug for treating Sjögren's syndrome can generally be a systemic therapeutic drug (such as levamisole, transfer factor coenzyme Q10, thymosin), a glucocorticoid drug (such as prednisone), or an immunosuppressive drug (such as hydroxychloroquine, azathioprine, iguratimod).

[0046] The active ingredient of the drug for treating vasculitis can generally be a glucocorticoid drug (such as prednisone, methylprednisolone, dexamethasone) or an immunosuppressant drug (such as cyclophosphamide, cyclosporine, azathioprine).

[0047] The active ingredient of the drug for treating idiopathic inflammatory myopathy can generally be a glucocorticoid drug (such as dexamethasone, prednisone, hydrocortisone, methylprednisolone), or an immunosuppressant drug (such as cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolate mofetil).

[0048] The active ingredients of the drug for treating systemic sclerosis can generally be anti-fibrotic drugs (such as colchicine), vasoactive drugs (such as nifedipine and benzathine), naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, or tocilizumab.

[0049] The active ingredients of the drug for treating neuropsychiatric disorders can generally be drugs for treating schizophrenia, antidepressant drugs, drugs for treating opioid abuse or drugs for treating anxiety disorders, preferably drugs for treating schizophrenia.

[0050] The drug for treating schizophrenia is preferably a phenothiazine (e.g. chlorpromazine), a thioxanthene (e.g. chlorprothixene), a butyrophenone (e.g. haloperidol), a dibenzodiazepine (e.g. olanzapine, clozapine), a benzisoxazole (e.g. risperidone, paliperidone), a benzisothiazole (e.g. ziprasidone), a diphenylthiazepine (e.g. quetiapine), or a quinolone (e.g. aripiprazole), more preferably a benzisoxazole (e.g. paliperidone).

[0051] The antidepressant drugs can generally be tricyclic antidepressants (such as imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (such as moclobemide), selective serotonin reuptake inhibitors (such as sertraline), serotonin and norepinephrine reuptake inhibitors (such as venlafaxine), serotonin block and reuptake inhibitors (such as trazodone), norepinephrine and dopamine reuptake inhibitors (such as bupropion), norepinephrine inhibitors (such as reboxetine), or α2 adrenergic receptor blockers (such as mirtazapine).

[0052] The drug for treating opioid abuse may generally be buprenorphine or methadone.

[0053] The anxiety-treating drugs may generally be benzodiazepines (eg, diazepam), 5-HT1A receptor partial agonists (eg, buspirone), beta-adrenergic receptor blockers (eg, propranolol), or valproate.

[0054] The active ingredient of the drug for treating hyperlipidemia can generally be a statin (such as simvastatin, atorvastatin, pravastatin), a fibrate (such as fenofibrate, bezafibrate, gemfibrozil), or a nicotinic acid (such as niacin).

[0055] Among them, the active ingredients of the drug for treating tumors can generally be anti-breast cancer drugs (such as azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol, cetuximab or leuprolide), anti-prostate cancer drugs (such as degarelix, leuprolide, histrelin, flunitrium, estramustine, cyproterone acetate), anti-ovarian cancer drugs (such as carboplatin, topotecan, methotrexate), anti-rectal cancer drugs (such as panitumumab), anti-colon cancer drugs (such as bevacizumab, oxaliplatin), anti-liver cancer drugs (such as sorafenib), anti-lung cancer drugs (such as erlotinib, gefitinib, docetaxel), anti-cancer drugs (e.g., fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), anti-pancreatic cancer drugs (e.g., nimotuzumab), anti-esophageal cancer drugs (e.g., docetaxel, paclitaxel, cisplatin, gemcitabine, seracycline, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), anti-skin cancer drugs (e.g., fluorouracil), anti-lymphoma drugs (e.g., vincristine, bexarotene, dacarbazine, etoposide), anti-myeloma drugs (e.g., bortezomib), anti-cervical cancer drugs (e.g., bleomycin), or, anti-bladder cancer drugs (e.g., epirubicin, bacillus Calmette-Guérin).

[0056] The active ingredients of the medicine for treating chronic dental diseases are generally nitroimidazole drugs (such as metronidazole, tinidazole, ornidazole), penicillin drugs, minocycline, or chlorhexidine acetate. The chronic dental diseases in the treatment of chronic dental diseases generally refer to caries or periodontal disease.

[0057] Wherein, the active ingredient of the drug for treating chronic low back pain is preferably a non-steroidal analgesic drug, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen, or voltaren, more preferably ibuprofen or meloxicam;

[0058] The active ingredients of the drugs for treating leukemia are generally drugs that interfere with nucleic acid biosynthesis (such as cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect the DNA structure and function of cancer cells (such as busulfan, mitomycin, chlorambucil, phenylalanine mustard, cyclophosphamide), drugs that interfere with the transcription process and prevent RNA synthesis (such as daunorubicin, doxorubicin, adriamycin, aclarubicin), drugs that inhibit protein synthesis and function (such as vindesine, vincristine, L-aspartate, homoharringtonine), interferon, fludarabine, arsenite, etoposide, or carmustine.

[0059] Among them, the active pharmaceutical ingredients acting on the circulatory system preferably include active pharmaceutical ingredients for treating chronic heart failure, coronary heart disease, congenital heart disease, chronic infective endocarditis, or chronic pericarditis.

[0060] The active ingredients of the drug for treating coronary heart disease can generally be drugs that improve symptoms of angina pectoris (such as puerarin, isosorbide mononitrate), drugs that inhibit platelet aggregation (such as aspirin, clopidogrel bisulfate, ticagrelor), drugs that lower lipids and stabilize plaques (such as atorvastatin, rosuvastatin, pravastatin), drugs that inhibit sympathetic nerve activity (such as metoprolol, bisoprolol fumarate), or drugs that improve myocardial remodeling (such as angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists), preferably drugs that improve symptoms of angina pectoris, and more preferably puerarin.

[0061] The active ingredients of the drug for treating chronic heart failure can generally be cardiotonic drugs (such as digitalis, digoxin, cedilanid), vasodilator drugs (such as sodium nitroprusside, nitroglycerin, converting enzyme inhibitors (such as enalapril, lenoprolol, etc.), or diuretics (such as furosemide, hydrochlorothiazide, spironolactone).

[0062] The active ingredient of the drug for treating congenital heart disease can generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide or coenzyme Q10.

[0063] The active ingredient of the drug for treating chronic infective endocarditis can generally be an antibiotic (eg, vancomycin, cephalosporin, penicillin, aminoglycoside).

[0064] The active ingredient of the medicine for treating chronic pericarditis can generally be digitalis.

[0065] The active pharmaceutical ingredients acting on the respiratory system may generally include active pharmaceutical ingredients for treating chronic obstructive pulmonary emphysema, asthma, chronic cor pulmonale, chronic respiratory failure, or silicosis or pulmonary fibrosis.

[0066] The active ingredients of the drugs for treating chronic obstructive pulmonary emphysema can generally be bronchodilators (including beta-receptor agonists and anticholinergic drugs), inhaled hormones (such as budesonide, fluticasone), theophylline antiasthmatics (such as theophylline), expectorants (such as carbocysteine, fudosteine), glucocorticoids, or antibiotics (such as penicillins, glycosides and cephalosporins).

[0067] The active ingredients of the asthma-treating drugs are generally commonly used inhaled drugs (e.g., beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (e.g., salbutamol), sustained-release theophylline, leukotriene modifiers (which can be used in combination), anticholinergics (e.g., isoproscopolamine), or antihistamines (e.g., astemizole, ketotifen).

[0068] The active ingredients of the drug for treating chronic cor pulmonale can generally be antibiotics (such as amoxicillin, cefuroxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (such as selective β2 receptor stimulants, theophylline drugs), drugs that eliminate nonspecific airway inflammation (such as prednisone), inhaled drugs (such as beconazole), or respiratory stimulants (such as lobeline, doxapram, duloxetine, etc.).

[0069] The active ingredients of the drug for treating chronic respiratory failure can generally be drugs for relieving bronchospasm and removing phlegm (such as salbutamol, acetylcysteine, etc.).

[0070] The active ingredients of the medicine for treating silicosis can generally be siping, acetylcysteine, aluminum preparations, closiperine, or salvia miltiorrhiza.

[0071] The active ingredients of the drug for treating pulmonary fibrosis can generally be pirfenidone, nintedanib, glucocorticoids (such as methylprednisolone, prednisone), immunosuppressants (such as azathioprine, methotrexate, etc.), colchicine, interferon, ACEI or statins, etc.

[0072] Among them, the active pharmaceutical ingredients acting on the digestive system generally include active pharmaceutical ingredients for treating chronic gastritis, treating peptic ulcers, treating intestinal tuberculosis, treating chronic enteritis, treating chronic diarrhea, treating chronic hepatitis, treating cirrhosis, treating chronic pancreatitis, or treating chronic cholecystitis.

[0073] The active ingredients of the drug for treating chronic gastritis can generally be analgesics (such as atropine, propantheline), PPI proton pump inhibitors (such as lansoprazole, omeprazole), H 2 Beta-blockers (such as cimetidine, ranitidine, aluminum hydroxide), digestive aids (pancreatic enzymes), or drugs that inhibit bile reflux (metoclopramide, metoclopramide, cholestyramine, sucralfate).

[0074] The active ingredient of the drug for treating peptic ulcer can generally be levofloxacin, tinidazole or omeprazole.

[0075] The active ingredient of the drug for treating intestinal tuberculosis can generally be rifampicin.

[0076] The active ingredients of the medicine for treating chronic enteritis can generally be anti-inflammatory analgesics, probiotics or antispasmodics (such as atropine, propantheline).

[0077] The active pharmaceutical ingredient for treating chronic diarrhea can generally be an antidiarrheal drug (such as montmorillonite powder, diphenoxylate, loperamide), an intestinal microbial preparation (such as lactobacillus, bifidobacterium), or a spasmodic analgesic (such as pinaverium bromide).

[0078] The active ingredients of the drugs for treating chronic hepatitis can generally be liver-protecting drugs (such as silymarin preparations, schisandra preparations, etc.), anti-fibrosis drugs (such as oral Chinese patent medicine preparations), antivirals (such as conventional interferons and pegylated interferons), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine, entecavir), or immunosuppressants (azathioprine).

[0079] The active ingredients of the drug for treating liver cirrhosis can generally be drugs for treating hepatitis B (such as nucleoside analogs), drugs for treating autoimmune hepatitis (such as glucocorticoids), anti-inflammatory drugs, liver-protecting drugs, anti-liver fibrosis drugs (such as reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, etc.), drugs for treating spontaneous bacterial peritonitis (such as antibiotics), or drugs for treating portal hypertension (such as carvedilol).

[0080] The active ingredients of the medicine for treating chronic pancreatitis can generally be analgesics (such as buprenorphine and fentanyl) and pancreatic enzyme treatment drugs (such as pancreatic enzymes).

[0081] The active ingredients of the drug for treating chronic cholecystitis can generally be antibacterial and anti-inflammatory drugs (such as levofloxacin, ciprofloxacin, amoxicillin), antispasmodics and analgesics, or choleretics (such as ursodeoxycholic acid).

[0082] The active pharmaceutical ingredients acting on the blood system may generally include active pharmaceutical ingredients for treating chronic anemia, chronic myeloid leukemia, or chronic lymphocytic leukemia.

[0083] The active ingredients of the drug for treating chronic anemia can generally be: trace elements (such as folic acid, vitamin B12, etc.), bone marrow stimulants (such as strychnine nitrate, scopolamine, hyoscyamine (scopolamine)), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight dextran iron, carboxymaltose iron, isomaltose iron, glucuronic acid iron, nano iron oxide, sorbitol iron, etc.), or erythropoiesis-promoting (recombinant human erythropoietin α, darbepoetin α).

[0084] The active ingredient of the drug for treating chronic myeloid leukemia can generally be: tyrosine kinase inhibitors (such as imatinib, nilotinib, bosutinib, ponatinib, etc.), or homoharringtonine.

[0085] The active ingredients of the drug for treating chronic lymphocytic leukemia can generally be: chemotherapy (such as nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted drugs (such as adranib, venetola, ibrutinib, imatinib, dasatinib, etc.), or monoclonal antibodies (such as ofatumumab, rituximab, atozumab, alemtuzumab, etc.).

[0086] The active pharmaceutical ingredients acting on the endocrine system may generally include active pharmaceutical ingredients for treating chronic lymphocytic thyroiditis, hyperthyroidism, or hypothyroidism.

[0087] The active ingredients of the drug for treating chronic lymphocytic thyroiditis can generally be: thyroid hormones (such as levothyroxine, thyroxine), or glucocorticoids (such as prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0088] The active ingredients of the drug for treating hyperthyroidism can generally be: thiouracils (such as propylthiouracil, methylthiouracil, etc.), imidazoles (such as methimazole, carbimazole), iodine and iodide (such as Lugol's solution), radioactive iodine (such as 131 iodine), or beta-receptor blockers (such as metoprolol, atenolol, bisoprolol, carvedilol, propranolol).

[0089] The active ingredient of the drug for treating hypothyroidism can generally be: thyroxine (eg levothyroxine, levothyroxine sodium, thyroxine).

[0090] In the present invention, the dosage of the pharmaceutically active ingredient is preferably 5-500 parts, more preferably 5-100 parts, such as 10 parts, 20 parts, 50 parts or 100 parts.

[0091] In the present invention, the R-vinyl silicone rubber is preferably methyl vinyl silicone rubber.

[0092] In the present invention, the vinyl content in the R-vinyl silicone rubber is preferably 0.17-0.23 mol%, for example, 0.17 mol%, 0.18 mol%, 0.19 mol%, 0.20 mol%, 0.21 mol%, 0.22 mol% or 0.23 mol%.

[0093] In the present invention, the amount of the hydrogen-containing silicone oil can be 0.3-20 parts, preferably 0.3-10 parts, such as 0.3 parts, 0.667 parts or 1 part.

[0094] In the present invention, the content of Si-H groups in the hydrogen-containing silicone oil is preferably 0.5-1.0 mol%, such as 0.75 mol%.

[0095] In the present invention, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is preferably (1-10):1, such as 1.5:1, 2:1, 3:1, 3.5:1, 4:1, 4.5:1 or 6:1.

[0096] In the present invention, the catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil, such as a platinum catalyst, a platinum catalyst, a rhodium catalyst, a palladium catalyst or a nickel catalyst, preferably a platinum catalyst and / or a platinum catalyst. When the catalyst is a platinum catalyst, the concentration of platinum in the platinum catalyst is preferably 1×10 3 ~1×10 5 ppm, for example 1×10 3 ppm, 1×10 4 ppm or 1×10 5 ppm.

[0097] In the present invention, the amount of the catalyst is preferably 0.000002-0.5 parts, more preferably 0.05-0.4 parts, such as 0.1 parts, 0.20 parts, 0.21 parts, 0.25 parts, 0.27 parts or 0.30 parts.

[0098] In the present invention, the pharmaceutical composition may further include an inhibitor, which generally refers to an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil. The inhibitor may be a hydrocarbon. The molecular structure of the hydrocarbon preferably contains at least one alkynyl group and one hydroxyl group, such as 2-methyl-3-butyn-2-ol. The amount of the inhibitor is preferably 0.03-2.0 parts, such as 0.49 parts or 0.98 parts.

[0099] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the particle size of the active pharmaceutical ingredient may be 0.001-200 μm, preferably 2-80 μm, such as 2-3 μm.

[0100] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the dosage of the active pharmaceutical ingredient is preferably 5-500 parts, such as 10 parts, 20 parts, 50 parts, 80 parts or 100 parts.

[0101] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the amount of the hydrogen-containing silicone oil can be 0.3-20 parts, preferably 0.3-5 parts, such as 0.3 parts, 0.5 parts, 0.667 parts or 1 part.

[0102] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the amount of the catalyst is preferably 0.10-0.30 parts, such as 0.10 parts, 0.20 parts, 0.21 parts, 0.25 parts or 0.30 parts, more preferably 0.20-0.25 parts.

[0103] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the content of vinyl in the R-vinyl silicone rubber may be 0.10%-0.50 mol%, preferably 0.10%-0.30 mol%, for example 0.18 mol%.

[0104] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the content of Si-H groups in the hydrogen-containing silicone oil may be 0.15-1.6 mol%, preferably 0.15-1.2 mol%, such as 0.75 mol%.

[0105] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is preferably (1.5-10):1, such as 1.5:1, 3.0:1 or 4.5:1, more preferably (3.0-4.5):1.

[0106] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0107] Gestodene: 10-500 parts;

[0108] R-vinyl silicone rubber: 100 parts;

[0109] Hydrogenated silicone oil: 0.3-20 parts;

[0110] Catalyst: 0.1-0.3 parts;

[0111] in:

[0112] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0113] The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0114] The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%;

[0115] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (1.5-6):1.

[0116] In the present invention, the pharmaceutical composition, more preferably, comprises the following raw material components:

[0117] Gestodene: 20-200 parts;

[0118] R-vinyl silicone rubber: 100 parts;

[0119] Hydrogenated silicone oil: 0.3-20 parts;

[0120] Catalyst: 0.2-0.25 parts;

[0121] in:

[0122] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0123] The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0124] The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%;

[0125] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (2-6):1.

[0126] In a preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 100 parts of gestodene, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.21 parts of platinum catalyst, and 0.98 parts of 2-methyl-3-butyn-2-ol;

[0127] Among them, the content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%, the content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 4.5:1.

[0128] In a more preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 100 parts of gestodene, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.21 parts of platinum catalyst, and 0.98 parts of 2-methyl-3-butyn-2-ol;

[0129] The content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 4.5:1, and the concentration of platinum in the platinum catalyst is 1×10 4 ppm.

[0130] In a preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 20 parts of gestodene, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.21 parts of platinum catalyst, and 0.98 parts of 2-methyl-3-butyn-2-ol;

[0131] Among them, the content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%, the content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 4.5:1.

[0132] In a more preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 20 parts of gestodene, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.21 parts of platinum catalyst, and 0.98 parts of 2-methyl-3-butyn-2-ol;

[0133] The content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 4.5:1, and the concentration of platinum in the platinum catalyst is 1×10 4 ppm.

[0134] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0135] Levonorgestrel: 5-200 parts;

[0136] R-vinyl silicone rubber: 100 parts;

[0137] Hydrogenated silicone oil: 0.3-20 parts;

[0138] Catalyst: 0.2-0.3 parts;

[0139] in:

[0140] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0141] The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0142] The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%;

[0143] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (1.5-4.5):1.

[0144] In a specific embodiment, the pharmaceutical composition is composed of the following raw material components: 10 parts of levonorgestrel, 100 parts of methyl vinyl silicone rubber, 0.667 parts of hydrogen-containing silicone oil, 0.25 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0145] The content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 1.5:1.

[0146] In a specific embodiment, the pharmaceutical composition is composed of the following raw material components: 50 parts of levonorgestrel, 100 parts of methyl vinyl silicone rubber, 0.667 parts of hydrogen-containing silicone oil, 0.25 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0147] The content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 1.5:1.

[0148] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the particle size of the active pharmaceutical ingredient may be 0.001-180 μm, for example, 0.01 μm, 0.1 μm, 0.5 μm, 1 μm, 5 μm, 20 μm, 60 μm, 80 μm or 100 μm.

[0149] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the dosage of the active pharmaceutical ingredient is preferably 10-500 parts, such as 100 parts, 150 parts or 200 parts.

[0150] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the amount of the hydrogen-containing silicone oil can be 0.3-20 parts, preferably 0.3-5 parts, such as 0.3 parts, 0.5 parts or 1 part.

[0151] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the amount of the catalyst is preferably 0.20-0.30 parts, such as 0.20 parts, 0.25 parts, 0.27 parts or 0.30 parts, more preferably 0.25-0.27 parts.

[0152] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the content of vinyl in the R-vinyl silicone rubber is 0.10%-0.30 mol%, for example, 0.17 mol%.

[0153] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.2 mol%, for example, 0.75 mol%.

[0154] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl group in the R-vinyl silicone rubber may be (1-6):1, preferably (2-6):1, for example 2:1, 3:1, 3.5:1 or 4:1, more preferably (3.0-3.5):1.

[0155] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0156] Levothyroxine sodium: 20-500 parts;

[0157] R-vinyl silicone rubber: 100 parts;

[0158] Hydrogenated silicone oil: 0.3-20 parts;

[0159] Catalyst: 0.2-0.3 parts;

[0160] in:

[0161] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0162] The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.30mol%;

[0163] The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.2 mol%;

[0164] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (1-6):1.

[0165] In a preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 100 parts of levothyroxine sodium, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.27 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0166] The content of vinyl in the methyl vinyl silicone rubber is 0.17 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 3:1.

[0167] In a more preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 100 parts of levothyroxine sodium, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.27 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0168] The content of vinyl in the methyl vinyl silicone rubber is 0.17 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 3:1, and the concentration of platinum in the platinum catalyst is 1×10 4 ppm.

[0169] In a preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 100 parts of levothyroxine sodium, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.27 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0170] The content of vinyl in the methyl vinyl silicone rubber is 0.17 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 3.5:1.

[0171] In a more preferred embodiment, the pharmaceutical composition is composed of the following raw material components: 100 parts of levothyroxine sodium, 100 parts of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.27 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0172] The content of vinyl in the methyl vinyl silicone rubber is 0.17 mol%, the content of Si-H in the hydrogen-containing silicone oil is 0.75 mol%, the molar ratio of Si-H in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 3.5:1, and the concentration of platinum in the platinum catalyst is 1×10 4 ppm.

[0173] The present invention also provides a stick core, the raw material components of which include the above-mentioned pharmaceutical composition. The active pharmaceutical ingredient is dispersed in the cross-linked structure of the stick core. The active pharmaceutical ingredient in the stick core may exist in a molecular, amorphous or crystalline form. The stick core may be used alone or in combination with a silicone tube. When the stick core is used in combination with the silicone tube, a suitable formula may be selected according to actual conditions.

[0174] The present invention also provides a method for preparing the stick core as described above, which comprises the following steps:

[0175] S1: dividing the R-vinyl silicone rubber into component A1 and component A2, mixing the component A1 and the catalyst to obtain component B1, and mixing the component A2 and the hydrogen-containing silicone oil to obtain component B2;

[0176] S2: mixing the component B1 and the component B2 to obtain a mixed rubber;

[0177] S3: mixing the mixed rubber and the active ingredient of the drug to obtain drug-loaded silica gel;

[0178] S4: The drug-loaded silica gel is extruded and vulcanized to obtain a stick core.

[0179] In S1, when the pharmaceutical composition further includes an inhibitor, the component A2, the hydrogen-containing silicone oil and the inhibitor are mixed to obtain the component B2.

[0180] In S1, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, such as drying at 30-60° C. (eg, 40° C.) for 1-24 h (eg, 12 h) for later use.

[0181] In S1, the preparation method of the component B1 or the component B2 can be conventional in the art. Generally, the components are mixed in an open mill and then thinly passed 4-6 times (for example, 5 times) and discharged in the form of flakes.

[0182] In S2, the step of mixing the component B1 and the component B2 may include the following steps: putting the component B1 and the component B2 in a weight ratio of 1:1 into an open mixing mill and mixing them for 4-6 times (for example, 5 times) to make the B1 and B2 component rubbers fully mixed and uniformly formed into a mixed rubber.

[0183] In S3, the mixing may include the following steps: putting the active pharmaceutical ingredient and the mixed rubber into an open mixer at a weight ratio of 1:(0.1-10) (e.g., 1:1 or 1:5) for mixing, so that the mixed rubber and the active pharmaceutical ingredient are fully mixed and uniformly formed into drug-loaded silica gel. The drug-loaded silica gel may be cut into strips.

[0184] In S4, the extrusion is generally performed in an extruder.

[0185] In S4, the vulcanization is generally performed in an oven. The vulcanization time may be 0.5-24 hours, such as 0.5 hours, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or 24 hours. The vulcanization temperature may be 50-160°C, such as 50°C, 70°C, 90°C or 110°C.

[0186] In S4, when the active pharmaceutical ingredient is gestodene, the vulcanization time is preferably 1-24 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours or 24 hours, more preferably 1-3 hours. The vulcanization temperature is preferably 70-110°C, such as 70°C, 90°C or 110°C.

[0187] In a preferred embodiment, in S4, the active pharmaceutical ingredient is gestodene, the vulcanization temperature is 90° C., and the vulcanization time is 1 hour.

[0188] In a preferred embodiment, in S4, the pharmaceutical active ingredient is levothyroxine sodium, the vulcanization temperature is 50° C., and the vulcanization time is 0.5 h.

[0189] In S4, when the active pharmaceutical ingredient is levonorgestrel, the vulcanization time is preferably 0.5-2h, such as 0.5h, 0.6h, 0.8h, 1h or 2h, more preferably 0.5-1.5h. The vulcanization temperature is preferably 70-110°C, such as 70°C, 90°C or 110°C, more preferably 90-110°C.

[0190] In a preferred embodiment, in S4, the active pharmaceutical ingredient is levonorgestrel, the vulcanization temperature is 110° C., and the vulcanization time is 1 h.

[0191] The present invention also provides a rod core, which is prepared by the above preparation method.

[0192] In the present invention, the diameter of the rod core is preferably 2.0-10 mm, such as 2.0 mm, 2.4 mm, 2.6 mm, 3 mm or 4 mm.

[0193] The length of the rod core is preferably 5-100 mm, for example 5 mm, 10 mm, 15 mm, 20 mm, 25 mm, 30 mm, 35 mm, 40 mm or 50 mm.

[0194] The drug release area of ​​the stick core is preferably 25-450mm 2 , for example 31.41mm 2 、37.69mm 2 、62.8mm 2 、69.08mm 2 、94.23mm 2 、94.24mm 2 、100.48mm 2 、125.6mm 2 、131.88mm 2 、157.07mm 2 、163.38mm 2 、188.4mm 2 、194.68mm 2 、202.53mm 2 、214.71mm 2 、219.91mm 2 、226.28mm 2 、251.2mm 2 、257.48mm 2 、296.73mm 2 、310.48mm 2 、314mm 2 、320.28mm 2 、390.93mm 2 or 418.81mm 2 .

[0195] The invention also provides an implant comprising the stick core and a silicone tube.

[0196] In the present invention, the silicone tube can be conventional in the art. Preferably, the raw material composition of the silicone tube includes the following components in parts by weight:

[0197] R-vinyl silicone rubber: 100 parts;

[0198] Hydrogenated silicone oil: 0.3-4.0 parts;

[0199] Catalyst: 0.000002-0.5 parts;

[0200] Reinforcing agent: 20-80 parts;

[0201] Wherein: R in the R-vinyl silicone rubber is substituted or unsubstituted C1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0202] The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0203] The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%;

[0204] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-5):1.

[0205] Wherein, the raw material composition of the silicone tube preferably also includes an inhibitor; the inhibitor is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil. The inhibitor may be an acetylene alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methyl butynol, and also 2-methyl-3-butyn-2-ol. The amount of the inhibitor may be 0.03-2.0 parts, preferably 0.3-1.0 parts, and for example 0.3 parts, 0.5 parts, 0.69 parts, 0.7 parts, 0.74 parts or 0.9 parts.

[0206] Among them, the amount of the hydrogen-containing silicone oil is preferably 0.4-2.8 parts, for example, 0.42 parts, 0.533 parts, 0.667 parts, 0.67 parts, 0.84 parts, 1.01 parts, 1.13 parts, 1.26 parts, 1.36 parts, 1.51 parts, 1.68 parts or 1.8 parts, more preferably 0.84-1.51 parts.

[0207] Wherein, the dosage of the catalyst is preferably 0.000002-0.1 parts, such as 0.01 parts.

[0208] The catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil, such as a platinum catalyst, a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst. When the catalyst is a platinum catalyst, the concentration of platinum in the platinum catalyst may be 3000 ppm, and 3000 ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million.

[0209] The vinyl content in the R-vinyl silicone rubber is preferably 0.18-0.23 mol%, for example 0.18 mol%.

[0210] Wherein, the content of Si-H groups in the hydrogen-containing silicone oil is preferably 0.36-1.6 mol%, for example, 0.36 mol%, 0.5 mol%, 0.75 mol%, 1.0 mol% or 1.6 mol%.

[0211] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber may be (0.8-4):1, such as 0.8:1, 1:1, 1.2:1, 1.5:1, 1.8:1 or 2:1, preferably (1.2-1.8):1 or (1.2-1.5):1.

[0212] The amount of the reinforcing agent is preferably 20-80 parts, more preferably 30-60 parts; for example, 30 parts, 35 parts, 40 parts, 45 parts, 50 parts or 60 parts.

[0213] The reinforcing agent may be conventional white carbon black in the art, such as one or more of white carbon black, diatomaceous earth, quartz powder, silica powder, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate and calcium carbonate, preferably white carbon black. The white carbon black is preferably fumed white carbon black, precipitated white carbon black, gel-processed white carbon black or surface-treated white carbon black, such as fumed white carbon black.

[0214] In the present invention, preferably, the raw material composition of the silica gel material comprises the following components in parts by weight:

[0215] Methyl vinyl silicone rubber: 100 parts;

[0216] Reinforcing agent: 30-45 parts;

[0217] Hydrogenated silicone oil: 0.42-2.52 parts;

[0218] Catalyst: 0.000002-0.015 parts;

[0219] Inhibitor: 0.3-0.9 parts;

[0220] Wherein: the content of vinyl in the methyl vinyl silicone rubber is 0.17-0.23 mol%;

[0221] The content of Si-H groups in the hydrogen-containing silicone oil is 0.5-1.0 mol%;

[0222] 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.

[0223] In a specific embodiment, the raw material composition of the silica gel material includes the following components in parts by weight:

[0224] Methyl vinyl silicone rubber: 100 parts;

[0225] Reinforcing agent: 40 parts;

[0226] Hydrogenated silicone oil: 0.667 parts;

[0227] Platinum catalyst: 0.01 parts;

[0228] Inhibitor: 0.69 parts;

[0229] Wherein: the content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%;

[0230] The content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol%;

[0231] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methyl vinyl silicone rubber is 1.5:1;

[0232] The concentration of platinum in the platinum catalyst is 3000 ppm.

[0233] In a specific embodiment, the raw material composition of the silica gel material includes the following components in parts by weight:

[0234] Methyl vinyl silicone rubber: 100 parts;

[0235] Reinforcing agent: 50 parts;

[0236] Hydrogenated silicone oil: 0.533 parts;

[0237] Platinum catalyst: 0.01 parts;

[0238] Inhibitor: 0.74 parts;

[0239] Wherein: the content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%;

[0240] The content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol%;

[0241] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methyl vinyl silicone rubber is 1.2:1;

[0242] The concentration of platinum in the platinum catalyst is 3000 ppm.

[0243] In the present invention, the preparation method of the silicone tube can adopt method one or method two;

[0244] Method 1: When the raw material composition of the silicone tube does not include an inhibitor, the preparation method of the silicone tube includes the following steps:

[0245] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0246] S2: In the presence of the catalyst, mixing the mixture A and the hydrogen-containing silicone oil to obtain a mixture B;

[0247] S3: Extruding the mixture B into a tube, and then subjecting it to catalytic addition;

[0248] Method 2: When the raw material composition of the silicone tube includes an inhibitor, the preparation method of the silicone tube includes the following steps:

[0249] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0250] S2: the mixture A is equally divided into component A1 and component A2, the component A1 is mixed with the catalyst to obtain component B1, and the component A2 is mixed with the hydrogen-containing silicone oil and the inhibitor to obtain component B2;

[0251] S3: mixing the component B1 and the component B2 to obtain a mixture B;

[0252] S4: The mixture B is formed into a tube through an extrusion process, and then subjected to catalytic addition.

[0253] In the present invention, in the method 1 and the method 2, the reinforcing agent can be pretreated by conventional methods in the art, for example, drying at 100-210° C. for 1-24 hours, or drying at 130° C. for 18 hours.

[0254] In the present invention, in the method 1 and the method 2, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, for example, drying at 30-60°C for 1-24h, or drying at 40°C for 18h.

[0255] In the present invention, in the method 1 and the method 2, the mixing step in S1 may be: after wrapping the reinforcing agent with the R-vinyl silicone rubber, the mixture is extruded into a thin film by an open mill and then pressed into a sheet.

[0256] In the present invention, in the method 1 and the method 2, the mixing step in S1 is preferably: kneading the R-vinyl silicone rubber and the reinforcing agent in a kneader at 30° C. for 30 minutes, and then taking them out; making triangle wraps on an open mill with a roller spacing of 1-10 mm (for example, 1 mm) and then rolling the sheets, and then leaving them for 18 hours to obtain the mixture A.

[0257] In the present invention, in the method 1 and the method 2, the mixture A can be placed in a desiccator at room temperature for 18-72 hours.

[0258] In the present invention, in the method 1, before the catalytic addition, the mixture B can be subjected to the following post-treatment: triangular thinning in an open mill for 4 to 6 times, and then uniformly cutting the material into sheets.

[0259] In the present invention, in the second method, the step of mixing the component B1 and the component B2 can be: putting the component B1 and the component B2 in a ratio of 1:1 into an open mixing mill, making triangle packages for 4 to 6 times, and then evenly cutting the materials into slices.

[0260] In the present invention, in the method 1, the catalytic addition step in S3 may be: subjecting the mixture B to a first sulfurization treatment and a second sulfurization treatment in sequence.

[0261] The temperature of the first sulfurization treatment may be 250-330°C, such as 270°C, 300°C or 330°C.

[0262] The time of the first vulcanization treatment may be 2-30 seconds, for example, 15 seconds.

[0263] The temperature of the second vulcanization treatment may be 150-280°C, such as 150°C, 180°C, 210°C or 240°C.

[0264] The second vulcanization treatment may be performed for 0.1-5 min, for example, 2 min.

[0265] In the present invention, in the method 2, the catalytic addition step in S4 can be as described above.

[0266] In the present invention, according to the conventional art, the inner diameter of the silicone tube is generally equal to the outer diameter of the rod core. The outer diameter of the silicone tube is preferably 2.0-5.0 mm, such as 2.4 mm or 2.6 mm.

[0267] The length of the silicone tube is preferably 0.9-5 cm, for example 0.9 cm, 1 cm, 1.9 cm, 2 cm, 2.9 cm, 3 cm, 3.9 cm, 4 cm, 4.4 cm or 5 cm.

[0268] The wall thickness of the silicone tube is preferably 0.2-0.5 mm, such as 0.2 mm, 0.3 mm, 0.4 mm or 0.5 mm.

[0269] In a specific embodiment, the outer diameter of the silicone tube is 2.4 mm, the length of the silicone tube is 0.9 cm, and the wall thickness of the silicone tube is 0.2 mm.

[0270] The invention provides a method for preparing an implant, which comprises the following steps: filling the stick core into the silicone tube.

[0271] The invention also provides an implant prepared by the preparation method.

[0272] The present invention also provides an application of the stick core as a release rate regulating medium in a sustained-release or controlled-release preparation.

[0273] In the present invention, the vinyl content in the R-vinyl silicone rubber refers to the molar percentage, and the molar percentage of vinyl refers to the number of moles of vinyl per 100 moles of R-vinyl silicone rubber.

[0274] In the present invention, the Si-H group content in the hydrogen-containing silicone oil refers to the molar percentage, and the molar percentage of hydrogen content refers to the number of moles of hydrogen in every 100 moles of the hydrogen-containing silicone oil.

[0275] In the present invention, the room temperature refers to 25°C + 5℃.

[0276] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0277] The reagents and raw materials used in the present invention are commercially available.

[0278] The positive and progressive effects of the present invention are:

[0279] (1) Compared with the reservoir drug powder type implant, the reservoir-skeleton type implant provided by the present invention can reduce drug loss and save drug costs; reduce the sudden release phenomenon; release the drug more smoothly, control the release amount within the effective treatment window, and achieve long-term stable release; at the same time, speed up the production speed and improve the production efficiency;

[0280] (2) Both the skeleton-type implant and the reservoir-skeleton-type implant provided by the present invention can be used as marketed preparations, for example, a levonorgestrel subcutaneous implant. BRIEF DESCRIPTION OF THE DRAWINGS

[0281] Figure 1 is the release amount of gestodene skeleton stick core.

[0282] Figure 2 This is the effect of the vulcanization time of the silicone rod core on the release amount.

[0283] Figure 3 This is the effect of different drug release areas of the silicone rod core on the release amount.

[0284] Figure 4 It is the daily release of reservoir-skeleton type gestodene.

[0285] Figure 5 is the release amount of different cross-linking agent molar ratios.

[0286] Figure 6 is the release amount at different release areas.

[0287] Figure 7 In vitro release of levothyroxine sodium from two-piece silicone rod cores.

[0288] Figure 8 This is the effect of different vulcanization temperatures of the silicone rod core on the release amount.

[0289] Fig. 9 This is the effect of different vulcanization times of the silicone rod core on the release amount.

[0290] Fig.10 In vitro release of levonorgestrel from a silicone rod core.

[0291] Fig.11 This is the effect of the release area of ​​the silicone rod core on the release amount.

[0292] Fig.12 In vitro release of a reservoir-matrix levonorgestrel implant. DETAILED DESCRIPTION

[0293] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0294] The information of the instruments and reagents used in the following examples and comparative examples are shown in Tables 1 and 2 below:

[0295] Table 1

[0296] Small precision mixing mill Dongguan Xilong Electrical Machinery Equipment Co., Ltd. Φ16 Silicone Rubber Extruder Hebei Xulang Machinery Equipment Manufacturing Co., Ltd. 101-2AB Electric Blast Drying Oven Tianjin Test Instrument Co., Ltd. 3020N outer diameter measuring instrument Shanghai Pinzhong Testing Equipment Co., Ltd. V3.0 Intelligent Measurement System Microscope Shenzhen Zhongwei Technology Co., Ltd. XS105 Electronic Analytical Balance Mettler-Toledo Instruments Ltd. SMD200-2 Electronic Analytical Balance Ohaus International Trading Co., Ltd. QL-5E Electronic Tensile Testing Machine Xiamen Qunlong Instrument Co., Ltd. Ultima IV X-ray Diffractometer Beijing Hongchangxin Technology Co., Ltd. Zeiss Sigma 300 Scanning Electron Microscope Carl Zeiss Shanghai Management Co., Ltd. CHA-S Constant Temperature Oscillator Changzhou Guohua Electric Co., Ltd. LC-10ATVP High Performance Liquid Chromatograph Shimadzu Corporation CNC ultrasonic cleaner (KQ-250DE model) Kunshan Ultrasonic Instrument Co., Ltd. Vacuum kneading machine (small) Laizhou Zhongtai Chemical Machinery Co., Ltd. XPE electronic analytical balance Mettler-Toledo Instruments Ltd. Vertical hot air vulcanization tunnel Hebei Xulang Machinery Equipment Manufacturing Co., Ltd. Horizontal hot air vulcanization tunnel Hebei Xulang Machinery Equipment Manufacturing Co., Ltd.

[0297] Table 2

[0298] Gestodene (purity 98%) Hebei Mokai Technology Co., Ltd. Levothyroxine Sodium (Purity 99%) Shanghai Meilian Biotechnology Co., Ltd. Levonorgestrel (purity 98.5%) Hebei Mokai Technology Co., Ltd. Methyl vinyl polysiloxane Dongjue Silicone Group Co., Ltd. H-75 Hydrogenated Silicone Oil Guangdong Guiye New Material Technology Co., Ltd. Platinum Catalyst Guangdong Guiye New Material Technology Co., Ltd. 2-Methyl-3-butyn-2-ol Jiuding Chemical Technology Co., Ltd. KN-300N Adhesive Kanglibang Polymer New Materials Co., Ltd. Chromatography Methanol Shandong Yuwang Chemical Reagent Co., Ltd. Acetonitrile (chromatographic grade) Shandong Yuwang Chemical Reagent Co., Ltd. Ethanol (analytical grade) Shandong Yuwang Chemical Reagent Co., Ltd. HB-615 Fumed Silica Yichang Huifu Silicon Materials Co., Ltd. Anhydrous ethanol Shandong Yuwang Chemical Reagent Co., Ltd.

[0299] The relevant terms are explained as follows: skeleton-type implant, also known as skeleton-type rod core, refers to only a rod core without a silicone tube on the outside; reservoir-skeleton-type implant is a rod core with a layer of silicone tube on the outside; the vinyl content in methyl vinyl silicone rubber refers to the molar percentage, and the molar percentage of vinyl refers to the number of moles of vinyl per 100 moles of R-vinyl silicone rubber; the Si-H group hydrogen content in hydrogen-containing silicone oil refers to the molar percentage, and the molar percentage of Si-H group hydrogen content refers to the number of moles of Si-H group hydrogen per 100 moles of hydrogen-containing silicone oil.

[0300] 1. Gestodene skeleton core

[0301] 1.1 Preparation of Gestodene Skeleton Core

[0302] Since the silicone rod core is made by mixing drugs and silicone rubber and then vulcanizing, the addition of drugs will hinder the cross-linking of silicone rubber macromolecules to a certain extent during the vulcanization process. Therefore, compared with silicone tubes, silicone rod cores are more difficult to vulcanize. In addition, in order to ensure the stability of the drugs, higher requirements are placed on the proportion and dosage of each component in the silicone prescription.

[0303] Example 1-1

[0304] Basic prescription

[0305] The gestodene skeleton type rod core is a rod-shaped silicone rod core prepared by mixing the model drug gestodene with silicone rubber. The prescription consists of 20PHR of gestodene, 100PHR of methyl vinyl silicone rubber, hydrogen-containing silicone oil, 0.1PHR of platinum catalyst, and 0.98PHR of 2-methyl-3-butyn-2-ol.

[0306] Among them, the selected gestodene has a particle size of 2-3 μm after air flow grinding; the selected methyl vinyl silicone rubber, vinyl is the end-capping group of the silicone rubber, and the content of vinyl is in the range of 0.18%; the selected hydrogen-containing silicone oil, the content of Si-H group is 0.75 mol%, and the molar ratio of Si-H group in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 1.5:1; the selected platinum catalyst, the concentration of platinum is 10000 ppm; the selected 2-methyl-3-butyn-2-ol is the inhibitor.

[0307] Note: PHR (parts per hundreds of rubber) indicates the number of parts of the component per 100 parts of methyl vinyl silicone rubber; ppm (parts per million) is parts per million, indicating the mass concentration of platinum in the platinum catalyst.

[0308] Preparation process

[0309] (1) Drying pretreatment of raw rubber: Dry the methyl vinyl silicone rubber raw rubber at 40°C for 12 hours for later use.

[0310] (2) Preparation of component A and component B rubber: Take the prescribed amount of methyl vinyl silicone rubber raw rubber and divide it equally into two components A and B. Add the prescribed amount of hydrogenated silicone oil and 2-methyl-3-butyn-2-ol to component A, mix well in an open mill, and then pass it through a thin mill five times to unload it in the form of thin sheets. Add the prescribed amount of platinum catalyst to component B, mix well in an open mill, and then pass it through a thin mill five times to unload it in the form of thin sheets.

[0311] (3) Preparation of rubber compound: The prepared A and B component flakes are put into an open mixer at a ratio of 1:1 and mixed for 5 times to ensure that the A and B component rubbers are fully mixed and uniformly formed into a rubber compound.

[0312] (4) Preparation of drug-loaded silica gel: Take the prescribed amount of gestodene and the mixed rubber in a weight ratio of 1:5 on an open mixer, mix them evenly to prepare drug-loaded silica gel, and cut them into strips.

[0313] (5) Extrusion of silicone rod core: Install a die of appropriate size, set the extruder screw speed, and put the cut drug-loaded silicone strips into the extruder. The drug-loaded silicone is continuously extruded into a rod-shaped silicone rod core through the die mouth under the push of the screw.

[0314] (6) Vulcanization of silicone rod core: After extrusion, the silicone rod core is placed in an oven and vulcanized into an elastomer at a vulcanization temperature of 90°C and a vulcanization time of 1 hour.

[0315] (7) Preparation of silicone rod cores with different diameters: A die with a diameter of 1.9 mm was used to prepare the silicone rod core.

[0316] (8) Dimensional measurement and appearance inspection of silicone rod core: The diameter of the extruded silicone rod core was measured by infrared caliper, and the surface appearance of the silicone rod core was observed by electron microscope; the diameter of the gestodene skeleton-type rod core was 2 mm, the length was 1.5 cm, and the drug release area was 1.0048 cm 2 .

[0317] Example 1-2 to Example 1-5 (Investigation of Catalyst Amount)

[0318] Except that the amount of catalyst was adjusted to the following values ​​(see Table 3), the other operations and conditions were the same as those in Example 1-1.

[0319] Table 3

[0320] Platinum catalyst dosage (PHR) Elongation at break (%) Tensile strength(MPa) Tear strength (KN / m) Example 1-1 0.10 41.7±3.6 1.02±0.08 0.71±0.06 Example 1-2 0.20 75.3±4.3 1.70±0.13 1.18±0.09 Examples 1-3 0.21 87.1±3.5 2.06±0.12 1.43±0.08 Examples 1-4 0.25 68.4±6.2 1.50±0.09 1.04±0.14 Examples 1-5 0.30 54.5±3.8 1.21±0.14 0.90±0.06

[0321] The results in Table 3 show that with the increase in the amount of platinum catalyst, the mechanical indicators of the silicone rod core first significantly enhanced and then showed a slight downward trend. When the dosage was 0.1PHR, it could not be completely vulcanized due to the small amount of catalyst; the best performance was achieved when the amount of platinum catalyst was 0.21PHR; during the experiment, it was found that when the amount of platinum catalyst was increased to 0.25PHR, the rubber material was slightly hard during the drug-rubber mixing and silicone rod core extrusion process due to the excessive amount, resulting in rough extrusion of the silicone rod core and decreased mechanical properties; when the dosage was increased to 0.30PHR, due to the excessive amount, the texture was too hard and the mechanical properties were relatively poor.

[0322] Example 1-6 and Example 1-7 (investigation of the molar ratio of hydrogen-containing silicone oil)

[0323] Except that the molar ratio of hydrogenated silicone oil is adjusted to the following values ​​(see Table 4), the other operations and conditions are the same as those of Examples 1-3. The molar ratio of hydrogenated silicone oil refers to the molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber.

[0324] Table 4

[0325] Molar ratio of hydrogen silicone oil Elongation at break (%) Tensile strength(MPa) Tear strength (KN / m) Examples 1-6 3.0:1 112.3±5.8 2.30±0.22 1.59±0.15 Examples 1-7 4.5:1 136.7±7.6 2.57±0.20 1.78±0.14

[0326] The results in Table 4 show that as the amount of hydrogenated silicone oil increases, the elongation at break, tensile strength and tear strength of the silicone rod core gradually increase. Generally, in the addition reaction of addition-type silicone rubber, the molar ratio of hydrogenated silicone oil to silicone rubber vinyl is generally sufficient between 1.2 and 1.8. However, for the silicone rod core after drug-gel mixing, the presence of a large amount of drugs in silicone rubber will hinder the contact between the hydrogenated silicone oil silane and vinyl, resulting in incomplete reaction. Therefore, it is necessary to continue to increase the molar ratio, so that the hydrogenated silicone oil is more excessive, and more effective hydrogenated silicone oil can participate in the addition reaction, so that the reaction can be completed in the end, and the silicone rod core reaches the best vulcanization state. When the hydrogenated silicone oil is added to a certain amount, the molecular bonding and cross-linking degree inside the silicone tube is appropriate, and the mechanical properties reach the peak value. When the amount of input continues to increase, the molecular bonding and cross-linking points inside the silicone tube are too many, which increases the binding force of the particles around it, reduces elasticity, makes the silicone tube brittle, and deteriorates toughness, and reduces the elongation at break.

[0327] Example 1-8 and Example 1-9 (Study on Vulcanization Temperature)

[0328] Except that the vulcanization temperature was adjusted to the following values ​​(see Table 5), the remaining operations and conditions were the same as those of Examples 1-7.

[0329] Table 5

[0330] Vulcanization temperature Elongation at break (%) Tensile strength(MPa) Tear strength (KN / m) Examples 1-8 70℃ 70.1±6.5 1.51±0.16 1.04±0.11 Examples 1-9 110℃ 139.8±7.9 2.59±0.19 1.79±0.13

[0331] The results in Table 5 show that when the vulcanization temperature is 70°C, the elongation at break, tensile strength and tear strength of the silicone rod core are not high, and the vulcanization effect is not good. When the vulcanization temperature is 90°C and 110°C, the mechanical indicators of the silicone rod core are good and the difference is not large. During the experiment, it was found that when the vulcanization temperature is between 110°C and 150°C, the color of the silicone rod core becomes darker due to the high temperature and the mechanics is not tested. Therefore, considering the mechanical properties of the silicone rod core and the thermal stability of the drug, the suitable vulcanization temperature range is 70-110°C.

[0332] 1.2 In vitro release of gestodene skeleton stick core:

[0333] Content determination and in vitro release determination method of gestodene skeleton stick core

[0334] (1) Chromatographic conditions

[0335] Chromatographic column: C18 column (250 mm × 4.60 mm, 5 μm);

[0336] Mobile phase: methanol-water (80:20, v / v);

[0337] Column temperature: 30°C;

[0338] Detection wavelength: 239nm;

[0339] Flow rate: 1 mL min -1 ;

[0340] Injection volume: 20 μL.

[0341] (2) In vitro release test method

[0342] Using the horizontal oscillation method, take one implant and fix the two ends of the implant to the bottom and wall of a 50mL stoppered conical flask with a silicone adhesive (to prevent the implant from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it for 12 hours to allow the silicone adhesive to cure completely. Accurately measure 50mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it. The temperature is set to 37°C and the amplitude is 100r·min. -1 The medium was replaced with an equal volume every 24 hours. The release solution was filtered through a 0.22 μm microporous filter membrane and detected according to chromatographic conditions with an injection volume of 20 μL.

[0343] According to relevant literature and patent reports, 10-20 μg of gestodene can achieve drug efficacy after being released every day. In this experiment, a silicone rod core with a diameter of 2.0 mm, a length of 1.5 cm, a vulcanization temperature of 90°C, and a vulcanization time of 1 h (the rod core prescription is the same as that of Example 1-7) was selected for a 35-day in vitro release study.

[0344] according to Figure 1 As shown in Table 6, the results show that the release of gestodene skeleton core stick for 35 days can be maintained within the effective therapeutic window of 10-20 μg / d, but there is a problem of unstable release and a downward trend in daily release.

[0345] Table 6

[0346] Release time (d) 1 5 10 15 20 25 30 35 Release amount (μg / d) 26.28 17.25 19.62 14.28 11.35 16.34 13.94 9.88

[0347] 1.3 Preparation of silicone tube:

[0348] Table 7 Prescription, vulcanization process and dimensions of silicone tube

[0349]

[0350]

[0351] Note: The vinyl content of methyl vinyl silicone rubber is 0.18%; the Si-H content of hydrogen-containing silicone oil is 0.75%, and the molar ratio of Si-H groups in hydrogen-containing silicone oil to vinyl groups in methyl vinyl silicone rubber is 1.5:1; the selected platinum catalyst has a platinum concentration of 3000ppm.

[0352] The specific process is as follows:

[0353] (1) Drying pretreatment of the rubber compound: Place the reinforcing agent fumed silica in an oven at 130°C and dry it for 18 hours, and dry the methyl vinyl silicone rubber at 40°C for 18 hours.

[0354] (2) Preparation of rubber compound: The prescribed amount of fumed silica and methyl vinyl silicone rubber raw rubber were put into a kneader and kneaded at 30°C for 30 min to make the fumed silica and raw rubber evenly mixed. The rubber compound was then taken out and transferred to an open mixer for thin extrusion (roller spacing of 1 mm). The rubber compound was further mixed more thoroughly by the shearing action of the two rollers of the open mixer. The rubber compound was then unloaded from the open mixer in the form of a thin sheet, wrapped with plastic wrap, put into a ziplock bag, and placed in a desiccator for 18 h for use.

[0355] (3) Preparation of components A and B: The rubber mixture is divided into two components A and B. The prescribed amount of hydrogenated silicone oil and 2-methyl-3-butyn-2-ol are added to component A, mixed evenly in an open mill, and then thinned several times and unloaded in the form of thin slices. The prescribed amount of platinum catalyst is added to component B, mixed evenly in an open mill, and then thinned several times and unloaded in the form of thin slices. The prepared components A and B are wrapped in plastic wrap, put into self-sealing bags, and placed in a desiccator for 18 hours for use.

[0356] (4) Mixing of components A and B: Put the parked components A and B into an open mixing mill at a ratio of 1:1 and make triangle wraps for 5 times to ensure that the components A and B are fully mixed. Unload them from the open mixing mill in the form of thin sheets and cut them into strips.

[0357] (5) Extrusion of silicone tube: Install a mold of appropriate size, set the extruder screw speed, put the cut silicone strips into the extruder, and the rubber is continuously extruded into a silicone tube through the mold mouth under the push of the rotating screw.

[0358] (6) First vulcanization treatment: The silicone tube extruded from the mold mouth first passes through a front drying channel (vertical hot air vulcanization channel) for rapid high-temperature vulcanization, which is the first vulcanization treatment. It allows the silicone tube to quickly change from a sticky and soft state to an elastic state and initially shape it.

[0359] (7) Second vulcanization treatment: After the first vulcanization, the silicone tube enters the post-drying tunnel (horizontal hot air vulcanization tunnel) for further vulcanization, which is the second vulcanization treatment. This allows the silicone tube to undergo a more complete vulcanization reaction and reach the optimal cross-linking state. The finished silicone tube is then continuously transported out through the conveyor belt of the post-drying tunnel.

[0360] 1.4 Preparation of reservoir-framework type gestodene implant:

[0361] Examples 1-10

[0362] (1) Treatment of silicone tube: Prepare silicone tube according to the above 1.3. Take an addition-type silicone tube with an outer diameter of 2.4 cm that meets the requirements of appearance and various performances. Cut it into the required length. The cutting length is 0.4 cm longer than the silicone rod core, and 0.2 cm is reserved for the sealing glue at both ends of the implant. The cut silicone tube is placed in a beaker and soaked in 75% ethanol for 15 minutes, then rinsed repeatedly with 75% ethanol several times and naturally air-dried.

[0363] (2) Assembly of silicone rod core and silicone tube:

[0364] Silicone rod core: except that the weight ratio of gestodene to the mixed rubber in step (4) is adjusted to 1:1 in the preparation process, the rest of the formulation and process are the same as those of Example 1-7; the diameter of the rod core is 0.2 cm and the length is 1.5 cm.

[0365] Soak the cut silicone tube in petroleum ether to swell it for 2 minutes. After the silicone tube is swelled, take it out from the petroleum ether and quickly shake off the petroleum ether remaining on the surface of the silicone tube. The swollen silicone tube will quickly shrink and return to its original shape after being taken out of the petroleum ether. At this time, immediately and quickly insert the cut silicone rod core into the middle position of the silicone tube with tweezers, so that the same length of space is reserved at both ends of the silicone tube to prepare for sealing. After assembly, let the implant dry naturally for 20 hours to evaporate the residual petroleum ether.

[0366] (3) End sealing of implant: The two ends of the naturally air-dried implant are sealed with sealing glue and left at room temperature for 20 hours to allow the sealing glue to solidify, thereby obtaining a reservoir-framework type gestodene implant.

[0367] 1.5 Investigation of factors affecting the in vitro release of reservoir-framework type gestodene implants:

[0368] The in vitro test method for the reservoir-skeleton type gestodene implant is the same as that of "1.2 In vitro release of gestodene skeleton type stick core".

[0369] (1) Investigation of the vulcanization time of the silicone rod core

[0370] Example 1-11 and Example 1-12

[0371] Except that the vulcanization time of the silicone rod core is adjusted to the following values ​​(see Table 8), the other operations and conditions are the same as those of Examples 1-10.

[0372] Table 8

[0373] Vulcanization time Examples 1-10 1h Examples 1-11 2h Examples 1-12 3h

[0374] The reservoir-framework type gestodene implants prepared in Examples 1-10, 1-11 and 1-12 were used to conduct a 30-day in vitro release test to examine the effect of the vulcanization time of the silicone rod core on the release of the reservoir-framework type gestodene implant.

[0375] Figure 2 The results in Table 9 show that the average daily release of the three groups of implants within 30 days is not much different. The stability of the drug release curve when the curing time is 1h and 2h is slightly better than that of 3h. Taking into account the thermal stability of the drug, when the curing time is 1h, the silicone rod core can reach the optimal curing state and the drug release stability is also good.

[0376] Table 9 Drug release at different curing times μg / d

[0377] Release time (d) 1 5 10 15 20 25 30 Sulfurization 1h 33.72 32.05 28.87 27.19 25.82 25.44 24.06 Sulfurization 2h 31.49 29.90 29.43 27.95 25.67 24.70 23.53 Vulcanization 3h 33.94 30.56 25.48 24.23 24.31 24.42 23.70

[0378] (2) Investigation of the drug release area of ​​the silicone rod core

[0379] During the drug release process of the implant, the medium enters the surface of the silicone rod core through the silicone tube, dissolves the drug in the silicone rod core and then releases it to the outside of the silicone tube. Therefore, the contact area between the medium and the silicone rod core is the drug release area of ​​the silicone rod core, which will directly affect the drug release of the implant. The drug release area of ​​the silicone rod core is calculated using the lateral surface area calculation formula of the cylinder as follows:

[0380] S=πd×L, S: drug release area of ​​silicone rod core, d: diameter of silicone rod core, L: length of silicone rod core

[0381] It can be seen from the formula that when the diameter of the silicone rod core is fixed, the drug release area of ​​the silicone rod core can be changed by changing the length of the silicone rod core. Therefore, in this experiment, as shown in Table 10, the outer diameter of the silicone tube was fixed at 2.4mm, the wall thickness was 0.2mm, the diameter of the silicone rod core was fixed at 0.2cm, and the lengths of the silicone rod core were cut to 0.5, 1.5, 2.5, and 3.5cm, respectively. They were assembled with the silicone tube into implants for 30 days of in vitro release to examine the change pattern of in vitro drug release with the drug release area of ​​the silicone rod core.

[0382] Table 10 Effect of drug release area on in vitro release of reservoir-framework type gestodene implant

[0383]

[0384]

[0385] Note: Except for using the above-mentioned drug release area, the preparation of the reservoir-framework type gestodene implant is the same as that of Example 1-10.

[0386] according to Figure 3 The results in Table 11 show that as the drug release area of ​​the silicone rod core increases, the daily drug release of the reservoir-skeleton type gestodene implant increases accordingly. The drug release amount is linearly related to the drug release area of ​​the silicone rod core.

[0387] Table 11 Drug release amount μg / d at different release areas

[0388] Release time (d) 1 5 10 15 20 25 30 <![CDATA[0.3141cm 2 ]]> 13.34 11.41 20.86 19.39 9.73 6.19 7.37 <![CDATA[0.9424cm 2 ]]> 33.72 32.05 28.87 27.19 25.82 25.44 24.06 <![CDATA[1.5707cm 2 ]]> 65.89 45.71 42.69 36.73 37.06 26.01 34.27 <![CDATA[2.1991cm 2 ]]> 86.28 80.55 73.67 64.00 55.58 55.03 55.37

[0389] 6. In vitro release of gestodene from a reservoir-framework implant

[0390] Except for the dimensions in Table 12, the formula and preparation process of the stick core are the same as those of Examples 1-10, and the preparation of the reservoir-framework type gestodene implant is the same as in Section 1.4 above.

[0391] Table 12

[0392]

[0393] A 150-day long-term in vitro release experiment was conducted on the reservoir-framework type gestodene implant. Figure 4 As shown in Table 13. The results show that the average daily release of the final implant for 150 days is about 19.5 μg, the drug release stability is good, and there is no obvious burst release behavior. This shows that the drug release behavior of the implant within 150 days meets the requirements, and the implant can achieve controlled release for at least 5 months.

[0394] Table 13

[0395] Release time (d) Release amount (μg) Release time (d) Release amount (μg) 1 33.72 80 16.78 5 32.05 85 18.57 10 28.87 90 18.43 15 27.19 95 17.83 20 25.82 100 17.85 25 25.44 105 15.66 30 24.06 110 15.45 35 22.83 115 15.88 40 21.58 120 12.23 45 21.32 125 15.56 50 19.48 130 17.04 55 19.30 135 18.31 60 17.26 140 11.81 65 17.41 145 15.71 70 17.87 150 13.90 75 17.82

[0396] 2. Levothyroxine Sodium Skeleton Core

[0397] 2.1 Preparation of Levothyroxine Sodium Skeleton Rod Core

[0398] Example 2-1

[0399] The prescription consists of 100 PHR of levothyroxine sodium, 100 PHR of methyl vinyl silicone rubber, 0.3 PHR of hydrogen-containing silicone oil, 0.27 PHR of platinum catalyst, and 0.49 PHR of 2-methyl-3-butyn-2-ol.

[0400] Among them, the selected particle size of levothyroxine sodium is 80μm; the selected methyl vinyl silicone rubber, vinyl is the end-capping group of the silicone rubber, and the content range of vinyl is 0.17%; the selected hydrogen-containing silicone oil, the content of Si-H group is 0.75mol%, and the molar ratio of Si-H group in the hydrogen-containing silicone oil to vinyl in the methyl vinyl silicone rubber is 2:1; the selected platinum catalyst, the concentration of platinum is 10000ppm; the selected 2-methyl-3-butyn-2-ol is the inhibitor.

[0401] The preparation of the levothyroxine sodium skeleton-type stick core was the same as that of Example 1-1 except that the above-mentioned prescription was adopted and the vulcanization temperature was adjusted to 50°C and the vulcanization time was adjusted to 0.5h. The diameter of the levothyroxine sodium skeleton-type stick core was 3 mm, the length was 4 cm, and the drug release area was 3.9003 cm 2 .

[0402] Example 2-2 to Example 2-4

[0403] Except for using the following catalyst dosage (see Table 14), the other operations and conditions are the same as Example 2-1.

[0404] Table 14 Prescription and vulcanization of silicone rod core under different catalyst dosages

[0405]

[0406] The amount of platinum catalyst added has a great influence on the formability of the rod core. Too little catalyst will result in the core not being able to completely cross-link, easily deforming or breaking, and having poor mechanical properties. Too much catalyst will cause oversulfurization, the texture will be hard, affecting the rubber processing, and may also cause breakage.

[0407] The effect of catalyst dosage on the degree of cross-linking of the implant is shown in Table 14. The vulcanization molding of the implant when the catalyst dosage is in the range of 0.20PHR to 0.30PHR was investigated. The experiment found that when the amount of catalyst is less than 0.20PHR, the implant is still in an "under-vulcanization" state no matter how long it has been, and it cannot be completely vulcanized and molded at 0.20PHR. In the range of 0.25PHR, the implant can be molded after vulcanization for 5h, and in the range of 0.27PHR, the implant has good moldability after vulcanization for half an hour, and at 0.3PHR, the implant has become hard and cannot be extruded before molding, and is in an "over-vulcanization" state.

[0408] 2.2 Content determination and in vitro release determination method of levothyroxine sodium skeleton stick core:

[0409] (1) Chromatographic conditions

[0410] Chromatographic column: SinoDetectHCL-C18 column (4.6×250mm, 5μm)

[0411] Mobile phase: acetonitrile-0.1% TFA (50:50, v / v)

[0412] Column temperature: 30°C

[0413] Detection wavelength: 225nm

[0414] Flow rate: 1 mL min -1

[0415] Injection volume: 20 μL

[0416] (2) In vitro release test method

[0417] Using the horizontal oscillation method, take 1 tube / set of subcutaneous implants and fix them in a 20 mL sample bottle using a silicone adhesive; accurately measure an appropriate amount of 0.1% BSA release medium into the sample bottle, keep the preparation below the liquid level of the release medium, and place it at an amplitude of 100 r·min. -1 The release was carried out in a thermostatic oscillator at 37°C. Samples were taken every 24 hours, the release medium was replaced, the solution was filtered through a 0.22μm filter membrane, and then sampled according to the chromatographic conditions, and the detection was recorded.

[0418] 2.3 Investigation of factors affecting the in vitro release of levothyroxine sodium skeleton implant:

[0419] Example 2-5 to Example 2-7 (molar ratio of cross-linking agent dosage)

[0420] Except for adopting the following molar ratio of cross-linking agent, the other operations and conditions are the same as those in Example 2-1.

[0421] The molar ratio of the cross-linking agent dosage affects the degree of vulcanization cross-linking of the implant, while the degree of cross-linking network affects the later release diffusion rate. The specific prescription is shown in Table 15.

[0422] Table 15 Silicone rod core prescription under different cross-linking agent ratios

[0423]

[0424] The results of different cross-linking ratios were Figure 5As shown in Table 16, when the molar ratio of the cross-linking agent is 2:1, the amount added is too small, the formed channels are small, the internal branches of the implant are arranged in disorder, the release of the drugs mixed therein is blocked, and the release amount is small. When the molar ratio of the cross-linking agent is 4:1, the amount of cross-linking agent added is too much, the internal cross-linking structure is unstable, and side reactions are prone to occur, resulting in changes in the internal structure and hindering the release of drugs. When the ratio is 3:1 and 3.5:1, the internal mesh channels are more suitable for drug diffusion, the release amount is closer to the release requirement, and the release is smoother.

[0425] Table 16 Effect of different cross-linking agent molar ratios on drug release μg / d

[0426] Release time (d) 1d 5d 10d 15d 20d 25d 30d Crosslinker molar ratio 2:1 34.85 39.61 39.65 22.36 16.48 21.22 12.43 Crosslinker molar ratio 3:1 63.53 69.15 54.99 59.56 54.99 57.43 48.79 Crosslinker molar ratio 3.5:1 58.34 49.93 45.21 42.71 42.51 48.07 37.54 Crosslinker molar ratio 4:1 44.42 46.66 44.61 31.58 26.24 31.32 20.44

[0427] Note: The test object in Table 16 is one levothyroxine sodium skeleton implant.

[0428] Example 2-8 to Example 2-10 (drug release area)

[0429] Except for preparing the rod core into the following dimensions, the other operations and conditions (composition and amount of the rod core) are the same as those of Example 2-5.

[0430] The skeleton implant is a cylinder, and the drug is released through the sides and two bottoms of the cylinder. The drug release area is related to the diameter and length of the implant. Considering patient compliance, implants with diameters of 2 mm and 3 mm and different lengths were investigated.

[0431] S 释药面积 =2S 底 +S 侧 =2πr 2 +πdL

[0432] r: implant bottom radius d: implant bottom diameter L: implant length

[0433] The drug release areas of skeleton-type implants with different diameters and lengths are shown in Table 17, and the effect of different drug release areas on the in vitro release of skeleton-type implants was investigated.

[0434] Table 17 Release area of ​​silicone rod cores of different sizes

[0435]

[0436] The results of drug release area are as follows Figure 6 As shown in Table 18, when the diameter is 3 mm and the length is increased to 4 cm, it is found that the daily release of the preparation is significantly increased and the release is more stable.

[0437] Table 18 Drug release amount μg / d at different release areas

[0438] Release time (d) 1 5 10 15 20 25 30 <![CDATA[2.02503cm 2 ]]> 33.25 30.04 33.94 28.45 26.55 25.98 26.46 <![CDATA[2.9673cm 2 ]]> 43.36 39.51 41.79 41.58 42.24 40.35 36.70 <![CDATA[3.9003cm 2 ]]> 59.22 61.43 61.72 59.43 56.96 58.23 54.66

[0439] Note: The test object in Table 18 is one levothyroxine sodium skeleton implant.

[0440] 2.4 In vitro release of levothyroxine sodium skeleton implant:

[0441] An in vitro release test was conducted on the levothyroxine sodium skeleton implant prepared in Example 2-10.

[0442] A set of two levothyroxine sodium skeleton implants was used for long-term release for one month. The in vitro release profile was as follows Figure 7 As shown in Table 19, the drug release shows a slow downward trend. This is because the outer layer of drug is gradually dissolved and released, making the blank annular carrier area larger and larger, the distance for the solvent molecules to enter the implant and the distance for the drug to diffuse outward after dissolution become longer, the diffusion rate slows down, and the daily release amount gradually decreases. The release amount is maintained at 100-120μg / d within one month. The results show that the prepared skeleton implant can effectively release the drug for one month.

[0443] Table 19

[0444] Release time (d) 1 5 10 15 20 25 30 Release amount (μg / d) 119.46 119.48 119.79 120.23 113.92 115.91 105.96

[0445] 3. Levonorgestrel skeleton silicone rod core

[0446] 3.1 Preparation of levonorgestrel skeleton silicone rod core

[0447] Example 3-1

[0448] Basic prescription

[0449] Levonorgestrel 10PHR; Methylvinyl silicone rubber 100PHR; Hydrogenated silicone oil 0.667PHR; 2-methyl-3-butyn-2-ol (inhibitor) 0.49PHR; Platinum catalyst 0.25PHR;

[0450] Among them, the selected methyl vinyl silicone rubber has vinyl as the end-capping group of the silicone rubber and the content of vinyl is 0.18%; the selected hydrogen-containing silicone oil has a Si-H group content of 0.75 mol%, and the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber is 1.5:1; the selected platinum catalyst has a platinum concentration of 10000 ppm; the process is: vulcanization temperature 110°C, vulcanization time 1h.

[0451] Note: PHR (parts per hundreds of rubber) means the number of parts of the component per 100 parts of base polymer.

[0452] Preparation method

[0453] The preparation method of the levonorgestrel skeleton silicone stick core is the same as that of Example 1-1 except that the above-mentioned prescription is used; the diameter of the levonorgestrel skeleton silicone stick core is 2 mm, the length is 4 cm, and the drug release area is 2.5748 cm 2 .

[0454] 3.2 In vitro release determination method of levonorgestrel matrix implant

[0455] (1) Chromatographic conditions

[0456] Chromatographic column: C18 column (250mm×4.60mm)

[0457] Mobile phase: acetonitrile-water (70:30, v / v)

[0458] Column temperature: 30°C

[0459] Detection wavelength: 240nm

[0460] Flow rate: 1 mL min -1

[0461] Injection volume: 20 μL

[0462] (2) In vitro release test method

[0463] The release rate was determined by the horizontal oscillation method: a set of implants was taken and fixed in a 100 mL stoppered conical bottle with an adhesive. 100 mL of distilled water was accurately measured as the release medium. The stoppered conical bottle was placed in a constant temperature oscillator and the amplitude was set to 100 r·min- 1 , the temperature is 37℃, ensuring that the implant is always below the liquid surface, sampling is carried out every 24 hours and the same volume of release medium is replaced, and the sample solution is filtered through a 0.22μm microporous filter membrane and tested according to the "chromatographic conditions".

[0464] 3.3 Investigation of the process of levonorgestrel skeleton silicone rod core:

[0465] The most important process factors affecting the vulcanization molding of silicone rod core are vulcanization temperature and vulcanization time. Vulcanization temperature is related to whether the silicone rod core can be vulcanized and molded. Too high temperature may cause drug decomposition and affect drug release; too low temperature may not make the silicone rod core completely vulcanized. The vulcanization time also faces the same problem. Too long or too short time may affect the release behavior of the drug.

[0466] Example 3-2 and Example 3-3 (Effect of Vulcanization Temperature)

[0467] Except for the following vulcanization temperature (see Table 20), the remaining operations and conditions are the same as those in Example 3-1.

[0468] Table 20

[0469] Example 3-2 Example 3-1 Example 3-3 Vulcanization temperature 90℃ 110℃ 130℃

[0470] Effects of different silicone rod core curing temperatures on in vitro release Figure 8 As shown in Table 21, when the core vulcanization temperature is 90℃ and 110℃, the daily release is similar, and the daily release is significantly reduced at 130℃. At 110℃, the daily release and mechanical properties are the best.

[0471] Table 21 Release of drugs at different curing temperatures μg / d

[0472] Release time (d) 1 5 10 15 20 25 30 35 90℃ 21.47 21.64 21.27 21.81 21.84 20.09 22.26 19.70 110℃ 24.14 21.38 20.39 19.83 21.27 17.01 18.67 21.65 130℃ 29.82 18.27 15.52 15.41 15.23 14.88 13.70 12.57

[0473] Note: The test object in Table 21 is one levonorgestrel matrix implant.

[0474] Example 3-4 and Example 3-5 (Effect of Curing Time)

[0475] Except for the following vulcanization time (see Table 22), the remaining operations and conditions are the same as those in Example 3-1.

[0476] Table 22

[0477] Example 3-1 Embodiment 3-4 Embodiment 3-5 Vulcanization time 1h 0.5h 2h

[0478] Effects of different silicone rod core curing times on in vitro release Fig. 9 As shown in Table 23, the daily release of the silicone rod core with a curing time of 0.5h prepared into a skeleton-type implant is relatively high, while the difference in daily release of the silicone rod core with a curing time of 1h and 2h prepared into an implant is not obvious. When the curing time is 1h, the daily release and mechanical properties are better, and the time cost of the preparation process is lower.

[0479] Table 23 Release of drugs at different curing times μg / d

[0480] Release time (d) 1 5 10 15 20 25 30 35 0.5h 29.16 27.97 32.26 27.14 32.62 27.71 31.08 26.59 1h 24.14 21.38 20.39 19.83 21.27 17.01 18.67 21.65 2h 18.67 23.21 26.05 24.79 27.46 24.50 26.31 22.40

[0481] Note: The test object in Table 23 is one levonorgestrel matrix implant.

[0482] 3.4 In vitro release of skeleton-type silicone rod core:

[0483] The levonorgestrel silicone stick core prepared in Example 3-1 was released for 35 days. From the release curve ( Fig.10 As shown in Tables 21-22, the release can be maintained within the effective therapeutic window, but the release is not stable and the daily release amount shows a downward trend.

[0484] 3.5. Preparation of reservoir-framework levonorgestrel implant

[0485] Embodiment 3-6

[0486] Preparation of reservoir-framework levonorgestrel implant:

[0487] The reservoir-framework type levonorgestrel implant was prepared according to the aforementioned "1.4 Preparation of reservoir-framework type gestodene implant": the prescription, vulcanization process and size information of the silicone tube and rod core are shown in Table 24 and Table 25 respectively. Apart from this, the other steps are the same as the preparation method of the reservoir-framework type gestodene implant.

[0488] Table 24 Final formula, vulcanization process and dimensions of silicone tube

[0489]

[0490] Note: The vinyl content of methyl vinyl silicone rubber is 0.18%; the content of Si-H group in hydrogenated silicone oil is 0.75%, and the molar ratio of Si-H group to vinyl group in methyl vinyl silicone rubber is 1.2:1; platinum catalyst, the concentration of platinum is 3000ppm.

[0491] Table 25 Final formulation, vulcanization process and dimensions of drug-loaded silicone rod core

[0492]

[0493]

[0494] Note: The vinyl content of methyl vinyl silicone rubber is 0.18%; the content of Si-H group in hydrogenated silicone oil is 0.75%, and the molar ratio of Si-H group to vinyl group in methyl vinyl silicone rubber is 1.5:1; platinum catalyst, the concentration of platinum is 10000ppm.

[0495] 3.6. Investigation of factors affecting the in vitro release of levonorgestrel reservoir-matrix levonorgestrel implants:

[0496] The in vitro release determination method of reservoir-skeleton type levonorgestrel implant is the same as “3.2 In vitro release determination method of levonorgestrel skeleton implant”.

[0497] Investigation of drug release area

[0498] Except for using the dimensions in Table 26, the remaining operations and conditions are the same as those of Examples 3-6.

[0499] The implant is cylindrical in appearance, with both ends sealed by end-capping glue. The drug is completely released through the side of the entire preparation. The drug release area directly determines the degree of contact between the drug and the body fluid and the drug release path of the drug diffusion outward, and plays a pivotal role in drug release. The drug release area of ​​the implant S = π·d·L, where d is the diameter of the silicone rod core and L is the length of the silicone rod core. According to Table 27, reservoir-skeleton type levonorgestrel implants of different specifications were prepared to investigate the effect of the drug release area on the in vitro release experiment.

[0500] Table 26 Effect of drug release area on daily release

[0501]

[0502] Effects of different drug release areas on in vitro release Fig.11 As shown in Table 27, with the increase of drug release area, the daily release amount gradually increased. The in vitro daily release amount was positively correlated with the drug release area of ​​the implant. The drug release area had an important influence on the daily release amount of the reservoir-skeleton type levonorgestrel implant.

[0503] Table 27 Drug release amount μg / d at different release areas

[0504] Release time (d) 1 5 10 15 20 25 30 35 <![CDATA[62.8mm 2 ]]> 5.21 8.37 9.23 10.32 10.38 6.70 7.46 6.75 <![CDATA[125.6mm 2 ]]> 13.85 14.13 14.50 14.88 15.55 10.91 13.70 14.23 <![CDATA[188.4mm 2 ]]> 15.77 19.36 22.61 25.18 18.99 18.65 17.82 19.11 <![CDATA[251.2mm 2 ]]> 22.66 22.83 23.91 20.33 27.31 18.79 24.50 27.89 <![CDATA[314.0mm 2 ]]> 34.15 37.46 39.09 34.40 36.97 36.30 33.49 36.49

[0505] Note: The test object in Table 27 is one reservoir-matrix type levonorgestrel implant.

[0506] The increase in the drug release area of ​​the implant increases the contact area with the release medium. The diffusion area of ​​the drug after dissolving in the medium also increases accordingly, and the pathway for drug release increases, so the daily release amount has a clear upward trend.

[0507] Compared with the levonorgestrel skeleton implant, the release amount of the reservoir-skeleton type levonorgestrel implant with a controlled release membrane is more stable. Under the action of the controlled release membrane, the diffusion path of the drug in the implant wrapped with the controlled release membrane increases, the diffusion rate of the drug in the membrane is lower than the diffusion rate in the skeleton, and the drug release amount is relatively low; in addition, the controlled release membrane also slows down the formation of the blank area of ​​the silicone rod core, maintains a certain drug concentration inside the membrane, and enables the implant to maintain a stable release.

[0508] Table 28

[0509] Release time (d) Release amount (μg) Release time (d) Release amount (μg) 1 48.28 5 42.76 95 45.04 10 40.78 100 44.57 15 39.65 105 39.23 20 42.53 110 38.77 25 34.07 115 36.28 30 40.28 120 36.40 35 43.29 125 35.83 40 38.94 130 37.48 45 39.88 135 34.94 50 39.95 140 42.52 55 35.79 145 44.36 60 35.65 150 41.21 65 42.83 155 40.82 70 39.90 160 36.56 75 39.65 165 37.67 80 44.44 170 41.20 85 42.63 175 46.09 90 39.99 180 43.11

[0510] Note: The test subjects in Table 28 are 2 reservoir-matrix type levonorgestrel implants.

[0511] For the silicone rod core, the drug release area is 251.2 mm 2 The in vitro release test of the reservoir-matrix levonorgestrel implant was conducted. Fig.12 The results of Table 28 show that the average daily release of the final implant for 180 days is about 40 μg, the drug release stability is good, and there is no obvious burst release behavior. This shows that the drug release behavior of the implant within 180 days meets the requirements, and the implant can achieve controlled release for at least 6 months.

Claims

1. A pharmaceutical composition, characterized in that In parts by weight, it includes the following raw material components: Active pharmaceutical ingredient: 1-1000 parts; R-vinyl silicone rubber: 100 parts; Hydrogenated silicone oil; Catalyst: 0.000002-1 part; in: The R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 straight-chain alkane or branched alkane, a substituted or unsubstituted C6-C 20 Aromatics; The content of vinyl in the R-vinyl silicone rubber is 0.10%-0.50mol%; The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%; The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):

1.

2. The pharmaceutical composition according to claim 1, characterized in that The active pharmaceutical ingredient is an active drug with a solubility of ≤100 mg / mL (with water as solvent), preferably including active pharmaceutical ingredients acting on the reproductive system, or active pharmaceutical ingredients acting on the urinary system, or active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition, or active pharmaceutical ingredients used to treat chronic diseases related to connective tissue and rheumatism, or active pharmaceutical ingredients used to treat hyperlipidemia, tumors, neuropsychiatric diseases, chronic dental diseases, simple obesity, chronic low back pain or leukemia, or active pharmaceutical ingredients acting on the circulatory system, or active pharmaceutical ingredients acting on the respiratory system, or active pharmaceutical ingredients acting on the digestive system, or active pharmaceutical ingredients acting on the blood system, or active pharmaceutical ingredients acting on the endocrine system; in, The active pharmaceutical ingredient acting on the reproductive system is preferably an active pharmaceutical ingredient for contraception; the active pharmaceutical ingredient for contraception is preferably levonorgestrel, gestodene, gestrinone or steroidal estrogen; The active pharmaceutical ingredient acting on the urinary system is preferably an active pharmaceutical ingredient for treating chronic nephritis, chronic renal failure, or chronic prostatitis; The active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition are preferably active pharmaceutical ingredients for treating diabetes, nutritional deficiency, gout, or osteoporosis; The active pharmaceutical ingredient for treating chronic diseases involving connective tissue and rheumatism is preferably an active pharmaceutical ingredient for treating rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjögren's syndrome, vasculitis, idiopathic inflammatory myopathy, systemic sclerosis, or osteoarthritis; The active ingredient of the drug for treating hyperlipidemia is preferably a statin (e.g., simvastatin, atorvastatin, pravastatin), a fibrate (e.g., fenofibrate, bezafibrate, gemfibrozil), or a nicotinic acid (e.g., niacin); The active ingredient of the drug for treating tumors is preferably an anti-breast cancer drug (such as azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol acetate, cetuximab or leuprolide), an anti-prostate cancer drug (such as degarelix, leuprolide, histrelin, flunitrium, estramustine, cyproterone acetate), an anti-ovarian cancer drug (such as carboplatin, topotecan, methotrexate), an anti-rectal cancer drug (such as panitumumab), an anti-colon cancer drug (such as bevacizumab, oxaliplatin), an anti-liver cancer drug (such as sorafenib), an anti-lung cancer drug (such as erlotinib, gefitinib, docetabine) , anti-renal cancer drugs (e.g., pazopanib, everolimus, temsirolimus), anti-gastric cancer drugs (e.g., 5-fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), anti-pancreatic cancer drugs (e.g., nimotuzumab), anti-esophageal cancer drugs (e.g., docetaxel, paclitaxel, cisplatin, gemcitabine, tegafur, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), anti-skin cancer drugs (e.g., 5-fluorouracil), anti-lymphoma drugs (e.g., vincristine, bexarotene, dacarbazine, etoposide), anti-myeloma drugs (e.g., bortezomib), anti-cervical cancer drugs (e.g., bleomycin), or, anti-bladder cancer drugs (e.g., epirubicin, bacillus Calmette-Guérin); The active ingredient of the drug for treating chronic dental diseases is preferably a nitroimidazole drug (such as metronidazole, tinidazole, ornidazole), a penicillin drug, minocycline, or chlorhexidine acetate; The active ingredient of the drug for treating chronic low back pain is preferably a non-steroidal analgesic drug, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen, or voltaren, more preferably ibuprofen or meloxicam; The active pharmaceutical ingredient acting on the circulatory system is preferably an active pharmaceutical ingredient for treating chronic heart failure, coronary heart disease, congenital heart disease, chronic infective endocarditis, or chronic pericarditis; The active pharmaceutical ingredient acting on the respiratory system is preferably an active pharmaceutical ingredient for treating chronic obstructive pulmonary emphysema, asthma, chronic cor pulmonale, chronic respiratory failure, or silicosis or pulmonary fibrosis; The active pharmaceutical ingredient acting on the digestive system is preferably an active pharmaceutical ingredient for treating chronic gastritis, peptic ulcer, intestinal tuberculosis, chronic enteritis, chronic diarrhea, chronic hepatitis, cirrhosis, chronic pancreatitis, or chronic cholecystitis; The active pharmaceutical ingredient acting on the blood system is preferably an active pharmaceutical ingredient for treating chronic anemia, chronic myeloid leukemia, or chronic lymphocytic leukemia; The active pharmaceutical ingredient acting on the endocrine system is preferably an active pharmaceutical ingredient for treating chronic lymphocytic thyroiditis, hyperthyroidism, or hypothyroidism; the active pharmaceutical ingredient for treating hypothyroidism is preferably a thyroxine, more preferably levothyroxine, levothyroxine sodium or thyroxine.

3. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition meets one or more of the following conditions: (1) The dosage of the active pharmaceutical ingredient is 5-500 parts, preferably 5-100 parts, such as 10 parts, 20 parts, 50 parts or 100 parts; (2) The R-vinyl silicone rubber is methyl vinyl silicone rubber; (3) The vinyl content of the R-vinyl silicone rubber is 0.17-0.23 mol%, such as 0.17 mol%, 0.18 mol%, 0.19 mol%, 0.20 mol%, 0.21 mol%, 0.22 mol% or 0.23 mol%; (4) The amount of the hydrogen-containing silicone oil is 0.3-20 parts, preferably 0.3-10 parts, for example 0.3 parts, 0.667 parts or 1 part; (5) The content of Si-H groups in the hydrogen-containing silicone oil is 0.5-1.0 mol%, for example 0.75 mol%; (6) The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (1-10):1, for example, 1.5:1, 2:1, 3:1, 3.5:1, 4:1, 4.5:1 or 6:1; (7) The catalyst is a catalyst that can catalyze the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil, such as a platinum catalyst, a platinum catalyst, a rhodium catalyst, a palladium catalyst or a nickel catalyst, preferably a platinum catalyst and / or a platinum catalyst; (8) The amount of the catalyst is 0.000002-0.5 parts, preferably 0.05-0.4 parts, such as 0.1 parts, 0.20 parts, 0.21 parts, 0.25 parts, 0.27 parts or 0.30 parts; and, (9) Preferably, the pharmaceutical composition further comprises an inhibitor, wherein the inhibitor is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil; the amount of the inhibitor is preferably 0.03-2.0 parts, for example 0.49 parts or 0.98 parts.

4. The pharmaceutical composition according to claim 2, characterized in that When the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the pharmaceutical composition satisfies one or more of the following conditions: (1) The particle size of the active pharmaceutical ingredient is 0.001-200 μm, preferably 2-80 μm, for example 2-3 μm; (2) The dosage of the active pharmaceutical ingredient is 5-500 parts, for example, 10 parts, 20 parts, 50 parts, 80 parts or 100 parts; (3) The amount of the hydrogen-containing silicone oil is 0.3-20 parts, preferably 0.3-5 parts, for example 0.3 parts, 0.5 parts, 0.667 parts or 1 part; (4) The amount of the catalyst is 0.10-0.30 parts, such as 0.10 parts, 0.20 parts, 0.21 parts, 0.25 parts or 0.30 parts, preferably 0.20-0.25 parts; (5) The vinyl content in the R-vinyl silicone rubber is 0.10%-0.50mol%, preferably 0.10%-0.30mol%, for example 0.18mol%; (6) The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.6 mol%, preferably 0.15-1.2 mol%, for example 0.75 mol%; (7) The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (1.5-10):1, for example, 1.5:1, 3.0:1 or 4.5:1, more preferably (3.0-4.5):

1.

5. The pharmaceutical composition according to claim 2, characterized in that When the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the pharmaceutical composition satisfies one or more of the following conditions: (1) The particle size of the pharmaceutical active ingredient is 0.001-180 μm, for example, 0.01 μm, 0.1 μm, 0.5 μm, 1 μm, 5 μm, 20 μm, 60 μm, 80 μm or 100 μm; (2) The dosage of the active pharmaceutical ingredient is 10-500 parts, for example, 100 parts, 150 parts or 200 parts; (3) The amount of the hydrogen-containing silicone oil is 0.3-20 parts, preferably 0.3-5 parts, for example 0.3 parts, 0.5 parts or 1 part; (4) The amount of the catalyst is 0.20-0.30 parts, such as 0.20 parts, 0.25 parts, 0.27 parts or 0.30 parts, preferably 0.25-0.27 parts; (5) The vinyl content in the R-vinyl silicone rubber is 0.10%-0.30 mol%, for example 0.17 mol%; (6) The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.2 mol%, for example 0.75 mol%; (7) The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (1-6):1, preferably (2-6):1, such as 2:1, 3:1, 3.5:1 or 4:1, and more preferably (3.0-3.5):

1.

6. A rod core, characterized in that: The raw material components thereof include the pharmaceutical composition as described in any one of claims 1 to 5.

7. A method for preparing a rod core as claimed in claim 6, characterized in that: It includes the following steps: S1: dividing the R-vinyl silicone rubber into component A1 and component A2, mixing the component A1 and the catalyst to obtain component B1, and mixing the component A2 and the hydrogen-containing silicone oil to obtain component B2; S2: mixing the component B1 and the component B2 to obtain a mixed rubber; S3: mixing the mixed rubber and the active pharmaceutical ingredient to obtain drug-loaded silica gel; S4: The drug-loaded silica gel is extruded and vulcanized to obtain a stick core.

8. An implant, characterized in that: It comprises the rod core and the silicone tube as claimed in claim 6.

9. A method for preparing the implant as claimed in claim 8, characterized in that: It includes the following steps: The stick core as claimed in claim 6 is filled into the silicone tube.

10. Use of the stick core according to claim 6 as a release rate regulating medium in a sustained-release preparation.

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