Pharmaceutical composition, drug-loaded rod core, implant, preparation method therefor, and use thereof

Abstract

Provided in the present invention are a pharmaceutical composition, a drug-loaded rod core, an implant, a preparation method therefor, and the use thereof. The pharmaceutical composition comprises 1-1000 parts of a drug active ingredient, 100 parts of R-vinyl silicone rubber, hydrogen-containing silicone oil, and 0.000002-1 part of a catalyst. R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 linear alkane or branched alkane or a substituted or unsubstituted C6-C20 aromatic hydrocarbon; and the content of vinyl in the R-vinyl silicone rubber is 0.10-0.50 mol%. The content of Si-H group in the hydrogen-containing silicone oil is 0.15-1.6 mol%, and the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl in the R-vinyl silicone rubber is (0.5-20):1. The implant provided by the present invention can reduce drug loss, reduce the phenomenon of burst release, achieve more stable drug release and involve a greatly improved production speed.

Description

Pharmaceutical composition, drug-loaded rod core, implant, and preparation method and application thereof

[0001] This application claims priority to Chinese patent application No. 202311180554X, filed on September 13, 2023. This application incorporates the entire text of the aforementioned Chinese patent application.

[0002] This application claims priority to Chinese Patent Application No. 2023111805535, filed on September 13, 2023. This application incorporates the entirety of the aforementioned Chinese Patent Application.

[0003] This application claims priority to Chinese patent application No. 2023111805554, filed on September 13, 2023. This application incorporates the entirety of the aforementioned Chinese patent application. Technical Field

[0004] The present invention relates to a pharmaceutical composition, a drug-loaded rod core, an implant, and a preparation method and application thereof. Background Art

[0005] An implantable drug delivery system (IDDS) is a drug delivery system that can stably release drugs to specific sites of action. Its primary advantage is that it delivers drugs at a sustained, stable rate, requiring less drug to treat the disease, thus significantly reducing drug toxicity and side effects for better therapeutic outcomes. An implantable drug delivery system 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, minimizing side effects from frequent dosing and avoiding issues like first-pass and peak-valley effects associated with oral administration.

[0006] IDDS can be categorized primarily as solid drug-loaded implants, injectable implants, and implantable pumps, depending on the drug's form within the formulation and how it is administered. Solid drug-loaded implants, in which the drug is dispersed in a carrier material and surgically implanted in the form of columns, rods, pellets, or tablets, can be implanted subcutaneously or at a specific target site. They are currently the most widely used IDDS.

[0007] Solid drug-loaded implants offer the advantages of simple and convenient use, safe and stable carrier materials, and low cost. Furthermore, compared to solid drug-loaded implants that are implanted at specific target sites, subcutaneous implants are more technologically mature. Subcutaneous implants such as Norplant and Implanon have been used in contraceptive applications for decades, with proven safety and effectiveness.

[0008] Implantable drug delivery systems have a wide range of applications. Beyond the well-known contraceptive field, clinical trials are also gradually underway in other long-term medication areas. For example, in cancer treatment, the development of local implant technology has enabled many traditional anti-cancer drugs to find new uses. In HIV prevention and treatment, long-term implants can replace daily oral administration, preventing missed doses that could affect drug effectiveness. Furthermore, implantable drug delivery systems are also being used in the treatment of long-term medications such as diabetes, mental illnesses, addiction withdrawal, and cardiovascular disease, with promising future applications.

[0009] Traditional solid drug-loaded implants are primarily prepared by filling silicone tubes with drug powder. This slow filling process results in a large amount of drug adsorbed to the tube walls, resulting in drug waste and slow dispensing. Furthermore, these implants present a number of drawbacks in practical use, including severe burst release, poor drug release stability, and low production efficiency. Therefore, the development of a novel solid drug-loaded implant is urgently needed.

[0010] Summary of the Invention

[0011] The present invention addresses the technical problem of overcoming the drawbacks of existing solid drug-loaded implants, such as severe drug waste, severe burst release, poor drug release stability, and slow production speeds. The invention provides a pharmaceutical composition, a core rod, and an implant, as well as preparation methods and applications thereof. The implant provided by the present invention can reduce drug loss and burst release, provide more stable drug release, and significantly increase production speeds.

[0012] The present invention solves the above technical problems through the following technical solutions:

[0013] The present invention provides a pharmaceutical composition comprising the following raw material components in parts by weight:

[0014] Active pharmaceutical ingredient: 1-1000 parts;

[0015] R-vinyl silicone rubber: 100 parts;

[0016] Hydrogenated silicone oil;

[0017] Catalyst: 0.000002-1 part;

[0018] in:

[0019] 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 aromatic hydrocarbons;

[0020] The vinyl content in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0021] The content of Si-H groups in the hydrogenated silicone oil is 0.15-1.6 mol%;

[0022] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1.

[0023] In the present invention, the structural formula of the R-vinyl silicone rubber may be as follows:

[0024] Wherein, m, n, and p are natural numbers, R1 and R2 may be conventional substituent groups in the art, and R and R' may be conventional end-capping groups in the art.

[0025] For example, when R1=R2=CH3, it corresponds to dimethyl silicone rubber;

[0026] For example, when R1=CH3, R2=CH=CH2, it corresponds to methyl vinyl silicone rubber;

[0027] For example, when R1=Ph, R2=CH=CH2, it corresponds to methylphenyl vinyl silicone rubber;

[0028] For example, when R1=CH3CH2CF3, R2=CH=CH2, it corresponds to fluorosilicone rubber;

[0029] For example, when R1=CH3CH2CN and R2=CH=CH2, it corresponds to nitrile silicone rubber.

[0030] 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 for treating chronic diseases involving connective tissue and rheumatism, or an active pharmaceutical ingredient for treating hyperlipidemia, treating tumors, treating neuropsychiatric diseases, treating chronic dental diseases, treating simple obesity, treating chronic low back pain or treating 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.

[0031] The active pharmaceutical ingredients acting on the reproductive system may include active pharmaceutical ingredients for contraception.

[0032] The active ingredients of the contraceptive drugs may be conventional ones in the art, and preferably include levonorgestrel, gestodene, gestrinone or steroidal estrogen.

[0033] The steroidal estrogen is preferably estradiol.

[0034] Among them, the active pharmaceutical ingredients acting on the urinary system preferably include active pharmaceutical ingredients for treating chronic prostatitis, treating chronic nephritis, treating chronic renal failure, or treating chronic prostatitis.

[0035] The active ingredient of the drug for treating chronic prostatitis is preferably a non-steroidal anti-inflammatory drug, more preferably ibuprofen. Generally, the drug for treating chronic prostatitis can be: antibiotics (such as fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin, etc.), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin, etc.), tetracyclines (tetracycline), α-receptor blockers (such as doxazosin, terazosin, etc.), non-steroidal anti-inflammatory drugs (such as ibuprofen, diclofenac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib, etc.), analgesics (such as acetaminophen, etc.), opioids (such as morphine, fentanyl, nalbuphine, pentazocine, etc.), anti-neuropathic pain drugs (such as 5-hydroxytryptamine, duloxetine, venlafaxine), anti-epileptics (such as pregabalin, etc.), M receptor blockers (such as solifenacin, tolterodine, etc.).

[0036] 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-blockers (such as atenolol, bisoprolol, carvedilol or propranolol), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide or bumetanide), immunosuppressants (such as prednisone, Ainopril, methylprednisolone, cyclophosphamide or dexamethasone), or statins (such as fluvastatin, simvastatin or pravastatin).

[0037] 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 preparations (such as ferrous fumarate), compound amino acids, α-keto acids, and recombinant human erythropoietin.

[0038] The drug for treating chronic prostatitis can be: antibiotics (such as fluoroquinolones (norfloxacin, enoxacin, ofloxacin, ciprofloxacin), macrolides (erythromycin, roxithromycin, azithromycin, acetylspiramycin), tetracyclines (tetracycline), α-receptor blockers (such as doxazosin, terazosin), non-steroidal anti-inflammatory drugs (such as ibuprofen, diclofenac, loxoprofen, flurbiprofen axetil, ketorolac, celecoxib), analgesics (such as acetaminophen), opioids (such as morphine, fentanyl, nalbuphine, pentazocine), anti-neuropathic pain drugs (such as 5-hydroxytryptamine, duloxetine, venlafaxine), anti-epileptics (such as pregabalin), or M receptor blockers (such as solifenacin, tolterodine), preferably non-steroidal anti-inflammatory drugs, more preferably ibuprofen.

[0039] Among them, the active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition preferably include active pharmaceutical ingredients for treating diabetes, nutritional deficiency diseases, gout, or osteoporosis.

[0040] The active ingredient of the anti-diabetic drug can generally be an anti-type 1 diabetes drug (such as insulin) or an anti-type 2 diabetes drug. The anti-type 2 diabetes drug can be a sulfonylurea drug (such as glimepiride, gliquidone), a glinide drug (such as repaglinide, nateglinide), a metformin drug (such as metformin), an α-glucosidase inhibitor (such as acarbose, voglibose), a DPP-4 inhibitor (such as sitagliptin), a GLP-1 receptor agonist (such as liraglutide, exenatide) or an SGLT-2 inhibitor (such as dapagliflozin, empagliflozin).

[0041] 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).

[0042] 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 drug (e.g., benzbromarone, probenecid), or a uric acid synthesis blocker drug (e.g., allopurinol), preferably an anti-gout attack drug, more preferably ibuprofen.

[0043] The active ingredients of the anti-osteoporosis drugs can generally be bisphosphonates (such as alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonates, clodronate disodium, zoledronic acid sodium, risedronate sodium), calcitonin drugs (such as salmon calcitonin), estrogen drugs (such as estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) drugs (such as raloxifene, benzothiophene), RANKL inhibitor drugs, parathyroid hormone drugs, glutamine monofluorophosphate drugs, strontium salt drugs (such as strontium ranelate), active vitamin D and analogs (such as calcitriol, α-calciferol), or vitamin K (such as menatetrenone).

[0044] 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.

[0045] The active ingredient of the drug for treating rheumatoid arthritis can be a glucocorticoid drug (such as hydrocortisone, dexamethasone, prednisone), a slow-acting anti-rheumatic 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.

[0046] The active ingredient of the drug for treating osteoarthritis is preferably an analgesic, such as ibuprofen, Voltaren, meloxicam, celecoxib, loxoprofen sodium, and nimesulide, more preferably ibuprofen or meloxicam. Generally, the drug for treating osteoarthritis can be a drug for nourishing cartilage, an opioid (such as oxycodone or chimantin).

[0047] The active ingredient of the drug for treating systemic lupus erythematosus can generally be a non-steroidal anti-inflammatory drug (such as naproxen, ibuprofen), an antimalarial drug, a glucocorticoid drug (such as prednisone acetate, methylprednisolone), an immunosuppressant drug (such as methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), or a biological drug (such as rituximab, belimumab).

[0048] The active ingredients of the drugs for treating ankylosing spondylitis can generally be non-steroidal drugs (such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, and erecoxib), disease-modifying anti-rheumatic drugs (such as pyridine, methotrexate, and hydroxychloroquine), glucocorticoid drugs (such as prednisone, prednisolone, and diprospan), or biological TNF-α antagonists (such as etanercept).

[0049] 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).

[0050] The active ingredient of the drug for treating vasculitis can generally be a glucocorticoid drug (eg, prednisone, methylprednisolone, dexamethasone) or an immunosuppressant drug (eg, cyclophosphamide, cyclosporine, azathioprine).

[0051] 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).

[0052] The active ingredients of the drugs for treating systemic sclerosis can generally be anti-fibrotic drugs (such as colchicine), vasoactive drugs (such as nifedipine, nifedipine), naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, or tocilizumab.

[0053] The active ingredient of the drug for treating neuropsychiatric disorders can generally be a drug for treating schizophrenia, an antidepressant drug, a drug for treating opioid abuse, or a drug for treating anxiety disorders, preferably a drug for treating schizophrenia.

[0054] 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).

[0055] The antidepressant drugs can generally be tricyclic antidepressants (such as imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (such as moclobemide), selective serotonin reuptake inhibitors (such as sertraline), serotonin and norepinephrine reuptake inhibitors (such as venlafaxine), serotonin blockers and reuptake inhibitors (such as trazodone), norepinephrine and dopamine reuptake inhibitors (such as bupropion), norepinephrine inhibitors (such as reboxetine), or α2 adrenergic receptor blockers (such as mirtazapine).

[0056] The drug for treating opioid abuse may generally be buprenorphine or methadone.

[0057] 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.

[0058] 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).

[0059] 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 acetate, 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), drugs (e.g., pazopanib, everolimus, temsirolimus), anti-gastric 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, tegafur, 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, BCG).

[0060] The active ingredient of the drug for treating chronic dental diseases may generally be nitroimidazole drugs (such as metronidazole, tinidazole, ornidazole), penicillins, minocycline, or chlorhexidine acetate. The chronic dental disease in the treatment of chronic dental diseases generally refers to caries or periodontal disease.

[0061] Wherein, the drug for treating simple obesity can generally be orlistat.

[0062] Among them, 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.

[0063] Among them, 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-aspartame, homoharringtonine), interferon, fludarabine, arsenite, etoposide, or carmustine.

[0064] Among them, the active pharmaceutical ingredients acting on the circulatory system preferably include active pharmaceutical ingredients for treating chronic heart failure, treating coronary heart disease, treating congenital heart disease, treating chronic infective endocarditis, or treating chronic pericarditis.

[0065] The active ingredients of the drugs for treating coronary heart disease can generally be drugs that improve angina symptoms (such as puerarin, isosorbide mononitrate), anti-platelet aggregation drugs (such as aspirin, clopidogrel bisulfate, ticagrelor), lipid-lowering and plaque-stabilizing drugs (such as atorvastatin, rosuvastatin, pravastatin), sympathetic nerve activity inhibition (such as metoprolol, bisoprolol fumarate), or drugs that improve myocardial remodeling (such as angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists), preferably drugs that improve angina symptoms, and more preferably puerarin.

[0066] The active ingredients of the drugs for treating chronic heart failure can generally be cardiotonic drugs (such as digitalis, digoxin, cedilanid), vasodilator drugs (such as sodium nitroprusside, nitroglycerin, converting enzyme inhibitors (such as enalapril, lenocort, etc.), or diuretics (such as furosemide, hydrochlorothiazide, spironolactone).

[0067] The active ingredient of the drug for treating congenital heart disease can generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide or coenzyme Q10.

[0068] The active ingredient of the drug for treating chronic infective endocarditis can generally be an antibiotic (eg, vancomycin, cephalosporin, penicillin, aminoglycoside).

[0069] The active ingredient of the medicine for treating chronic pericarditis can generally be digitalis.

[0070] 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.

[0071] The active ingredients of the drugs for treating chronic obstructive pulmonary emphysema can generally be bronchodilators (including beta-receptor agonists and anticholinergic drugs), inhaled hormones (such as budesonide, fluticasone), theophylline antiasthmatics (such as theophylline), expectorants (such as carbocysteine, fudosteine), and glucocorticoids or antibiotics (such as penicillins, glycosides and cephalosporins) can also be appropriately selected when the condition requires.

[0072] The active ingredients of the asthma treatment drugs can generally be commonly used inhaled drugs (such as beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (such as salbutamol), sustained-release theophylline, leukotriene modifiers (which can be used in combination), anticholinergics (such as isoproscopolamine), or antihistamines (such as astemizole, ketotifen).

[0073] The active ingredients of the drugs for treating chronic cor pulmonale can generally be antibiotics (such as amoxicillin, ceftizoxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (such as selective β2 receptor stimulants, theophylline drugs), drugs that eliminate nonspecific airway inflammation (such as prednisone), inhaled drugs (such as beconazole), or respiratory stimulants (such as lobeline, doxapram, duxil, etc.).

[0074] The active ingredient of the drug for treating chronic respiratory failure can generally be a drug for relieving bronchospasm and removing phlegm (such as salbutamol, acetylcysteine, etc.).

[0075] The active ingredients of the medicine for treating silicosis can generally be siping, acetylcysteine, aluminum preparations, closiperine, or salvia miltiorrhiza.

[0076] 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.

[0077] 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.

[0078] The active ingredients of the drugs for treating chronic gastritis can generally be analgesics (such as atropine, propantheline), PPI proton pump inhibitors (such as lansoprazole, omeprazole) can be used for increased gastric acid, H2 receptor blockers (such as cimetidine, ranitidine, aluminum hydroxide ammonium) can be used for those with mild symptoms, digestive aids (pancreatic enzymes), or drugs that inhibit bile reflux (metoclopramide, moclobemide, cholestyramine, sucralfate can be used, which can bind to bile acids).

[0079] The active ingredient of the drug for treating peptic ulcer can generally be levofloxacin, tinidazole or omeprazole.

[0080] The active ingredient of the drug for treating intestinal tuberculosis can generally be rifampicin.

[0081] The active ingredients of the medicine for treating chronic enteritis can generally be anti-inflammatory analgesics, probiotics or antispasmodics (such as atropine, propantheline).

[0082] 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 spasm analgesic (such as pinaverium bromide).

[0083] The active ingredients of the drugs for treating chronic hepatitis can generally be hepatoprotective drugs (such as silymarin preparations, schisandra preparations, etc.), anti-fibrosis drugs (such as oral Chinese patent medicine preparations), antivirals (such as conventional interferon and pegylated interferon), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine, entecavir), or immunosuppressants (azathioprine).

[0084] The active ingredients of the drugs for treating liver cirrhosis can generally be drugs for treating hepatitis B (such as nucleoside analogs), drugs for treating autoimmune hepatitis (such as glucocorticoids), anti-inflammatory drugs, liver-protecting drugs, anti-liver fibrosis drugs (such as reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizate, etc.), drugs for treating spontaneous bacterial peritonitis (such as antibiotics), or drugs for treating portal hypertension (such as carvedilol).

[0085] 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).

[0086] The active ingredient of the drug for treating chronic cholecystitis can generally be an antibacterial and anti-inflammatory drug (such as levofloxacin, ciprofloxacin, amoxicillin), an antispasmodic and analgesic drug, or a choleretic drug (such as ursodeoxycholic acid).

[0087] 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.

[0088] 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, hyoscyamine, hyoscyamine (scopolamine)), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight dextran iron, carboxymaltose iron, isomaltose iron, glucuronic acid iron, nano iron oxide, sorbitol iron, etc.), or erythropoiesis-stimulating agents (recombinant human erythropoietin α, darbepoetin α).

[0089] 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.

[0090] The active ingredients of the drugs for treating chronic lymphocytic leukemia can generally be: chemotherapy (such as nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted drugs (such as adranib, venetula, ibrutinib, imatinib, dasatinib, etc.), or monoclonal antibodies (such as ofatumumab, rituximab, atuzumab, alemtuzumab, etc.).

[0091] The active pharmaceutical ingredients acting on the endocrine system may generally include active pharmaceutical ingredients for treating chronic lymphocytic thyroiditis, hyperthyroidism, or hypothyroidism.

[0092] The active ingredient 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).

[0093] 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).

[0094] The active ingredient of the drug for treating hypothyroidism can generally be: thyroxine (such as levothyroxine, levothyroxine sodium, thyroxine).

[0095] In the present invention, the dosage of the pharmaceutical active ingredient is preferably 5-500 parts, more preferably 5-100 parts, such as 10 parts, 20 parts, 50 parts or 100 parts.

[0096] In the present invention, the R-vinyl silicone rubber is preferably methyl vinyl silicone rubber.

[0097] 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%.

[0098] In the present invention, the amount of the hydrogen-containing silicone oil can be 0.3-20 parts, preferably 0.3-10 parts, for example 0.3 parts, 0.667 parts or 1 part.

[0099] In the present invention, the content of Si-H groups in the hydrogen-containing silicone oil is preferably 0.5-1.0 mol%, for example 0.75 mol%.

[0100] In the present invention, the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is preferably (1-10):1, for example, 1.5:1, 2:1, 3:1, 3.5:1, 4:1, 4.5:1 or 6:1.

[0101] In the present invention, the catalyst can 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.

[0102] 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.

[0103] In the present invention, the pharmaceutical composition may further include an inhibitor. The inhibitor 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 compound. The hydrocarbon compound preferably contains at least one alkynyl group and one hydroxyl group in its molecular structure, such as 2-methyl-3-butyn-2-ol. The inhibitor is preferably used in an amount of 0.03-2.0 parts, for example, 0.49 parts or 0.98 parts.

[0104] In the present invention, when the pharmaceutical active ingredient is the pharmaceutical active ingredient acting on the reproductive system, the particle size of the pharmaceutical active ingredient may be 0.001-200 μm, preferably 2-80 μm, for example 2-3 μm.

[0105] 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.

[0106] 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, for example 0.3 parts, 0.5 parts, 0.667 parts or 1 part.

[0107] 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.

[0108] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the vinyl content in the R-vinyl silicone rubber may be 0.10%-0.50 mol%, preferably 0.10%-0.30 mol%, such as 0.18 mol%.

[0109] 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 hydrogenated silicone oil may be 0.15-1.6 mol%, preferably 0.15-1.2 mol%, for example 0.75 mol%.

[0110] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the reproductive system, the molar ratio of the Si-H group in the hydrogenated silicone oil to the vinyl group in the R-vinyl silicone rubber is preferably (1.5-10):1, for example, 1.5:1, 3.0:1 or 4.5:1, more preferably (3.0-4.5):1.

[0111] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0112] Gestodene: 10-500 parts;

[0113] R-vinyl silicone rubber: 100 parts;

[0114] Hydrogenated silicone oil: 0.3-20 parts;

[0115] Catalyst: 0.1-0.3 parts;

[0116] in:

[0117] 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 aromatic hydrocarbons;

[0118] The vinyl content in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0119] The content of Si-H groups in the hydrogenated silicone oil is 0.15-1.6 mol%;

[0120] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (1.5-6):1.

[0121] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0122] Gestodene: 20-200 parts;

[0123] R-vinyl silicone rubber: 100 parts;

[0124] Hydrogenated silicone oil: 0.3-20 parts;

[0125] Catalyst: 0.2-0.25 parts;

[0126] in:

[0127] 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 aromatic hydrocarbons;

[0128] The vinyl content in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0129] The content of Si-H groups in the hydrogenated silicone oil is 0.15-1.6 mol%;

[0130] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (2-6):1.

[0131] 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;

[0132] The vinyl content in the methyl vinyl silicone rubber is 0.18 mol%, the Si-H content in the hydrogenated silicone oil is 0.75 mol%, and the molar ratio of the Si-H group in the hydrogenated silicone oil to the vinyl content in the methyl vinyl silicone rubber is 4.5:1.

[0133] 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;

[0134] The vinyl content in the methyl vinyl silicone rubber is 0.18 mol%, the Si-H content in the hydrogenated silicone oil is 0.75 mol%, the molar ratio of the Si-H groups in the hydrogenated silicone oil to the vinyl content in the methyl vinyl silicone rubber is 4.5:1, and the platinum concentration in the platinum catalyst is 1×10 4 ppm.

[0135] 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;

[0136] The vinyl content in the methyl vinyl silicone rubber is 0.18 mol%, the Si-H content in the hydrogenated silicone oil is 0.75 mol%, and the molar ratio of the Si-H group in the hydrogenated silicone oil to the vinyl content in the methyl vinyl silicone rubber is 4.5:1.

[0137] 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;

[0138] The vinyl content in the methyl vinyl silicone rubber is 0.18 mol%, the Si-H content in the hydrogenated silicone oil is 0.75 mol%, the molar ratio of the Si-H groups in the hydrogenated silicone oil to the vinyl content in the methyl vinyl silicone rubber is 4.5:1, and the platinum concentration in the platinum catalyst is 1×10 4 ppm.

[0139] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0140] Levonorgestrel: 5-200 parts;

[0141] R-vinyl silicone rubber: 100 parts;

[0142] Hydrogenated silicone oil: 0.3-20 parts;

[0143] Catalyst: 0.2-0.3 parts;

[0144] in:

[0145] 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 aromatic hydrocarbons;

[0146] The vinyl content in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0147] The content of Si-H groups in the hydrogenated silicone oil is 0.15-1.6 mol%;

[0148] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (1.5-4.5):1.

[0149] 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 hydrogenated silicone oil, 0.25 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0150] The vinyl content in the methyl vinyl silicone rubber is 0.18 mol%, the Si-H content in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl content in the methyl vinyl silicone rubber is 1.5:1.

[0151] 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 hydrogenated silicone oil, 0.25 parts of platinum catalyst, and 0.49 parts of 2-methyl-3-butyn-2-ol;

[0152] The vinyl content in the methyl vinyl silicone rubber is 0.18 mol%, the Si-H content in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl content in the methyl vinyl silicone rubber is 1.5:1.

[0153] In the present invention, when the pharmaceutical active ingredient is the pharmaceutical active ingredient acting on the endocrine system, the particle size of the pharmaceutical active 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.

[0154] 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.

[0155] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the amount of the hydrogenated silicone oil can be 0.3-20 parts, preferably 0.3-5 parts, such as 0.3 part, 0.5 part or 1 part.

[0156] 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.

[0157] In the present invention, when the active pharmaceutical ingredient is the active pharmaceutical ingredient acting on the endocrine system, the vinyl content in the R-vinyl silicone rubber is 0.10%-0.30 mol%, for example, 0.17 mol%.

[0158] 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 hydrogenated silicone oil is 0.15-1.2 mol%, for example, 0.75 mol%.

[0159] In the present invention, when the pharmaceutical active ingredient is the pharmaceutical active ingredient acting on the endocrine system, the molar ratio of the Si-H group in the hydrogenated 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.

[0160] In the present invention, the pharmaceutical composition preferably comprises the following raw material components:

[0161] Levothyroxine sodium: 20-500 parts;

[0162] R-vinyl silicone rubber: 100 parts;

[0163] Hydrogenated silicone oil: 0.3-20 parts;

[0164] Catalyst: 0.2-0.3 parts;

[0165] in:

[0166] 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 aromatic hydrocarbons;

[0167] The vinyl content in the R-vinyl silicone rubber is 0.10%-0.30mol%;

[0168] The content of Si-H groups in the hydrogenated silicone oil is 0.15-1.2 mol%;

[0169] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (1-6):1.

[0170] 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;

[0171] The vinyl content in the methyl vinyl silicone rubber is 0.17 mol%, the Si-H content in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl content in the methyl vinyl silicone rubber is 3:1.

[0172] 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;

[0173] The vinyl content in the methyl vinyl silicone rubber is 0.17 mol%, the Si-H content in the hydrogenated silicone oil is 0.75 mol%, the molar ratio of the Si-H groups in the hydrogenated silicone oil to the vinyl content in the methyl vinyl silicone rubber is 3:1, and the concentration of platinum in the platinum catalyst is 1×10 4 ppm.

[0174] 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;

[0175] The vinyl content in the methyl vinyl silicone rubber is 0.17 mol%, the Si-H content in the hydrogen-containing silicone oil is 0.75 mol%, and the molar ratio of the Si-H group in the hydrogen-containing silicone oil to the vinyl content in the methyl vinyl silicone rubber is 3.5:1.

[0176] 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;

[0177] The vinyl content in the methyl vinyl silicone rubber is 0.17 mol%, the Si-H content in the hydrogenated silicone oil is 0.75 mol%, the molar ratio of the Si-H groups in the hydrogenated silicone oil to the vinyl content in the methyl vinyl silicone rubber is 3.5:1, and the platinum concentration in the platinum catalyst is 1×10 4 ppm.

[0178] The present invention also provides a stick core, the raw materials of which include the pharmaceutical composition described above. The pharmaceutically active ingredient is dispersed in the cross-linked structure of the stick core. The pharmaceutically active ingredient in the stick core may be present 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 and silicone tube are used in combination, an appropriate formulation may be selected based on actual circumstances.

[0179] The present invention also provides a method for preparing the stick core as described above, which comprises the following steps:

[0180] S1: separating the R-vinyl silicone rubber into component A1 and component A2, mixing the component A1 with the catalyst to obtain component B1, and mixing the component A2 with the hydrogen-containing silicone oil to obtain component B2;

[0181] S2: mixing the component B1 and the component B2 to obtain a rubber mixture;

[0182] S3: mixing the rubber mixture and the active pharmaceutical ingredient to obtain drug-loaded silica gel;

[0183] S4: The drug-loaded silica gel is extruded and vulcanized to obtain a rod core.

[0184] 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 component B2.

[0185] In S1, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, for example, drying at 30-60° C. (eg, 40° C.) for 1-24 h (eg, 12 h) for later use.

[0186] 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.

[0187] 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 mill and mixing them for 4-6 times (for example, 5 times) to ensure that the B1 and B2 component rubbers are fully mixed and uniformly formed into a mixed rubber.

[0188] In S3, the mixing may include the following steps: adding the active pharmaceutical ingredient and the rubber compound at a weight ratio of 1:(0.1-10) (e.g., 1:1 or 1:5) into an open mill for mixing, so that the rubber compound and the active pharmaceutical ingredient are fully mixed and uniformly formed into a drug-loaded silica gel. The drug-loaded silica gel may be cut into strips.

[0189] In S4, the extrusion is generally performed in an extruder.

[0190] In S4, the vulcanization is generally performed in an oven. The vulcanization time can 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 can be 50-160°C, such as 50°C, 70°C, 90°C, or 110°C.

[0191] In S4, when the pharmaceutical active ingredient is gestodene, the vulcanization time is preferably 1-24 hours, for example, 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, for example, 70°C, 90°C, or 110°C.

[0192] In a preferred embodiment, in S4, the pharmaceutical active ingredient is gestodene, the vulcanization temperature is 90° C., and the vulcanization time is 1 hour.

[0193] 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.

[0194] In S4, when the pharmaceutical active ingredient is levonorgestrel, the vulcanization time is preferably 0.5-2 hours, such as 0.5 hours, 0.6 hours, 0.8 hours, 1 hour, or 2 hours, more preferably 0.5-1.5 hours. The vulcanization temperature is preferably 70-110°C, such as 70°C, 90°C, or 110°C, more preferably 90-110°C.

[0195] In a preferred embodiment, in S4, the pharmaceutical active ingredient is levonorgestrel, the vulcanization temperature is 110° C., and the vulcanization time is 1 hour.

[0196] The present invention also provides a rod core, which is prepared by the above preparation method.

[0197] 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.

[0198] 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.

[0199] 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 418.81mm2 .

[0200] The present invention also provides an implant comprising the stick core and a silicone tube.

[0201] 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:

[0202] R-vinyl silicone rubber: 100 parts;

[0203] Hydrogenated silicone oil: 0.3-4.0 parts;

[0204] Catalyst: 0.000002-0.5 parts;

[0205] Reinforcing agent: 20-80 parts;

[0206] Wherein: R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 straight chain alkane or branched chain alkane, a substituted or unsubstituted C6-C 20 aromatic hydrocarbons;

[0207] The vinyl content in the R-vinyl silicone rubber is 0.10%-0.50mol%;

[0208] The content of Si-H groups in the hydrogenated silicone oil is 0.18-1.6 mol%;

[0209] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-5):1.

[0210] The raw material composition of the silicone tube preferably also includes an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogenated silicone oil. The inhibitor can be an alkynol compound, a nitrogen-containing compound, or an organic peroxide, such as methylbutynol or 2-methyl-3-butyn-2-ol. The inhibitor can be used in an amount of 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.

[0211] Among them, the amount of the hydrogen-containing silicone oil is preferably 0.4-2.8 parts, such as 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.

[0212] The amount of the catalyst is preferably 0.000002-0.1 parts, for example 0.01 parts.

[0213] The catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between R-vinyl silicone rubber and hydrogenated 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, where 3000 ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million.

[0214] The vinyl content in the R-vinyl silicone rubber is preferably 0.18 to 0.23 mol%, for example 0.18 mol%.

[0215] The content of Si-H groups in the hydrogenated 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%.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] In the present invention, preferably, the raw material composition of the silica gel material comprises the following components in parts by weight:

[0220] Methyl vinyl silicone rubber: 100 parts;

[0221] Reinforcing agent: 30-45 parts;

[0222] Hydrogenated silicone oil: 0.42-2.52 parts;

[0223] Catalyst: 0.000002-0.015 parts;

[0224] Inhibitor: 0.3-0.9 parts;

[0225] Wherein: the vinyl content in the methyl vinyl silicone rubber is 0.17-0.23 mol%;

[0226] The content of Si-H groups in the hydrogenated silicone oil is 0.5-1.0 mol%;

[0227] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methyl vinyl silicone rubber is (1.2-1.8):1.

[0228] In a specific embodiment, the raw material composition of the silica gel material includes the following components in parts by weight:

[0229] Methyl vinyl silicone rubber: 100 parts;

[0230] Reinforcing agent: 40 parts;

[0231] Hydrogenated silicone oil: 0.667 parts;

[0232] Platinum catalyst: 0.01 parts;

[0233] Inhibitor: 0.69 parts;

[0234] Wherein: the content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%;

[0235] The content of Si-H groups in the hydrogenated silicone oil is 0.75 mol%;

[0236] 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;

[0237] The concentration of platinum in the platinum catalyst is 3000 ppm.

[0238] In a specific embodiment, the raw material composition of the silica gel material includes the following components in parts by weight:

[0239] Methyl vinyl silicone rubber: 100 parts;

[0240] Reinforcing agent: 50 parts;

[0241] Hydrogenated silicone oil: 0.533 parts;

[0242] Platinum catalyst: 0.01 parts;

[0243] Inhibitor: 0.74 parts;

[0244] Wherein: the content of vinyl in the methyl vinyl silicone rubber is 0.18 mol%;

[0245] The content of Si-H groups in the hydrogenated silicone oil is 0.75 mol%;

[0246] 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;

[0247] The concentration of platinum in the platinum catalyst is 3000 ppm.

[0248] In the present invention, the preparation method of the silicone tube can adopt method 1 or method 2;

[0249] 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:

[0250] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0251] S2: mixing the mixture A and the hydrogen-containing silicone oil in the presence of the catalyst to obtain a mixture B;

[0252] S3: Extruding the mixture B into a tube, and then performing catalytic addition;

[0253] 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:

[0254] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0255] 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;

[0256] S3: mixing the component B1 and the component B2 to obtain a mixture B;

[0257] S4: The mixture B is formed into a tube through an extrusion process, and then subjected to catalytic addition.

[0258] 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.

[0259] 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 1-24 hours, or drying at 40°C for 18 hours.

[0260] In the present invention, in the method 1 and the method 2, the mixing step in S1 may be: wrapping the reinforcing agent with the R-vinyl silicone rubber, extruding the rubber into a thin layer using an open mill, and pressing the rubber into sheets.

[0261] 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; triangularly wrapping them on an open mill with a roller spacing of 1-10 mm (for example, 1 mm) and then rolling them into a sheet, and then leaving them for 18 hours to obtain the mixture A.

[0262] 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.

[0263] In the present invention, in the method 1, before the catalytic addition, the mixture B may 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.

[0264] 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 mill, making triangular thin wraps 4 to 6 times, and then evenly cutting and slicing.

[0265] 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.

[0266] The temperature of the first vulcanization treatment may be 250-330°C, such as 270°C, 300°C or 330°C.

[0267] The time of the first vulcanization treatment may be 2-30 seconds, for example, 15 seconds.

[0268] The temperature of the second vulcanization treatment may be 150-280°C, such as 150°C, 180°C, 210°C or 240°C.

[0269] The second vulcanization treatment may be performed for 0.1-5 min, for example, 2 min.

[0270] In the present invention, in the second method, the catalytic addition step in S4 can be as described above.

[0271] In the present invention, according to conventional techniques in the art, the inner diameter of the silicone tube is generally equal to the outer diameter of the rod core, and the outer diameter of the silicone tube is preferably 2.0-5.0 mm, such as 2.4 mm or 2.6 mm.

[0272] 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.

[0273] 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.

[0274] 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.

[0275] The present invention provides a method for preparing an implant, which comprises the following steps: filling the stick core into the silicone tube.

[0276] The present invention also provides an implant prepared by the above preparation method.

[0277] The present invention also provides an application of the stick core as a release rate regulating medium in a sustained-release preparation.

[0278] Implants are generally categorized as skeleton-type implants and reservoir-type implants. A skeleton-type implant is a drug formulation that is prepared by mixing a drug with a carrier and then, using a catalyst, a cross-linking agent, and high temperature, using extrusion or molding techniques to create a subcutaneous implant with defined mechanical properties. Reservoir-type implants are typically prepared by directly filling a silicone tube with the API or by encapsulating the skeleton-type implant.

[0279] In practical applications, many drugs require a daily release of milligrams or more to be effective (e.g., paliperidone, risperidone, ketotifen fumarate, celecoxib, and meloxicam). Because reservoir-type implants diffuse into the body through silicone tubes, their daily release is typically only tens of micrograms, making them difficult to meet the requirements for high-dose drug release. Frame-type implants offer advantages such as rapid and high-volume release, with daily drug release rates ranging from several to dozens of times greater than that of reservoir-type implants. However, their release is uneven, with a gradually decreasing release rate, resulting in unstable blood drug concentrations and even ineffectiveness.

[0280] In the prior art, the methods of adding pH regulators and punching holes in silicone tubes are usually used to increase the drug release rate, but the increase in drug release rate is not obvious, and it is difficult to achieve a drug release rate of milligrams per day.

[0281] In response to the defects of the prior art reservoir-type implants, which have a small release amount and high requirements for drug molecular weight and solubility, and the framework-type implants, which have uneven drug release, the present invention uses a pharmaceutical active ingredient with an average particle size of 1-1000 nm, which can significantly improve the solubility of the drug; and has better compatibility with silicone rubber. The resulting framework-type implant and reservoir-type implant have significantly increased release rates and stable drug release behavior. At the same time, the invention has a wide range of applications, is suitable for a variety of drugs, and can achieve large-dose stable release.

[0282] The present invention solves the above technical problems through the following technical solutions.

[0283] During the research and development process, the applicant creatively discovered that the average particle size of common active pharmaceutical ingredients is 2-180 μm. However, whether it is a skeleton-type implant or a reservoir-type implant, nano-sizing the active pharmaceutical ingredients can significantly increase their release rate in the release medium. At the same time, the compatibility of the active pharmaceutical ingredients with silicone rubber is further improved after nano-sizing, and more types of drugs are applicable.

[0284] The present invention provides a raw material composition for a drug-loaded stick core, which comprises the following components in parts by weight:

[0285] Active pharmaceutical ingredient: 1-1000 parts;

[0286] R-vinyl silicone rubber: 100 parts;

[0287] Hydrogenated silicone oil: 0.45-20 parts;

[0288] Catalyst: ≥0.000002 parts, preferably 0.000002-1 parts;

[0289] in:

[0290] The average particle size of the active pharmaceutical ingredient is 1-1000 nm;

[0291] 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 aromatic hydrocarbons;

[0292] The vinyl content in the R-vinyl silicone rubber is 0.1-0.5 mol%;

[0293] The content of Si-H groups in the hydrogenated silicone oil is 0.18-1.6 mol%;

[0294] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1;

[0295] Optionally, an inhibitor is further included, and the inhibitor is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil.

[0296] In the present invention, the active pharmaceutical ingredients may include active pharmaceutical ingredients that act on the reproductive system, or active pharmaceutical ingredients that act on the urinary system, or active pharmaceutical ingredients that act on chronic diseases related to metabolism and nutrition, or active pharmaceutical ingredients used to treat chronic diseases related to connective tissue and rheumatism, or active pharmaceutical ingredients used to treat hyperlipidemia, tumors, neuropsychiatric diseases, chronic dental diseases (caries, periodontal disease), simple obesity, chronic low back pain or leukemia, or active pharmaceutical ingredients that act on the circulatory system, or active pharmaceutical ingredients that act on the respiratory system, or active pharmaceutical ingredients that act on the digestive system, or active pharmaceutical ingredients that act on the blood system, or active pharmaceutical ingredients that act on the endocrine system.

[0297] The active pharmaceutical ingredients acting on the reproductive system may include active pharmaceutical ingredients for contraception, or steroidal estrogens.

[0298] The active pharmaceutical ingredient for contraception may be conventional in the art, and preferably includes levonorgestrel, gestodene or gestrinone.

[0299] The steroidal estrogen is preferably estradiol.

[0300] Wherein, the active pharmaceutical ingredient acting on the urinary system may be as described above.

[0301] The active pharmaceutical ingredients acting on chronic diseases related to metabolism and nutrition can be as described above.

[0302] Wherein, the active pharmaceutical ingredient for treating chronic diseases involving connective tissue and rheumatism can be as described above.

[0303] Wherein, the active ingredient of the drug for treating neuropsychiatric disease can be as described above.

[0304] Wherein, the drug for treating hyperlipidemia can be as described above.

[0305] Wherein, the active ingredient of the anti-tumor drug can be as described above.

[0306] The active pharmaceutical ingredients for treating chronic dental diseases (such as caries and periodontal disease) may be as described above.

[0307] Wherein, the active ingredient of the medicine for treating simple obesity can be as described above.

[0308] Wherein, the active ingredients of the medicine for treating chronic low back pain can be as described above.

[0309] Wherein, the active ingredient of the drug for treating leukemia can be as described above.

[0310] Wherein, the active pharmaceutical ingredient acting on the circulatory system may be as described above.

[0311] Wherein, the active pharmaceutical ingredient acting on the respiratory system may be as described above.

[0312] Wherein, the active pharmaceutical ingredient acting on the digestive system may be as described above.

[0313] Wherein, the active pharmaceutical ingredient acting on the blood system may be as described above.

[0314] Wherein, the active pharmaceutical ingredient acting on the endocrine system may be as described above.

[0315] In the present invention, the active pharmaceutical ingredient is not particularly limited and may be a conventional sustained-release pharmaceutical ingredient in the art that requires long-term drug release, preferably an active pharmaceutical ingredient with a solubility of ≤100 mg / mL (with water as solvent).

[0316] In the present invention, the dosage of the active pharmaceutical ingredient may be 1-800 parts, for example, 100 parts.

[0317] In the present invention, the average particle size of the pharmaceutical active ingredient may be 10-900 nm, preferably 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 120 nm, 150 nm, 198 nm, 200 nm, 208 nm, 212 nm, 220 nm, 300 nm, 308 nm, 350 nm, 400 nm, 430 nm, 500 nm, 600 nm, 646 nm, 700 nm, 800 nm, 820 nm or 900 nm. Within the particle size range of the present invention, the smaller the particle size, the faster the release rate and the greater the daily release amount. If the particle size of the pharmaceutical active ingredient is too large, the release effect is equivalent to that of conventional micrometer-level particles; if the particle size of the pharmaceutical active ingredient is too small, its surface area is too small, and agglomeration is likely to occur, resulting in poor product stability.

[0318] In the present invention, R in the R-vinyl silicone rubber may be a substituted or unsubstituted C1-C5 straight-chain alkane, such as a methyl group.

[0319] When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber.

[0320] The methyl vinyl silicone rubber may be conventional methyl vinyl silicone rubber in the art, for example, methyl vinyl silicone rubber having a relative molecular weight of 100,000-800,000 g / mol.

[0321] 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%.

[0322] In the present invention, the hydrogen-containing silicone oil can be conventional hydrogen-containing silicone oil in the art, such as hydrogen-containing silicone oil purchased from Guangdong Guiye New Material Technology Co., Ltd.

[0323] In the present invention, the amount of the hydrogen-containing silicone oil used may be 0.5-20 parts, preferably 1.2-6.3 parts, for example 1.33 parts, 2.67 parts, 3.56 parts or 4.44 parts.

[0324] In the present invention, the content of Si-H groups in the hydrogenated silicone oil may be 0.36-1.6 mol%, such as 0.36 mol%, 0.5 mol%, 0.75 mol%, 1.0 mol% or 1.6 mol%, preferably 0.5-1 mol%.

[0325] 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 (0.8-20):1, for example, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 3.0:1, 4.0:1, 4.2:1, 5.0:1, 8.0:1, 10.0:1 or 15.0:1.

[0326] In the present invention, the catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil, such as a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst.

[0327] Wherein, the concentration of platinum in the platinum catalyst is preferably 1×10 3 -1×10 5 ppm, for example 1×10 4 ppm.

[0328] In the present invention, the amount of the catalyst can be 2×10 -6 -1 part, for example, 0.000005 part, 0.00001 part, 0.00002 part, 0.00003 part, 0.1 part, 0.2 part, 0.21 part, 0.25 part or 0.3 part, preferably 0.03-0.3 part, more preferably 0.1-0.3 part.

[0329] In the present invention, the inhibitor can be a conventional inhibitor in the art that can inhibit the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil at room temperature, such as acetylenic alcohol compounds, nitrogen-containing compounds or organic peroxides, such as methyl butynol, and also such as 2-methyl-3-butyn-2-ol.

[0330] In the present invention, the amount of the inhibitor may be 0.03-2.5 parts, preferably 0.1-2.0 parts, more preferably 0.3-1.0 parts, such as 0.3 parts, 0.5 parts, 0.7 parts, 0.9 parts or 0.98 parts.

[0331] In some preferred embodiments of the present invention, the raw material composition of the drug-loaded rod core may include the following components in parts by weight:

[0332] (1) Nanoparticle active ingredient, with an average particle size of 10-900 nm and an addition amount of 100 PHR;

[0333] (2) Methyl vinyl silicone rubber, vinyl content of 0.18 mol%, added in an amount of 100 PHR;

[0334] (3) hydrogenated silicone oil, with a Si-H group content of 0.75 mol%, added in an amount of 4.44 PHR;

[0335] (4) platinum catalyst, the concentration of platinum is 10000 ppm, and the addition amount is 0.21 PHR;

[0336] (5) 2-methyl-3-butyn-2-ol, added in an amount of 0.98 PHR;

[0337] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is 5:1.

[0338] In other preferred embodiments of the present invention, the raw material composition of the drug-loaded rod core may include the following components in parts by weight:

[0339] (1) Nano paliperidone, having an average particle size of 220 nm, 430 nm, 646 nm or 820 nm, and an addition amount of 100 PHR;

[0340] (2) Methyl vinyl silicone rubber, vinyl content of 0.18 mol%, added in an amount of 100 PHR;

[0341] (3) hydrogenated silicone oil, with a Si-H group content of 0.75 mol%, added in an amount of 4.44 PHR;

[0342] (4) platinum catalyst, the concentration of platinum is 10000 ppm, and the addition amount is 0.21 PHR;

[0343] (5) 2-methyl-3-butyn-2-ol, added in an amount of 0.98 PHR;

[0344] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is 5:1.

[0345] The present invention also provides a drug-loaded stick core, which is prepared from the raw material composition of the drug-loaded stick core.

[0346] In the present invention, the drug-loaded rod core can be a skeleton-type drug-loaded rod core or a hollow skeleton-type drug-loaded rod core. The drug-loaded rod core of the present invention can independently serve as the skeleton-type implant mentioned in the background art.

[0347] In the present invention, when the drug-loaded rod core is a skeleton-type drug-loaded rod core, the outer diameter of the drug-loaded rod core may be 1-10 mm, preferably 1-6 mm, such as 2 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0348] In the present invention, when the drug-loaded rod core is a hollow skeleton-type drug-loaded rod core, the outer diameter of the drug-loaded rod core may be 1-10 mm, preferably 1-6 mm, such as 2 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0349] In the present invention, when the drug-loaded rod core is a hollow skeleton type drug-loaded rod core, the inner diameter of the drug-loaded rod core can be 0.1 mm-4.0 mm, preferably 0.4 mm-2.0 mm, for example 0.4 mm, 0.6 mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.4 mm, 1.6 mm or 2.0 mm.

[0350] When the drug-loaded rod core is a hollow skeleton type drug-loaded rod core, preferably, the diameter ratio of the outer diameter to the inner diameter of the drug-loaded rod core is (1.5-50):1, for example, 2.14:1, 3:1, 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1.

[0351] The present invention also provides a method for preparing the drug-loaded stick core, which comprises the following steps:

[0352] (1) The R-vinyl silicone rubber is divided into component A1 and component B1, the component A1, the hydrogen-containing silicone oil and the inhibitor are mixed to obtain component A2, and the component B1 and the catalyst are mixed to obtain component B2; the components A2 and B2 are mixed to obtain a rubber mixture;

[0353] (2) mixing the rubber mixture and the active pharmaceutical ingredient to obtain drug-loaded silica gel;

[0354] (3) The drug-loaded silica gel is extruded and vulcanized to obtain a drug-loaded rod core.

[0355] In step (1), the R-vinyl silicone rubber can be pretreated by conventional methods in the art, for example, by drying at 30-60° C. (for example, 40° C.) for 1-24 h (for example, 12 h) for later use.

[0356] In step (1), 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, 6 times) and discharged in the form of flakes.

[0357] In step (1), the step of mixing the component A2 and the component B2 may include the following steps: putting the component A2 and the component B2 into an open mill at a weight ratio of 1:1 and mixing them for 4-6 times (for example, 4 times or 6 times) to ensure that the A2 and B2 component rubbers are fully mixed and uniformly formed into a mixed rubber.

[0358] In step (2), the active pharmaceutical ingredient is prepared by nano-crystallization, and the PDI after nano-crystallization can be less than 0.3. The nano-crystallization can be carried out by conventional nano-crystallization methods in the art, such as grinding.

[0359] The grinding may be performed by wet grinding. Preferably, a stabilizer and a grinding medium are added during the grinding process.

[0360] The grinding time may be no less than 15 minutes, preferably 15-250 minutes.

[0361] The grinding speed can be 300-500 r·min -1 , for example 400 r·min -1 .

[0362] The type of the stabilizer can be conventional in the art, preferably one or more of poloxamer 407, poloxamer 188, SDS, HPMC, Tween 80, PVP K30, PEO, TPGS and HPC, more preferably poloxamer 188 (P188), Tween 80, poloxamer 407 (P407), SDS or HPMC, such as poloxamer 188.

[0363] The grinding media may be any conventional grinding media in the art, such as zirconium oxide beads. The particle size of the zirconium oxide beads may be 0.1-0.3 mm, such as 0.1 mm, 0.2 mm or 0.3 mm.

[0364] The grinding may be followed by freeze-drying.

[0365] In step (2), the step of mixing the rubber mix and the active pharmaceutical ingredient may include the following steps: placing the rubber mix and the active pharmaceutical ingredient in an open mixer and mixing them, so that the rubber mix 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.

[0366] The mass ratio of the rubber mix to the active pharmaceutical ingredient may be 1:(0.01-10), preferably 1:(1-5), for example 1:1.

[0367] In step (3), the drug loaded rod core can be a skeleton type drug loaded rod core or a hollow skeleton type drug loaded rod core. In the present invention, the skeleton type drug loaded rod core or the hollow skeleton type drug loaded rod core can be obtained by adjusting the extrusion molding parameters.

[0368] In step (3), the extrusion is generally carried out in a screw extruder.

[0369] In step (3), during the extrusion molding, the screw speed of the extruder can be 1-15 r·min -1 , for example 4r·min -1 、6r·min -1 or 7 r·min -1 .

[0370] In step (3), when the drug-loaded rod core is a skeleton-type drug-loaded rod core, the diameter of the die used in the extrusion molding can be 1-10 mm, preferably 1-6 mm, such as 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0371] In step (3), when the drug-loaded rod core is a skeleton-type drug-loaded rod core, the diameter of the die used in the extrusion molding can be 1-10 mm, preferably 1-6 mm, such as 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0372] In step (3), when the drug-loaded rod core is a skeleton-type drug-loaded rod core, the diameter of the core mold used during the extrusion molding is preferably 0.1mm-4.0mm, preferably 0.4mm-2.0mm, for example, 0.4mm, 0.58mm, 0.6mm, 0.8mm, 0.97mm, 1.0mm, 1.2mm, 1.38mm, 1.4mm, 1.6mm or 2.0mm.

[0373] Preferably, when the drug-loaded rod core is a skeleton-type drug-loaded rod core, during the extrusion molding, the diameter ratio of the mouth die to the core die is (1.5-50):1, for example, 2.14:1, 3:1, 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1.

[0374] In step (3), the vulcanization is generally carried out in an oven.

[0375] In step (3), the vulcanization temperature is preferably 30-120°C, for example, 30°C, 50°C, 60°C, 65°C, 70°C, 80°C, 90°C, 100°C or 120°C.

[0376] In step (3), the vulcanization time is preferably 10-100 min, for example, 10 min, 20 min, 30 min, 40 min, 50 min, 70 min or 100 min.

[0377] The present invention also provides a reservoir-type implant comprising the drug-loaded rod core and a silicone tube.

[0378] In the present invention, the outer diameter of the silicone tube may be 2.0-10 mm, preferably 2.0-6.4 mm, such as 2.4 mm or 2.6 mm, 3.2 mm or 3.4 mm.

[0379] In the present invention, the wall thickness of the silicone tube may be 0.1-1.0 mm, for example, 0.2 mm, 0.3 mm, 0.4 mm or 0.5 mm.

[0380] In the present invention, the length of the silicone tube may be 1.5-10 cm, for example, 1.9 cm or 4.4 cm.

[0381] In the present invention, the drug release area of ​​the silicone tube can be 0.618-31.4 cm 2 , preferably 0.4-15.0cm 2 ; For example, 0.69cm 2 、1.38cm 2 , 2.07cm 2 、2.76cm 2 、3.45cm 2 or 3.77cm 2 .

[0382] In the present invention, the diameter of the drug-loaded rod core may be 1-10 mm, preferably 1-6 mm, such as 1.6 mm, 2.0 mm or 3.0 mm.

[0383] In the present invention, the length of the drug-loaded rod core may be 1.0-10 cm, preferably 1.0-4.0 cm, for example, 1.0 cm, 1.5 cm, 2.0 cm, 3.0 cm, 3.9 cm, 4.0 cm or 5.0 cm.

[0384] In the present invention, the raw material composition of the silicone tube may include the following components in parts by weight:

[0385] R-vinyl silicone rubber: 100 parts;

[0386] Reinforcing agent: 20-80 parts;

[0387] Hydrogenated silicone oil: 0.3-3.0 parts;

[0388] Catalyst: ≥0.000002 parts, preferably 0.000002-0.5 parts;

[0389] in:

[0390] 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 aromatic hydrocarbons;

[0391] The vinyl content in the R-vinyl silicone rubber is 0.10-0.50 mol%;

[0392] The content of Si-H groups in the hydrogenated silicone oil is 0.18-1.6 mol%;

[0393] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1;

[0394] Optionally, an inhibitor is further included, and the inhibitor is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil.

[0395] The type and amount of the R-vinyl silicone rubber can be as described above. In the present invention, "as described above" means that the selection range is the same as the above, and they are independent of each other and do not affect each other.

[0396] Among them, the reinforcing agent can be a conventional reinforcing agent in the art that can improve the hardness of the R-vinyl silicone rubber, such as one or more of white carbon black, diatomaceous earth, quartz powder, silicon powder, calcium carbonate, aluminum hydroxide, magnesium oxide, titanium dioxide, magnesium silicate, carbon black, zinc oxide, iron oxide, titanium dioxide, zirconium silicate and calcium carbonate, such as white carbon black.

[0397] The silica can be conventional silica in the art, such as fumed silica, precipitated silica, gel silica or surface-treated silica, preferably fumed silica.

[0398] The amount of the reinforcing agent is preferably 30-80 parts, such as 30 parts, 35 parts, 40 parts, 45 parts, 50 parts or 60 parts.

[0399] The type of the hydrogen-containing silicone oil, the content of Si-H groups in the hydrogen-containing silicone oil, and the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methyl vinyl silicone rubber may be as described above.

[0400] Wherein, the amount of the hydrogen-containing silicone oil is preferably 0.4-2.8 parts, for example, 0.42 parts, 0.67 parts, 0.84 parts, 1.01 parts, 1.07 parts, 1.26 parts, 1.36 parts, 1.51 parts, 1.68 parts or 2.52 parts.

[0401] The catalyst may be a conventional catalyst in the art that can catalyze the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil, such as a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst.

[0402] The concentration of platinum in the platinum catalyst may be 3000 ppm. 3000 ppm means that the mass concentration of platinum in the platinum catalyst is 3000 parts per million.

[0403] The amount of the catalyst is preferably 0.03-0.3 parts, more preferably 0.1-0.3 parts, such as 0.21 parts.

[0404] Among them, the inhibitor can be a conventional inhibitor in the art that can inhibit the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil at room temperature, such as acetylenic alcohol compounds, nitrogen-containing compounds or organic peroxides, such as methyl butynol, and also such as 2-methyl-3-butyn-2-ol.

[0405] Wherein, the dosage of the inhibitor is as described above.

[0406] In the present invention, the preparation method of the silicone tube comprises the following steps:

[0407] Method 1: When the raw material composition of the silica gel material does not include an inhibitor, the preparation method of the silica gel material comprises the following steps:

[0408] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0409] S2: In the presence of the catalyst, mixing the mixture A and the hydrogen-containing silicone oil to obtain a mixture B;

[0410] S3: The mixture B is formed into a tube through an extrusion process, and then subjected to catalytic addition; alternatively, the catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

[0411] Method 2: When the raw material composition of the silica gel material further includes an inhibitor, the preparation method of the silica gel material includes the following steps:

[0412] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0413] S2: dividing the mixture A into component A1 and component A2, mixing the component A1 with the catalyst to obtain component B1, and mixing the component A2 with the hydrogen-containing silicone oil and the inhibitor to obtain component B2;

[0414] S3: mixing the component B1 and the component B2 to obtain a mixture B;

[0415] S4: The mixture B is formed into a tube through an extrusion process, and then subjected to catalytic addition; alternatively, the catalytic addition process is carried out in a tubular mold to obtain the silicone tube.

[0416] 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. (eg, 130° C.) for 1-24 hours (eg, 12 hours or 24 hours) for later use.

[0417] In the method 1 and the method 2, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, such as drying at 30-60° C. (eg, 40° C.) for 1-24 hours (eg, 12 hours or 24 hours) for later use.

[0418] Among them, in the method 1 and the method 2, the mixing step in S1 can be: after wrapping the reinforcing agent with the R-vinyl silicone rubber, the reinforcing agent is squeezed into a thin layer by an open mill, and then sheeted.

[0419] In the method 1 and the method 2, the mixture A can be placed in a desiccator at room temperature for 24-72 hours (for example, 24 hours) for standby use.

[0420] Among them, in the method 1 and the method 2, the mixing step in S1 can be: kneading the R-vinyl silicone rubber and the reinforcing agent in a kneader at 30°C for 30 minutes, and then taking them out; triangular wrapping them on an open mill with a roller spacing of 1-10 mm (for example, 1 mm) for 5 times to roll out the sheet, and then leaving it for 24 hours to obtain the mixture A.

[0421] In the method 1, before the catalytic addition, the mixture B may be subjected to the following post-treatment: triangular thinning in an open mill for 4-6 times (for example, 6 times), and then uniformly cutting the material into sheets.

[0422] 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 mill, making triangular thin wraps 4-6 times (for example, 6 times), and then evenly cutting and slicing.

[0423] Among them, in the method 1, the catalytic addition step in S3 can be: subjecting the mixture B to a first heat treatment and a second heat treatment in sequence; preferably, a third heat treatment is further included after the second heat treatment.

[0424] The temperature of the first heat treatment may be 250-360°C, such as 270-300°C, and for example 270°C, 280°C or 300°C.

[0425] The time of the first heat treatment may be about 5 seconds.

[0426] The temperature of the second heat treatment may be 120-300°C, such as 180-280°C, and for example 180°C, 260°C or 280°C.

[0427] The second heat treatment may last for about 2 minutes.

[0428] The temperature of the third heat treatment may be 150-250°C, for example 180°C.

[0429] The third heat treatment may be performed for 24-48 hours, for example, 48 hours.

[0430] The third heat treatment may be performed in an oven.

[0431] Wherein, in the method 2, the catalytic addition step in S4 can be as described above.

[0432] The present invention provides a method for preparing the reservoir-type implant, which comprises the following steps: cutting the silicone tube into segments, filling the drug-loaded rod core, and sealing both ends with silicone to obtain the reservoir-type implant.

[0433] In the present invention, preferably, after being cut into segments, the length of the silicone tube is 0.4 cm longer than the drug-loaded rod core. The extra length is used for sealing, for example, 0.2 cm is reserved for sealing glue at both ends of the implant.

[0434] In the present invention, preferably, before the filling, the silicone tube is also cleaned and swelled.

[0435] The cleaning may be performed by soaking in ethanol and repeatedly rinsing with ethanol for 10-60 minutes, for example 15 minutes.

[0436] The swelling can be achieved by soaking the tube in petroleum ether for 1-2 minutes. Since the swollen silicone tube will quickly shrink and return to its original shape after being removed from the petroleum ether, the drug-loaded rod core must be quickly inserted into the silicone tube.

[0437] In the present invention, the sealing may further include a curing operation.

[0438] The curing can be carried out by standing at room temperature for 12-24 hours, for example 24 hours.

[0439] The present invention also provides a reservoir-type implant, which comprises a powder-type medicine core and a silicone tube; the powder-type medicine core comprises a pharmaceutically active ingredient, and the average particle size of the pharmaceutically active ingredient is 1-1000 nm.

[0440] In the present invention, the dimensions of the silicone tube (including outer diameter, wall thickness, length and drug release area) can be as described above.

[0441] In the present invention, the diameter of the drug-loaded segment in the reservoir-type implant may be 1-10 mm, preferably 1-6 mm, such as 1.6 mm, 2.0 mm or 3.0 mm.

[0442] In the present invention, the length of the drug-loaded section in the reservoir-type implant is preferably 1.0-10 cm, more preferably 1.0-4.0 cm, such as 1.0 cm, 1.5 cm, 2.0 cm, 3.0 cm, 3.9 cm, 4.0 cm or 5.0 cm.

[0443] In the present invention, the average particle size of the pharmaceutical active ingredient may be 10-900 nm, preferably 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 120 nm, 150 nm, 198 nm, 200 nm, 208 nm, 212 nm, 220 nm, 300 nm, 308 nm, 350 nm, 400 nm, 430 nm, 500 nm, 600 nm, 646 nm, 700 nm, 800 nm, 820 nm, or 900 nm.

[0444] In the present invention, the powder-type drug core may further include a poorly soluble auxiliary material.

[0445] Wherein, the average particle size of the poorly soluble excipient may be 1-200 μm.

[0446] The poorly soluble excipient may include a silicon material. The pore size of the silicon material may be less than 1 μm, for example, 0 nm, 5 nm, 10 nm, 18 nm, 50 nm, or 100 nm. Those skilled in the art will appreciate that when the pore size of the silicon material is 0 nm, the silicon material is a non-porous silicon material.

[0447] In the silicon material, the content of silicon dioxide may be greater than 50%, preferably 80%, 90%, 95%, 99% or 99.8%.

[0448] The poorly soluble auxiliary material may include one or more of white carbon black, AL-1FP mesoporous silica, XDP3050 mesoporous silica and XDP3150 mesoporous silica.

[0449] The white carbon black is preferably fumed white carbon black, precipitated white carbon black, gel white carbon black or white carbon black obtained by surface treatment method.

[0450] Preferably, the poorly soluble auxiliary material is one or more of white carbon black, AL-1FP mesoporous silica, XDP3050 mesoporous silica and XDP3150 mesoporous silica.

[0451] More preferably, the poorly soluble auxiliary material is one or more of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica.

[0452] In the present invention, the poorly soluble auxiliary material may further include a poorly soluble weak acid and / or a poorly soluble weak base.

[0453] The sparingly soluble weak acid preferably includes one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, and more preferably includes boric acid and / or fumaric acid.

[0454] The sparingly soluble weak base preferably includes one or more of magnesium hydroxide, aluminum hydroxide, zinc hydroxide, ferrous hydroxide and magnesium oxide; more preferably includes one or more of magnesium hydroxide, aluminum hydroxide and zinc hydroxide.

[0455] The insoluble auxiliary material may also be white carbon black and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, white carbon black and molybdic acid, white carbon black and silicic acid, white carbon black and tungstic acid, or white carbon black and germanic acid.

[0456] Alternatively, the poorly soluble auxiliary material may also be white carbon black, ferrous hydroxide and / or magnesium oxide; for example, white carbon black and ferrous hydroxide, or white carbon black and magnesium oxide.

[0457] Alternatively, the insoluble auxiliary material can also be AL-1FP mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, AL-1FP mesoporous silicon and molybdic acid, AL-1FP mesoporous silicon and silicic acid, AL-1FP mesoporous silicon and tungstic acid, or AL-1FP mesoporous silicon and germanic acid.

[0458] Alternatively, the poorly soluble auxiliary material may also be AL-1FP mesoporous silica, ferrous hydroxide and / or magnesium oxide; for example, AL-1FP mesoporous silica and ferrous hydroxide, or AL-1FP mesoporous silica and magnesium oxide.

[0459] Alternatively, the poorly soluble auxiliary material may also be XDP3050 mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, XDP3050 mesoporous silicon and molybdic acid, XDP3050 mesoporous silicon and silicic acid, XDP3050 mesoporous silicon and tungstic acid, or XDP3050 mesoporous silicon and germanic acid.

[0460] Alternatively, the poorly soluble auxiliary material may also be XDP3050 mesoporous silica, ferrous hydroxide and / or magnesium oxide; for example, XDP3050 mesoporous silica and ferrous hydroxide, or XDP3050 mesoporous silica and magnesium oxide.

[0461] Alternatively, the poorly soluble auxiliary material may also be XDP3150 mesoporous silicon and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, XDP3150 mesoporous silicon and molybdic acid, XDP3150 mesoporous silicon and silicic acid, XDP3150 mesoporous silicon and tungstic acid, or XDP3150 mesoporous silicon and germanic acid.

[0462] Alternatively, the poorly soluble auxiliary material may also be XDP3150 mesoporous silica, ferrous hydroxide and / or magnesium oxide; for example, XDP3150 mesoporous silica and ferrous hydroxide, or XDP3150 mesoporous silica and magnesium oxide.

[0463] In the present invention, the content of the bulk drug may be 10%-99.9%, such as 50%-99.5%, and another example is 95%; the percentage is the mass percentage of the bulk drug in the pharmaceutical composition.

[0464] The content of the poorly soluble excipient may be 0.1%-90%, such as 0.1%-50%, and further such as 0.5%-5%; the percentage is the mass percentage of the poorly soluble excipient in the pharmaceutical composition.

[0465] In the present invention, when the insoluble excipients are two or three of white carbon black, AL-1FP mesoporous silica, and XDP3050 mesoporous silica, their mass ratio can be any ratio. For example, when the insoluble excipients are two of white carbon black, AL-1FP mesoporous silica, and XDP3050 mesoporous silica, their mass ratio is (0.001-1000):1.

[0466] For another example, when the poorly soluble excipients are XDP3150 mesoporous silica and fumaric acid, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

[0467] For another example, when the insoluble auxiliary materials are fumed silica and boric acid, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

[0468] For another example, when the poorly soluble auxiliary materials are XDP3050 mesoporous silica and magnesium hydroxide, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

[0469] For another example, when the poorly soluble auxiliary materials are AL-1FP mesoporous silica and zinc hydroxide, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

[0470] In the present invention, the raw material composition and preparation method of the silicone tube can be as described above.

[0471] The present invention provides a method for preparing the reservoir-type implant, which comprises the following steps: cutting the silicone tube into segments, sealing one end with silicone, filling the powder-type medicine core, and sealing the other end with silicone to obtain the reservoir-type implant.

[0472] In the present invention, preferably, after being cut into segments, the length of the silicone tube is 0.4 cm longer than the drug-loaded segment.

[0473] In the present invention, preferably, the process of cleaning the silicone tube is also included before the filling.

[0474] The cleaning may be performed by soaking in ethanol and repeatedly rinsing with ethanol for 10-60 minutes, for example 15 minutes.

[0475] In the present invention, the sealing may further include a curing operation.

[0476] The curing can be carried out by standing at room temperature for 12-24 hours, for example 24 hours.

[0477] The present invention also provides a raw material composition of the drug-loaded rod core, and the use of the drug-loaded rod core or the reservoir-type implant as a release rate regulating medium in a sustained-release preparation.

[0478] As mentioned above, implants can be categorized as skeleton-type and reservoir-type. Reservoir-type implants offer the advantage of stable drug release, maintaining a steady zero-order release rate throughout the effective period (which can last for several years), maintaining stable blood drug concentrations and delivering excellent therapeutic effects. However, since the drug must diffuse into the body through the silicone tube, very high molecular weight and water solubility requirements are imposed. Only drugs with a molecular weight less than 800 and a solubility less than 10 mg / mL can be released. Even if drug release is possible, the dosage is very low, typically only tens of micrograms per day. This significantly limits the application of certain high-dose drugs, making them impractical.

[0479] The production process of skeleton-type implants is relatively simple, and they have the advantage of fast drug release. The daily drug release amount is several to dozens of times that of reservoir-type implants. However, their release is not smooth, and the drug release rate will gradually decrease, resulting in unstable blood drug concentration and even no drug effect.

[0480] In view of the defects of the existing reservoir-type implants in the art, such as high requirements for drug molecular weight and solubility, small release dose, and inability to meet the needs of large-dose drugs, and the defects of the skeleton-type implants in unstable drug release, causing fluctuations in blood drug concentration, poisoning, or ineffectiveness, the present invention also provides a hollow drug-loaded rod core, a preparation method, and an application thereof.

[0481] The present invention solves the above technical problems through the following technical solutions.

[0482] The present invention provides a hollow skeleton-type drug-loaded rod core, the raw material composition of which comprises the following components in parts by weight:

[0483] Active pharmaceutical ingredient: 1-1000 parts;

[0484] R-vinyl silicone rubber: 100 parts;

[0485] Hydrogenated silicone oil: 0.45-20 parts;

[0486] Catalyst: ≥0.000002 parts;

[0487] in:

[0488] 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 aromatic hydrocarbons;

[0489] The vinyl content in the R-vinyl silicone rubber is 0.1-0.5 mol%;

[0490] The content of Si-H groups in the hydrogenated silicone oil is 0.18-1.6 mol%;

[0491] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1.

[0492] In the present invention, the dosage of the pharmaceutical active ingredient may be 1-800 parts, for example, 10 parts, 30 parts, 50 parts, 60 parts, 100 parts, 120 parts, 150 parts, 250 parts, 500 parts or 600 parts.

[0493] In the present invention, R in the R-vinyl silicone rubber may be a substituted or unsubstituted C1-C5 straight-chain alkane, such as a methyl group.

[0494] When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber.

[0495] The methyl vinyl silicone rubber may be conventional methyl vinyl silicone rubber in the art, for example, methyl vinyl silicone rubber having a relative molecular weight of 100,000-800,000 g / mol.

[0496] 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%, 0.22 mol% or 0.23 mol%.

[0497] In the present invention, the hydrogen-containing silicone oil can be conventional hydrogen-containing silicone oil in the art, such as hydrogen-containing silicone oil purchased from Guangdong Guiye New Material Technology Co., Ltd.

[0498] In the present invention, the amount of the hydrogen-containing silicone oil can be 0.5-20 parts, preferably 1.2-6.3 parts, for example, 1.33 parts, 2 parts, 2.67 parts, 3 parts, 3.56 parts or 4.44 parts.

[0499] In the present invention, the content of Si-H groups (hydrogen content) in the hydrogen-containing silicone oil is preferably 0.5-1.5 mol%, such as 0.75 mol%, 0.8 mol%, 1.0 mol% or 1.2 mol%.

[0500] 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 (0.8-20):1, for example, 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 3.0:1, 4:1, 4.5:1, 5:1, 8:1, 10:1 or 15:1, preferably (3-8):1 or (3-6):1.

[0501] In the present invention, the raw material composition may optionally further include an inhibitor. The inhibitor may be a conventional inhibitor in the art capable of inhibiting the addition reaction between R-vinyl silicone rubber and hydrogen-containing silicone oil at room temperature, such as an acetylenic alcohol compound, a nitrogen-containing compound, or an organic peroxide, further such as methylbutynol, and further such as 2-methyl-3-butyn-2-ol.

[0502] In the present invention, the dosage of the inhibitor may be 0.000002-1 part, preferably 0.03-5 parts, more preferably 0.1-2.0 parts, such as 0.3-1.0 parts, and further such as 0.3 parts, 0.5 parts, 0.7 parts, 0.9 parts or 0.98 parts.

[0503] In the present invention, 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 rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst.

[0504] The concentration of platinum in the platinum catalyst may be 10,000 ppm, which means that the mass concentration of platinum in the platinum catalyst is 10,000 parts per million.

[0505] In the present invention, the amount of the catalyst may be 0.000002-0.5 parts, such as 0.000005 parts, 0.00001 parts, 0.00002 parts, 0.00003 parts, 0.1 parts, 0.2 parts, 0.21 parts, 0.25 parts or 0.3 parts, preferably 0.03-0.3 parts, more preferably 0.1-0.3 parts.

[0506] In the present invention, the vulcanization principle of the two-component addition-type silicone rubber is as follows: the two-component addition-type room temperature vulcanized silicone rubber, for example, uses vinyl polydimethylsiloxane as the base polymer and hydrogen-containing silicone oil as the cross-linking agent. Under the catalytic action of a catalyst (such as a platinum catalyst), the vinyl group and the hydrogen group undergo a silylation reaction to form a cross-linked network structure. The cross-linked structure can control the release of drugs. The reaction formula is shown below.

[0507] After mixing with the cross-linking agent and catalyst, the raw rubber can react at room temperature. However, the mixing and processing of the rubber compound requires a certain amount of time. If the reactants are cured early during the operation, the desired shape and properties will not be obtained. This is especially true for addition-type silicone rubber. Therefore, it is generally required that the catalytic reaction has almost no effect before vulcanization (mixing at room temperature), and reacts rapidly when the vulcanization temperature is reached. The method of suppressing the reaction is usually to add an inhibitor. The inhibitor can form a certain form of complex with the platinum catalyst. The effective inhibitor can be placed with the rubber compound for a considerable period of time, and can only be vulcanized when heated to a certain vulcanization temperature. The more commonly used ones are acetylenic alcohol compounds, nitrogen-containing compounds, organic peroxides, etc. with good compatibility.

[0508] In the present invention, the active pharmaceutical ingredient is not particularly limited and can be a conventional sustained-release pharmaceutical ingredient in the art that requires long-term drug release, such as drugs used in the fields of contraception, schizophrenia, hormones, and anti-tumor.

[0509] In the present invention, the pharmaceutical active ingredient can be as described above.

[0510] In the present invention, the active drug may include conventional drugs in the art, for example, one or more of a macromolecular drug with good solubility, a small molecule drug with good solubility, a macromolecular drug with poor solubility, and a small molecule drug with poor solubility.

[0511] Among them, the macromolecular drug with good solubility can be a conventional active drug in the art with a drug solubility of >10 mg / mL (with water as solvent) and a drug molecular weight greater than 800 Da, preferably including an active drug with a drug solubility of >30 mg / mL (with water as solvent) and a drug molecular weight >800 Da, such as one or more of exenatide, semaglutide, Centella asiatica total glycosides and human growth hormone.

[0512] Among them, the small molecule drug with good solubility can be an active drug with a conventional drug solubility of >10 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da in the art, preferably including an active drug with a drug solubility of >30 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da, such as metformin hydrochloride and / or doxorubicin hydrochloride.

[0513] The poorly soluble macromolecular drug may be a conventional active drug in the art having a solubility of ≤10 mg / mL (in water as a solvent) and a molecular weight of >800 Da, preferably including an active drug having a solubility of ≤5 mg / mL (in water as a solvent) and a molecular weight of >800 Da, such as one or more of bovine insulin, paclitaxel, and levothyroxine sodium.

[0514] Among them, the small molecule drug with poor solubility can be an active drug with a conventional drug solubility of ≤10 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da in the art, preferably including an active drug with a drug solubility of ≤5 mg / mL (with water as solvent) and a drug molecular weight of ≤800 Da, such as one or more of estradiol, gestodene, meloxicam, ganciclovir, puerarin and paliperidone.

[0515] In some preferred embodiments of the present invention, the raw material composition of the hollow skeleton type rod core may include the following components in parts by weight:

[0516] In some preferred embodiments of the present invention, the raw material composition of the hollow skeleton type rod core may include the following components in parts by weight:

[0517] In the present invention, the ratio of the outer diameter to the inner diameter of the hollow skeleton drug-loaded rod core can be 1.5-50:1, for example, 2.14:1, 3:1, 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1.

[0518] In the present invention, the outer diameter of the hollow skeleton-type drug-loaded rod core may be 1 mm to 10 mm, preferably 2.0 mm, 3.0 mm, 4 mm or 5 mm.

[0519] In the present invention, the inner diameter of the hollow skeleton drug-loaded rod core may be 0.1 mm-4.0 mm, preferably 0.40 mm-2.0 mm, for example 0.4 mm, 0.6 mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.4 mm, 1.6 mm or 2.0 mm.

[0520] In a preferred embodiment, the outer diameter of the hollow skeleton-type drug-loaded rod core may be 3 mm, and the inner diameter may be 0.6-1.4 mm, 0.6 mm, 1.0 mm or 1.4 mm.

[0521] In some preferred embodiments of the present invention, the specifications of the hollow skeleton-type stick core are shown in the following table, and the pharmaceutical active ingredient is preferably paliperidone;

[0522] The present invention also provides a method for preparing a hollow skeleton-type drug-loaded rod core, which comprises the following method:

[0523] S1: dividing the R-vinyl silicone rubber into component A1 and component B1;

[0524] When the raw material composition contains an inhibitor, the component A1 is mixed with the hydrogen-containing silicone oil and the inhibitor to obtain component A2; the component B1 is mixed with the catalyst to obtain component B2;

[0525] S2: mixing the component A2 and the component B2 to obtain a rubber compound;

[0526] S3: mixing the rubber mixture and the active pharmaceutical ingredient to obtain drug-loaded silica gel;

[0527] S4: The drug-loaded silica gel is extruded and vulcanized to obtain a hollow skeleton-type drug-loaded rod core.

[0528] In S1, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, for example, drying at 30-60° C. (eg, 40° C.) for 1-24 h (eg, 12 h) for later use.

[0529] In S1, the preparation method of the component A1 or the component B1 can be conventional in the art. Generally, the components are mixed in an open mill and then thinly passed 4-6 times and discharged in the form of flakes.

[0530] In S2, the step of mixing the component A2 and the component B2 may include the following steps: putting the component A2 and the component B2 into an open mill at a weight ratio of 1:1 and mixing them 4-6 times to make the B1 and B2 component rubbers fully mixed and uniformly formed into a mixed rubber.

[0531] In S3, the step of mixing the rubber mix and the active pharmaceutical ingredient may include the following steps: placing the rubber mix and the active pharmaceutical ingredient in an open mixer and mixing them, so that the rubber mix 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.

[0532] In S4, the extrusion is generally performed in a screw extruder.

[0533] In S4, during the extrusion, the screw speed of the extruder can be 1-15 r·min -1 , for example 4r·min -1 or 6 r·min -1 .

[0534] In S4, during the extrusion, the diameter of the die used is preferably 1-10 mm, for example, 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0535] In S4, during the extrusion, the diameter of the core die used is preferably 0.1-4 mm, for example, 0.58 mm, 0.8 mm, 0.97 mm, 1.2 mm or 1.38 mm.

[0536] In S4, the vulcanization is generally performed in an oven.

[0537] In S4, the vulcanization temperature may be 25-120°C, preferably 60-90°C, for example 30°C, 50°C, 60°C, 65°C, 70°C, 80°C, 90°C, 100°C or 120°C.

[0538] In S4, the vulcanization time may be 10-200 min, preferably 10-60 min, for example, 10 min, 20 min, 30 min, 40 min or 50 min.

[0539] The present invention also provides an application of the hollow skeleton-type drug-loaded rod core as a release rate regulating medium in a sustained-release preparation.

[0540] In the present invention, the vinyl content in the R-vinyl silicone rubber refers to the mole percentage, and the mole percentage of vinyl refers to the number of moles of vinyl in every 100 moles of R-vinyl silicone rubber.

[0541] In the present invention, the hydrogen content or Si-H group content in the hydrogen-containing silicone oil refers to the mole percentage, and the mole percentage of hydrogen content refers to the number of moles of hydrogen in every 100 moles of the hydrogen-containing silicone oil.

[0542] In the present invention, PHR refers to the mass parts of each specific component per 100 mass parts of R-vinyl silicone rubber (such as methyl vinyl silicone rubber).

[0543] In the present invention, the room temperature refers to 25°C±5°C.

[0544] On the basis of conforming to the common sense in this field, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0545] The reagents and raw materials used in the present invention are commercially available.

[0546] The positive progress effect of the present invention is:

[0547] (1) Compared with the drug powder-reservoir implant, the reservoir-skeleton implant provided by the present invention can reduce drug loss and save drug costs; reduce the phenomenon of sudden release; release the drug more smoothly, control the release amount within the effective therapeutic window, and achieve long-term stable release; at the same time, accelerate production speed and improve production efficiency;

[0548] (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.

[0549] (3) The present invention utilizes active pharmaceutical ingredients with an average particle size of 1-1000 nm, which significantly improves drug solubility and enhances compatibility with silicone rubber. The resulting framework-type and reservoir-type implants exhibit significantly increased release rates. For example, the release rate of paliperidone from the present invention can be increased by 3-10 times compared to active pharmaceutical ingredients with conventional particle sizes.

[0550] (4) When the average particle size of paliperidone is 200-300 nm, its release rate can be increased by 4-8 times; when it is 300-400 nm, its release rate can be increased by 3-4 times; when it is 400-600 nm, its release rate can be increased by 2-3 times; when it is 800-900 nm, its release rate can be increased by 1-1.2 times.

[0551] (5) The present invention has a wide range of applications and is applicable to a variety of drugs, achieving stable release of large doses. For example, the release rate of estradiol, meloxicam, and exemestane can be increased by 4-10 times.

[0552] (6) The present invention uses R-vinyl silicone rubber, hydrogenated silicone oil, a catalyst, and other components as the basic silicone rubber formulation. The model drug and silicone rubber are mixed using extrusion technology to form a hollow skeleton-type drug-loaded rod core. This invention combines the advantages of both traditional reservoir-type implants and skeleton-type implants, as follows:

[0553] ①Simple production process: basically the same as the production process of skeleton-type implants, reducing production links and saving costs;

[0554] ② Wide range of drug applications: Applicable to all drugs, not affected by drug molecular weight, solubility, physicochemical properties, particle size, crystal form, etc.; active ingredients with molecular weight >800Da or molecular weight ≤800Da; and active ingredients with solubility >10mg / mL or solubility ≤10mg / mL are all applicable;

[0555] ③Stable release: By reducing the degree of slowing down of the release rate, zero-order release can be achieved, with stable blood drug concentration, precise efficacy, and meeting clinical needs;

[0556] ④ Large release amount: The drug release area is increased, the drug is released on both the inner and outer surfaces, and the drug release rate is increased. The released dose is several times that of traditional skeleton-type implants and dozens to hundreds of times that of reservoir-type implants. BRIEF DESCRIPTION OF THE DRAWINGS

[0557] Figure 1 shows the release of gestodene skeleton stick core.

[0558] Figure 2 shows the daily release of gestodene from the reservoir-matrix formulation.

[0559] Figure 3 shows the release amount at different cross-linking agent molar ratios.

[0560] Figure 4 shows the effect of different vulcanization times on the release of the silicone rod core.

[0561] FIG5 shows the in vitro release of levonorgestrel from the silicone rod core.

[0562] Figure 6 shows the effect of the release area of ​​the silicone rod core on the release amount.

[0563] FIG7 shows the in vitro release results of the paliperidone skeleton-type stick cores before and after nano-sizing prepared in Example 4-2 and Example 4-1.

[0564] FIG8 shows the in vitro release results of the paliperidone hollow skeleton rod cores before and after nano-sizing prepared in Example 5-2 and Example 5-1.

[0565] FIG9 shows the in vitro release results of the paliperidone skeleton reservoir implants before and after nano-sizing prepared in Example 6-2 and Example 6-1.

[0566] FIG10 shows the in vitro release results of the paliperidone drug powder reservoir implants before and after nano-sizing prepared in Example 7-2 and Example 7-1.

[0567] FIG11 shows the in vitro release results of the paliperidone hollow skeleton nanorod cores with different inner diameters prepared in Example 10-1 and the paliperidone hollow skeleton rod cores with different inner diameters prepared in Example 10-2.

[0568] FIG12 is a comparison of the in vitro release results of the paliperidone hollow skeleton nano-rod cores with different particle sizes prepared in Example 11 and the paliperidone hollow skeleton rod cores prepared in Example 5-2.

[0569] FIG13 shows the in vitro release results of the estradiol hollow skeleton rod cores before and after nano-sizing prepared in Example 8-2 and Example 8-1.

[0570] FIG14 shows the in vitro release results of the meloxicam hollow skeleton stick cores before and after nano-sizing prepared in Example 9-2 and Example 9-1.

[0571] FIG15 is a photograph of the skeleton-type rod core prepared in Example 19-4 ( FIG15 left) and the hollow skeleton-type rod core prepared in Example 15-1 ( FIG15 right). DETAILED DESCRIPTION

[0572] The present invention is further illustrated by way of examples below, but the present invention is not limited to the scope of the examples. Experimental methods in the following examples where specific conditions are not specified were performed according to conventional methods and conditions, or selected according to the product specifications.

[0573] The information of the instruments and reagents used in the following examples and comparative examples is shown in Tables 1 and 2 below:

[0574] Table 1

[0575] Table 2

[0576] The relevant terms are explained as follows: skeleton-type implant, also known as skeleton-type rod core, refers to a rod core only 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.

[0577] 1. Gestodene skeleton core

[0578] 1.1 Preparation of Gestodene Skeleton Stick Core

[0579] 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.

[0580] Example 1-1

[0581] Basic prescription

[0582] The gestodene skeleton-type rod core is a rod-shaped silicone rod core prepared by mixing the model drug gestodene with silicone rubber. The formula 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.

[0583] Among them, the selected gestodene has a particle size of 2-3 μm after air flow grinding; the selected methyl vinyl silicone rubber has a vinyl group as the end-capping group of the silicone rubber, and the vinyl content range 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 10,000 ppm; and the selected 2-methyl-3-butyn-2-ol is an inhibitor.

[0584] 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) indicates the mass concentration of platinum in the platinum catalyst.

[0585] Preparation process

[0586] (1) Drying pretreatment of raw rubber: Dry the methyl vinyl silicone rubber raw rubber at 40℃ for 12 hours.

[0587] (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 it in an open mill, and then pass it through the mill for 5 times to unload it in the form of thin slices. Add the prescribed amount of platinum catalyst to component B, mix it in an open mill, and then pass it through the mill for 5 times to unload it in the form of thin slices.

[0588] (3) Preparation of rubber compound: put the prepared A and B component sheets into the open mill at a ratio of 1:1 and mix them for 5 times to ensure that the A and B component rubbers are fully mixed and uniformly formed into a rubber compound.

[0589] (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 mill and mix them evenly to prepare drug-loaded silica gel, which is then cut into strips.

[0590] (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.

[0591] (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.

[0592] (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.

[0593] (8) Dimensional measurement and appearance inspection of the silicone rod core: The diameter of the extruded silicone rod core was measured using an infrared caliper, and the surface appearance of the silicone rod core was observed using an 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 .

[0594] Example 1-2 to Example 1-5 (Investigation of Catalyst Amount)

[0595] 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.

[0596] Table 3

[0597] 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, due to the small amount of catalyst, it could not be completely vulcanized; the best 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, due to the excessive amount, the rubber material was slightly hard during the drug-rubber mixing and silicone rod core extrusion process, resulting in rough extrusion of the silicone rod core and a decrease in mechanical properties; when the amount was increased to 0.30PHR, due to the excessive amount, the texture was too hard and the mechanical properties were relatively poor.

[0598] Example 1-6 and Example 1-7 (Investigation of the molar ratio of hydrogenated silicone oil)

[0599] The remaining operations and conditions were the same as in Examples 1-3, except that the molar ratio of the hydrogenated silicone oil was adjusted to the following values ​​(see Table 4). The molar ratio of the hydrogenated silicone oil refers to the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methyl vinyl silicone rubber.

[0600] Table 4

[0601] The results in Table 4 show that increasing the amount of hydrogenated silicone oil increases the elongation at break, tensile strength, and tear strength of the silicone rod core. Generally, in addition reactions of addition-forming silicone rubber, a molar ratio of hydrogenated silicone oil to vinyl groups in the silicone rubber is sufficient between 1.2 and 1.8. However, for silicone rod cores containing a drug-gel mixture, the presence of a large amount of drug in the silicone rubber hinders contact between the hydrogenated silicone oil's silane groups and the vinyl groups, leading to incomplete reaction. Therefore, it is necessary to further increase the molar ratio to achieve a greater excess of hydrogenated silicone oil, increasing the available hydrogenated silicone oil available for the addition reaction, ultimately achieving a complete reaction and optimal vulcanization of the silicone rod core. When a certain amount of hydrogenated silicone oil is added, the silicone tube achieves optimal molecular bonding and cross-linking, reaching peak mechanical properties. However, as the amount of hydrogenated silicone oil continues to increase, the excessive molecular bonding and cross-linking points within the silicone tube increase the binding force of the surrounding particles, reducing elasticity, making the silicone tube brittle, and reducing toughness, resulting in a decrease in elongation at break.

[0602] Example 1-8 and Example 1-9 (Investigation of vulcanization temperature)

[0603] Except that the vulcanization temperature was adjusted to the following values ​​(see Table 5), the other operations and conditions were the same as those of Examples 1-7.

[0604] Table 5

[0605] 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 mechanical properties were 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.

[0606] 1.2 In vitro release of gestodene skeleton stick core:

[0607] Content determination and in vitro release determination method of gestodene skeleton stick core

[0608] (1) Chromatographic conditions

[0609] Chromatographic column: C18 column (250 mm × 4.60 mm, 5 μm);

[0610] Mobile phase: methanol-water (80:20, v / v);

[0611] Column temperature: 30°C;

[0612] Detection wavelength: 239nm;

[0613] Flow rate: 1 mL min -1 ;

[0614] Injection volume: 20 μL.

[0615] (2) In vitro release experimental method

[0616] Using the horizontal oscillation method, take one implant and secure its ends to the bottom and wall of a 50mL stoppered Erlenmeyer flask with silicone adhesive (to prevent the implant from floating on the liquid surface, which could lead to inaccurate release results). After adhesion, allow the silicone adhesive to cure completely for 12 hours. Accurately measure 50mL of distilled water as the release medium and inject it into the Erlenmeyer flask. Place the flask in a constant-temperature air shaker and shake it at 37°C and an amplitude of 100 r / min. -1 The medium was replaced with an equal volume every 24 h. The release solution was filtered through a 0.22 μm microporous filter membrane and detected according to chromatographic conditions with an injection volume of 20 μL.

[0617] According to relevant literature and patent reports, gestodene release of 10-20 μg per day can achieve drug efficacy. 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 formula is the same as that of Example 1-7) was selected for a 35-day in vitro release study.

[0618] According to Figure 1 and Table 6, the results show that the release of gestodene skeleton core can be maintained within the effective therapeutic window of 10-20 μg / d for 35 days, but there is a problem of unstable release and the daily release amount shows a downward trend.

[0619] Table 6

[0620] 1.3 Preparation of silicone tube:

[0621] Table 7 Prescription, vulcanization process and dimensions of silicone tube

[0622] Note: The vinyl content of methyl vinyl silicone rubber is 0.18%; the Si-H group content of hydrogenated silicone oil is 0.75%, and the molar ratio of Si-H groups in hydrogenated silicone oil to vinyl groups in methyl vinyl silicone rubber is 1.5:1; the platinum concentration of the selected platinum catalyst is 3000 ppm.

[0623] The specific process is as follows:

[0624] (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.

[0625] (2) Preparation of rubber compound: Put the prescribed amount of fumed silica and methyl vinyl silicone rubber into a kneader and knead them at 30°C for 30 minutes to make the fumed silica and rubber evenly mixed. Then take out the rubber compound to obtain the rubber compound, transfer it to an open mill for extrusion (roller spacing is 1 mm), and use the shearing effect of the two rollers of the open mill to further mix the rubber more thoroughly. Then, unload the rubber compound from the open mill in the form of a thin sheet, wrap the rubber compound with plastic wrap, put it into a ziplock bag, and put it into a desiccant for 18 hours for use.

[0626] (3) Preparation of Components A and B: The rubber mix 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 and mixed in an open mill. The mixture is then thinned several times and discharged in the form of thin sheets. The prescribed amount of platinum catalyst is added to Component B and mixed in an open mill. The mixture is then thinned several times and discharged in the form of thin sheets. The prepared Components A and B are wrapped in plastic wrap, placed in ziplock bags, and placed in a desiccator for 18 hours for later use.

[0627] (4) Mixing of components A and B: Put the parked components A and B into the open mill at a ratio of 1:1 and make triangular thin rolls 5 times to ensure that the components A and B are fully mixed. Unload them in the form of thin slices on the open mill and cut them into strips.

[0628] (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.

[0629] (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 take shape.

[0630] (7) Second vulcanization treatment: After the first vulcanization, the silicone tube enters the post-drying channel (horizontal hot air vulcanization channel) to continue vulcanization, which is the second vulcanization treatment. This makes the vulcanization reaction of the silicone tube more complete and reaches the optimal cross-linking state. The finished silicone tube is then continuously transported out through the conveyor belt of the post-drying channel.

[0631] 1.4 Preparation of Depot-Framework Gestodene Implant:

[0632] Examples 1-10

[0633] (1) Silicone tubing preparation: Prepare silicone tubing according to Section 1.3 above. Take a 2.4 cm outer diameter addition-type silicone tubing that meets all applicable appearance and performance requirements and cut it to the required length, leaving 0.4 cm longer than the silicone rod core, leaving 0.2 cm for the sealing adhesive at each end of the implant. Place the cut silicone tubing in a beaker and soak it in 75% ethanol for 15 min. Rinse it repeatedly with 75% ethanol several times and allow it to air dry.

[0634] (2) Assembly of silicone rod core and silicone tube:

[0635] Silicone rod core: Except for adjusting the weight ratio of gestodene to the rubber compound in step (4) to 1:1 in the preparation process, the rest of the formulation and process are the same as those in Example 1-7; the diameter of the rod core is 0.2 cm and the length is 1.5 cm.

[0636] Soak the cut silicone tube in petroleum ether to swell for 2 minutes. After the silicone tube is swollen, take it out of 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 use tweezers to insert the cut silicone rod core into the middle position of the silicone tube, leaving the same length of space at both ends of the silicone tube in preparation for sealing. After assembly is completed, let the implant dry naturally for 20 hours to evaporate the residual petroleum ether.

[0637] (3) End sealing of implant: Seal both ends of the naturally air-dried implant with sealing glue and leave it at room temperature for 20 hours to allow the sealing glue to solidify, thereby obtaining the reservoir-skeleton type gestodene implant.

[0638] 1.5 Investigation of factors affecting the in vitro release of reservoir-framework type gestodene implants:

[0639] The in vitro testing method for the reservoir-skeleton type gestodene implant is the same as that for "1.2 In vitro release of gestodene skeleton type rod core".

[0640] (1) Investigation of the vulcanization time of the silicone rod core

[0641] Example 1-11 and Example 1-12

[0642] Except that the curing time of the silicone rod core was adjusted to the following values ​​(see Table 8), the other operations and conditions were the same as those of Examples 1-10.

[0643] Table 8

[0644] A 30-day in vitro release test was conducted using the reservoir-framework type gestodene implants prepared in Examples 1-10, 1-11, and 1-12 to investigate the effect of the curing time of the silicone rod core on the release of the reservoir-framework type gestodene implant.

[0645] 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 drug release stability when the curing time is 1 hour and 2 hours is slightly better than that when it is 3 hours. Taking into account the thermal stability of the drug, when the curing time is 1 hour, the silicone rod core can reach the optimal curing state and the drug release stability is also good.

[0646] Table 9 Drug release at different curing times μg / d

[0647] (2) Investigation of the drug release area of ​​the silicone rod core

[0648] 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 formula for the lateral surface area of ​​the cylinder as follows:

[0649] S=πd×L, S: drug release area of ​​silicone rod core, d: diameter of silicone rod core, L: length of silicone rod core

[0650] 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 2.4 mm, the wall thickness was 0.2 mm, the diameter of the silicone rod core was fixed at 0.2 cm, and the lengths of the silicone rod cores were cut to 0.5, 1.5, 2.5, and 3.5 cm, respectively. They were assembled with the silicone tube into implants for 30 days of in vitro release to investigate the change in the in vitro drug release amount with the drug release area of ​​the silicone rod core.

[0651] Table 10 Effect of drug release area on in vitro release of reservoir-framework type gestodene implant

[0652] 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.

[0653] The results in Table 11 show that as the release area of ​​the silicone rod core increases, the daily release rate of the reservoir-skeleton type gestodene implant increases accordingly. The release rate is linearly related to the release area of ​​the silicone rod core.

[0654] Table 11 Drug release amount in different release areas μg / d

[0655] 1.6. In vitro release of gestodene from a reservoir-matrix implant

[0656] Except for the dimensions shown in Table 12, the formula and preparation process of the stick core were the same as those of Examples 1-10. The preparation of the reservoir-framework type gestodene implant was the same as described in Section 1.4 above.

[0657] Table 12

[0658] A 150-day long-term in vitro release experiment was conducted on the reservoir-framework type gestodene implant. The results are shown in Figure 2 and Table 13. The results showed that the average daily release of the implant over 150 days was approximately 19.5 μg, with good release stability and no obvious burst release. This indicates that the implant's release behavior over 150 days met the requirements and that the implant can achieve controlled release for at least five months.

[0659] Table 13

[0660] 2. Levothyroxine Sodium Skeleton Core

[0661] 2.1 Preparation of Levothyroxine Sodium Skeleton Rod Core

[0662] Example 2-1

[0663] The prescription consists of 100 PHR of levothyroxine sodium, 100 PHR of methyl vinyl silicone rubber, 0.3 PHR of hydrogenated silicone oil, 0.27 PHR of platinum catalyst, and 0.49 PHR of 2-methyl-3-butyn-2-ol.

[0664] Among them, the selected levothyroxine sodium has a particle size of 80 μm; the selected methyl vinyl silicone rubber has a vinyl group as the end-capping group of the silicone rubber, and the vinyl content range is 0.17%; the selected hydrogenated silicone oil has a Si-H group content of 0.75 mol%, and the molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methyl vinyl silicone rubber is 2:1; the selected platinum catalyst has a platinum concentration of 10,000 ppm; and the selected 2-methyl-3-butyn-2-ol is the inhibitor.

[0665] The preparation of the levothyroxine sodium skeleton core was the same as that in Example 1-1 except that the above-mentioned formula was used and the curing temperature and curing time were adjusted to 50°C and 0.5h. The diameter of the levothyroxine sodium skeleton core was 3 mm, the length was 4 cm, and the drug release area was 3.9003 cm. 2 .

[0666] Example 2-2 to Example 2-4

[0667] Except for using the following catalyst dosage (see Table 14), the other operations and conditions are the same as those in Example 2-1.

[0668] Table 14 Prescription and vulcanization of silicone rod core under different catalyst dosages

[0669] The amount of platinum catalyst added has a great influence on the formability of the rod core. Too little catalyst will cause the core to not be completely cross-linked, easily deformed or broken, and have poor mechanical properties; too much catalyst will cause oversulfurization, the texture will be hard, affecting the processing of the rubber material, and may also cause breakage.

[0670] The effect of catalyst dosage on the cross-linking degree of the implant is shown in Table 14. The vulcanization molding of the implant with a catalyst dosage in the range of 0.20PHR to 0.30PHR was investigated. The experiment found that when the amount of catalyst was less than 0.20PHR, the implant was still in an "under-vulcanization" state no matter how long it took, and it could not be completely vulcanized and molded at 0.20PHR. In the range of 0.25PHR, the implant could be molded after vulcanization for 5 hours, and in the range of 0.27PHR, the implant had good moldability after vulcanization for half an hour, and at 0.3PHR, the implant had become hard and could not be extruded before molding, and was in an "over-vulcanization" state.

[0671] 2.2 Content determination and in vitro release determination method of levothyroxine sodium skeleton stick core:

[0672] (1) Chromatographic conditions

[0673] Chromatographic column: SinoDetectHCL-C18 column (4.6×250mm, 5μm)

[0674] Mobile phase: acetonitrile-0.1% TFA (50:50, v / v)

[0675] Column temperature: 30°C

[0676] Detection wavelength: 225nm

[0677] Flow rate: 1 mL min -1

[0678] Injection volume: 20 μL

[0679] (2) In vitro release experimental method

[0680] Using the horizontal oscillation method, take 1 tube / set of subcutaneous implants and fix them in a 20 mL sample bottle using silicone adhesive. Accurately measure an appropriate amount of 0.1% BSA release medium into the sample bottle, keeping the preparation below the liquid level of the release medium, and place it in an oscillation chamber with an amplitude of 100 r·min. -1 The release was carried out in a thermostatic oscillator at 37°C. Sampling was performed every 24 hours, the release medium was replaced, and the solution was filtered through a 0.22 μm filter membrane. The sample was injected according to the chromatographic conditions and the detection was recorded.

[0681] 2.3 Investigation of factors affecting the in vitro release of levothyroxine sodium matrix implants:

[0682] Example 2-5 to Example 2-7 (crosslinking agent dosage molar ratio)

[0683] Except for adopting the following molar ratio of cross-linking agent, other operations and conditions are the same as those in Example 2-1.

[0684] The molar ratio of the cross-linking agent affects the degree of vulcanization cross-linking of the implant, while the degree of cross-linking network affects the later release and diffusion rate. The specific prescription is shown in Table 15.

[0685] Table 15 Silicone rod core formulations with different crosslinking agent ratios

[0686] The results of investigating different cross-linking ratios are shown in Figure 3 and Table 16. When the molar ratio of the cross-linking agent is 2:1, the amount added is too small, the formed channels are relatively few, and the internal branches of the implant are arranged in a disordered order, which blocks the release of the mixed drug and results in a small release amount. When the molar ratio of the cross-linking agent is 4:1, the amount of cross-linking agent added is too large, the internal cross-linking structure is unstable, and side reactions are prone to occur, causing changes in the internal structure and hindering the release of the drug. When the ratio is 3:1 and 3.5:1, the internal network channels are more suitable for drug diffusion, the release amount is closer to the release requirement, and the release is more stable.

[0687] Table 16 Effect of different cross-linker molar ratios on drug release μg / d

[0688] Note: The test object in Table 16 is one levothyroxine sodium matrix implant.

[0689] Example 2-8 to Example 2-10 (drug release area)

[0690] Except for preparing the rod core into the following dimensions, the other operations and conditions (composition and amount of the rod core) were the same as those in Example 2-5.

[0691] The skeleton-type implant is a cylindrical device that releases drugs 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. 释药面积 =2S 底 +S 侧 =2πr 2 +πdL

[0692] r: implant bottom radius d: implant bottom diameter L: implant length

[0693] The drug release areas of skeleton-type implants with different diameters and lengths are shown in Table 17. The effect of different drug release areas on the in vitro release of the skeleton-type implants was investigated.

[0694] Table 17 Release area of ​​silicone rod cores of different sizes

[0695] The results of drug release area are 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 amount of the preparation is significantly increased, and the release is more stable.

[0696] Table 18 Drug release amount in different release areas μg / d

[0697] Note: The test object in Table 18 is one levothyroxine sodium matrix implant.

[0698] 2.4 In vitro release of levothyroxine sodium matrix implant:

[0699] An in vitro release test was conducted on the levothyroxine sodium skeleton implant prepared in Example 2-10.

[0700] A set of two levothyroxine sodium skeleton implants were subjected to long-term release for one month. The in vitro release profile is shown in Table 19. The drug release showed a slowly decreasing trend. This was because the outer layer of drug 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 became longer, the diffusion rate slowed down, and the daily release amount gradually decreased. The release amount was maintained at 100-120 μg / d within one month. The results showed that the prepared skeleton implant can effectively release the drug for one month.

[0701] Table 19

[0702] 3. Levonorgestrel skeleton silicone rod core

[0703] 3.1 Preparation of Levonorgestrel Skeleton Silicone Rod Core

[0704] Example 3-1

[0705] Basic prescription

[0706] Levonorgestrel 10 PHR; Methylvinyl silicone rubber 100 PHR; Hydrogenated silicone oil 0.667 PHR; 2-methyl-3-butyn-2-ol (inhibitor) 0.49 PHR; Platinum catalyst 0.25 PHR;

[0707] Among them, the selected methyl vinyl silicone rubber has vinyl as the end-capping group of the silicone rubber and the vinyl content is 0.18%; the selected hydrogen-containing silicone oil has an 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 10,000 ppm; the process is: vulcanization temperature 110°C, vulcanization time 1h.

[0708] Note: PHR (parts per hundreds of rubber) indicates the number of parts of the component per 100 parts of base polymer.

[0709] Preparation method

[0710] The preparation method of the levonorgestrel skeleton silicone rod core was the same as that of Example 1-1 except that the above-mentioned prescription was used. The diameter of the levonorgestrel skeleton silicone rod core was 2 mm, the length was 4 cm, and the drug release area was 2.5748 cm. 2 .

[0711] 3.2 In vitro release determination method of levonorgestrel matrix implant

[0712] (1) Chromatographic conditions

[0713] Chromatographic column: C18 column (250mm×4.60mm)

[0714] Mobile phase: acetonitrile-water (70:30, v / v)

[0715] Column temperature: 30°C

[0716] Detection wavelength: 240nm

[0717] Flow rate: 1 mL min -1

[0718] Injection volume: 20 μL

[0719] (2) In vitro release experimental method

[0720] The release rate was determined by the horizontal oscillation method: a set of implants was fixed to each other in a 100 mL stoppered conical flask with an adhesive. 100 mL of distilled water was accurately measured as the release medium. The stoppered conical flask was placed in a constant temperature oscillator with an amplitude of 100 r / min. -1 , the temperature is 37℃, ensuring that the implant is always below the liquid surface, sampling is carried out every 24 hours and the release medium is replaced with an equal volume, and the sample solution is filtered through a 0.22μm microporous filter membrane and tested according to the "chromatographic conditions".

[0721] 3.3 Investigation of the Levonorgestrel Skeleton Silicone Rod Core Process:

[0722] The most important process factors affecting the curing and molding of silicone rod cores are curing temperature and curing time. Curing temperature determines whether the silicone rod core can be cured and molded. Excessively high temperatures may cause drug decomposition, affecting drug release; while excessively low temperatures may prevent complete curing of the silicone rod core. The same applies to curing time; either too long or too short a time can affect drug release.

[0723] Example 3-2 and Example 3-3 (Effect of Vulcanization Temperature)

[0724] Except for adopting the following vulcanization temperature (see Table 20), the other operations and conditions are the same as those in Example 3-1.

[0725] Table 20

[0726] The effects of different silicone core curing temperatures on in vitro release are shown in Table 21. Daily release was similar when the core was cured at 90°C and 110°C, but significantly decreased at 130°C. The daily release and mechanical properties were optimal at 110°C.

[0727] Table 21 Drug release at different curing temperatures μg / d

[0728] Note: The test object in Table 21 is one levonorgestrel matrix implant.

[0729] Example 3-4 and Example 3-5 (Influence of Curing Time)

[0730] Except for the following vulcanization time (see Table 22), the remaining operations and conditions are the same as those in Example 3-1.

[0731] Table 22

[0732] The effects of different silicone rod curing times on in vitro release are shown in Figure 4 and Table 23. Silicone rods cured for 0.5 hours exhibited a relatively high daily release rate when prepared into skeleton-type implants, while no significant difference in daily release was observed between silicone rods cured for 1 hour and 2 hours. A 1-hour curing time resulted in better daily release and mechanical properties, while also reducing the time cost of the preparation process.

[0733] Table 23 Drug release at different curing times μg / d

[0734] Note: The test object in Table 23 is one levonorgestrel matrix implant.

[0735] 3.4 In vitro release of skeleton-type silicone rod core:

[0736] The levonorgestrel silicone rod core prepared in Example 3-1 was released for 35 days. From the release curve (Figure 5 and Tables 21-22), it can be seen that the release can be maintained within the effective therapeutic window, but there is an uneven release, and the daily release amount shows a downward trend.

[0737] 3.5 Preparation of Reservoir-Framework Levonorgestrel Implant

[0738] Examples 3-6

[0739] Preparation of reservoir-matrix levonorgestrel implant:

[0740] 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. Other than that, the other steps are the same as the preparation method of the reservoir-framework type gestodene implant.

[0741] Table 24 Final formula, vulcanization process and dimensions of silicone tube

[0742] Note: The vinyl content of methyl vinyl silicone rubber is 0.18%; the Si-H group content 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; the platinum catalyst has a platinum concentration of 3000 ppm.

[0743] Table 25 Final formulation, curing process and dimensions of drug-loaded silicone rod core

[0744] Note: The vinyl content of methyl vinyl silicone rubber is 0.18%; the Si-H content of 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; the platinum catalyst has a platinum concentration of 10,000 ppm.

[0745] 3.6. Investigation of factors affecting the in vitro release of levonorgestrel reservoir-matrix levonorgestrel implants:

[0746] The in vitro release determination method of the reservoir-matrix type levonorgestrel implant is the same as that of “3.2 In vitro release determination method of the levonorgestrel matrix type implant”.

[0747] Investigation of drug release area

[0748] Except for using the dimensions in Table 26, the remaining operations and conditions are the same as those in Examples 3-6.

[0749] The implant is cylindrical in appearance, capped at both ends with end-capping glue. The drug is released entirely through the lateral surfaces of the entire formulation. The drug release area directly determines the degree of contact between the drug and body fluids and the outward diffusion pathway of the drug, playing a crucial role in drug release. The implant's drug release area S = π·d·L, where d is the diameter of the silicone rod core and L is the length of the silicone rod core. Reservoir-framework levonorgestrel implants of varying sizes were prepared according to Table 27 to investigate the effect of the drug release area on in vitro release.

[0750] Table 26 Effect of drug release area on daily release amount

[0751] The effects of different drug release areas on in vitro release are shown in Figure 6 and Table 27. As the drug release area increases, the daily release amount gradually increases. The in vitro daily release amount is positively correlated with the drug release area of ​​the implant. The drug release area has an important influence on the daily release amount of the reservoir-skeleton type levonorgestrel implant.

[0752] Table 27 Drug release amount in different release areas μg / d

[0753] Note: The test object in Table 27 is one reservoir-matrix type levonorgestrel implant.

[0754] 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 drug release pathway increases, so the daily release amount has a significant upward trend.

[0755] Compared to levonorgestrel matrix implants, reservoir-matrix levonorgestrel implants with a controlled-release membrane offer more stable release. The membrane increases the drug's diffusion pathways within the implant, reducing the drug diffusion rate within the membrane to a lower rate than within the matrix, resulting in a relatively low release rate. Furthermore, the membrane slows the formation of a blank area within the silicone rod core, maintaining a consistent drug concentration within the membrane and enabling a steady release from the implant.

[0756] Table 28

[0757] Note: The test subjects in Table 28 are 2 reservoir-matrix type levonorgestrel implants.

[0758] For the silicone rod core, the drug release area is 251.2 mm 2 In vitro release testing of a reservoir-matrix levonorgestrel implant was conducted. The results in Table 28 show that the average daily release of the implant over 180 days was approximately 40 μg, with good release stability and no significant burst release. This indicates that the implant's release behavior over 180 days meets the requirements and that the implant can achieve controlled release for at least six months.

[0759] Example 4-1 Paliperidone skeleton nanorod core

[0760] A. Basic prescription:

[0761] (1) Nano paliperidone, with an average particle size of 220 nm and an addition amount of 100 PHR;

[0762] (2) Methyl vinyl silicone rubber, vinyl content of 0.18 mol%, added in an amount of 100 PHR;

[0763] (3) hydrogenated silicone oil, with a Si-H group content of 0.75 mol%, added in an amount of 4.44 PHR;

[0764] (4) platinum catalyst, the concentration of platinum is 10000 ppm, and the addition amount is 0.21 PHR;

[0765] (5) 2-methyl-3-butyn-2-ol, added in an amount of 0.98 PHR;

[0766] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is 5:1.

[0767] 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) indicates the mass concentration of platinum in the platinum catalyst.

[0768] B. Preparation process:

[0769] (1) Drying pretreatment of raw rubber: Dry the methyl vinyl silicone rubber raw rubber at 40℃ for 12 hours.

[0770] (2) Preparation of component A and component B rubber: Take the prescribed amount of raw rubber and divide it equally into two components, A and B. Add hydrogenated silicone oil and inhibitor to component A, mix it in an open mill, and then pass it through several times to remove it in the form of thin sheets. Add platinum catalyst to component B, mix it in an open mill, and then pass it through several times to remove it in the form of thin sheets.

[0771] (3) Preparation of rubber compound: put the prepared A and B component sheets into the open mill at a ratio of 1:1 and mix them for 6 times to ensure that the A and B component rubbers are fully mixed and uniformly formed into a rubber compound.

[0772] (4) Preparation of drug-loaded silica gel: Nano paliperidone and mixed rubber were mixed evenly on an open mill at a drug-to-gel weight ratio of 1:1 to prepare drug-loaded silica gel, which was then cut into strips.

[0773] Nano paliperidone was obtained by nano-processing the raw material paliperidone. Specifically, a planetary ball mill was used for wet grinding. 0.4 g of the stabilizer poloxamer 188 was added to 2 g of the raw material paliperidone. Zirconia beads with a diameter of 0.1 mm were used as the grinding medium. The grinding time was controlled to be 50 min and the rotation speed was 400 r / min. -1 After grinding, the freeze-drying process is adopted, and the nano-freeze-dried powder is obtained after freeze-drying.

[0774] (5) Extrusion of the rod core: Install a die with a diameter of 2.96 mm and set the extruder screw speed to 7 r / min -1 The cut drug-loaded silicone strips are put into the extruder, and the drug-loaded silicone is continuously extruded into rod cores through the die mouth under the push of the screw.

[0775] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized at 80°C for 50 minutes to form an elastomer.

[0776] The diameter of the paliperidone skeleton nanorod core is determined by the diameter of the die. The outer diameter of the rod core prepared in this embodiment is 3 mm.

[0777] Example 4-2 Paliperidone skeleton core

[0778] A. Basic prescription

[0779] (1) The amount of paliperidone added was 100 PHR, and the average particle size was 5 μm;

[0780] (2)-(5) are the same as the prescriptions (2)-(5) of Example 4-1.

[0781] B. Preparation process

[0782] Compared with Example 4-1, the difference of Example 4-2 is that the raw material paliperidone is directly used in step (4), and the other operations are the same as Example 4-1.

[0783] Example 5-1 Paliperidone Hollow Skeleton Nanorod Core

[0784] A. Basic prescription

[0785] Same basic recipe as Example 4-1.

[0786] B. Preparation process

[0787] The preparation process of (1) to (4) and (6) is the same as that of Example 4-1.

[0788] (5) Extrusion of hollow skeleton rod core: Install a 2.96 mm diameter die and a 1.4 mm diameter core die, and set the extruder screw speed to 7 r / min -1The cut drug-loaded silicone strips are put into the extruder, and the drug-loaded silicone is continuously extruded through the die mouth into a hollow skeleton rod core under the push of the screw.

[0789] The outer diameter of the paliperidone hollow skeleton nanorod core is determined by the diameter of the die, and the inner diameter is determined by the diameter of the core mold. The outer diameter of the rod core prepared in this embodiment is 3 mm and the inner diameter is 1.4 mm.

[0790] Example 5-2 Paliperidone Hollow Skeleton Rod Core

[0791] A. Basic prescription

[0792] Same basic recipe as Example 4-2.

[0793] B. Preparation process

[0794] Compared with Example 5-1, the difference of Example 5-2 is that the raw material paliperidone is directly used in step (4), and the other operations are the same as Example 5-1.

[0795] Example 6-1 Paliperidone skeleton reservoir nano-type implant

[0796] A. Basic prescription:

[0797] It consists of a silicone tube and a paliperidone skeleton nanorod core with an average particle size of 220 nm, which is prepared by the preparation method of Example 4-1.

[0798] a. Basic prescription of silicone tube

[0799] The basic formula of silicone tube consists of base polymer, reinforcing agent, cross-linking agent, catalyst and inhibitor.

[0800] (1) The selected base polymer is methyl vinyl polysiloxane, vinyl is the end-capping group of polysiloxane, the vinyl content is 0.18 mol%, and the addition amount is 100 PHR;

[0801] (2) The selected reinforcing agent is fumed silica, and the addition amount is 40PHR;

[0802] (3) The crosslinking agent selected is hydrogenated silicone oil, the Si-H group content of which is 0.75 mol%, and the addition amount is 1.07 PHR;

[0803] (4) The selected platinum catalyst has a platinum concentration of 3000 ppm and an addition amount of 0.21 PHR;

[0804] (5) The selected inhibitor was 2-methyl-3-butyn-2-ol, and the addition amount was 0.98 PHR.

[0805] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methylvinyl polysiloxane is 1.2:1.

[0806] b. Basic formula of paliperidone skeleton nanorod core

[0807] The basic formula of the paliperidone skeleton nanorod core was the same as that prepared in Example 4-1; wherein the average particle size of paliperidone was 220 nm.

[0808] B. Preparation process

[0809] (1) Preparation of silicone tube:

[0810] ① Drying pretreatment of the rubber material: Place the reinforcing agent fumed silica in a 130℃ oven and dry it for 12 hours, and dry the methyl vinyl silicone rubber at 40℃ for 12 hours.

[0811] ② Preparation of rubber mix: put the prescribed amount of fumed silica and methyl vinyl silicone rubber into a kneader, knead for 30 minutes at 30℃ to make the fumed silica and raw rubber evenly mixed, then take out the rubber mix to obtain the rubber mix, transfer it to an open mill for extrusion and thinning, and make triangle wrap thinning 5 times with a roller spacing of 1mm. Use the shearing effect of the two rollers of the open mill to further mix the rubber, and then unload the rubber from the open mill in the form of sheets, wrap the rubber with plastic wrap, put it into a ziplock bag, and put it in a desiccant for 24 hours.

[0812] ③ Preparation of Components A and B: Divide the rubber mix equally into Components A and B. Add the prescribed amount of hydrogenated silicone oil and inhibitor to Component A, mix thoroughly on an open mill, and thinly pass through several times to remove the mixture in the form of thin sheets. Add the prescribed amount of platinum catalyst to Component B, mix thoroughly on an open mill, and thinly pass through several times to remove the mixture in the form of thin sheets. Wrap the prepared Components A and B separately in plastic wrap, place them in ziplock bags, and store in a desiccator for 24 hours.

[0813] ④ Mixing of components A and B: Add the parked components A and B into the mixing mill at a ratio of 1:1, and make triangular rolls 6 times to ensure that the components A and B are fully mixed. Unload them in the form of slices on the mixing mill and cut them into strips.

[0814] ⑤ Extrusion of silicone tube: Install a die with a diameter of 2.96 mm and set the extruder screw speed to 7 r / min -1 , put the cut silicone strips into the extruder, and the rubber is continuously extruded into silicone tubes through the die mouth under the push of the rotating screw.

[0815] ⑥ The first vulcanization treatment: The silicone tube extruded from the mold mouth first passes through a front drying channel (vertical hot air vulcanization channel) for rapid high-temperature vulcanization, which is the first vulcanization treatment (temperature is 300°C, vulcanization time is about 5s), so that the silicone tube quickly changes from a sticky and soft state to an elastic state, and is initially shaped.

[0816] ⑦ Second vulcanization treatment: After the first vulcanization, it enters the post-drying channel (horizontal hot air vulcanization channel) to continue vulcanization, which is the second vulcanization treatment (temperature is 280°C, vulcanization time is about 2 minutes), so that the vulcanization reaction of the silicone tube is more complete and reaches the optimal cross-linking state. The finished silicone tube is then continuously transported out through the conveyor belt of the post-drying channel; a silicone tube with an outer diameter of 3.4 mm and a wall thickness of 0.2 mm is prepared.

[0817] (2) Preparation of paliperidone skeleton nanorod core: The preparation method is the same as that of paliperidone skeleton nanorod core in Example 4-1.

[0818] (3) Silicone Tubing Treatment: Take an addition-type silicone tube that meets all requirements for appearance and performance, cut it to a length of 4.4 cm, 0.4 cm longer than the paliperidone skeleton nanorod core, and leave 0.2 cm for the sealing glue at each end of the implant. Place the cut silicone tube in a beaker and soak it in 75% ethanol for 15 minutes. Then rinse it repeatedly with 75% ethanol several times and let it air dry.

[0819] (4) Assembly of the paliperidone skeleton nanorod core and the silicone tube: Soak the silicone tube in petroleum ether to swell for 1-2 minutes. After the silicone tube swells, remove it 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 removed from the petroleum ether. At this time, immediately and quickly insert the cut paliperidone skeleton nanorod core (4 cm in length and 3 mm in outer diameter) into the middle position of the silicone tube with tweezers, leaving the same length of space at both ends of the silicone tube for sealing. After assembly, let the implant dry naturally for 24 hours to evaporate the residual petroleum ether.

[0820] (5) End sealing of the implant: Seal the two ends of the naturally air-dried implant with sealing glue and leave it at room temperature for 24 hours to allow the sealing glue to solidify, thereby obtaining the paliperidone implant.

[0821] The paliperidone skeleton reservoir nano-type implant prepared by the above preparation method comprises a skeleton-type drug-loaded rod core with a diameter of 3.0 mm and a length of 4.0 cm; a silicone tube with an outer diameter of 3.4 mm, a wall thickness of 0.2 mm, and a length of 4.4 cm, and a drug release area of ​​3.77 cm. 2 .

[0822] Example 6-2 Paliperidone skeleton reservoir implant

[0823] A. Basic prescription

[0824] It consists of a silicone tube and the skeleton-type rod core prepared in Example 4-2.

[0825] a. Basic prescription of silicone tube

[0826] The basic formula of the silicone tube prepared in Example 6-1 is the same.

[0827] b. Basic formula of skeleton core

[0828] The basic formula of the skeleton-type rod core is the same as that of Example 4-2.

[0829] B. Preparation process

[0830] Compared with Example 6-1, the difference of Example 6-2 is that the rod core is different; specifically, the paliperidone skeleton nano-type rod core prepared in step (2) is replaced with the paliperidone skeleton type rod core prepared in Example 4-2, and the other operations are the same as Example 6-1.

[0831] Example 7-1 Paliperidone drug powder reservoir nano-type implant

[0832] A. Basic prescription:

[0833] The invention consists of a silicone tube and a nanopowder core. The silicone tube has the same basic formula as the silicone tube prepared in Example 6-1. The nanopowder core is paliperidone with an average particle size of 220 nm.

[0834] B. Preparation process:

[0835] Compared with Example 6-1, the difference of Example 7-1 lies in the different rod core; specifically, on the one hand, the paliperidone skeleton nano-rod core obtained in step (2) is changed to a nano-powder-type drug core; on the other hand, in step (4), after the silicone tube is cleaned with ethanol, one end of the silicone tube is first sealed with silicone sealing glue, and the nano-powder-type drug core is filled through the drug filling funnel, and the other end is sealed with silicone in step (5).

[0836] The paliperidone powder reservoir nano-type implant prepared by the above preparation method has an outer diameter of 3.4 mm, a wall thickness of 0.2 mm, a length of 4.4 cm, and a drug release area of ​​3.77 cm. 2 ; The diameter of the drug-loaded segment is 3.0 mm and the length is 4.0 cm.

[0837] Example 7-2 Paliperidone Powder Reservoir Implant

[0838] A. Basic prescription

[0839] The invention consists of a silicone tube and a powder core. The silicone tube has the same basic formula as the silicone tube prepared in Example 6-1. The powder core is paliperidone with an average particle size of 5 μm.

[0840] B. Preparation process

[0841] Compared with Example 7-1, the difference of Example 7-2 is that the rod core is different; specifically, the nano-powder type core is changed to a powder type core, and other operations are the same as Example 7-1.

[0842] Example 8-1 Estradiol Hollow Skeleton Nanorod Core

[0843] Based on Example 5-1, only the active ingredient of the drug was changed from nano-paliperidone to nano-estradiol, and the average particle size of nano-estradiol was 198 nm.

[0844] Example 8-2 Estradiol Hollow Skeleton Rod Core

[0845] Based on Example 8-1, only the active ingredient of the drug was changed from nano-estradiol to estradiol, and the average particle size of estradiol was 66 μm.

[0846] Example 9-1 Meloxicam Hollow Skeleton Nano-Rod Core

[0847] Based on Example 5-1, only the active ingredient of the drug was changed from nano paliperidone to nano meloxicam, and the average particle size of nano meloxicam was 308 nm.

[0848] Example 9-2 Meloxicam hollow skeleton stick core

[0849] Based on Example 9-1, only the active ingredient was changed from nano-meloxicam to meloxicam, and the average particle size of meloxicam was 80 μm.

[0850] Example 10-1 Paliperidone hollow skeleton nanorod cores with different inner diameters

[0851] On the basis of Example 5-1, only the size of the core mold during the extrusion of the hollow skeleton type rod core was changed to 0.58 mm, 0.97 mm and 1.38 mm, respectively, to obtain a paliperidone hollow skeleton nano-type rod core with an outer diameter of 3 mm and an inner diameter of 0.6 mm, 1.0 mm and 1.4 mm, respectively.

[0852] Example 10-2 Paliperidone hollow skeleton cores with different inner diameters

[0853] Based on Example 5-2, only the core die size during the extrusion of the hollow skeleton rod core was changed to 0.58 mm, 0.97 mm, and 1.38 mm, respectively. Paliperidone hollow skeleton nanorod cores with an outer diameter of 3 mm and inner diameters of 0.6 mm, 1.0 mm, and 1.4 mm were obtained. In other words, compared with Example 10-1, Example 10-2 differs in that paliperidone is directly used as the raw material in step (4). All other operations are the same as in Example 10-1.

[0854] Example 11 Paliperidone hollow skeleton nanorod cores with different particle sizes

[0855] On the basis of Example 5-1, only the grinding time during the nano-processing of the raw material paliperidone was changed to prepare paliperidone hollow skeleton nanorod cores with average particle sizes of 820 nm, 646 nm, 430 nm and 220 nm, respectively.

[0856] Examples 12-14 are based on Example 4-1, and the types of stabilizers, grinding media and grinding time during the grinding process are investigated.

[0857] Example 12 Investigation of Stabilizer Types

[0858] Active ingredient: stabilizer = 5:1, ball mill speed is 400r·min -1 The grinding medium was 0.2 mm zirconium oxide beads, the grinding medium was 20 mL, and the grinding time was 50 min. The effects of stabilizer types poloxamer 188 (P188), Tween 80, poloxamer 407 (P407), SDS, and HPMC on the average particle size and PDI (PDI is a dimensionless value reflecting the width of the particle size distribution, ranging from 0 to 1. The smaller the value, the more uniform the particle size and the more concentrated the particle size distribution) of the active pharmaceutical ingredient after grinding were investigated.

[0859] Table 29 Effect of different types of stabilizers on average particle size and PDI

[0860] The results show that the effects of the above five stabilizers all meet the experimental requirements, and the PDI are all less than 0.3.

[0861] Example 13 Investigation of Grinding Media Types

[0862] Active ingredient: stabilizer = 5:1, ball mill speed is 400r·min -1 , poloxamer 188 as stabilizer, grinding medium 20 mL, grinding time 50 min, and the effects of 0.1 mm, 0.2 mm, and 0.3 mm zirconia beads on the average particle size and PDI of the active pharmaceutical ingredient after grinding were investigated.

[0863] Table 30 Effect of different grinding media types on average particle size and PDI

[0864] The results show that as the diameter of the zirconia beads increases, the average particle size and PDI also increase. Zirconia beads with a diameter of 0.1-0.3 mm have a PDI of < 0.3, which meets the experimental requirements. Using 0.1 mm zirconia beads as the grinding medium, the final PDI and average particle size are the smallest in the same grinding time.

[0865] Example 14 Grinding time investigation

[0866] Active ingredient: stabilizer = 5:1, ball mill speed is 400r·min -1 , poloxamer 188 as stabilizer, 0.1 mm zirconium oxide beads as grinding media, and the effects of grinding time of 15 min, 25 min, 35 min, 45 min, 50 min, and 60 min on the average particle size and PDI of the active pharmaceutical ingredient after grinding were investigated.

[0867] Table 31 Effect of different grinding times on average particle size and PDI

[0868] The results showed that paliperidone of different particle sizes was obtained by using 0.1 mm zirconium oxide beads and grinding time ranging from 15 to 60 min during the grinding process.

[0869] According to Examples 12-14, the ball mill speed is 400 r / min. -1 Using P188 as a stabilizer, 0.1mm zirconium oxide beads as grinding media, and grinding process parameters of 50 minutes, and then using freeze-drying process after grinding, freeze-drying for 24 hours, the obtained nano freeze-dried powder can significantly improve the drug release when used in implants.

[0870] Effect Example 1 In vitro release investigation

[0871] 1. Test conditions:

[0872] (1) Chromatographic conditions for in vitro release of paliperidone

[0873] Chromatographic column: Chromatographic column (4.6 × 100 mm, 2.7 μm);

[0874] Mobile phase: methanol: water (45:55, v / v) (pH adjusted to 3 with phosphoric acid);

[0875] Column temperature: 35°C;

[0876] Detection wavelength: 280nm;

[0877] Flow rate: 1.0 mL min -1 ;

[0878] Injection volume: 20 μL.

[0879] (2) Chromatographic conditions for in vitro release of estradiol

[0880] Chromatographic column: C18 column (250 mm × 4 mm, 5 μm)

[0881] Mobile phase: acetonitrile-water (55:45, v / v)

[0882] Column temperature: 25°C

[0883] Detection wavelength: 202nm

[0884] Flow rate: 0.8 mL min -1

[0885] Injection volume: 20 μL

[0886] (3) Chromatographic conditions for in vitro release of meloxicam

[0887] Chromatographic column: C18 column (4.6 mm × 150 mm, 5 μm);

[0888] Mobile phase: methanol: 0.5% phosphoric acid aqueous solution (70:30, v / v);

[0889] Column temperature: room temperature;

[0890] Detection wavelength: 270nm;

[0891] Flow rate: 1.0 mL min -1 ;

[0892] Injection volume: 20 μL.

[0893] 2. In vitro release test method

[0894] Using the horizontal oscillation method, take a rod core and fix the ends of the rod core to the bottom and wall of a 100mL conical flask with silicone adhesive (to prevent the rod core from floating on the liquid surface and causing inaccurate release results). After adhesion, let it stand for 12 hours to allow the adhesive to cure completely. Accurately measure 100mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it at 37°C and an amplitude of 100 r / min. -1 , replace the same volume of medium every 1 day.

[0895] 3. Release results

[0896] (1) Paliperidone skeleton core

[0897] Table 32 In vitro release results of paliperidone skeleton core prepared in Example 4-2

[0898] Table 33 In vitro release results of paliperidone skeleton nanorod core prepared in Example 4-1

[0899] The results showed that after the drug was nanosized, the release rate of the paliperidone skeleton nanorod core was about four times higher than the original rate (as shown in Figure 7).

[0900] (2) Paliperidone hollow skeleton core

[0901] Table 34 In vitro release results of the paliperidone hollow skeleton core prepared in Example 5-2

[0902] Table 35 In vitro release results of the paliperidone hollow skeleton nanorod core prepared in Example 5-1

[0903] The results showed that after the drug was nanosized, the release rate of paliperidone from the hollow skeleton nanorod core was about four times higher than the original rate (as shown in Figure 8).

[0904] (3) Paliperidone skeleton reservoir implant

[0905] Table 36 In vitro release results of paliperidone matrix reservoir implant prepared in Example 6-2

[0906] Table 37 In vitro release results of paliperidone skeleton reservoir nano-type implant prepared in Example 6-1

[0907] The results showed that after the drug was nanosized, the release rate of paliperidone skeleton reservoir nano-type implant was about 3.5 times the original rate.

[0908] (As shown in Figure 9)

[0909] (4) Paliperidone powder reservoir implant

[0910] Table 38 In vitro release results of paliperidone drug powder reservoir implant prepared in Example 7-2

[0911] Table 39 In vitro release results of the paliperidone powder reservoir nano-implant prepared in Example 7-1

[0912] The results showed that after the drug was nanosized, the release rate of the paliperidone drug powder reservoir nano-implant was about 6 times faster than the original. (As shown in Figure 10)

[0913] (5) Comparison of in vitro release results of paliperidone hollow skeleton nanorod cores with different inner diameters

[0914] The in vitro release results of the paliperidone hollow skeleton nanorod cores with different inner diameters prepared in Example 10-1 and the paliperidone hollow skeleton rod cores with different inner diameters prepared in Example 10-2 are shown in FIG11 .

[0915] Table 40 In vitro release results of paliperidone hollow skeleton cores with different inner diameters

[0916] Table 41 In vitro release results of paliperidone hollow skeleton nanorod cores with different inner diameters

[0917] The results showed that as the inner diameter of the paliperidone hollow skeleton nanorod core increased, the in vitro release dose also increased significantly.

[0918] (6) Comparison of in vitro release results of paliperidone hollow skeleton nanorod cores with different particle sizes

[0919] The in vitro release results of the paliperidone hollow skeleton nanorod cores with average particle sizes of 820 nm, 646 nm, 430 nm and 220 nm prepared in Example 11 and the paliperidone hollow skeleton rod cores prepared in Example 5-2 are shown in FIG12 .

[0920] Table 42 In vitro release results of paliperidone hollow skeleton nanorod cores with different particle sizes

[0921] The results showed that paliperidone rod cores of different particle sizes exhibited different release rates, with smaller particle sizes resulting in faster release rates. Among the paliperidone hollow skeleton nanorod cores of varying particle sizes, the release rate of paliperidone was approximately four times that of the pre-nanostructured paliperidone at 220 nm, three times that of the pre-nanostructured paliperidone at 430 nm, two times that of the pre-nanostructured paliperidone at 646 nm, and 1.5 times that of the pre-nanostructured paliperidone at 820 nm.

[0922] (7) Estradiol hollow skeleton rod core

[0923] Table 43 In vitro release results of the estradiol hollow skeleton stick core prepared in Example 8-2

[0924] Table 44 In vitro release results of estradiol hollow skeleton nanorod core prepared in Example 8-1

[0925] (8) Meloxicam hollow skeleton rod core

[0926] Table 45 In vitro release results of the meloxicam hollow skeleton stick core prepared in Example 9-2

[0927] Table 46 In vitro release results of the meloxicam hollow skeleton nanorod core prepared in Example 9-1

[0928] The results showed that the release rate of estradiol at 198 nm was about 4 times that before grinding ( FIG. 13 ), and the release rate of meloxicam at 308 nm was about 5 times that before grinding ( FIG. 14 ).

[0929] Conclusion of the full article: Nanosized drugs can be used in skeleton-type implants, hollow skeleton-type implants, skeleton reservoir-type implants, and drug powder reservoir-type implants. Compared with non-nanosized drugs, the release rate can be increased by 2-8 times. In addition, nanosized drugs have better compatibility with silica gel, which is more conducive to the production of implants.

[0930] Example 15-18 Paliperidone Hollow Skeleton Stick Core

[0931] Hollow skeleton rod core formulation and process investigation

[0932] (1) Using tensile strength, elongation at break and tear strength as evaluation indicators, the effects of the amount of catalyst, amount of hydrogenated silicone oil, vulcanization temperature and vulcanization time on the mechanical properties of the skeleton rod core were studied.

[0933] Tensile strength (Ts) is the maximum tensile stress a specimen experiences until fracture. It represents the material's resistance to maximum uniform plastic deformation and can be used to describe the rod's maximum resistance to external damage. Elongation at break (Eb) is the ratio of the elongation at break to the original length of the specimen. It represents the specimen's deformation range and can indicate the range of deformation the rod can withstand before fracture. Tear strength (T) is the strength required to tear the specimen and represents the rod's ability to resist tearing.

[0934] (2) Mechanical properties determination method:

[0935] Place the prepared skeleton rod core symmetrically on the upper and lower clamps of the servo system tensile testing machine, set the clamp distance to 50 mm, prepare the elongation test device, and set the tensile rate of the sample to 200 mm min -1 , start the tensile testing machine. Record the maximum tensile stress during the stretching process, the length of the sample when stretched to fracture, and the force required to tear the sample. Calculate the elongation at break, tensile strength, and tear strength of the sample according to the following formulas. Elongation at break (%) E b =100(L b -L0) / L0

[0936] L b - gauge length of the specimen at break, mm, L0 - initial gauge length of the specimen, mm. Tensile strength (MPa) Ts = Fm / Wt

[0937] Fm-the maximum force recorded, W-the width of the narrow part of the cutter, mm, t-the thickness of the length of the sample. Tear strength (KN / m) T=F / t

[0938] F is the maximum force required to tear the specimen, t is the thickness of the specimen (mm).

[0939] Example 15 Investigation of Catalyst Dosage

[0940] 1. The basic formula and mechanical properties of the hollow skeleton rod core are shown in Table 47.

[0941] Table 47

[0942] 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) indicates the mass concentration of platinum in the platinum catalyst.

[0943] 2. Preparation process of hollow skeleton rod core:

[0944] (1) Drying pretreatment of raw rubber: Dry the methyl vinyl silicone rubber raw rubber at 40℃ for 12 hours.

[0945] (2) Preparation of component A and B rubber: Take the prescribed amount of R-vinyl silicone rubber and divide it equally into two components, A1 and B1. Add hydrogenated silicone oil and inhibitor to component A1, mix it evenly in an open mill, pass it through several thin passes, and remove it in the form of thin flakes to obtain component A2. Add platinum catalyst to component B1, mix it evenly in an open mill, pass it through several thin passes, and remove it in the form of thin flakes to obtain component B2.

[0946] (3) Preparation of rubber compound: put the prepared A2 and B2 component sheets into the open mill at a ratio of 1:1 and mix them 4 to 6 times to ensure that the A2 and B2 component rubbers are fully mixed and uniformly formed into a rubber compound.

[0947] (4) Preparation of drug-loaded silica gel: Paliperidone and the mixed rubber were mixed evenly on an open mixer to prepare drug-loaded silica gel, which was then cut into strips.

[0948] (5) Extrusion of hollow skeleton rod core: Install a 2.96 mm diameter die, a 1.38 mm diameter core die, and set the extruder screw speed to 4 r·min -1 The cut drug-loaded silicone strips are put into the extruder, and the drug-loaded silicone is continuously extruded through the die mouth into a hollow skeleton rod core under the push of the screw.

[0949] Among them, the size of the hollow skeleton type rod core: the outer diameter of the hollow skeleton type rod core is determined by the diameter of the mouth die, and the inner diameter is determined by the diameter of the core die.

[0950] (6) Vulcanization of the hollow skeleton rod core: After the rod core is extruded, it is placed in an oven and vulcanized at 80°C for 30 minutes to form an elastomer.

[0951] 3. The results show that as the catalyst dosage increases, the mechanical properties of the rod core first significantly increase and then slightly decrease, reaching the best performance at a catalyst dosage of 0.21 PHR. During the experiment, it was found that when the catalyst dosage was increased to 0.25 PHR and 0.3 PHR, the rubber compound became slightly stiff during the drug-rubber mixing and drug-core extrusion process due to excessive dosage, resulting in rough extrusion of the rod core and decreased mechanical properties. Therefore, a catalyst dosage of 10,000 ppm can be selected with a range of 0.1-0.3 PHR, with 0.21 PHR being the most preferred.

[0952] Example 16 Investigation of the amount of hydrogenated silicone oil used

[0953] 1. The basic formula and mechanical properties of the hollow skeleton rod core are shown in Table 48.

[0954] 2. The preparation process of the fixed hollow skeleton rod core is the same as that in Example 15.

[0955] Table 48

[0956] 3. Results show that as the amount of hydrogenated silicone oil increases, the mechanical properties of the rod core gradually improve. Generally, in the addition reaction of addition-forming silicone rubber, a molar ratio of hydrogenated silicone oil to silicone rubber vinyl group between 1.2 and 1.5 is sufficient. However, for the drug-gel mixed rod core, the presence of a large amount of drug in the silicone rubber hinders the contact between the hydrogenated silicone oil's silane groups and the vinyl groups, resulting in an incomplete reaction. Therefore, it is necessary to further increase the molar ratio to achieve a greater excess of hydrogenated silicone oil and more effective hydrogenated silicone oil available for the addition reaction, ultimately achieving a complete reaction and optimal cure of the drug core. In this experiment, a molar ratio of hydrogenated silicone oil of 2.0-6.0 was selected.

[0957] Example 17 Investigation of vulcanization temperature

[0958] 1. The basic formula for the fixed hollow skeleton rod core is that of Example 16-3.

[0959] 2. The preparation process of the hollow skeleton rod core is the same as that of Example 15, except that:

[0960] (5) Extrusion of rod core: Install a die with a diameter of 2.96 mm, a core die with an inner diameter of 1.38 mm, and set the extruder screw speed to 6 r / min. - 1The cut drug-loaded silicone strips are put into the extruder, and the drug-loaded silicone is continuously extruded into rod cores through the die mouth under the push of the screw.

[0961] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized (the vulcanization process and mechanical property data are shown in Table 49) into an elastomer.

[0962] Table 49

[0963] 3. The results show that when the vulcanization temperature is 30-60°C, the mechanical properties are poor and the vulcanization effect is poor. When the vulcanization temperature is 60-90°C, the mechanical properties of the core first improve and then deteriorate, and continue to decline from 90-120°C. Therefore, considering the mechanical properties of the core and the thermal stability of the drug, the vulcanization temperature is selected to be 60-90°C, preferably 65-90°C.

[0964] Example 18 Investigation of vulcanization time

[0965] 1. The basic formula for the fixed hollow skeleton rod core is that of Example 16-3.

[0966] 2. The preparation process of the hollow skeleton rod core is the same as that of Example 15, except that:

[0967] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized (the vulcanization process and mechanical properties data are shown in Table 50) into an elastomer.

[0968] Table 50

[0969] 3. The results show that the core reaches its optimal mechanical properties at a vulcanization time of 30 minutes. However, the mechanical properties of the core do not increase with increasing vulcanization time at vulcanization times of 40 and 50 minutes, respectively. This indicates that the core reaches its optimal vulcanization state at a vulcanization temperature of 80°C and within 30 minutes. The vulcanization time of the present invention can be 10-60 minutes.

[0970] In summary, the final formulation and process for the hollow skeleton rod core are as follows: 100 PHR of paliperidone; 100 PHR of methylvinyl silicone rubber with a 0.18% vinyl content; 4.4 PHR of hydrogenated silicone oil with a 0.75 mol% hydrogen content; a molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the methylvinyl silicone rubber of 5:1; 0.75 mol% hydrogen in the hydrogenated silicone oil; 0.21 PHR of platinum catalyst with a platinum concentration of 10,000 ppm; 0.98 PHR of 2-methyl-3-butyn-2-ol; a curing temperature of 80°C; and a curing time of 30 minutes. Unless otherwise specified, the basic formulation and process for the hollow skeleton rod core described below are used in accordance with this document.

[0971] Example 19 Paliperidone Hollow Skeleton Stick Core

[0972] 1. Basic formula and preparation process of hollow skeleton rod core

[0973] Except for the size of the hollow skeleton rod core, the basic formula and preparation process are the same as the optimal formula and process obtained in Examples 15-18. -1 .

[0974] 2. Investigation of the extrusion size of hollow skeleton rod core

[0975] 2.1 Effect of die diameter and core mold diameter on the diameter of hollow skeleton rod core

[0976] The effects of different die and core mold diameters on the diameter of the hollow skeleton core were investigated. The die determines the outer diameter of the hollow skeleton core, while the core mold determines its inner diameter. Using different die and core molds, hollow skeleton cores of varying sizes were produced, as shown in Table 51.

[0977] Table 51 Hollow skeleton rod cores of different sizes

[0978] Experimental results: After the drug-loaded rod core passes through the mouth die and core die, the actual diameter is slightly larger than the diameter of the die. Mouth dies and core dies of different diameters can be matched according to actual needs to prepare hollow skeleton-type rod cores with an outer diameter of 1.8-6mm and an inner diameter of 0.4-2mm.

[0979] Unless otherwise specified, a 2.96 mm die and a 1.38 mm core die were selected in the following examples, and a hollow skeleton-type rod core with an outer diameter of 3 mm and an inner diameter of 1.40 mm was finally prepared.

[0980] Example 19-4 Paliperidone Skeleton-Type Stick Core (Solid Skeleton-Type Stick Core)

[0981] 1. The basic formula is the same as that of the hollow skeleton rod core in Example 19-3.

[0982] 2. Preparation process of skeleton type rod core

[0983] Steps (1)-(4) are the same as in Example 19-3;

[0984] (5) Extrusion of the rod core: Install a die with a diameter of 2.96 mm and set the extruder screw speed to 6 r / min -1 The cut drug-loaded silicone strips are put into the extruder. The drug-loaded silicone is continuously extruded through the die mouth under the push of the screw into a rod core. The diameter of the skeleton-type rod core is 3mm. Among them, the size of the rod core: the diameter of the skeleton-type rod core is determined by the die diameter.

[0985] (6) Vulcanization of the rod core: After extrusion, the rod core is placed in an oven and vulcanized at 80°C for 30 minutes to form an elastomer.

[0986] FIG15 is a photograph of the skeleton-type rod core prepared in Example 19-4 (left side of FIG15 ) and the hollow skeleton-type rod core prepared in Example 15-1 (right side of FIG15 ).

[0987] Example 20-1 Estradiol Hollow Skeleton Rod Core

[0988] 1. Basic formula: The same as the basic formula of Example 19-3, except that the drug is replaced with estradiol in equal amounts.

[0989] 2. The preparation process is the same as that of Example 19-3 except that the vulcanization temperature is 70°C and the vulcanization time is 50 min.

[0990] Example 20-2 Estradiol skeleton stick core

[0991] 1. The basic formula is the same as that of Example 20-1.

[0992] 2. The preparation process is the same as that of Example 19-4 except that the vulcanization temperature is 70°C and the vulcanization time is 50 min.

[0993] Example 21-1 Gestodene Hollow Skeleton Stick Core

[0994] 1. Basic formula: replace the drug with gestodene in equal amounts, and the molar ratio of hydrogenated silicone oil to vinyl in methyl vinyl silicone rubber is 4.5:1. The rest is the same as in Example 19-3.

[0995] 2. The preparation process is the same as that of Example 19-3 except that the vulcanization temperature is 90°C and the vulcanization time is 50 min.

[0996] Example 21-2 Gestodene Skeleton Stick Core

[0997] 1. The basic formula is the same as that of Example 21-1.

[0998] 2. The preparation process is the same as that of Example 19-4 except that the vulcanization temperature is 90°C and the vulcanization time is 50 min.

[0999] Example 22-1 Levothyroxine Sodium Hollow Skeleton Rod Core

[1000] 1. Basic formula: replace the drug with levothyroxine sodium in equal amounts, and the molar ratio of hydrogenated silicone oil to vinyl in methyl vinyl silicone rubber is 3:1. The rest is the same as in Example 19-3.

[1001] 2. The preparation process is the same as Example 19-3 except that the vulcanization temperature is 50°C.

[1002] Example 22-2 Levothyroxine Sodium Skeleton-Type Rod Core

[1003] 1. The basic formula is the same as that of Example 22-1.

[1004] 2. Preparation process The vulcanization temperature is 50°C, and the rest is the same as Example 19-4.

[1005] Example 23-1 Metformin Hydrochloride Hollow Skeleton Stick Core

[1006] 1. The amount of metformin hydrochloride added in the basic formula was adjusted to 30 PHR, and the rest was the same as Example 19-3.

[1007] 2. The preparation process is the same as that of Example 19-3.

[1008] Example 23-2 Metformin hydrochloride skeleton stick core

[1009] 1. The basic formula is the same as that of Example 23-1.

[1010] 2. The preparation process is the same as that of Example 19-4.

[1011] Example 24-1 Paclitaxel Hollow Skeleton Rod Core

[1012] 1. Basic prescription: The amount of paclitaxel added was adjusted to 80 PHR, and the rest was the same as Example 19-3.

[1013] 2. The preparation process is the same as that of Example 19-3 except that the vulcanization temperature is 75°C.

[1014] Example 24-2 Paclitaxel skeleton core

[1015] 1. The basic formula is the same as that of Example 24-1.

[1016] 2. The preparation process is the same as that of Example 19-4 except that the vulcanization temperature is 75°C.

[1017] Example 25-1 Centella asiatica total glycosides hollow skeleton stick core

[1018] 1. The amount of total glycosides in the basic formula was adjusted to 40 PHR, and the rest was the same as in Example 19-3.

[1019] 2. The preparation process is the same as that of Example 15.

[1020] Example 25-2 Centella asiatica total glycoside skeleton stick core

[1021] 1. The basic formula is the same as that of Example 25-1.

[1022] 2. The preparation process is the same as that of Example 19-4.

[1023] Effect Example In vitro release study of different preparations

[1024] 1. Chromatographic conditions for in vitro release of paliperidone: Chromatographic column: Chromatographic column (4.6 × 100 mm, 2.7 μm); mobile phase: methanol: water (45:55, v / v) (pH adjusted to 3 with phosphoric acid); column temperature: 35°C; detection wavelength: 280 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[1025] 2. Chromatographic conditions for in vitro release of estradiol: Chromatographic column: C18 column (250 mm × 4 mm, 5 μm); mobile phase: acetonitrile-water (55:45, v / v); column temperature: 25°C; detection wavelength: 202 nm; flow rate: 0.8 mL min -1 ; Injection volume: 20μL.

[1026] 3. Chromatographic conditions for in vitro release of gestodene: Chromatographic column: Chromatographic column (4.6 mm × 250 mm, 5 μm); mobile phase: methanol: water (80:20, v / v); column temperature: 30°C; detection wavelength: 239 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[1027] 4. Chromatographic conditions for in vitro release of levothyroxine sodium: Column: SinoDetect C18 column (4.6*250 mm, 5 μm); Mobile phase: Acetonitrile-0.1% TFA (50:50, v / v); Column temperature: 30°C; Detection wavelength: 225 nm; Flow rate: 0.8 mL min -1 ; Injection volume: 20μL.

[1028] 5. In vitro release of metformin hydrochloride: Chromatographic column: Chromatographic column (4.6 × 100 mm, 2.7 μm); mobile phase: methanol: water (60:40, v / v) (pH adjusted to 3 with phosphoric acid); column temperature: 40°C; detection wavelength: 218 nm; flow rate: 1.0 mL min - 1 ; Injection volume: 20μL.

[1029] 6. Chromatographic conditions for in vitro release of paclitaxel: Chromatographic column: Chromatographic column (4.6 mm × 250 mm, 5 μm); mobile phase: acetonitrile: water (45:55, v / v); column temperature: 35°C; detection wavelength: 227 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[1030] 7. Chromatographic conditions for in vitro release of total glycosides from Centella asiatica: Chromatographic column: Chromatographic column (4.6 mm × 250 mm, 5 μm); methanol: water (60:40, v / v); column temperature: 35°C; detection wavelength: 276 nm; flow rate: 1.0 mL min -1 ; Injection volume: 20μL.

[1031] 8. In vitro release test method

[1032] Using the horizontal oscillation method, take a rod core and fix the ends of the core to the bottom and wall of a 100mL conical flask with silicone adhesive (to prevent the rod core from floating on the liquid surface and causing inaccurate release results). After adhesion, let it stand for 12 hours to allow the adhesive to completely cure. Accurately measure 100mL of distilled water as the release medium and inject it into the conical flask. Place the conical flask in a constant temperature air shaker and shake it at 37°C and an amplitude of 100 r·min. -1 , replace the same volume of medium every 1 day.

[1033] 9 In vitro release results

[1034] 9.1 In vitro release results of paliperidone hollow skeleton rod cores with different outer diameter to inner diameter ratios

[1035] Table 52 shows the in vitro release data of the paliperidone hollow skeleton core of Examples (19-1) to (19-3).

[1036] Table 52 In vitro release results of paliperidone hollow skeleton core with different outer diameter and inner diameter ratios

[1037] As can be seen from the above table, the release rates are different for different outer diameter to inner diameter ratios. For a given outer diameter, the smaller the inner diameter, the less water permeates and the slower the release rate. While ensuring good mechanical properties and a fast release rate, the size of the hollow skeleton rod core in the embodiment of the present invention is selected to be 3 mm in outer diameter and 1.40 mm in inner diameter.

[1038] 9.2 Comparison of in vitro release results of paliperidone

[1039] Tables 53 and 54 show the 150-day in vitro release data for the paliperidone skeleton core of Example 19-4 and the paliperidone hollow skeleton core of Example 19-3, respectively. This indicates that the release rate of the paliperidone skeleton core, when converted to a hollow skeleton core, is approximately 3-4 times higher than the original.

[1040] Table 53 Paliperidone skeleton core 150-day in vitro release data

[1041] Table 54 Paliperidone hollow skeleton core 150-day in vitro release data

[1042] 9.3 Comparison of in vitro estradiol release results

[1043] Tables 55 and 56 show the 150-day in vitro release data for the estradiol skeleton stick core of Example 20-2 and the estradiol hollow skeleton stick core of Example 20-1, respectively. As shown in Tables 55 and 56, the release rate of the estradiol hollow skeleton stick core is approximately four times higher than the original.

[1044] Table 55 Estradiol skeleton stick core 150 day in vitro release data

[1045] Table 56 Estradiol hollow skeleton stick core 150 day in vitro release data

[1046] 9.4 Comparison of Gestodene Release Results in Vitro

[1047] Tables 57 and 58 show the 150-day in vitro release data for the gestodene skeleton core of Example 21-2 and the gestodene hollow skeleton core of Example 21-1, respectively. As shown in Tables 57 and 58, the release rate of gestodene from the gestodene skeleton core is approximately 3-4 times higher than the original hollow skeleton core.

[1048] Table 57 Gestodene skeleton stick core 150-day in vitro release data

[1049] Table 58 Gestodene hollow skeleton stick core 150-day in vitro release data

[1050] 9.5 Comparison of in vitro release results of levothyroxine sodium

[1051] Tables 59 and 60 present the 150-day in vitro release data for the levothyroxine sodium skeleton-type stick core of Example 22-2 and the levothyroxine sodium skeleton-type hollow stick core of Example 22-1, respectively. As shown in Tables 59 and 60, the release rate of levothyroxine sodium hollow-type stick core prepared from the levothyroxine sodium skeleton-type stick core is approximately 3-4 times higher than the original.

[1052] Table 59 Levothyroxine Sodium Scaffold Core 150 Day In Vitro Release Data

[1053] Table 60 Levothyroxine Sodium Hollow Skeleton Rod Core 150 Days In Vitro Release Data

[1054] 9.6 Comparison of in vitro release results of metformin hydrochloride

[1055] Table 61 shows the in vitro release data for the metformin hydrochloride skeleton core of Example 23-2 and the metformin hydrochloride hollow skeleton core of Example 23-1. The table below shows that the hollow skeleton core can increase the drug release rate by approximately 4 times while maintaining stable drug release.

[1056] Table 61 In vitro release data of metformin hydrochloride skeleton type stick core (Example 23-2) and hollow skeleton type stick core (Example 23-1)

[1057] 9.7 Comparison of Paclitaxel In Vitro Release Results

[1058] Tables 62 and 63 show the in vitro release data of the paclitaxel skeleton rod core of Example 24-2 and the paclitaxel hollow skeleton rod core of Example 24-1, respectively. Tables 62 and 63 show that the release rate of the paclitaxel hollow skeleton rod core prepared from the paclitaxel skeleton rod core is approximately 3-4 times that of the original one.

[1059] Table 62 Paclitaxel skeleton core 150-day in vitro release data

[1060] Table 63 Paclitaxel hollow skeleton core 150-day in vitro release data

[1061] 9.8 Comparison of in vitro release results of total Centella asiatica glycosides

[1062] Table 64 shows the in vitro release data for the asiaticoside skeleton-type stick core of Example 25-2 and the asiaticoside hollow skeleton-type stick core of Example 25-1. The table below shows that the hollow skeleton-type stick core is suitable for active drugs with concentrations greater than 30 mg / mL (in water) and molecular weights greater than 800 Da, increasing their release rate by approximately 3-4 times while maintaining stable release.

[1063] Table 64 In vitro release data of the Centella asiatica total glycoside skeleton stick core (Example 25-2) and the Centella asiatica total glycoside hollow skeleton stick core (Example 25-1)

[1064] Although the above describes specific embodiments of the present invention, it should be understood by those skilled in the art that these are merely illustrative and that various changes or modifications may be made to these embodiments without departing from the principles and essence of the present invention. Therefore, the scope of protection of the present invention is defined by the appended claims.

Claims

1. A 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 leuprorelin). drugs such as leuprolide, histrelin, flunitrium, estramustine, cyproterone acetate), drugs for ovarian cancer (such as carboplatin, topotecan, methotrexate), drugs for colorectal cancer (such as panitumumab), drugs for colon cancer (such as bevacizumab, oxaliplatin), drugs for liver cancer (such as sorafenib), drugs for lung cancer (such as erlotinib, gefitinib, docitabine), drugs for kidney cancer (such as pazopanib, everolimus, temsirolimus), drugs for gastric cancer (such as fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), pancreatic cancer drugs (e.g., nimotuzumab), esophageal cancer drugs (e.g., docetaxel, paclitaxel, cisplatin, gemcitabine, tegafur, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), skin cancer drugs (e.g., fluorouracil), lymphoma drugs (e.g., vincristine, bexarotene, dacarbazine, etoposide), myeloma drugs (e.g., bortezomib), cervical cancer drugs (e.g., bleomycin), or bladder cancer drugs (e.g., epirubicin, 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; and / or, 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.

3. 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, such as 1.5:1, 3.0:1 or 4.5:1, more preferably (3.0-4.5):1; or, 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: (8) 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; (9) The dosage of the active pharmaceutical ingredient is 10-500 parts, for example, 100 parts, 150 parts or 200 parts; (10) 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; (11) 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; (12) The vinyl content in the R-vinyl silicone rubber is 0.10%-0.30 mol%, for example 0.17 mol%; (13) The content of Si-H groups in the hydrogen-containing silicone oil is 0.15-1.2 mol%, for example 0.75 mol%; (14) 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.

4. A rod core, characterized in that: The raw material components include the pharmaceutical composition as described in any one of claims 1 to 3; Optionally, the method for preparing the stick core comprises 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.

5. An implant, characterized in that: It comprises the rod core and the silicone tube as claimed in claim 4; Optionally, the method for preparing the implant comprises the following steps: filling the stick core as described in claim 4 into the silicone tube.

6. A raw material composition for a drug-loaded rod core, characterized in that: In parts by weight, it comprises the following components: Active pharmaceutical ingredient: 1-1000 parts; R-vinyl silicone rubber: 100 parts; Hydrogenated silicone oil: 0.45-20 parts; Catalyst: ≥ 0.000002 parts, preferably 0.000002-1 parts; in: The average particle size of the active pharmaceutical ingredient is 1-1000 nm; 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 0.1-0.5 mol%; The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%; The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):1; Optionally, an inhibitor is further included, wherein the inhibitor is an inhibitor capable of inhibiting the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil; Optionally, the raw material composition of the drug-loaded stick core meets one or more of the following conditions: ① The average particle size of the pharmaceutical active ingredient is 10-900nm, preferably 20nm, 40nm, 60nm, 80nm, 100nm, 120nm, 150nm, 198nm, 200nm, 208nm, 212nm, 220nm, 300nm, 308nm, 350nm, 400nm, 430nm, 500nm, 600nm, 646nm, 700nm, 800nm, 820nm or 900nm; ② The active ingredient of the drug is an active drug with a solubility of ≤100 mg / mL; ③ The active pharmaceutical ingredients include active pharmaceutical ingredients for contraception, such as levonorgestrel, gestodene, and gestrinone; the active pharmaceutical ingredients may include steroidal estrogens, such as estradiol; or, the active pharmaceutical ingredients include active pharmaceutical ingredients for treating hyperlipidemia, tumors, neuropsychiatric diseases, chronic dental diseases, simple obesity, chronic low back pain, or leukemia, and the active pharmaceutical ingredients for treating neuropsychiatric diseases are preferably drugs for treating schizophrenia, such as paliperidone; ④ The dosage of the active ingredient of the medicine is 1-800 parts; ⑤ The R-vinyl silicone rubber is methyl vinyl silicone rubber; the methyl vinyl silicone rubber is preferably a relative molecular weight of 100000-800000 g / mol methyl vinyl silicone rubber; ⑥ The content of vinyl in the R-vinyl silicone rubber is 0.17-0.23 mol%; ⑦ The amount of the hydrogen-containing silicone oil is 0.5-20 parts, preferably 1.2-6.3 parts; ⑧ The content of Si-H groups in the hydrogen-containing silicone oil is 0.36-1.6 mol%, preferably 0.5-1 mol%; ⑨ The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.8-20):1; ⑩The catalyst is a rhodium catalyst, a palladium catalyst or a platinum catalyst, preferably a platinum catalyst; Wherein, the concentration of platinum in the platinum catalyst is preferably 1×10 3 -1×10 5 ppm; ⑾The amount of the catalyst is 2×10 -6 -1 part, preferably 0.03-0.3 part, more preferably 0.1-0.3 part; ⑿ The inhibitor is an alkynol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, and 2-methyl-3-butyn-2-ol; ⒀The dosage of the inhibitor is 0.03-2.5 parts, preferably 0.1-2.0 parts, and more preferably 0.3-1.0 parts.

7. A drug-carrying rod core, characterized in that: It is prepared from the raw material composition of the drug-carrying rod core as claimed in claim 6; Preferably, the drug-loaded rod core is a skeleton-type drug-loaded rod core or a hollow skeleton-type drug-loaded rod core; Preferably, when the drug-carrying rod core is a skeleton-type drug-carrying rod core, the outer diameter of the drug-carrying rod core is 1-10 mm, preferably 1-6 mm; Preferably, when the drug-carrying rod core is a hollow skeleton-type drug-carrying rod core, the outer diameter of the drug-carrying rod core is 1-10 mm, preferably 1-6 mm; Preferably, when the drug-carrying rod core is a hollow skeleton-type drug-carrying rod core, the inner diameter of the drug-carrying rod core is 0.1 mm-4.0 mm, preferably 0.4 mm-2.0 mm; Preferably, when the drug-carrying rod core is a hollow skeleton-type drug-carrying rod core, the diameter ratio of the outer diameter to the inner diameter of the drug-carrying rod core is (1.5-50):1; Optionally, the method for preparing the drug-loaded stick core comprises the following steps: (1) The R-vinyl silicone rubber is divided into component A1 and component B1, the component A1, the hydrogen-containing silicone oil and the inhibitor are mixed to obtain component A2, and the component B1 and the catalyst are mixed to obtain component B2; the component A2 and the component B2 are mixed to obtain a mixed rubber; (2) mixing the mixed rubber and the active pharmaceutical ingredient to obtain drug-loaded silica gel; (3) The drug-loaded silica gel is extruded and vulcanized to obtain a drug-loaded rod core; Optionally, the method for preparing the drug-loaded stick core satisfies one or more of the following conditions: ① In step (1), the R-vinyl silicone rubber is dried at 30-60° C. for 1-24 h for later use; ② In step (1), the preparation method of the component B1 or the component B2 is to mix the components in an open mill, pass them through a thin mill 4-6 times, and unload them in the form of thin sheets; ③ In step (1), the step of mixing the component A2 and the component B2 comprises the following steps: putting the component A2 and the component B2 in a weight ratio of 1:1 into an open mixer and mixing them thinly for 4-6 times, so that the A2 and B2 component rubbers are fully mixed and uniformly formed into a mixed rubber; ④ In step (2), the active pharmaceutical ingredient is prepared by nano-crushing, and the PDI after nano-crushing is less than 0.3; preferably, the nano-crushing is carried out by wet grinding; ⑤ during the grinding process, a stabilizer and a grinding medium are also added; The stabilizer is preferably one or more of poloxamer 407, poloxamer 188, SDS, HPMC, Tween 80, PVP K30, PEO, TPGS and HPC, more preferably poloxamer 188, Tween 80, poloxamer 407, SDS or HPMC, such as poloxamer 188; The grinding medium is preferably zirconia beads; the particle size of the zirconia beads may be 0.1-0.3 mm, such as 0.1 mm, 0.2 mm or 0.3 mm; The grinding time may be no less than 15 minutes, preferably 15-250 minutes; the grinding speed may be 300-500 rpm -1 ; The grinding may also include freeze-drying operations; ⑥ In step (2), the step of mixing the rubber compound and the active pharmaceutical ingredient comprises the following steps: placing the rubber compound and the active pharmaceutical ingredient in an open mixer and mixing them, so that the rubber compound and the active pharmaceutical ingredient are fully mixed and uniformly formed into drug-loaded silica gel; the drug-loaded silica gel can be cut into strips; Wherein, the mass ratio of the rubber compound to the active pharmaceutical ingredient is 1:(0.01-10), preferably 1:(1-5); ⑦ In step (3), the drug-loaded rod core is a skeleton-type drug-loaded rod core or a hollow skeleton-type drug-loaded rod core; ⑧ In step (3), during the extrusion molding, the screw speed of the extruder is 1-15r·min -1 ; ⑨ In step (3), when the drug-loaded rod core is a skeleton-type drug-loaded rod core, the diameter of the die used in the extrusion molding is 1-10 mm, preferably 1-6 mm; ⑩ In step (3), when the drug-loaded rod core is a hollow skeleton-type drug-loaded rod core, the diameter of the die used in the extrusion molding is 1-10 mm, preferably 1-6 mm; ⑾ In step (3), when the drug-loaded rod core is a hollow skeleton-type drug-loaded rod core, the diameter of the core mold used during the extrusion molding is 0.1 mm-4.0 mm; Preferably, when the drug-loaded rod core is a hollow skeleton-type drug-loaded rod core, during the extrusion molding, the diameter ratio of the mouth die to the core die is (1.5-50):1; ⑿ In step (3), the vulcanization temperature is 30-120°C; ⒀In step (3), the vulcanization time is 10-100 min.

8. A reservoir-type implant, characterized in that: It comprises the drug-carrying rod core and the silicone tube as claimed in claim 7; Preferably, the outer diameter of the silicone tube is 2.0-10 mm, preferably 2.0-6.4 mm; Preferably, the wall thickness of the silicone tube is 0.1-1.0 mm; Preferably, the length of the silicone tube is 1.5-10 cm; Preferably, the drug release area of ​​the silicone tube is 0.628-31.4 cm 2 , preferably 0.4-15.0cm 2 ; Preferably, the diameter of the drug-carrying rod core is 1-10 mm, preferably 1-6 mm; Preferably, the length of the drug-loaded rod core is 1.0-10 cm, preferably 1.0-4.0 cm; Optionally, the preparation method of the reservoir-type implant comprises the following steps: cutting the silicone tube into segments, filling the drug-loaded rod core, and sealing both ends with silicone to obtain the reservoir-type implant.

9. A reservoir-type implant, characterized in that: It comprises a powder-type medicine core and a silicone tube; the powder-type medicine core comprises a medicine active ingredient, and the average particle size of the medicine active ingredient is 1-1000nm; Preferably, the silicone tube is the silicone tube as described in claim 8; Preferably, the diameter of the drug-carrying section in the reservoir-type implant is 1-10 mm, preferably 1-6 mm; Preferably, the length of the drug-carrying section in the reservoir-type implant is 1.0-10 cm, more preferably 1.0-4.0 cm; Preferably, the average particle size of the pharmaceutical active ingredient is 10-900 nm, preferably 20 nm, 40 nm, 60 nm, 80 nm, 100 nm, 120 nm, 150 nm, 198 nm, 200 nm, 208 nm, 212 nm, 220 nm, 300 nm, 308 nm, 350 nm, 400 nm, 430 nm, 500 nm, 600 nm, 646 nm, 700 nm, 800 nm, 820 nm, or 900 nm; Preferably, the powder-type drug core further includes a poorly soluble auxiliary material; Optionally, the preparation method of the reservoir-type implant comprises the following steps: cutting the silicone tube into segments, sealing one end with silicone, filling the powder-type medicine core, and sealing the other end with silicone to obtain the reservoir-type implant.

10. A hollow skeleton drug-loaded rod core, characterized in that: The raw material composition includes the following components in parts by weight: Active pharmaceutical ingredient: 1-1000 parts; R-vinyl silicone rubber: 100 parts; Hydrogenated silicone oil: 0.45-20 parts; Catalyst: ≥ 0.000002 parts; 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 0.1-0.5 mol%; The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%; The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.5-20):

1.

11. The hollow skeleton drug-loaded rod core according to claim 10, characterized in that: The raw material composition meets one or more of the following conditions: ① The dosage of the active ingredient of the medicine is 1-800 parts; ② The content of vinyl in the R-vinyl silicone rubber is 0.17-0.23 mol%; ③ The amount of the hydrogen-containing silicone oil is 0.5-20 parts; ④ The content of Si-H groups in the hydrogen-containing silicone oil is 0.5-1.5 mol%; ⑤ the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is (0.8-20):1; and, ⑥ The amount of the catalyst used is 0.000002-1 part.

12. The hollow skeleton drug-loaded rod core according to claim 11, characterized in that: The raw material composition meets one or more of the following conditions: ① The dosage of the active ingredient of the medicine is 10 parts, 30 parts, 50 parts, 60 parts, 100 parts, 120 parts, 150 parts, 250 parts, 500 parts or 600 parts; ② The content of vinyl in the R-vinyl silicone rubber is 0.17 mol%, 0.18 mol%, 0.19 mol%, 0.20 mol%, 0.22 mol% or 0.23 mol%; ③ The amount of the hydrogen-containing silicone oil is 1.2-6.3 parts, for example, 1.33 parts, 2 parts, 2.67 parts, 3 parts, 3.56 parts or 4.44 parts; ④ The content of Si-H groups in the hydrogen-containing silicone oil is 0.75 mol%, 0.8 mol%, 1.0 mol% or 1.2 mol%; ⑤ the molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the R-vinyl silicone rubber is 0.8:1, 1.0:1, 1.2:1, 1.5:1, 1.8:1, 2.0:1, 3.0:1, 4:1, 4.5:1, 5:1, 8:1, 10:1 or 15:1, preferably (3-8):1 or (3-6):1; and, ⑥ The amount of the catalyst is 0.000002-0.5 parts, for example 0.000005 parts, 0.00001 parts, 0.00002 parts, 0.00003 parts, 0.1 parts, 0.2 parts, 0.21 parts, 0.25 parts or 0.3 parts; preferably 0.03-0.3 parts, more preferably 0.1-0.3 parts.

13. The hollow skeleton drug-loaded rod core according to claim 10, characterized in that: The raw material composition meets one or more of the following conditions: ① R in the R-vinyl silicone rubber is a substituted or unsubstituted C1-C5 straight chain alkane; When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber; Wherein, the methyl vinyl silicone rubber may be a methyl vinyl silicone rubber having a relative molecular weight of 100000-800000 g / mol; ② The catalyst is a rhodium catalyst, a palladium catalyst or a platinum catalyst; Wherein, the concentration of platinum in the platinum catalyst may be 10000 ppm; ③ The raw material composition further includes an inhibitor, which 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 acetylenic alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, and also 2-methyl-3-butyn-2-ol; The inhibitor may be used in an amount of 0.03-5 parts, preferably 0.1-2.0 parts, more preferably 0.3-1.0 parts, such as 0.3 parts, 0.5 parts, 0.7 parts, 0.9 parts or 0.98 parts; ④ The active ingredient of the drug is one or more of a macromolecular drug with good solubility, a small molecule drug with good solubility, a macromolecular drug with poor solubility, and a small molecule drug with poor solubility; The macromolecular drug with good solubility is an active drug with water as solvent, drug solubility>10mg / mL, and drug molecular weight>800Da; The small molecule drug with good solubility is an active drug with water as solvent, drug solubility>10mg / mL, and drug molecular weight ≤800Da; The poorly soluble macromolecular drug is an active drug with water as solvent, drug solubility ≤10 mg / mL, and drug molecular weight >800 Da; The poorly soluble small molecule drug is an active drug with water as solvent, drug solubility ≤10 mg / mL, and drug molecular weight ≤800 Da; Preferably, The macromolecular drug with good solubility is an active drug with water as solvent, drug solubility>30 mg / mL, and drug molecular weight>800 Da, such as one or more of exenatide, semaglutide, Centella asiatica glycosides and human growth hormone; The small molecule drug with good solubility is an active drug with water as solvent, drug solubility>30 mg / mL, and drug molecular weight ≤800 Da, such as metformin hydrochloride and / or doxorubicin hydrochloride. The poorly soluble macromolecular drug is an active drug with water as solvent, drug solubility ≤5 mg / mL (with water as solvent), and drug molecular weight >800 Da, such as one or more of bovine insulin, paclitaxel, and levothyroxine sodium; The poorly soluble small molecule drug is an active drug with water as solvent, drug solubility ≤5 mg / mL (with water as solvent), and drug molecular weight ≤800 Da, such as one or more of estradiol, gestodene, meloxicam, ganciclovir, puerarin and paliperidone; ⑤ In the hollow skeleton drug-loaded rod core, the ratio of the outer diameter to the inner diameter of the hollow skeleton drug-loaded rod core is 1.5-50:1, for example, 2.14:1, 3:1, 4:1, 5:1, 8:1, 10:1, 15:1, 20:1, 25:1, 30:1, 35:1 or 40:1; Alternatively, the outer diameter of the hollow skeleton-type drug-loaded rod core is 1 mm to 10 mm, preferably 2.0 mm, 3.0 mm, 4 mm or 5 mm; Alternatively, the inner diameter of the hollow skeleton-type drug-loaded rod core is 0.1 mm-4.0 mm, preferably 0.40 mm-2.0 mm, for example 0.4 mm, 0.6 mm, 0.8 mm, 1.0 mm, 1.2 mm, 1.4 mm, 1.6 mm or 2.0 mm; Preferably, the outer diameter of the hollow skeleton-type drug-loaded rod core is 3 mm, and the inner diameter is 0.6-1.4 mm, 0.6 mm, 1.0 mm or 1.4 mm.

14. A method for preparing a hollow skeleton drug-loaded rod core according to any one of claims 10 to 13, characterized in that: It includes the following methods: S1: dividing the R-vinyl silicone rubber into component A1 and component B1; When the raw material composition contains an inhibitor, the component A1, the hydrogen-containing silicone oil and the inhibitor are mixed to obtain component A2; the component B1 and the catalyst are mixed to obtain component B2; S2: mixing the component A2 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 hollow skeleton-type drug-loaded rod core; Preferably, the preparation method satisfies one or more of the following conditions: ① In S1, the R-vinyl silicone rubber is pretreated by the following method: drying at 30-60° C. for 1-24 hours; ② In S1, the preparation method of the component A1 or the component B1 comprises the following steps: mixing the components in an open mill and then thinly passing them 4-6 times; ③ In S2, the step of mixing the component A2 and the component B2 comprises the following steps: putting the component A2 and the component B2 in a weight ratio of 1:1 into an open mixing mill and mixing them thinly for 4-6 times, so that the B1 and B2 component rubbers are fully mixed and uniformly formed into a mixed rubber; ④ In S3, the step of mixing the rubber mix and the active pharmaceutical ingredient comprises the following steps: putting the rubber mix and the active pharmaceutical ingredient into an open mixer for mixing, so that the rubber mix and the active pharmaceutical ingredient are fully mixed and uniformly formed into drug-loaded silica gel; ⑤ In S4, during the extrusion, the screw speed of the extruder is 1-15 r·min -1 , for example 4r·min -1 or 6 r·min -1 ; ⑥ In S4, during the extrusion, the die diameter used is 1-10 mm, for example, 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm; ⑦ In S4, during the extrusion, the diameter of the core die used is 0.1-4 mm, such as 0.58 mm, 0.8 mm, 0.97 mm, 1.2 mm or 1.38 mm; ⑧ In S4, the vulcanization temperature is 25-120°C, preferably 60-90°C, for example 30°C, 50°C, 60°C, 65°C, 70°C, 80°C, 90°C, 100°C or 120°C; ⑨ In S4, the vulcanization time is 10-200 min, preferably 10-60 min, for example 10 min, 20 min, 30 min, 40 min or 50 min.

15. Use of the stick core as claimed in claim 4, the raw material composition of the drug-loaded stick core as claimed in claim 6, the drug-loaded stick core as claimed in claim 7, or the reservoir-type implant as claimed in claim 8 or 9, or the hollow skeleton drug-loaded stick core as claimed in any one of claims 10 to 13 as a release rate regulating medium in a sustained-release preparation.

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