Drug-loaded rod core, raw material composition thereof, implant and preparation and application of drug-loaded rod core

Abstract

The invention discloses a drug-loaded rod core, a raw material composition thereof, an implant, preparation and application. The raw material composition of the drug-loaded rod core comprises the following components in parts by weight: 1-1000 parts of active pharmaceutical ingredients; 100 parts of R-vinyl silicone rubber; 0.45 to 20 parts of hydrogen-containing silicone oil; the content of a catalyst is greater than or equal to 0.000002 part, preferably 0.000002-1 part; wherein the average particle size of the active pharmaceutical ingredients is 1-1000 nm. According to the invention, the drug active ingredients with the average particle size of 1-1000nm are adopted, so that the solubility of the drug can be obviously improved; the compatibility with silicon rubber is better, the release speed of the obtained skeleton type implant and storage type implant is obviously improved, and the drug release behavior is stable; meanwhile, the application range is wide, the preparation method is suitable for various drugs, and large-dose stable release is achieved.

Description

Technical Field

[0001] The invention relates to a drug-carrying rod core and a raw material composition, an implant, and preparation and application thereof. Background Art

[0002] Since the concept of "sustained-release preparations" was proposed, sustained-release preparations used in contraception, schizophrenia, hormones, anti-tumor and other fields have made great progress, effectively avoiding problems such as surgical injuries and low oral compliance. Sustained-release preparations that can release drugs for a long time, especially subcutaneous implants, have very broad prospects.

[0003] Implants can generally be divided into skeleton-type implants and reservoir-type implants. A skeleton-type implant is a drug preparation that is prepared by mixing the drug with a carrier, using a catalyst, a cross-linking agent, and high temperature, and then using extrusion or molding to prepare it into a drug preparation with certain mechanical properties that can be implanted under the human skin. A reservoir-type implant is generally a drug preparation prepared by directly filling the raw material into a silicone tube.

[0004] In practical applications, there are many drugs that need to be released in milligrams or more to be effective (such as paliperidone, risperidone, ketotifen fumarate, celecoxib, meloxicam, etc.). Since the drug needs to diffuse into the body through the silicone tube, the daily release of the reservoir-type implant is generally only tens of micrograms, which is difficult to meet the release requirements of large doses of drugs; the skeleton-type implant has the advantages of fast drug release and large release amount, and the daily drug release amount is about several to dozens of times that of the reservoir-type implant, but its release is not stable, and the drug release rate will gradually decline, resulting in unstable blood drug concentration and even no drug effect.

[0005] In the prior art, the method of adding pH adjusting agents and punching holes in silicone tubes is 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. Summary of the invention

[0006] The technical problem to be solved by the present invention is to overcome the defects of the prior art that the release amount of reservoir-type implants is small, the requirements for drug molecular weight and solubility are high, and the drug release of skeleton-type implants is not stable, and provide a drug-loaded rod core and its raw material composition, implant, preparation and application. The present invention adopts active pharmaceutical ingredients with an average particle size of 1-1000nm, which can significantly improve the solubility of the drug; and it has better compatibility with silicone rubber, and the release rate of the obtained skeleton-type implant and reservoir-type implant is significantly improved, and the drug release behavior is stable; at the same time, the application range is wide, suitable for a variety of drugs, and large-dose stable release is achieved.

[0007] The present invention solves the above technical problems through the following technical solutions.

[0008] During the research and development process, the applicant creatively discovered that the average particle size of common drug active ingredients is 2-180μm, and whether it is a skeleton-type implant or a reservoir-type implant, the release rate of the drug active ingredients in the release medium can be significantly improved after nano-sizing; at the same time, the compatibility of the drug active ingredients with silicone rubber is further improved after nano-sizing, and more types of drugs are applicable.

[0009] The present invention provides a raw material composition for a drug-carrying stick core, which comprises the following components in parts by weight:

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

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

[0012] Hydrogenated silicone oil: 0.45-20 parts;

[0013] Catalyst: ≥ 0.000002 parts, preferably 0.000002-1 parts;

[0014] in:

[0015] The average particle size of the active pharmaceutical ingredient is 1-1000 nm;

[0016] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C 20 Aromatics;

[0017] The content of vinyl in the R-vinyl silicone rubber is 0.1-0.5 mol%;

[0018] The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%;

[0019] 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;

[0020] Optionally, an inhibitor is also included, and the inhibitor is an inhibitor that can inhibit the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil.

[0021] 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.

[0022] The active pharmaceutical ingredients acting on the reproductive system may include active pharmaceutical ingredients for contraception, or steroidal estrogens.

[0023] The active ingredients of the contraceptive drugs may be conventional ones in the art, and preferably include levonorgestrel, gestodene or gestrinone.

[0024] The steroidal estrogen is preferably estradiol.

[0025] Among them, the active pharmaceutical ingredients acting on the urinary system preferably include active pharmaceutical ingredients for treating chronic nephritis, treating chronic renal failure, or treating chronic prostatitis.

[0026] 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.).

[0027] The drugs for treating chronic nephritis can generally be: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan, etc.), calcium channel blockers (such as amlodipine, felodipine, nifedipine, etc.), beta-receptor blockers (such as atenolol, bisoprolol, carvedilol, propranolol, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide, etc.), immunosuppressants (such as prednisone, Enova, methylprednisolone, cyclophosphamide, dexamethasone, etc.), statins lipid-lowering drugs (such as fluvastatin, simvastatin, pravastatin).

[0028] The drugs for treating chronic renal failure generally include: angiotensin converting enzyme inhibitors (such as benazepril, ramipril, fosinopril, perindopril, cilazapril, enalapril, etc.), angiotensin II receptor blockers (such as irbesartan, valsartan, losartan, etc.), diuretics (such as furosemide, spironolactone, hydrochlorothiazide, bendrofluazide, bumetanide, etc.), iron preparations (ferrous fumarate, etc.), compound amino acids, α-keto acids, and recombinant human erythropoietin.

[0029] 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.

[0030] The anti-gout active ingredient is preferably an anti-gout attack drug, such as colchicine, indomethacin, diclofenac, ibuprofen, rofecoxib, prednisone, hydrocortisone, prednisolone, aspirin, diflunisal, aminosalicylic acid, salsalate, benolate, more preferably ibuprofen. Generally, the anti-gout drug can also be a uricosuric agent drug (such as benzbromarone, probenecid), a uric acid synthesis blocker drug (such as allopurinol).

[0031] The anti-diabetic drugs can generally be anti-type 1 diabetes drugs (such as insulin) and anti-type 2 diabetes drugs. The anti-type 2 diabetes drugs can be sulfonylurea drugs (such as glimepiride, gliquidone), glinides (such as repaglinide, nateglinide), metformin drugs (such as metformin), α-glucosidase inhibitors (such as acarbose, voglibose), DPP-4 inhibitors (such as sitagliptin), GLP-1 receptor agonists (such as liraglutide, exenatide) or SGLT-2 inhibitors (such as dapagliflozin, empagliflozin).

[0032] The drugs for treating nutritional deficiency diseases can generally be drugs for gastrointestinal diseases (such as omeprazole, mosapride) and nutritional supplements (such as vitamin E).

[0033] The anti-osteoporosis drugs can generally be bisphosphonates (e.g., alendronate sodium, ibandronate sodium, pamidronate sodium, aminobisphosphonates, clodronate disodium, zoledronic acid sodium, risedronate sodium), calcitonin drugs (e.g., salmon calcitonin), estrogen drugs (e.g., estradiol, estradiol benzoate, estradiol acetate, estradiol valerate), selective estrogen receptor modulators (SERMs) drugs (e.g., raloxifene, benzothiophene), RANKL inhibitor drugs, parathyroid hormone drugs, monofluoroglutamine drugs, strontium salt drugs (e.g., strontium ranelate), active vitamin D and analogs (e.g., calcitriol, α-calciferol), vitamin K (e.g., menatetrenone).

[0034] 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.

[0035] The active ingredient of the drug for treating rheumatoid arthritis is preferably a non-steroidal anti-inflammatory drug, such as aspirin, meloxicam, celecoxib, ibuprofen, nimesulide, nabumetone, more preferably meloxicam or ibuprofen. Generally, the drug for treating rheumatoid arthritis can be a glucocorticoid drug (such as hydrocortisone, dexamethasone, prednisone), a slow-acting antirheumatic drug (such as methotrexate, cyclophosphamide, azathioprine, cyclosporine, leflunomide).

[0036] The active ingredient of the drug for treating osteoarthritis is preferably an analgesic, such as ibuprofen, Voltaren, meloxicam, celecoxib, loxoprofen sodium nimesulide, more preferably ibuprofen or meloxicam. Generally, the drug for treating osteoarthritis can be a drug for nourishing cartilage, an opioid (such as oxycodone, chimantin).

[0037] The drugs for treating systemic lupus erythematosus can generally be non-steroidal anti-inflammatory drugs (such as naproxen, ibuprofen), antimalarial drugs, glucocorticoid drugs (such as prednisone acetate, methylprednisolone), immunosuppressant drugs (such as methotrexate, cyclophosphamide, azathioprine, methotrexate, cyclosporine, mycophenolate mofetil, tacrolimus), and biological drugs (such as rituximab, belimumab).

[0038] The drugs for treating ankylosing spondylitis can generally be non-steroidal drugs (such as diclofenac sodium, etoricoxib, celecoxib, nabumetone, and ericoxib), disease-modifying antirheumatic drugs (such as pyridine sulfamethoxazole, methotrexate, and hydroxychloroquine), glucocorticoid drugs (such as prednisone, prednisolone, and diprosone), and biological TNF-a antagonists (such as etanercept).

[0039] The drugs for treating Sjögren's syndrome can generally be systemic therapeutic drugs (such as levamisole, transfer factor coenzyme Q10, thymosin), glucocorticoid drugs (such as prednisone), and immunosuppressive drugs (such as hydroxychloroquine, azathioprine, and ilamod).

[0040] The drugs for treating vasculitis can generally be glucocorticoid drugs (such as prednisone, methylprednisolone, dexamethasone) and immunosuppressant drugs (such as cyclophosphamide, cyclosporine, azathioprine).

[0041] The drugs for treating idiopathic inflammatory myopathy can generally be glucocorticoid drugs (such as dexamethasone, prednisone, hydrocortisone, methylprednisolone), immunosuppressant drugs (such as cyclophosphamide, azathioprine, methotrexate, cyclosporine, tacrolimus, mycophenolate mofetil, mycophenolate mofetil).

[0042] The drugs for treating systemic sclerosis can generally be anti-fibrotic drugs (such as colchicine), vasoactive drugs (such as nifedipine, benzathine) and several other commonly used drugs (such as naproxen, nifedipine, bosentan, sildenafil, epoprostenol, nintedanib, tocilizumab).

[0043] Among them, the active ingredients of the drugs for treating neuropsychiatric disorders can generally be drugs for treating schizophrenia, antidepressants, drugs for treating opioid abuse or drugs for treating anxiety disorders; preferably, drugs for treating schizophrenia, more preferably, phenothiazines (such as chlorpromazine), thioxanthenes (such as chlorprothixene), butyrophenones (such as haloperidol), dibenzodiazepines (such as olanzapine, clozapine), benzisoxazoles (such as risperidone, paliperidone), benzisothiazoles (such as ziprasidone), diphenylthiazepines (such as quetiapine), quinolones (such as aripiprazole), and further preferably, benzisoxazoles (such as paliperidone).

[0044] The antidepressant drugs can generally be tricyclic antidepressants (such as imipramine, clomipramine, amitriptyline), monoamine oxidase inhibitors (such as moclobemide), selective serotonin reuptake inhibitors (such as sertraline), serotonin and norepinephrine reuptake inhibitors (such as venlafaxine), serotonin block and reuptake inhibitors (such as trazodone), norepinephrine and dopamine reuptake inhibitors (such as bupropion), norepinephrine inhibitors (such as reboxetine), α2 adrenergic receptor blockers (such as mirtazapine).

[0045] The drug for treating opioid abuse may generally be buprenorphine or methadone.

[0046] The anxiety-treating drugs may generally be benzodiazepines (eg, diazepam), 5-HT1A receptor partial agonists (eg, buspirone), β-adrenergic receptor blockers (eg, propranolol), and valproate.

[0047] Among them, the therapeutic drugs for treating hyperlipidemia can generally be statins (such as simvastatin, atorvastatin, pravastatin), fibrates (such as fenofibrate, bezafibrate, gemfibrozil), and nicotinic acids (such as niacin).

[0048] Among them, the anti-tumor drug can generally be an anti-breast cancer drug (such as azacitidine, docetaxel, buserelin, tamoxifen, mitoxantrone, doxorubicin, paclitaxel, capecitabine, goserelin, cyclophosphamide, megestrol acetate, cetuximab or leuprolide), an anti-prostate cancer drug (such as degarelix, leuprolide, histrelin, flunitrium, estramustine, cyproterone acetate), an anti-ovarian cancer drug (such as carboplatin, topotecan, methotrexate), an anti-rectal cancer drug (such as panitumumab), an anti-colon cancer drug (such as bevacizumab, oxaliplatin), an anti-liver cancer drug (such as sorafenib), an anti-lung cancer drug (such as erlotinib, gefitinib, docetabine) , anti-renal cancer drugs (e.g. pazopanib, everolimus, temsirolimus), anti-gastric cancer drugs (e.g. 5-fluorouracil, mitomycin, cisplatin, doxorubicin, etoposide), anti-pancreatic cancer drugs (e.g. nimotuzumab), anti-esophageal cancer drugs (e.g. docetaxel, paclitaxel, cisplatin, gemcitabine, tegafur, irinotecan, oxaliplatin, gefitinib, trastuzumab, anlotinib), anti-skin cancer drugs (e.g. 5-fluorouracil), anti-lymphoma drugs (e.g. vincristine, bexarotene, dacarbazine, etoposide), anti-myeloma drugs (e.g. bortezomib), anti-cervical cancer drugs (e.g. bleomycin) or anti-bladder cancer drugs (e.g. epirubicin, bacillus Calmette-Guérin).

[0049] Among them, the drugs for treating chronic dental diseases (such as caries and periodontal disease) can generally be divided into nitroimidazole drugs (such as metronidazole, tinidazole, ornidazole), penicillin drugs, and other commonly used drugs (minocycline, chlorhexidine acetate).

[0050] Wherein, the drug for treating simple obesity can generally be orlistat.

[0051] Wherein, the active ingredient of the drug for treating chronic low back pain is preferably a non-steroidal analgesic drug, such as ibuprofen, celecoxib, tramadol, oxycodone, meloxicam, loxoprofen, acetaminophen, voltaren, more preferably ibuprofen or meloxicam;

[0052] The drugs for treating leukemia are generally drugs that interfere with nucleic acid biosynthesis (such as cytarabine, methotrexate, 6-mercaptopurine), drugs that directly affect the DNA structure and function of cancer cells (such as busulfan, mitomycin, chlorambucil, phenylalanine mustard, cyclophosphamide), drugs that interfere with the transcription process and prevent RNA synthesis (such as daunorubicin, doxorubicin, adriamycin, aclarubicin), drugs that inhibit protein synthesis and function (such as vindesine, vincristine, L-aspartate, homoharringtonine), and other commonly used drugs (such as interferon, fludarabine, arsenite, etoposide, and carmustine).

[0053] Wherein, the active pharmaceutical ingredients acting on the circulatory system preferably include active pharmaceutical ingredients for treating chronic heart failure, coronary heart disease, congenital heart disease, or chronic infective endocarditis or chronic pericarditis;

[0054] The active ingredients of the drugs for treating coronary heart disease can generally be drugs for improving angina symptoms (such as puerarin, isosorbide mononitrate), drugs for antiplatelet aggregation (such as aspirin, clopidogrel bisulfate, ticagrelor), drugs for lipid-lowering and plaque-stabilizing (such as atorvastatin, rosuvastatin, pravastatin), drugs for inhibiting sympathetic nerve activity (such as metoprolol, bisoprolol fumarate), and drugs for improving myocardial remodeling (such as angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists); preferably, the drugs for improving angina symptoms are puerarin; the active ingredients of the drugs for treating chronic heart failure can generally be cardiotonic drugs (such as digitalis, digoxin, cedilanid), vasodilator drugs (such as sodium nitroprusside, nitroglycerin, converting enzyme inhibitors (such as enalapril, lenoprolol, etc.), and diuretics (such as furosemide, hydrochlorothiazide, spironolactone).

[0055] The active ingredient of the drug for treating congenital heart disease can generally be digitalis, furosemide, spironolactone, phentolamine, quinidine, digoxin, hydrochlorothiazide or coenzyme Q10.

[0056] The active ingredient of the drug for treating chronic infective endocarditis can generally be an antibiotic (eg, vancomycin, cephalosporin, penicillin, aminoglycoside).

[0057] The active ingredient of the medicine for treating chronic pericarditis can generally be digitalis.

[0058] Among them, the active pharmaceutical ingredients acting on the respiratory system may generally include active pharmaceutical ingredients for treating chronic obstructive pulmonary emphysema, treating asthma, treating chronic cor pulmonale, treating chronic respiratory failure, treating silicosis or treating pulmonary fibrosis.

[0059] The active ingredients of the drugs for treating chronic obstructive pulmonary emphysema can generally be bronchodilators (including beta-receptor agonists and anticholinergic drugs), inhaled hormones (such as budesonide and fluticasone), theophylline antiasthmatics (such as theophylline), expectorants (such as carbocysteine ​​and fudosteine), and glucocorticoids and antibiotics (such as penicillins, glycosides and cephalosporins) can also be appropriately selected when the condition requires.

[0060] The active ingredients of the asthma-treating drugs are generally commonly used inhaled drugs (e.g., beclomethasone, budesonide, fluticasone, mometasone), β2 agonists (e.g., salbutamol), sustained-release theophylline, leukotriene modifiers (which can be used in combination), anticholinergics (e.g., isoproscopolamine), and antihistamines (e.g., astemizole, ketotifen).

[0061] The active ingredients of the drugs for treating chronic cor pulmonale can generally be antibiotics (such as amoxicillin, cefuroxime, cefuroxime, levofloxacin), corticosteroid anti-inflammatory bronchodilators (such as selective β2 receptor stimulants, theophylline drugs), drugs that eliminate nonspecific airway inflammation (such as prednisone), inhaled drugs (such as beconazole), respiratory stimulants (such as lobeline, doxapram, duloxetine, etc.).

[0062] The active ingredients of the drug for treating chronic respiratory failure can generally be drugs for relieving bronchospasm and removing phlegm (such as salbutamol, acetylcysteine, etc.).

[0063] The active ingredients of the medicine for treating silicosis can generally be siping, acetylcysteine, aluminum preparations, closiperine, and salvia miltiorrhiza.

[0064] 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.

[0065] Among them, the active pharmaceutical ingredients acting on the digestive system generally include active pharmaceutical ingredients for treating chronic gastritis, treating peptic ulcers, treating intestinal tuberculosis, treating chronic enteritis, treating chronic diarrhea, treating chronic hepatitis, treating cirrhosis, treating chronic pancreatitis, and treating chronic cholecystitis.

[0066] The active ingredients of the drugs for treating chronic gastritis can generally be used to relieve pain (atropine, propantheline, etc. can be used), PPI proton pump inhibitors (such as lansoprazole, omeprazole, etc.) can be used for increased gastric acid, H2 receptor blockers (such as cimetidine, ranitidine, aluminum hydroxide ammonium, etc.) can be used for those with milder symptoms, digestive aids (pancreatic enzymes can be added), and bile reflux (metoclopramide and metoclopramide, cholestyramine, and sucralfate can bind to bile acid).

[0067] The active ingredients of the drug for treating peptic ulcer are generally levofloxacin, metronidazole and omeprazole.

[0068] The active ingredient of the drug for treating intestinal tuberculosis can generally be rifampicin.

[0069] The active ingredients of the medicine for treating chronic enteritis can generally be anti-inflammatory analgesics, probiotics, antispasmodics and analgesics (such as atropine and propantheline).

[0070] The active ingredients of the medicine for treating chronic diarrhea can generally be antidiarrheal drugs (such as montmorillonite powder, diphenoxylate, loperamide), intestinal microbial preparations (such as lactobacillus, bifidobacterium), and spasmodic analgesics (such as pinaverium bromide).

[0071] The active ingredients of the drugs for treating chronic hepatitis can generally be liver-protecting drugs (such as silymarin preparations, schisandra preparations, etc.), anti-fibrosis drugs (such as oral Chinese patent medicine preparations), antivirals (such as conventional interferons and pegylated interferons), oral nucleoside antiviral drugs (such as lamivudine, adefovir dipivoxil, telbivudine, entecavir), and immunosuppressants (azathioprine).

[0072] The active ingredients of the drug for treating liver cirrhosis can generally be drugs for treating hepatitis B (such as nucleoside analogs), drugs for treating autoimmune hepatitis (such as glucocorticoids), anti-inflammatory drugs, liver-protecting drugs, anti-liver fibrosis drugs (such as reduced glutathione, polyene phosphatidylcholine, magnesium isoglycyrrhizinate, etc.), drugs for treating spontaneous bacterial peritonitis (such as antibiotics), and drugs for treating portal hypertension (such as carvedilol).

[0073] The active ingredients of the drug for treating chronic pancreatitis can generally be analgesics (such as buprenorphine, fentanyl) and pancreatic enzyme treatment drugs (such as pancreatic enzymes).

[0074] The active ingredients of the drug for treating chronic cholecystitis can generally be antibacterial and anti-inflammatory drugs (such as levofloxacin, ciprofloxacin, amoxicillin), antispasmodics and analgesics, and choleretics (such as ursodeoxycholic acid).

[0075] Among them, the active pharmaceutical ingredients acting on the blood system generally include active pharmaceutical ingredients for treating chronic anemia, treating chronic myeloid leukemia, and treating chronic lymphocytic leukemia.

[0076] The drugs for treating chronic anemia generally include: trace elements (such as folic acid, vitamin B12, etc.), bone marrow stimulants (such as strychnine nitrate, scopolamine, hyoscyamine, etc.), adenosylcobalamin, glucocorticoids (prednisone, methylprednisone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, prednisone), iron preparations (such as ferrous fumarate, ferrous gluconate, ferrous succinate, ferrous lactate, sucrose iron, low molecular weight dextran iron, carboxymaltose iron, isomaltose iron, glucuronic acid iron, nano iron oxide, sorbitol iron, etc.), and erythropoiesis-stimulating agents (recombinant human erythropoietin α, darbepoetin α, etc.).

[0077] The drugs for treating chronic myeloid leukemia generally include: tyrosine kinase inhibitors (such as imatinib, nilotinib, bosutinib, ponatinib, etc.), homoharringtonine.

[0078] The drugs for treating chronic lymphocytic leukemia generally include: chemotherapy drugs (such as nimustine, fludarabine, chlorambucil, bendamustine, etc.), targeted drugs (such as adranib, venetola, ibrutinib, imatinib, dasatinib, etc.), and monoclonal antibodies (such as ofatumumab, rituximab, atozumab, alemtuzumab, etc.).

[0079] Among them, the active pharmaceutical ingredients acting on the endocrine system may generally include active pharmaceutical ingredients for treating chronic lymphocytic thyroiditis, hyperthyroidism, and hypothyroidism.

[0080] The drugs for treating chronic lymphocytic thyroiditis generally include: thyroid hormones (such as levothyroxine, thyroxine), glucocorticoids (such as prednisone, methylprednisone, betamethasone, beclomethasone dipropionate, prednisolone, hydrocortisone, dexamethasone, prednisone).

[0081] The drugs for treating hyperthyroidism generally include: thiouracils (such as propylthiouracil, methylthiouracil, etc.), imidazoles (such as methimazole, carbimazole, etc.), iodine and iodide (such as Lugol's solution, etc.), radioactive iodine (such as 131 iodine, etc.), beta-receptor blockers (such as metoprolol, atenolol, bisoprolol, carvedilol, propranolol, etc.).

[0082] The drugs for treating hypothyroidism generally include: thyroxine (eg, levothyroxine, levothyroxine sodium, thyroxine, etc.).

[0083] 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).

[0084] In the present invention, the dosage of the active pharmaceutical ingredient may be 1-800 parts, for example 100 parts.

[0085] In the present invention, the average particle size of the active pharmaceutical 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 larger the daily release amount. If the particle size of the active pharmaceutical ingredient is too large, the release effect is equivalent to the conventional micron level; if the particle size of the active pharmaceutical ingredient is too small, its surface area is too small, and agglomeration is likely to occur, resulting in poor stability of the product.

[0086] In the present invention, R in the R-vinyl silicone rubber may be substituted or unsubstituted C 1 -C 5 A straight chain alkane such as methyl.

[0087] When the R is a methyl group, the R-vinyl silicone rubber is a methyl vinyl silicone rubber.

[0088] 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.

[0089] 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%.

[0090] In the present invention, the hydrogen-containing silicone oil may be conventional hydrogen-containing silicone oil in the art, for example, hydrogen-containing silicone oil purchased from Guangdong Guiye New Material Technology Co., Ltd.

[0091] In the present invention, the amount of the hydrogen-containing silicone oil can be 0.5-20 parts, preferably 1.2-6.3 parts, such as 1.33 parts, 2.67 parts, 3.56 parts or 4.44 parts.

[0092] In the present invention, the content of Si-H groups in the hydrogen-containing 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%.

[0093] 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.

[0094] 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.

[0095] Wherein, the concentration of platinum in the platinum catalyst is preferably 1×10 3 -1×10 5 ppm, for example 1×10 4 ppm.

[0096] 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, it is 0.03-0.3 part, and more preferably, it is 0.1-0.3 part.

[0097] In the present invention, the inhibitor may be a conventional inhibitor in the art that can inhibit the addition reaction between methyl vinyl silicone rubber and hydrogen-containing silicone oil at room temperature, such as acetylenic alcohol compounds, nitrogen-containing compounds or organic peroxides, such as methyl butynol, and also such as 2-methyl-3-butyn-2-ol.

[0098] In the present invention, the dosage 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.

[0099] 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:

[0100] (1) Nanoparticle active ingredient, with an average particle size of 10-900 nm and an addition amount of 100 PHR;

[0101] (2) methyl vinyl silicone rubber, vinyl content of 0.18 mol%, added in an amount of 100 PHR;

[0102] (3) hydrogen-containing silicone oil, the Si-H content of which is 0.75 mol%, and the amount added is 4.44 PHR;

[0103] (4) platinum catalyst, the concentration of platinum is 10000 ppm, and the addition amount is 0.21 PHR;

[0104] (5) 2-methyl-3-butyn-2-ol, added in an amount of 0.98 PHR;

[0105] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is 5:1.

[0106] In other preferred embodiments of the present invention, the raw material composition of the drug-loaded stick core may include the following components in parts by weight:

[0107] (1) Nano paliperidone, with an average particle size of 220 nm, 430 nm, 646 nm or 820 nm, added in an amount of 100 PHR;

[0108] (2) methyl vinyl silicone rubber, vinyl content of 0.18 mol%, added in an amount of 100 PHR;

[0109] (3) hydrogen-containing silicone oil, the Si-H content of which is 0.75 mol%, and the amount added is 4.44 PHR;

[0110] (4) platinum catalyst, the concentration of platinum is 10000 ppm, and the addition amount is 0.21 PHR;

[0111] (5) 2-methyl-3-butyn-2-ol, added in an amount of 0.98 PHR;

[0112] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is 5:1.

[0113] The present invention also provides a drug-carrying rod core, which is prepared from the raw material composition of the drug-carrying rod core.

[0114] 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 be independently used as the skeleton-type implant mentioned in the background technology.

[0115] 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.

[0116] 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.

[0117] 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 may 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.

[0118] 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.

[0119] The present invention also provides a method for preparing the drug-loaded rod core, which comprises the following steps:

[0120] (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;

[0121] (2) mixing the mixed rubber and the active pharmaceutical ingredient to obtain drug-loaded silica gel;

[0122] (3) The drug-loaded silica gel is extruded and vulcanized to obtain a drug-loaded rod core.

[0123] In step (1), the R-vinyl silicone rubber can be pretreated by conventional methods in the art, such as drying at 30-60° C. (eg, 40° C.) for 1-24 h (eg, 12 h) for later use.

[0124] 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.

[0125] 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 in an open mixing mill at a weight ratio of 1:1 and mixing them for 4-6 times (for example, 4 times or 6 times) to make the A2 and B2 component rubbers fully mixed and uniformly formed into a mixed rubber.

[0126] In step (2), the active pharmaceutical ingredient is prepared by nano-crystallization, and the PDI after nano-crystallization is less than 0.3. The nano-crystallization can be prepared by conventional nano-crystallization methods in the art, such as grinding.

[0127] The grinding may be performed by wet grinding. Preferably, a stabilizer and a grinding medium are added during the grinding process.

[0128] The grinding time may be no less than 15 min, preferably 15-250 min.

[0129] The grinding speed can be 300-500 r·min -1 , for example 400r·min -1 .

[0130] 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.

[0131] The type of the grinding media can be conventional in the art, such as zirconium oxide beads. The particle size of the zirconium oxide beads can be 0.1-0.3 mm, such as 0.1 mm, 0.2 mm or 0.3 mm.

[0132] The grinding may be followed by freeze-drying.

[0133] In step (2), the step of mixing the rubber compound and the active pharmaceutical ingredient may include the following steps: putting the rubber compound and the active pharmaceutical ingredient into an open mixer for mixing, 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 may be cut into strips.

[0134] The mass ratio of the rubber compound to the active pharmaceutical ingredient may be 1:(0.01-10), preferably 1:(1-5), for example 1:1.

[0135] In step (3), the drug loaded rod core may 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 may be obtained by adjusting the extrusion molding parameters.

[0136] In step (3), the extrusion is generally carried out in a screw extruder.

[0137] 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 .

[0138] 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, for example 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0139] 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, for example 2 mm, 2.96 mm, 3.5 mm, 4 mm, 4.5 mm or 5 mm.

[0140] 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 0.1 mm-4.0 mm, preferably 0.4 mm-2.0 mm, for example 0.4 mm, 0.58 mm, 0.6 mm, 0.8 mm, 0.97 mm, 1.0 mm, 1.2 mm, 1.38 mm, 1.4 mm, 1.6 mm or 2.0 mm.

[0141] 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.

[0142] In step (3), the vulcanization is generally carried out in an oven.

[0143] 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.

[0144] 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.

[0145] The invention also provides a reservoir-type implant, which comprises the drug-loaded rod core and a silicone tube.

[0146] 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.

[0147] In the present invention, the wall thickness of the silicone tube may be 0.1-1.0 mm, such as 0.2 mm, 0.3 mm, 0.4 mm or 0.5 mm.

[0148] In the present invention, the length of the silicone tube may be 1.5-10 cm, such as 1.9 cm or 4.4 cm.

[0149] In the present invention, the drug release area of ​​the silicone tube can be 0.618-31.4cm 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 .

[0150] 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.

[0151] In the present invention, the length of the drug-loaded rod core may be 1.0-10 cm, 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.

[0152] In the present invention, the raw material composition of the silicone tube may include the following components in parts by weight:

[0153] R-vinyl silicone rubber: 100 parts;

[0154] Reinforcing agent: 20-80 parts;

[0155] Hydrogenated silicone oil: 0.3-3.0 parts;

[0156] Catalyst: ≥ 0.000002 parts, preferably 0.000002-0.5 parts;

[0157] in:

[0158] The R in the R-vinyl silicone rubber is a substituted or unsubstituted C 1 -C 5 Straight-chain or branched alkanes, substituted or unsubstituted C 6 -C20 Aromatics;

[0159] The content of vinyl in the R-vinyl silicone rubber is 0.10-0.50 mol%;

[0160] The content of Si-H groups in the hydrogen-containing silicone oil is 0.18-1.6 mol%;

[0161] 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;

[0162] Optionally, an inhibitor is also included, and the inhibitor is an inhibitor that can inhibit the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil.

[0163] 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, which are independent of each other and do not affect each other.

[0164] 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.

[0165] The white carbon black can be conventional white carbon black in the art, such as fumed white carbon black, precipitated white carbon black, gel white carbon black or surface treated white carbon black, preferably fumed white carbon black.

[0166] Wherein, 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.

[0167] 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.

[0168] Among them, 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.

[0169] 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.

[0170] 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.

[0171] The amount of the catalyst is preferably 0.03-0.3 parts, more preferably 0.1-0.3 parts, such as 0.21 parts.

[0172] 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.

[0173] Wherein, the dosage of the inhibitor is as described above.

[0174] In the present invention, the preparation method of the silicone tube comprises the following steps:

[0175] 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:

[0176] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0177] S2: In the presence of the catalyst, mixing the mixture A and the hydrogen-containing silicone oil to obtain a mixture B;

[0178] 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.

[0179] 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:

[0180] S1: uniformly mixing the R-vinyl silicone rubber and the reinforcing agent to obtain a mixture A;

[0181] 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;

[0182] S3: mixing the component B1 and the component B2 to obtain a mixture B;

[0183] 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.

[0184] In the method 1 and the method 2, the reinforcing agent can be pretreated by conventional methods in the art, such as drying at 100-210° C. (eg, 130° C.) for 1-24 h (eg, 12 h or 24 h) for use.

[0185] Among them, in the method 1 and the method 2, the R-vinyl silicone rubber can be pretreated by conventional methods in the art, such as drying at 30-60° C. (such as 40° C.) for 1-24 h (such as 12 h or 24 h) for use.

[0186] 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, use an open mill to extrude it into a thin pass, and press it into a sheet.

[0187] 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 use.

[0188] 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 and thinning them 5 times on an open mill with a roller spacing of 1-10mm (for example, 1mm), and then rolling the sheets, and then leaving them for 24 hours to obtain the mixture A.

[0189] Wherein, in the method 1, before the catalytic addition, the mixture B may be subjected to the following post-treatment: triangularly wrapped and thinned in an open mill for 4-6 times (for example, 6 times), and then uniformly cut into sheets.

[0190] Among them, in the second method, the step of mixing the component B1 and the component B2 can be: putting the component B1 and the component B2 in a ratio of 1:1 into an open mixing mill to make triangle wraps 4-6 times (for example 6 times), and then evenly cutting the materials into slices.

[0191] Among them, in the method one, 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 also included after the second heat treatment.

[0192] 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.

[0193] The time of the first heat treatment may be about 5 seconds.

[0194] The temperature of the second heat treatment may be 120-300°C, such as 180-280°C, and such as 180°C, 260°C or 280°C.

[0195] The second heat treatment may last for about 2 minutes.

[0196] The temperature of the third heat treatment may be 150-250°C, for example 180°C.

[0197] The third heat treatment may be performed for 24-48 hours, for example 48 hours.

[0198] The third heat treatment may be performed in an oven.

[0199] Wherein, in the method 2, the catalytic addition step in S4 can be as described above.

[0200] The invention provides a method for preparing the reservoir type implant, which comprises the following steps: cutting the silicone tube into segments, filling the drug-carrying rod core, and sealing both ends with silicone to obtain the reservoir type implant.

[0201] In the present invention, preferably, after being cut into segments, the length of the silicone tube is 0.4 cm longer than that of the drug-carrying 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.

[0202] In the present invention, preferably, before the filling, the silicone tube is also cleaned and swollen.

[0203] The cleaning may be performed by soaking in ethanol and repeatedly rinsing with ethanol. The soaking time may be 10-60 minutes, for example 15 minutes.

[0204] The swelling can be performed by soaking in petroleum ether for 1-2 minutes. Since the swollen silicone tube will shrink and return to its original state quickly after being taken out of petroleum ether, the drug-loaded rod core needs to be quickly inserted into the silicone tube.

[0205] In the present invention, the sealing may further include a curing operation.

[0206] The curing can be performed by standing at room temperature for 12-24 hours, for example 24 hours.

[0207] 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 medicine active ingredient, and the average particle size of the medicine active ingredient is 1-1000nm.

[0208] 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.

[0209] In the present invention, the diameter of the drug-carrying section 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.

[0210] 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.

[0211] 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.

[0212] In the present invention, the powder-type drug core may further include poorly soluble auxiliary materials.

[0213] Wherein, the average particle size of the poorly soluble auxiliary material may be 1-200 μm.

[0214] Wherein, the poorly soluble auxiliary material may include silicon material. The pore size of the silicon material may be less than 1 μm; for example, 0 nm, 5 nm, 10 nm, 18 nm, 50 nm or 100 nm. Those skilled in the art will understand that when the pore size of the silicon material is 0 nm, the silicon material is a non-porous silicon material.

[0215] In the silicon material, the content of silicon dioxide may be greater than 50%, preferably 80%, 90%, 95%, 99% or 99.8%.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] More preferably, the poorly soluble auxiliary material is one or more of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica.

[0220] In the present invention, the poorly soluble auxiliary material may also include a poorly soluble weak acid and / or a poorly soluble weak base.

[0221] The poorly soluble weak acid preferably includes one or more of boric acid, fumaric acid, molybdic acid, silicic acid, tungstic acid and germanic acid, and more preferably includes boric acid and / or fumaric acid.

[0222] 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.

[0223] The poorly soluble auxiliary material may also be white carbon black and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, white carbon black and molybdic acid, white carbon black and silicic acid, white carbon black and tungstic acid, or white carbon black and germanic acid.

[0224] 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.

[0225] Alternatively, the poorly soluble auxiliary material may also be AL-1FP mesoporous silica and one or more of molybdic acid, silicic acid, tungstic acid and germanic acid; for example, AL-1FP mesoporous silica and molybdic acid, AL-1FP mesoporous silica and silicic acid, AL-1FP mesoporous silica and tungstic acid, or AL-1FP mesoporous silica and germanic acid.

[0226] Alternatively, the poorly soluble auxiliary material may also be AL-1FP mesoporous silica, and ferrous hydroxide and / or magnesium oxide; for example, AL-1FP mesoporous silica and ferrous hydroxide, or AL-1FP mesoporous silica and magnesium oxide.

[0227] 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.

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] The content of the poorly soluble excipient may be 0.1%-90%, such as 0.1%-50%, and another example is 0.5%-5%; the percentage is the mass percentage of the poorly soluble excipient in the pharmaceutical composition.

[0233] In the present invention, when the insoluble auxiliary material is two or three of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica, the mass ratio thereof can be any ratio. For example, when the insoluble auxiliary material is two of white carbon black, AL-1FP mesoporous silica and XDP3050 mesoporous silica, the mass ratio thereof is (0.001-1000):1.

[0234] For another example, when the poorly soluble auxiliary materials are XDP3150 mesoporous silica and fumaric acid, the mass ratio thereof may be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

[0235] For another example, when the poorly soluble 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.

[0236] 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.

[0237] For another example, when the poorly soluble auxiliary material is AL-1FP mesoporous silica and zinc hydroxide, the mass ratio thereof can be (0.01-100):1, preferably 9:1, 1.5:1 or 0.43:1.

[0238] In the present invention, the raw material composition and preparation method of the silicone tube can be as described above.

[0239] The 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.

[0240] In the present invention, preferably, after being cut into segments, the length of the silicone tube is 0.4 cm longer than the drug-carrying segment.

[0241] In the present invention, preferably, before the filling, the silicone tube is cleaned.

[0242] The cleaning may be performed by soaking in ethanol and repeatedly rinsing with ethanol. The soaking time may be 10-60 minutes, for example 15 minutes.

[0243] In the present invention, the sealing may further include a curing operation.

[0244] The curing can be performed by standing at room temperature for 12-24 hours, for example 24 hours.

[0245] The present invention also provides a use of the raw material composition of the drug-loaded rod core, the drug-loaded rod core or the reservoir-type implant as a release rate regulating medium in a sustained-release preparation.

[0246] On the basis of being in accordance with the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0247] The reagents and raw materials used in the present invention are commercially available.

[0248] The positive and progressive effects of the present invention are:

[0249] (1) The present invention uses active pharmaceutical ingredients with an average particle size of 1-1000 nm, which can significantly improve the solubility of the drug; and its compatibility with silicone rubber is better, and the release rate of the obtained skeleton-type implant and reservoir-type implant is significantly improved. Taking paliperidone as an example, compared with the active pharmaceutical ingredient using conventional particle size, the release rate of the implant of the present invention can be increased by 3-10 times.

[0250] (2) 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.

[0251] (3) The present invention has a wide range of applications and is suitable for a variety of drugs to achieve stable release of large doses. For example, the release rate of estradiol, meloxicam, and exemestane can be increased by 4-10 times. BRIEF DESCRIPTION OF THE DRAWINGS

[0252] Figure 1 The in vitro release results of the paliperidone skeleton-type stick cores before and after nano-crystallization prepared in Comparative Example 1 and Example 1 are shown.

[0253] Figure 2The in vitro release results of the paliperidone hollow skeleton stick cores before and after nano-sizing prepared in Comparative Example 2 and Example 2 are shown.

[0254] Figure 3 The in vitro release results of the paliperidone skeleton reservoir implants before and after nano-sizing prepared in Comparative Example 3 and Example 3 are shown.

[0255] Figure 4 The in vitro release results of the paliperidone drug powder reservoir implants before and after nano-sizing prepared in Comparative Example 4 and Example 4 are shown.

[0256] Figure 5 These are the in vitro release results of the paliperidone hollow skeleton nano-rod cores with different inner diameters prepared in Example 7 and the paliperidone hollow skeleton-type rod cores with different inner diameters prepared in Comparative Example 7.

[0257] Figure 6 This is a comparison chart of the in vitro release results of the paliperidone hollow skeleton nano-rod cores with different particle sizes prepared in Example 8 and the paliperidone hollow skeleton type rod cores prepared in Comparative Example 2.

[0258] Figure 7 The in vitro release results of the estradiol hollow skeleton stick cores before and after nano-scaling prepared in Comparative Example 5 and Example 5 are shown.

[0259] Figure 8 The in vitro release results of the meloxicam hollow skeleton stick cores before and after nano-sizing prepared in Comparative Example 6 and Example 6. DETAILED DESCRIPTION

[0260] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0261] Example 1 Paliperidone skeleton nanorod core

[0262] A. Basic prescription:

[0263] (1) Nano paliperidone, with an average particle size of 220 nm and an addition amount of 100 PHR;

[0264] (2) methyl vinyl silicone rubber, vinyl content of 0.18 mol%, added in an amount of 100 PHR;

[0265] (3) hydrogen-containing silicone oil, the Si-H content of which is 0.75 mol%, and the amount added is 4.44 PHR;

[0266] (4) platinum catalyst, the concentration of platinum is 10000 ppm, and the addition amount is 0.21 PHR;

[0267] (5) 2-methyl-3-butyn-2-ol, added in an amount of 0.98 PHR;

[0268] The molar ratio of Si-H groups in the hydrogenated silicone oil to vinyl groups in the R-vinyl silicone rubber is 5:1.

[0269] Note: PHR (parts per hundreds of rubber) indicates the number of parts of the component per 100 parts of methyl vinyl silicone rubber; ppm (parts per million) is parts per million, indicating the mass concentration of platinum in the platinum catalyst.

[0270] B. Preparation process:

[0271] (1) Drying pretreatment of raw rubber: Dry the methyl vinyl silicone rubber raw rubber at 40°C for 12 hours for later use.

[0272] (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 hydrogen-containing silicone oil and inhibitor to component A, mix it in an open mill, and then pass it through several times to unload it in the form of thin sheets. Add platinum catalyst to component B, mix it in an open mill, and then pass it through several times to unload it in the form of thin sheets.

[0273] (3) Preparation of rubber compound: The prepared A and B component flakes are put into an open mixer at a ratio of 1:1 and mixed for 6 times to ensure that the A and B component rubbers are fully mixed and uniformly formed into a rubber compound.

[0274] (4) Preparation of drug-loaded silica gel: Nano-paliperidone and mixed rubber were mixed evenly on an open mixer at a drug-to-gel weight ratio of 1:1 to prepare drug-loaded silica gel, which was then cut into strips.

[0275] Nano paliperidone is obtained by nano-processing raw material paliperidone. Specifically, a planetary ball mill is used for wet grinding. 0.4 g of stabilizer poloxamer 188 is added to 2 g of raw material paliperidone. Zirconia beads with a diameter of 0.1 mm are used as grinding media. The grinding time is controlled to be 50 min and the rotation speed is 400 r·min. -1 After grinding, the freeze-drying process is adopted, and the nano-freeze-dried powder is taken out after freeze-drying to obtain the nano-freeze-dried powder.

[0276] (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 a rod core through the die mouth under the push of the screw.

[0277] (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.

[0278] 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.

[0279] Comparative Example 1 Paliperidone skeleton core

[0280] A. Basic prescription

[0281] (1) The amount of paliperidone added is 100 PHR, and the average particle size is 5 μm;

[0282] (2)-(5) are the same as the prescriptions (2)-(5) of Example 1.

[0283] B. Preparation process

[0284] Compared with Example 1, the difference of Comparative Example 1 is that the raw material paliperidone is directly used in step (4), and the other operations are the same as those of Example 1.

[0285] Example 2 Paliperidone Hollow Skeleton Nano-Rod Core

[0286] A. Basic prescription

[0287] Same basic recipe as Example 1.

[0288] B. Preparation process

[0289] The preparation process of (1) to (4) and (6) is the same as that of Example 1.

[0290] (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. -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-type rod core under the push of the screw.

[0291] 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.

[0292] Comparative Example 2 Paliperidone hollow skeleton core

[0293] A. Basic prescription

[0294] Same basic recipe as Comparative Example 1.

[0295] B. Preparation process

[0296] Compared with Example 2, the difference of Comparative Example 2 is that the raw material paliperidone is directly used in step (4), and the other operations are the same as those of Example 2.

[0297] Example 3 Paliperidone skeleton reservoir nano-type implant

[0298] A. Basic prescription:

[0299] It consists of a silicone tube and a paliperidone skeleton nanorod core with an average particle size of 220 nm prepared by the preparation method of Example 1.

[0300] a. Basic prescription of silicone tube

[0301] The basic formula of silicone tube consists of base polymer, reinforcing agent, cross-linking agent, catalyst and inhibitor.

[0302] (1) The selected base polymer is methyl vinyl polysiloxane, the vinyl group is the end-capping group of the polysiloxane, the content of the vinyl group is 0.18 mol%, and the added amount is 100 PHR;

[0303] (2) The selected reinforcing agent is fumed silica, and the addition amount is 40 PHR;

[0304] (3) The selected crosslinking agent is hydrogen-containing silicone oil, the Si-H group content of which is 0.75 mol%, and the added amount is 1.07 PHR;

[0305] (4) The selected platinum catalyst has a platinum concentration of 3000 ppm and an addition amount of 0.21 PHR;

[0306] (5) The selected inhibitor is 2-methyl-3-butyn-2-ol, and the added amount is 0.98 PHR.

[0307] The molar ratio of Si-H groups in the hydrogen-containing silicone oil to vinyl groups in the methylvinyl polysiloxane is 1.2:1.

[0308] b. Basic formula of paliperidone skeleton nanorod core

[0309] The basic formula of the paliperidone skeleton nanorod core was prepared in the same manner as in Example 1; wherein the average particle size of paliperidone was 220 nm.

[0310] B. Preparation process

[0311] (1) Preparation of silicone tube:

[0312] 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 raw rubber at 40℃ for 12 hours.

[0313] ② Preparation of rubber compound: Put the prescribed amount of fumed silica and methyl vinyl silicone rubber raw rubber into a kneader, knead for 30 minutes at 30°C to make the fumed silica and raw rubber evenly mixed, then take out the rubber compound to obtain the rubber compound, transfer it to an open mixing mill for extrusion and thinning, and make triangle wrapping and thinning 5 times with a roller distance of 1mm. Use the shearing action of the two rollers of the mixing mill to further mix the rubber compound, and then unload the rubber compound from the mixing mill in the form of thin sheets, wrap the rubber compound with plastic wrap and put it into a ziplock bag, and put it in a desiccant for 24 hours for use.

[0314] ③ Preparation of components A and B: The rubber mixture is divided into two components A and B. Add the prescribed amount of hydrogenated silicone oil and inhibitor to component A, mix it in an open mill, and then pass it through several times to unload it in the form of thin slices. Add the prescribed amount of platinum catalyst to component B, mix it in an open mill, and then pass it through several times to unload it in the form of thin slices. Wrap the prepared components A and B with plastic wrap, put them into self-sealing bags, and put them in a desiccator for 24 hours for use.

[0315] ④ Mixing of components A and B: Put the parked components A and B into the mixing mill at a ratio of 1:1, make a triangle bag and pass it 6 times to make the components A and B fully mixed. Unload them in the form of slices on the mixing mill and cut them into strips.

[0316] 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 a silicone tube through the die mouth under the push of the rotating screw.

[0317] 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.

[0318] 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 3.4mm and a wall thickness of 0.2mm is prepared.

[0319] (2) Preparation of paliperidone skeleton nanorod core: The preparation method of paliperidone skeleton nanorod core is the same as that in Example 1.

[0320] (3) Treatment of silicone tube: Take an addition-type silicone tube with qualified appearance and various performances, cut it to a length of 4.4 cm, 0.4 cm longer than the paliperidone skeleton nanorod core, and reserve 0.2 cm for the sealing glue at both ends 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 naturally.

[0321] (4) Assembly of paliperidone skeleton nanorod core and silicone tube: Soak the silicone tube in petroleum ether to swell for 1-2 minutes. After swelling, 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 shrink and return to its original shape quickly after being taken out of the petroleum ether. At this time, immediately and quickly insert the cut paliperidone skeleton nanorod core (4 cm rod core, 3 mm outer diameter) into the middle position of the silicone tube with tweezers, so that the same length of space is reserved at both ends of the silicone tube for sealing. After assembly, let the implant dry naturally for 24 hours to evaporate the residual petroleum ether.

[0322] (5) Sealing 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.

[0323] The paliperidone skeleton reservoir nano-type implant prepared by the above preparation method, wherein the drug-carrying rod core is a skeleton-type drug-carrying rod core with a diameter of 3.0 mm and a length of 4.0 cm; the outer diameter of the silicone tube is 3.4 mm, the wall thickness is 0.2 mm, the length is 4.4 cm, and the drug release area is 3.77 cm 2 .

[0324] Comparative Example 3 Paliperidone skeleton reservoir implant

[0325] A. Basic prescription

[0326] It consists of a silicone tube and a skeleton-type rod core prepared in Comparative Example 1.

[0327] a. Basic prescription of silicone tube

[0328] The basic recipe of the silicone tube prepared in Example 3.

[0329] b. Basic formula of skeleton core

[0330] The basic formula of the skeleton-type rod core prepared in Comparative Example 1.

[0331] B. Preparation process

[0332] Compared with Example 3, the difference of Comparative Example 3 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 Comparative Example 1, and the other operations are the same as those of Example 3.

[0333] Example 4 Paliperidone drug powder reservoir nano implant

[0334] A. Basic prescription:

[0335] It consists of a silicone tube and a nano powder type drug core. The basic formula of the silicone tube is the same as that of the silicone tube prepared in Example 3. The nano powder type drug core is paliperidone with an average particle size of 220 nm.

[0336] B. Preparation process:

[0337] Compared with Example 3, the difference of Example 4 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).

[0338] The paliperidone drug 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 section is 3.0 mm and the length is 4.0 cm.

[0339] Comparative Example 4 Paliperidone powder reservoir implant

[0340] A. Basic prescription

[0341] It consists of a silicone tube and a powder core. The silicone tube has the same basic formula as the silicone tube prepared in Example 3. The powder core is paliperidone with an average particle size of 5 μm.

[0342] B. Preparation process

[0343] Compared with Example 4, the difference of Comparative Example 4 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 4.

[0344] Example 5 Estradiol Hollow Skeleton Nano-Rod Core

[0345] On the basis of Example 2, 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.

[0346] Comparative Example 5 Estradiol Hollow Skeleton Rod Core

[0347] On the basis of Example 5, only the active ingredient of the drug was changed from nano-estradiol to estradiol, and the average particle size of estradiol was 66 μm.

[0348] Example 6 Meloxicam Hollow Skeleton Nano-Rod Core

[0349] On the basis of Example 2, 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.

[0350] Comparative Example 6 Meloxicam hollow skeleton rod core

[0351] On the basis of Example 6, only the active ingredient of the drug was changed from nano-meloxicam to meloxicam, and the average particle size of meloxicam was 80 μm.

[0352] Example 7 Paliperidone hollow skeleton nanorod cores with different inner diameters

[0353] On the basis of Example 2, only the size of the core die 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.

[0354] Comparative Example 7 Paliperidone hollow skeleton core with different inner diameters

[0355] On the basis of Comparative Example 2, only the size of the core die 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. In other words, compared with Example 7, the difference of Comparative Example 7 is that the raw material paliperidone is directly used in step (4), and the other operations are the same as Example 7.

[0356] Example 8 Paliperidone hollow skeleton nanorod cores with different particle sizes

[0357] On the basis of Example 2, only the grinding time during the nano-processing of the raw material paliperidone was changed to prepare paliperidone hollow skeleton nano-rod cores with average particle sizes of 820 nm, 646 nm, 430 nm and 220 nm, respectively.

[0358] Examples 9-11 are based on Example 1, and the types of stabilizers, grinding media and grinding time during the grinding process are investigated.

[0359] Example 9 Investigation of stabilizer types

[0360] Active ingredient: stabilizer = 5:1, ball mill speed 400r·min -1The grinding media was 0.2 mm zirconium oxide beads, the grinding media 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.

[0361] Table 1 Effect of different types of stabilizers on average particle size and PDI

[0362]

[0363] The results show that the effects of the above five stabilizers all meet the experimental requirements, and the PDI is less than 0.3.

[0364] Example 10 Investigation of grinding media types

[0365] Active ingredient: stabilizer = 5:1, ball mill speed 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.

[0366] Table 2 Effect of different grinding media types on average particle size and PDI

[0367]

[0368] The results show that as the diameter of the zirconia beads gradually increases, the average particle size and PDI both increase. The PDI of 0.1-0.3mm zirconia beads is less than 0.3, which meets the experimental requirements. Using 0.1mm zirconia beads as grinding media, the final grinding PDI and average particle size are the smallest in the same time.

[0369] Example 11 Grinding time investigation

[0370] Active ingredient: stabilizer = 5:1, ball mill speed 400r·min -1 , poloxamer 188 as stabilizer, 0.1 mm zirconia 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 ingredients after grinding were investigated.

[0371] Table 3 Effect of different grinding time on average particle size and PDI

[0372]

[0373]

[0374] 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.

[0375] According to Examples 9-11, the speed of the ball mill used during grinding 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 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.

[0376] Effect Example 1 In vitro release study

[0377] 1. Test conditions:

[0378] (1) Chromatographic conditions for in vitro release of paliperidone

[0379] Chromatographic column: C18 column (4.6 × 100 mm, 2.7 μm);

[0380] Mobile phase: methanol: water (45:55, v / v) (pH adjusted to 3 with phosphoric acid);

[0381] Column temperature: 35°C;

[0382] Detection wavelength: 280nm;

[0383] Flow rate: 1.0 mL min -1 ;

[0384] Injection volume: 20 μL.

[0385] (2) Chromatographic conditions for in vitro release of estradiol

[0386] Chromatographic column: C18 column (250mm×4mm, 5μm)

[0387] Mobile phase: acetonitrile-water (55:45, v / v)

[0388] Column temperature: 25℃

[0389] Detection wavelength: 202nm

[0390] Flow rate: 0.8 mL min -1

[0391] Injection volume: 20 μL

[0392] (3) Chromatographic conditions for in vitro release of meloxicam

[0393] Chromatographic column: C18 column (4.6 mm × 150 mm, 5 μm);

[0394] Mobile phase: methanol: 0.5% phosphoric acid aqueous solution (70:30, v / v);

[0395] Column temperature: room temperature;

[0396] Detection wavelength: 270nm;

[0397] Flow rate: 1.0 mL min -1 ;

[0398] Injection volume: 20 μL.

[0399] 2. In vitro release test method

[0400] Using the horizontal oscillation method, take a stick core and fix the two ends of the stick core to the bottom and wall of a 100mL conical flask with silicone adhesive (to prevent the stick core from floating on the liquid surface and causing inaccurate release results). After adhesion, leave it 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. The temperature is set to 37°C and the amplitude is 100r·min. -1 The medium was replaced with an equal volume every 1 day.

[0401] 3. Release results

[0402] (1) Paliperidone skeleton core

[0403] Table 4 In vitro release results of paliperidone skeleton core prepared in Comparative Example 1

[0404]

[0405] Table 5 In vitro release results of paliperidone skeleton nanorod core prepared in Example 1

[0406]

[0407] The results showed that after the drug was nanosized, the release rate of the paliperidone skeleton nanorod core was about 4 times higher than the original. Figure 1 (shown)

[0408] (2) Paliperidone hollow skeleton core

[0409] Table 6 In vitro release results of the paliperidone hollow skeleton core prepared in Comparative Example 2

[0410]

[0411] Table 7 In vitro release results of the paliperidone hollow skeleton nanorod core prepared in Example 2

[0412]

[0413] The results showed that after the drug was nanosized, the release rate of the paliperidone hollow skeleton nanorod core was about 4 times higher than the original. Figure 2 (shown)

[0414] (3) Paliperidone skeleton reservoir implant

[0415] Table 8 In vitro release results of paliperidone skeleton reservoir implant prepared in comparative example 3

[0416]

[0417] Table 9 In vitro release results of paliperidone skeleton reservoir nano-type implant prepared in Example 3

[0418]

[0419]

[0420] The results showed that after the drug was nanosized, the release rate of paliperidone skeleton reservoir nano-implant was about 3.5 times the original.

[0421] (like Figure 3 (shown)

[0422] (4) Paliperidone powder reservoir implant

[0423] Table 10 In vitro release results of paliperidone drug powder reservoir implant prepared in Comparative Example 4

[0424]

[0425] Table 11 In vitro release results of paliperidone powder reservoir nano-type implant prepared in Example 4

[0426]

[0427]

[0428] The results showed that after the drug was nanosized, the release rate of the paliperidone drug powder reservoir nano-type implant was about 6 times the original. Figure 4 (shown)

[0429] (5) Comparison of in vitro release results of paliperidone hollow skeleton nanorods with different inner diameters

[0430] The in vitro release results of the paliperidone hollow skeleton nanorod cores with different inner diameters prepared in Example 7 and the paliperidone hollow skeleton type rod cores with different inner diameters prepared in Comparative Example 7 are shown in FIG. Figure 5 shown.

[0431] Table 12 In vitro release results of paliperidone hollow skeleton cores with different inner diameters

[0432]

[0433] Table 13 In vitro release results of paliperidone hollow skeleton nanorod cores with different inner diameters

[0434]

[0435] The results showed that as the inner diameter of the paliperidone hollow skeleton nanorod core increased, the in vitro release dose also increased significantly.

[0436] (6) Comparison of in vitro release results of paliperidone hollow skeleton nanorod cores with different particle sizes

[0437] The in vitro release results of the paliperidone hollow skeleton nano-rod cores with average particle sizes of 820 nm, 646 nm, 430 nm and 220 nm prepared in Example 8 and the paliperidone hollow skeleton nano-rod cores prepared in Comparative Example 2 are as follows: Figure 6 shown.

[0438] Table 14 In vitro release results of paliperidone hollow skeleton nanorod cores with different particle sizes

[0439]

[0440] The results showed that the release rates of paliperidone rod cores with different particle sizes were different, and the smaller the particle size, the faster the release rate. Among the above-mentioned paliperidone hollow skeleton nanorod cores with different particle sizes, the release rate of paliperidone with 220nm was about 4 times that before nano-sizing, the release rate of paliperidone with 430nm was about 3 times that before nano-sizing, the release rate of paliperidone with 646nm was about 2 times that before nano-sizing, and the release rate of paliperidone with 820nm was about 1.5 times that before nano-sizing.

[0441] (7) Estradiol hollow skeleton rod core

[0442] Table 15 In vitro release results of estradiol hollow skeleton stick core prepared in Comparative Example 5

[0443]

[0444] Table 16 In vitro release results of estradiol hollow skeleton nanorod core prepared in Example 5

[0445]

[0446] (8) Meloxicam hollow skeleton rod core

[0447] Table 17 In vitro release results of the meloxicam hollow skeleton stick core prepared in Comparative Example 6

[0448]

[0449] Table 18 In vitro release results of the meloxicam hollow skeleton nanorod core prepared in Example 6

[0450]

[0451] The results showed that the release rate of estradiol at 198 nm was about 4 times that before grinding ( Figure 7 ), the release rate of 308nm meloxicam is about 5 times that before grinding ( Figure 8 ).

[0452] Conclusion of the full article: Nano-sized 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-nano-sized drugs, the release rate can be increased by 2-8 times, and the nano-sized drugs have better compatibility with silica gel, which is more conducive to the production of implants.

Claims

1. 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 also included, and the inhibitor is an inhibitor that can inhibit the addition reaction between the R-vinyl silicone rubber and the hydrogen-containing silicone oil.

2. The raw material composition of the drug-loaded stick core according to claim 1, characterized in that: 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; and / or, the active pharmaceutical ingredient is an active drug having a solubility of ≤100 mg / mL; And / or, 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; and / or, the dosage of the active ingredient of the medicine is 1-800 parts; And / or, the R-vinyl silicone rubber is methyl vinyl silicone rubber; the methyl vinyl silicone rubber is preferably methyl vinyl silicone rubber having a relative molecular weight of 100000-800000 g / mol; And / or, the content of vinyl in the R-vinyl silicone rubber is 0.17-0.23 mol%; And / or, the amount of the hydrogen-containing silicone oil is 0.5-20 parts, preferably 1.2-6.3 parts; and / or, the content of Si-H groups in the hydrogen-containing silicone oil is 0.36-1.6 mol%, preferably 0.5-1 mol%; And / or, 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 / or, the 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; And / or, the amount of the catalyst is 2×10 -6 -1 part, preferably 0.03-0.3 part, more preferably 0.1-0.3 part; And / or, the inhibitor is an acetylenic alcohol compound, a nitrogen-containing compound or an organic peroxide, such as methylbutynol, and also such as 2-methyl-3-butyn-2-ol; And / or, the inhibitor is used in an amount of 0.03-2.5 parts, preferably 0.1-2.0 parts, more preferably 0.3-1.0 parts.

3. 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 1 or 2; 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-loaded rod core is a hollow skeleton type drug-loaded rod core, the diameter ratio of the outer diameter to the inner diameter of the drug-loaded rod core is (1.5-50):

1.

4. A method for preparing the drug-loaded rod core according to claim 3, characterized in that: It includes 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.

5. The method for preparing the drug-loaded rod core according to claim 4, characterized in that: In step (1), the R-vinyl silicone rubber is dried at 30-60° C. for 1-24 h for later use; And / or, 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 slices; And / or, 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; And / or, 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; Preferably, a stabilizer and a grinding medium are also added during the grinding process; 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; And / or, in step (2), the step of mixing the rubber compound and the active pharmaceutical ingredient comprises the following steps: putting the rubber compound and the active pharmaceutical ingredient into an open mixer for mixing, 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); And / or, 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; And / or, in step (3), during the extrusion molding, the screw speed of the extruder is 1-15 r·min -1 ; And / or, 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; And / or, 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; And / or, 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; And / or, in step (3), the vulcanization temperature is 30-120°C; And / or, in step (3), the vulcanization time is 10-100 min.

6. A reservoir-type implant, characterized in that: It comprises the drug-carrying rod core and the silicone tube as claimed in claim 3; 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.

7. A method for preparing the reservoir-type implant as claimed in claim 6, characterized in that: It includes the following steps: The silicone tube is cut into sections, filled with the drug-loaded rod core, and both ends are sealed with silicone to obtain the reservoir-type implant.

8. 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 6; 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.

9. A method for preparing the reservoir-type implant as claimed in claim 8, characterized in that: It includes the following steps: The silicone tube is cut into sections, one end of which is sealed with silicone, filled with the powder-type medicine core, and the other end is sealed with silicone to obtain the reservoir-type implant.

10. Use of the raw material composition of the drug-loaded stick core according to claim 1 or 2, the drug-loaded stick core according to claim 3, or the reservoir-type implant according to claim 6 or 8 as a release rate regulating medium in a sustained-release preparation.

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