CN116650432A - 一种辛伐他汀缓释片及其制备方法 - Google Patents
一种辛伐他汀缓释片及其制备方法 Download PDFInfo
- Publication number
- CN116650432A CN116650432A CN202210147200.4A CN202210147200A CN116650432A CN 116650432 A CN116650432 A CN 116650432A CN 202210147200 A CN202210147200 A CN 202210147200A CN 116650432 A CN116650432 A CN 116650432A
- Authority
- CN
- China
- Prior art keywords
- simvastatin
- release tablet
- sustained
- coating
- weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 title claims abstract description 41
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 title claims abstract description 40
- 229960002855 simvastatin Drugs 0.000 title claims abstract description 40
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 20
- 238000002360 preparation method Methods 0.000 title abstract description 19
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid group Chemical group C(CC(O)(C(=O)O)CC(=O)O)(=O)O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 24
- 239000011248 coating agent Substances 0.000 claims description 21
- 238000000576 coating method Methods 0.000 claims description 21
- 239000003826 tablet Substances 0.000 claims description 19
- 238000002156 mixing Methods 0.000 claims description 18
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 16
- 229930195725 Mannitol Natural products 0.000 claims description 16
- 239000000594 mannitol Substances 0.000 claims description 16
- 235000010355 mannitol Nutrition 0.000 claims description 16
- 239000000463 material Substances 0.000 claims description 15
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 239000007888 film coating Substances 0.000 claims description 12
- 238000009501 film coating Methods 0.000 claims description 12
- 239000000945 filler Substances 0.000 claims description 11
- 238000000034 method Methods 0.000 claims description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 4
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 239000003381 stabilizer Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 239000000725 suspension Substances 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 230000004584 weight gain Effects 0.000 claims description 4
- 235000019786 weight gain Nutrition 0.000 claims description 4
- 229920001531 copovidone Polymers 0.000 claims description 3
- 230000001965 increasing effect Effects 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 238000010298 pulverizing process Methods 0.000 claims description 2
- 239000008213 purified water Substances 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 235000015424 sodium Nutrition 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 11
- 239000007787 solid Substances 0.000 abstract description 7
- 230000003111 delayed effect Effects 0.000 abstract description 3
- 238000011835 investigation Methods 0.000 abstract 1
- 229960001855 mannitol Drugs 0.000 description 13
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 12
- 239000000203 mixture Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 8
- 235000012000 cholesterol Nutrition 0.000 description 6
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 210000004185 liver Anatomy 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000035150 Hypercholesterolemia Diseases 0.000 description 4
- 108010028554 LDL Cholesterol Proteins 0.000 description 4
- 238000007908 dry granulation Methods 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 108010023302 HDL Cholesterol Proteins 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 108010069201 VLDL Cholesterol Proteins 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960004106 citric acid Drugs 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 238000005056 compaction Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 102000004506 Blood Proteins Human genes 0.000 description 1
- 108010017384 Blood Proteins Proteins 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010014476 Elevated cholesterol Diseases 0.000 description 1
- 108010010234 HDL Lipoproteins Proteins 0.000 description 1
- 102000015779 HDL Lipoproteins Human genes 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- 102000000853 LDL receptors Human genes 0.000 description 1
- 108010001831 LDL receptors Proteins 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- 229940123934 Reductase inhibitor Drugs 0.000 description 1
- 241000519995 Stachys sylvatica Species 0.000 description 1
- 208000001871 Tachycardia Diseases 0.000 description 1
- 230000005856 abnormality Effects 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- PBCJIPOGFJYBJE-UHFFFAOYSA-N acetonitrile;hydrate Chemical compound O.CC#N PBCJIPOGFJYBJE-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 210000000709 aorta Anatomy 0.000 description 1
- 150000001277 beta hydroxy acids Chemical group 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- RGJOEKWQDUBAIZ-UHFFFAOYSA-N coenzime A Natural products OC1C(OP(O)(O)=O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 RGJOEKWQDUBAIZ-UHFFFAOYSA-N 0.000 description 1
- 239000005516 coenzyme A Substances 0.000 description 1
- 229940093530 coenzyme a Drugs 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- KDTSHFARGAKYJN-UHFFFAOYSA-N dephosphocoenzyme A Natural products OC1C(O)C(COP(O)(=O)OP(O)(=O)OCC(C)(C)C(O)C(=O)NCCC(=O)NCCS)OC1N1C2=NC=NC(N)=C2N=C1 KDTSHFARGAKYJN-UHFFFAOYSA-N 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 208000002173 dizziness Diseases 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000000260 hypercholesteremic effect Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- -1 methylglutaryl coenzyme A Chemical compound 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000013546 non-drug therapy Methods 0.000 description 1
- 231100001160 nonlethal Toxicity 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000006794 tachycardia Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 229940072168 zocor Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Obesity (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明属于医药口服固体制剂技术领域，具体涉及一种辛伐他汀缓释片及其制备方法，本发明的目的是提供一种辛伐他汀缓释片的制备工艺，使辛伐他汀缓释片在稳定性期间，含量、有关物质、溶出度等各项常规检测指标都满足的前提下能够获得在稳定性期间累积溶出度相比市售参比制剂更加稳定的辛伐他汀片，本发明制备的辛伐他汀缓释片在加速条件下专察6个月后，含量、有关物质、溶出度关键质量属性均符合各国药典规定。通过在加速条件考察3个月后累积溶出度的对比研究，与参比制剂对比，制备的辛伐他汀缓释片在剧烈的存储条件下，累积溶出度更加稳定。本发明的缓释片有延时释放和平释放的效果。
Description
技术领域
本发明属于医药口服固体制剂技术领域，具体涉及一种辛伐他汀缓释片及其制备方法。
背景技术
辛伐他汀为甲基羟戊二酰辅酶A(HMG-COA)的还原酶抑制剂，抑制内源性胆同醇的合成，为血脂调节剂。文献资料表明，辛伐他汀有降低高脂血症家兔血清、肝脏和主动脉中胆固醇(TC)的含量，降低极低密度脂蛋白胆固醇(VLDL-C)和低密度脂蛋白胆固醇(LDL-C)水平的作用。辛伐他汀经口服后对肝脏有高度的选择性，其在肝脏中的浓度明显高于其他非靶性组织，辛伐他汀的大部分经肝组织吸收，转化为活性代谢物β-羟酸结构，可降低肝脏胆固醇的合成及调节低密度脂蛋白受体、促进低密度脂蛋白清除而降低细胞内胆固醇的水平，中度降低血清甘油三脂水平和增高血高密度脂蛋白水平，主要作用在肝脏发挥，随后从胆汁中排泄。只有低于5％口服剂量的辛伐他汀活性结构在外围中发现，而其中95％可与血浆蛋白结合。
在临床应用上，辛伐他汀主要用于治疗：1、高胆固醇血症，饮食疗法及其它非药物治疗效果欠佳时，可应用辛伐他汀降低原发性高胆固醇血症患者的总胆固醇和低密度脂蛋白胆固醇，辛伐他汀同时可升高高密度脂蛋白胆固醇并因此降低低密度脂蛋白胆固醇/高密度脂蛋白胆固醇及总胆固醇/高密度脂蛋白胆固醇的比率。在合并患高胆固醇血症和高甘油三酯血症的病人，且高胆固醇血症为主要异常时，降低升高的胆固醇水平。2、冠心病，对冠心病患者，辛伐他汀主要被用于：减少死亡的危险性，减少冠心病死亡及非致死性心肌梗塞的危险性，减少心肌血管再通手术(冠状动脉搭桥术及经皮气囊冠状动脉成形术)，延缓动脉粥样硬化的进展，包括新病灶及全堵塞的发生。
但是在辛伐他汀发挥治疗作用的同时，由于现有的辛伐他汀剂型为普通片剂或胶囊剂，都为短效剂型，在给药时存在以下缺陷：由于短效剂型的半衰期较短，药效时间短，为了充分发挥其治疗作用，需要一日数次给药，容易造成血药浓度波动大，导致出现头痛、心动过速、心悸、头昏等副反应。
发明内容
针对现有技术的不足，本发明的主要目的是提供一种降血脂的辛伐他汀缓释片及其制备方法，能够实现延迟释放和平缓释放药物的技术效果。本发明优选辅料的种类及其用量，结合中试过程中遇到的问题，对处方制备工艺进行优化，采用干法制粒，片芯硬度对溶出曲线的影响较小，颗粒粒径符合工艺要求，颗粒流动性较好，并且将颗粒制大，解决了湿法制粒步骤将颗粒制的过实导致溶出变慢、片芯可压性差、包衣片表面出现少量白点、含量丢失等问题，提升溶出度，提高批间均匀性，降低有关物质含量，增强长期稳定性。
本发明技术方案如下：
用包衣技术制成的固体缓释剂型是通过包衣膜来控制和调节剂型中药物在体内外的释放速率的，因此包衣材料的选择、包衣膜的组成在很大程度上决定了这种制剂的缓释和控释作用的成败。根据本发明，为了延长缓释片的缓释效果，本发明的包衣层选用的包衣材料不溶于水，而包衣层中的致孔剂在接触体液后溶解，使片剂给药后能够形成释药孔道，片芯中的药物只能通过这些孔道以达到释放的效果，从而实现延迟释放和平缓释放药物的效果，优选的，所述的包衣材料为胃溶型薄膜包衣预混剂欧巴代，它具有热稳定性好，易溶于乙醇、丙酮等溶剂，便于制备包衣溶液，且欧巴代与本发明选用的增塑剂之间具有良好的配伍性，同时与片芯中的骨架材料之间具有良好的协同作用。本发明的第一个目的在于提供一种包含辛伐他汀、填充剂、崩解剂、润滑剂和薄膜包衣预混剂的片剂。
进一步的，所述填充剂选自甘露醇、乳糖、淀粉、微晶纤维素中的一种或多种，优选为甘露醇和微晶纤维素；所述崩解剂选自低取代羟丙纤维素、共聚维酮、羧甲基淀粉钠中的一种；所述润滑剂为硬脂酸镁；所述薄膜包衣预混剂为胃溶型薄膜包衣预混剂欧巴代。
本发明提供的第一个方案，以重量份比计，原辅料处方包括：
本发明提供的第二个方案，所述原辅料处方中还可以在第一方案基础上包含稳定剂。
具体的，所述稳定剂为枸橼酸；所述原辅料处方中枸橼酸的重量份为1-3份。
以重量份比计，原辅料处方包括：
本发明的第二个目的在于提供一种制备上述辛伐他汀缓释片的方法，包括以下步骤；
(1)粉碎配料工序：将部分填充剂粉碎；
(2)混合工序；将步骤(1)中粉碎的填充剂与处方量的其他主辅料置于混合机中混合10min，加入处方量中2/3重量份的润滑剂继续混合5min；
(3)制粒工序；使用干法制粒机进行制粒；
(4)总混工序；将步骤(3)的颗粒置于混合机里，外加剩余1/3重量份的润滑剂混合5min。
(5)压片；
(6)包衣工序；将薄膜包衣预混剂用纯化水配制成固含量15％的混悬包衣液，进行包衣，包衣增重2％-5％，干燥，即得。
进一步的，所述步骤(1)中的部分填充剂为处方量的甘露醇；所述步骤(6)中包衣增重优选为3.5％
与现有技术相比，本发明带来的有益效果在于：
(1)通过干法制粒工艺，优化辅料的添加过程，解决了湿法制粒步骤将颗粒制的过实导致片芯可压性差、脆碎度不合格等问题；
(2)通过优化辅料组成和用量，使得辛伐他汀溶出稳定，溶出批间、批内均一性高，降低有关物质含量，提高长期稳定性。本发明的片剂在临睡前服用给药，次日凌晨开始能够持续释放药物并控制释放量，使血药浓度始终维持平稳水平，提高生物利用度。
(3)本发明的辛伐他汀缓释片具有迟释和平缓释放的效果，有利于控制患者的血脂，而且还能够降低心脑血管发病机率。
(4)本发明的辛伐他汀缓释片的制备方法，原料来源广泛，成本低，适合工业化生产。
具体实施例
为了使本发明的目的、技术方案更加清楚明白，以下结合实施例，对本发明做进一步的说明，但是本发明的保护范围并不限于这些实施例，实施例仅用于解释本发明。本领域技术人员应该理解的是，凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。下面结合实施例对本发明进一步描述，但本发明并不为实施例所限制。
实施例1：辛伐他汀缓释片
处方组成1000片
| 成分 | 重量(g) |
| 辛伐他汀 | 5 |
| 微晶纤维素 | 65 |
| 甘露醇 | 110 |
| 低取代羟丙纤维素 | 2 |
| 硬脂酸镁(内加) | 2 |
| 硬脂酸镁(外加) | 1 |
制备工艺：
取处方量的甘露醇粉碎，将粉碎后的甘露醇、辛伐他汀、微晶纤维素、低取代羟丙纤维素加入多项运动混合机，混合10分钟，之后再加入硬脂酸镁(内加)，进行干法制粒后与硬脂酸镁(外加)进行总混，混合完成后根据总混颗粒原料含量计算理论片重，进行压片，采用胃溶型薄膜包衣预混剂欧巴代配制成固含量15％的混悬包衣液，包衣，包衣增重3％，干燥，即得。
实施例2：辛伐他汀缓释片
处方组成1000片
| 成分 | 重量(g) |
| 辛伐他汀 | 6 |
| 乳糖 | 50 |
| 玉米淀粉 | 95 |
| 共聚维酮 | 2 |
| 硬脂酸镁(内加) | 2 |
| 硬脂酸镁(外加) | 2 |
| 枸橼酸 | 3 |
制备工艺：
取处方量的甘露醇粉碎，将粉碎后的甘露醇、辛伐他汀、微晶纤维素、低取代羟丙纤维素、枸橼酸加入多项运动混合机，混合10分钟，之后再加入硬脂酸镁(内加)，进行干法制粒后与硬脂酸镁(外加)进行总混，混合完成后根据总混颗粒原料含量计算理论片重，进行压片，采用胃溶型薄膜包衣预混剂欧巴代配制成固含量15％的混悬包衣液，包衣，包衣增重4％，干燥，即得。
实施例3：辛伐他汀缓释片
处方组成1000片
| 成分 | 重量(g) |
| 辛伐他汀 | 4 |
| 微晶纤维素 | 70 |
| 甘露醇 | 120 |
| 低取代羟丙纤维素 | 6 |
| 硬脂酸镁(内加) | 2 |
| 硬脂酸镁(外加) | 1 |
| 枸橼酸 | 1 |
制备工艺：
取处方量的甘露醇粉碎，将粉碎后的甘露醇、辛伐他汀、微晶纤维素、低取代羟丙纤维素、枸橼酸加入多项运动混合机，混合10分钟，之后再加入硬脂酸镁(内加)，进行干法制粒后与硬脂酸镁(外加)进行总混，混合完成后根据总混颗粒原料含量计算理论片重，进行压片，采用胃溶型薄膜包衣预混剂欧巴代配制成固含量15％的混悬包衣液，包衣，包衣增重3.5％，干燥，即得。
验证实施例
1、基本参量试验效果对比
表1实施例基本参量分析
| 可压性 | 平均硬度 | 重量差异 | 崩解时限(min) | 脆碎度 | |
| 实施例1 | 较好 | 51.5 | 符合要求 | 11 | 符合要求 |
| 实施例2 | 较好 | 49.8 | 符合要求 | 11 | 符合要求 |
| 实施例3 | 较好 | 52.3 | 符合要求 | 10 | 符合要求 |
| 参比制剂 | 较好 | 50.1 | 符合要求 | 9 | 符合要求 |
由表1可知：实施例1-3与参比制剂(辛伐他汀片，商品名：Zocor，规格：10mg，生产商：Merck Manufacturing Division，Merck Sharp&Dohme Limited)比较，硬度、崩解时限、脆碎度相近。
2、实施例和参比制剂所得片剂的稳定性比较
2.1有关物质检测
照高效液相色谱法(中国药典2020年版四部通则0512)试验，以十八烷基硅烷键合硅胶为填充剂(Agilent Eclipse XDB-CI8，6*150mm.5um或效能相当的色谱柱)；以0.2％磷酸二氢钾溶液(取磷酸二氢钾2.0g，加水100ml使溶解，并用磷酸调节pH值至2.5+0.l)为流动相A，以乙腈水(50：50)为流动相B，柱温为55℃检测波长为225nm。
将实施例的片子和参比制剂分别置于高温(40℃)、高湿(相对湿度75±5％)的恒温恒湿箱内加速试验6个月，分别于0天、6个月检测有关物质。
表2各实施例、参比制剂的有关物质试验结果
2.2溶出度稳定性检测
溶出方法：篮法，50rpm
溶出介质：0.1M盐酸溶液(标准介质)-900ml
加速一个月：60℃，75％RH
表3实施例3加速1个月稳定性的比较
表4参比制剂加速1个月稳定性的比较
由表3-4的数据可知，经过加速试验分析结果可以看出，参比制剂与0天样品相比，60℃-30天样品与加速一个月样品的溶出曲线无明显变化，但是75％RH-30天样品溶出快于其他样品5min，是由于高湿条件样品吸湿(吸湿增重2.3％)，导致溶出过快。而本发明实施例3溶出稳定且完全。本发明其他实施例溶出效果同样稳定，其他实施例也同样做了溶出稳定性实验，由于篇幅原因不一一列举，后续如有需要，皆可提供。
Claims (8)
1.一种辛伐他汀缓释片，其特征在于，包含辛伐他汀、填充剂、崩解剂、润滑剂和薄膜包衣预混剂。
2.根据权利要求1所述的辛伐他汀缓释片，其特征在于，所述填充剂选自甘露醇、乳糖、淀粉、微晶纤维素中的一种或多种，优选为甘露醇和玉米淀粉；所述崩解剂选自低取代羟丙纤维素、共聚维酮、羧甲基淀粉钠中的一种；所述润滑剂为硬脂酸镁；所述薄膜包衣预混剂为胃溶型薄膜包衣预混剂欧巴代。
3.根据权利要求2所述的辛伐他汀缓释片，其特征在于，以重量份比计，原辅料处方包括：
4.根据权利要求2所述的辛伐他汀缓释片，其特征在于，以重量份比计，原辅料处方包括：
5.根据权利要求1所述的辛伐他汀缓释片，其特征在于，所述原辅料处方中还可以包含稳定剂。
6.根据权利要求5所述的辛伐他汀缓释片，其特征在于，所述稳定剂为枸橼酸；所述原辅料处方中枸橼酸的重量份为1-3份。
7.根据权利要求1-6任一项所述的制备辛伐他汀缓释片的方法，包括以下步骤；
(1)粉碎配料工序：将部分填充剂粉碎；
(2)混合工序；将步骤(1)中粉碎的填充剂与处方量的其他主辅料置于混合机中混合，加入部分润滑剂继续混合；
(3)制粒工序；使用干法制粒机进行制粒；
(4)总混工序；将步骤(3)的颗粒置于混合机里，外加剩余的润滑剂混合；
(5)压片；
(6)包衣工序；将薄膜包衣预混剂用纯化水配制成混悬包衣液进行包衣，包衣增重，干燥，即得辛伐他汀缓释片。
8.根据权利要求7所述的方法，其特征在于，所述步骤(1)中的部分填充剂为处方量的甘露醇；所述步骤(6)中包衣增重优选为3.5％。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210147200.4A CN116650432A (zh) | 2022-02-17 | 2022-02-17 | 一种辛伐他汀缓释片及其制备方法 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210147200.4A CN116650432A (zh) | 2022-02-17 | 2022-02-17 | 一种辛伐他汀缓释片及其制备方法 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116650432A true CN116650432A (zh) | 2023-08-29 |
Family
ID=87724748
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202210147200.4A Pending CN116650432A (zh) | 2022-02-17 | 2022-02-17 | 一种辛伐他汀缓释片及其制备方法 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116650432A (zh) |
-
2022
- 2022-02-17 CN CN202210147200.4A patent/CN116650432A/zh active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| EP2844233B1 (en) | Oral tablet formulation consisting of fixed combination of rosuvastatin and ezetimibe for treatment of hyperlipidemia and cardiovascular diseases | |
| MX2007015764A (es) | Formulaciones estables con dosis fija que contienen una combinacion de antivirales, metodo para producirlas usando granulacion en seco. | |
| JP2017500303A (ja) | エゼチミブ及びロスバスタチンを含む経口用複合製剤 | |
| CN107669683B (zh) | 含有西格列汀与二甲双胍的药物组合物 | |
| KR20140087846A (ko) | 테모졸로미드를 포함하는 안정성이 개선된 약제학적 조성물 및 이의 제조방법 | |
| TWI406861B (zh) | 包含阿格列扎(aleglitazar)之醫藥組合物及其製造方法與用途 | |
| SK284950B6 (sk) | Spôsob prípravy galenických foriem fenofibrátu a ich použitie | |
| CN112516094B (zh) | 一种托匹司他片剂及其制备方法 | |
| CN100486568C (zh) | 洛索洛芬钠缓释制剂 | |
| CN116650432A (zh) | 一种辛伐他汀缓释片及其制备方法 | |
| CN103550205A (zh) | 辛伐他汀固体组合物 | |
| CN1994296B (zh) | 一种含有辛伐他汀的药物制剂 | |
| CN115671061A (zh) | 一种利格列汀片及其制备方法 | |
| CN109432032B (zh) | 一种瑞舒伐他汀钙片及其制备方法 | |
| CN106994121B (zh) | 一种用于治疗癌症的药物组合物 | |
| CN111617048B (zh) | 一种用于治疗非小细胞肺癌的厄洛替尼缓释制剂 | |
| CN110548015A (zh) | 一种阿普斯特片剂及其制备方法 | |
| EP2663283B1 (en) | High drug load tablet formulation of brivanib alaninate | |
| CN113368073A (zh) | 制备用于降低血液尿酸水平的药物制剂的方法 | |
| CN110859843A (zh) | 一种治疗动脉硬化合并心绞痛的药物组合物及制备方法 | |
| Onwuzuligbo et al. | Formulation and physicotechnical evaluation of a fixed dose combination of amlodipine, metformin and glibenclamide in the management of hypertension-diabetes mellitus comorbidity | |
| CN114306259B (zh) | 一种丙戊酸钠双层缓释片及其制备方法 | |
| EP3936119A1 (en) | Pharmaceutical composition of prolyl hydroxylase inhibitor and preparation method therefor | |
| CN115429765B (zh) | 一种盐酸索他洛尔缓释制剂及其制备方法 | |
| CN112336697B (zh) | 一种辛伐他汀脉冲释放片及其制备方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication |