CN111821300A - 一种利托那韦液体制剂及其适应症 - Google Patents
一种利托那韦液体制剂及其适应症 Download PDFInfo
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- NCDNCNXCDXHOMX-UHFFFAOYSA-N Ritonavir Natural products C=1C=CC=CC=1CC(NC(=O)OCC=1SC=NC=1)C(O)CC(CC=1C=CC=CC=1)NC(=O)C(C(C)C)NC(=O)N(C)CC1=CSC(C(C)C)=N1 NCDNCNXCDXHOMX-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 229960000311 ritonavir Drugs 0.000 title claims abstract description 46
- 238000002360 preparation method Methods 0.000 title claims abstract description 22
- 239000007788 liquid Substances 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 claims abstract description 11
- 241000711573 Coronaviridae Species 0.000 claims abstract description 10
- 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 45
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 33
- -1 polyoxyethylene Polymers 0.000 claims description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 9
- 239000004359 castor oil Substances 0.000 claims description 9
- 235000019438 castor oil Nutrition 0.000 claims description 9
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 7
- 239000012669 liquid formulation Substances 0.000 claims description 6
- 239000006184 cosolvent Substances 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000725 suspension Substances 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims 1
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 208000024891 symptom Diseases 0.000 abstract description 3
- 206010011224 Cough Diseases 0.000 abstract description 2
- 206010036790 Productive cough Diseases 0.000 abstract description 2
- 206010037660 Pyrexia Diseases 0.000 abstract description 2
- 206010038687 Respiratory distress Diseases 0.000 abstract description 2
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 5
- 239000000049 pigment Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 241000725303 Human immunodeficiency virus Species 0.000 description 4
- 229940100688 oral solution Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 3
- AXRYRYVKAWYZBR-UHFFFAOYSA-N Atazanavir Natural products C=1C=C(C=2N=CC=CC=2)C=CC=1CN(NC(=O)C(NC(=O)OC)C(C)(C)C)CC(O)C(NC(=O)C(NC(=O)OC)C(C)(C)C)CC1=CC=CC=C1 AXRYRYVKAWYZBR-UHFFFAOYSA-N 0.000 description 2
- 108010019625 Atazanavir Sulfate Proteins 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- 241000713340 Human immunodeficiency virus 2 Species 0.000 description 2
- 229960003277 atazanavir Drugs 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229960004525 lopinavir Drugs 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 102000035101 Aspartic proteases Human genes 0.000 description 1
- 108091005502 Aspartic proteases Proteins 0.000 description 1
- 241001420622 Meris Species 0.000 description 1
- 108010076039 Polyproteins Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
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- 238000001514 detection method Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 229940072250 norvir Drugs 0.000 description 1
- 150000004965 peroxy acids Chemical class 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960001852 saquinavir Drugs 0.000 description 1
- QWAXKHKRTORLEM-UGJKXSETSA-N saquinavir Chemical compound C([C@@H]([C@H](O)CN1C[C@H]2CCCC[C@H]2C[C@H]1C(=O)NC(C)(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)C=1N=C2C=CC=CC2=CC=1)C1=CC=CC=C1 QWAXKHKRTORLEM-UGJKXSETSA-N 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
- 229960002555 zidovudine Drugs 0.000 description 1
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Abstract
本发明公开了利托那韦在制备用于治疗新型冠状病毒（2019‑nCoV）的药物中的用途。利托那韦液体制剂可使新型冠状病毒（2019‑nCoV）感染的患者有效改善呼吸窘迫、咳嗽咳痰，发热等全身症状，延缓疾病进展，可以提高患者的生活质量，具有广泛的应用价值。本发明经过药物研究确定得到产品稳定性较好，用于预防和治疗新型冠状病毒的制剂。
Description
技术领域
本发明涉及托那韦及其液体制剂，具体涉及一种用于预防及治疗新型冠状病毒（2019-nCoV）的液体制剂及其制法和适应症，属于医药技术领域。
背景技术
利托那韦是一种肽类似物抑制剂，为人免疫缺陷病毒-1(HIV-1)和人免疫缺陷病毒-2(HIV-2)天冬氨酸蛋白酶的口服有效抑制剂，阻断该酶促使产生形态学上成熟HIV颗粒所需的聚蛋白，使HIV颗粒因而保持在未成熟的状态，从而减慢HIV在细胞中的蔓延，以防止新一轮感染的发生和延迟疾病的发展。本品对齐多夫定敏感的和齐多夫定与沙喹那韦耐药的HIV株一般均有效。
利托那韦由美国Abbott实验室在世界上率先研制成功。利托那韦口服溶液于1996年3月首先在美国上市，商品名为NORVIR®在美国已经被批准上市的利托那韦制剂包括利托那韦口服溶液、利托那韦软胶囊、利托那韦片、利托那韦/洛匹那韦复方溶液、利托那韦/洛匹那韦复方片和利托那韦/阿扎那韦复方片，除利托那韦/阿扎那韦复方片由Matrix LabsLTD（美吉斯）开发外，其余均为雅培公司产品。目前国内已有雅培公司进口的利托那韦片剂、上市销售，还未有口服溶液制剂上市销售。原料药有万全万特制药(厦门)有限公司，国药准字H20040411和上海迪赛诺化学制药有限公司，国药准字H20173132上市销售。
发明内容
利托那韦在制备治疗新型冠状病毒（2019-nCoV）的药物中的用途。
利托那韦液体制剂在制备治疗新型冠状病毒（2019-nCoV）的药物中的用途。
所述制剂包含利托那韦、潜溶剂、稳定剂、pH调节剂。潜溶剂为乙醇、丙二醇、聚氧乙烯蓖麻油，pH调节剂为枸橼酸或柠檬酸。
利托那韦液体制剂中活性成分利托那韦20mg~80mg/ml。
利托那韦液体制剂中潜溶剂：乙醇为35%~45%(v/v)，丙二醇为25%~35%(v/v)，聚氧乙烯蓖麻油为80mg~120mg/ml。由于利托那韦的水溶性较差故加入多个潜溶剂，可保证溶解性，同时有利于产品的稳定性。
利托那韦液体制剂中pH调节剂为枸橼酸或柠檬酸，调节至pH值为3.0~5.0。优选pH值为3.0~4.0。利托那韦的溶液对pH值比较敏感，在酸性环境下比较稳定，考虑到过酸在溶液配制过程中设备的腐蚀及患者服用时的刺激性，ph在3.0~4.0最优范围。
在2019年爆发新型冠状病毒（2019-nCoV）后，利托那韦在治疗新型冠状病毒（2019-nCoV）的患者可以改善呼吸窘迫、咳嗽咳痰，发热等全身症状，延缓疾病进展，可以提高患者的生活质量，具有广泛的应用价值。
利托那韦液体制剂选自口服液体剂、混悬剂。病毒感染的病人在配合治疗方面较差，易发生吞服片剂和胶囊剂有困难的情况，影响了药物治疗的顺应性。在儿科和老年医药学领域，此种现象更为严重，口服溶液剂对此问题迎刃而解，而且口服溶液剂口感良好，减少了患者服用的心理抵触。不仅如此，口服溶液剂在给药剂量上准确，由于剂型特点，可根据不同症状按量杯的体积给予合理的剂量。
具体实施方式
实施例1
处方组成：
制备工艺：
将利托那韦加入乙醇水溶液，继续丙二醇、聚氧乙烯蓖麻油，搅拌至利托那韦完全溶解，添加相应的香精、色素，用枸橼酸调节pH值至5.0。
实施例2
处方组成：
制备工艺：
将利托那韦加入乙醇水溶液，继续丙二醇、聚氧乙烯蓖麻油，搅拌至利托那韦完全溶解，添加相应的香精、色素，用枸橼酸调节pH值至4.0。
实施例3
处方组成：
制备工艺：
将利托那韦加入乙醇水溶液，继续丙二醇、聚氧乙烯蓖麻油，搅拌至利托那韦完全溶解，添加相应的香精、色素，用枸橼酸调节pH值至3.0。
实施例4
处方组成：
制备工艺：
将利托那韦加入乙醇水溶液，继续丙二醇、聚氧乙烯蓖麻油，搅拌至利托那韦完全溶解，添加相应的香精、色素，用枸橼酸调节pH值至3.0。
对比实施例1
处方组成：
制备工艺：
将利托那韦加入乙醇水溶液，继续丙二醇、聚氧乙烯蓖麻油，搅拌至利托那韦完全溶解，添加相应的香精、色素，用枸橼酸调节pH值至5.5。
实验结果：
将实施例1-4及对比实施例1制备的样品按《中国药典》2015版稳定性指导原则进行放样，样品0天及加速3月检测结果如下。
表1 实施例0天样品检测结果
表2 实施例加速3月样品检测结果
试验结论：
通过实施例1-5可知，pH值及乙醇、丙二醇用量对样品的稳定性影响较大，pH在3.0~5.0间稳定性较好，在此范围内pH越低样品越稳定。同时乙醇、丙二醇用量越大越有利于样品稳定。
Claims (8)
1.利托那韦在制备用于治疗新型冠状病毒（2019-nCoV）的药物中的用途。
2.利托那韦液体制剂在制备治疗新型冠状病毒（2019-nCoV）的药物中的用途。
3.如权利要求2所述的用途，其中所述制剂包含利托那韦、潜溶剂、稳定剂、pH调节剂；
潜溶剂为乙醇、丙二醇、聚氧乙烯蓖麻油，pH调节剂为枸橼酸或柠檬酸。
4.根据权利要求2所述的用途，其特征在于所述的利托那韦液体制剂中活性成分利托那韦20mg~80mg/ml。
5.根据权利要求2所述的用途，其特征在于所述的利托那韦液体制剂中潜溶剂：乙醇为35%~45%(v/v)，丙二醇为25%~35%(v/v)，聚氧乙烯蓖麻油为80mg~120mg/ml。
6.根据权利要求2所述的用途，其特征在于所述的利托那韦液体制剂中pH调节剂为枸橼酸或柠檬酸，调节至pH值为3.0~5.0。
7.根据权利要求2所述的用途，其特征在于所述的利托那韦液体制剂中pH调节剂为枸橼酸或柠檬酸，调节至pH值为3.0~4.0。
8.根据权利要求2所述的用途，其特征在于所述的利托那韦液体制剂选自口服液体剂、混悬剂。
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