CN109528636B - 托伐普坦口服溶液及其制备方法 - Google Patents
托伐普坦口服溶液及其制备方法 Download PDFInfo
- Publication number
- CN109528636B CN109528636B CN201811565747.6A CN201811565747A CN109528636B CN 109528636 B CN109528636 B CN 109528636B CN 201811565747 A CN201811565747 A CN 201811565747A CN 109528636 B CN109528636 B CN 109528636B
- Authority
- CN
- China
- Prior art keywords
- oral solution
- tolvaptan
- dosage
- regulator
- clear liquid
- 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.)
- Active
Links
- 229940100688 oral solution Drugs 0.000 title claims abstract description 58
- GYHCTFXIZSNGJT-UHFFFAOYSA-N tolvaptan Chemical compound CC1=CC=CC=C1C(=O)NC(C=C1C)=CC=C1C(=O)N1C2=CC=C(Cl)C=C2C(O)CCC1 GYHCTFXIZSNGJT-UHFFFAOYSA-N 0.000 title claims abstract description 55
- 229960001256 tolvaptan Drugs 0.000 title claims abstract description 54
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims abstract description 27
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims abstract description 10
- 229920000053 polysorbate 80 Polymers 0.000 claims abstract description 10
- 239000000022 bacteriostatic agent Substances 0.000 claims abstract description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 6
- 239000000796 flavoring agent Substances 0.000 claims abstract description 5
- 235000013355 food flavoring agent Nutrition 0.000 claims abstract description 5
- 239000008213 purified water Substances 0.000 claims description 8
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 claims description 6
- 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 6
- 229930195725 Mannitol Natural products 0.000 claims description 6
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 6
- 239000000594 mannitol Substances 0.000 claims description 6
- 235000010355 mannitol Nutrition 0.000 claims description 6
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 6
- 239000000811 xylitol Substances 0.000 claims description 6
- 235000010447 xylitol Nutrition 0.000 claims description 6
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 6
- 229960002675 xylitol Drugs 0.000 claims description 6
- 229940085605 saccharin sodium Drugs 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 3
- 239000012528 membrane Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 2
- 229940009662 edetate Drugs 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 7
- 238000012360 testing method Methods 0.000 abstract description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 abstract description 4
- 238000010521 absorption reaction Methods 0.000 abstract description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 abstract description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 abstract description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 abstract description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 abstract description 2
- 235000015165 citric acid Nutrition 0.000 abstract description 2
- 239000001530 fumaric acid Substances 0.000 abstract description 2
- 235000011087 fumaric acid Nutrition 0.000 abstract description 2
- 239000001630 malic acid Substances 0.000 abstract description 2
- 235000011090 malic acid Nutrition 0.000 abstract description 2
- 235000002906 tartaric acid Nutrition 0.000 abstract description 2
- 239000011975 tartaric acid Substances 0.000 abstract description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 abstract description 2
- 239000007788 liquid Substances 0.000 description 49
- 230000000052 comparative effect Effects 0.000 description 9
- 239000013078 crystal Substances 0.000 description 5
- 238000001556 precipitation Methods 0.000 description 5
- 235000006679 Mentha X verticillata Nutrition 0.000 description 4
- 235000002899 Mentha suaveolens Nutrition 0.000 description 4
- 235000001636 Mentha x rotundifolia Nutrition 0.000 description 4
- 238000002474 experimental method Methods 0.000 description 4
- 239000000047 product Substances 0.000 description 4
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 4
- 239000004299 sodium benzoate Substances 0.000 description 4
- 235000010234 sodium benzoate Nutrition 0.000 description 4
- 229940079593 drug Drugs 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 2
- KBZOIRJILGZLEJ-LGYYRGKSSA-N argipressin Chemical compound C([C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CSSC[C@@H](C(N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N1)=O)N)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCN=C(N)N)C(=O)NCC(N)=O)C1=CC=CC=C1 KBZOIRJILGZLEJ-LGYYRGKSSA-N 0.000 description 2
- 229940124274 edetate disodium Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 244000099147 Ananas comosus Species 0.000 description 1
- 235000007119 Ananas comosus Nutrition 0.000 description 1
- 101800001144 Arg-vasopressin Proteins 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 206010021036 Hyponatraemia Diseases 0.000 description 1
- XINCECQTMHSORG-UHFFFAOYSA-N Isoamyl isovalerate Chemical compound CC(C)CCOC(=O)CC(C)C XINCECQTMHSORG-UHFFFAOYSA-N 0.000 description 1
- 102100026383 Vasopressin-neurophysin 2-copeptin Human genes 0.000 description 1
- 108010004977 Vasopressins Proteins 0.000 description 1
- 102000002852 Vasopressins Human genes 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000009789 rate limiting process Methods 0.000 description 1
- 229940077276 samsca Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 229960003726 vasopressin Drugs 0.000 description 1
Images
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
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
-
- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- 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
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Diabetes (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Cardiology (AREA)
- Biochemistry (AREA)
- Obesity (AREA)
- Molecular Biology (AREA)
- Gastroenterology & Hepatology (AREA)
- Hospice & Palliative Care (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明公开了一种托伐普坦口服溶液及其制备方法,该托伐普坦口服溶液是由托伐普坦、吐温80以及药用辅料制成;药用辅料包括pH调节剂、矫味剂、抑菌剂以及水;其中,pH调节剂的用量为使口服溶液的pH值为5.5~6.5,pH调节剂选自枸橼酸、酒石酸、富马酸、苹果酸中的一种或者两种以上。本发明经过大量试验最终发现一定pH范围内的托伐普坦口服溶液具有较好的稳定性,从而可以改善现有的托伐普坦片剂服药顺应性较差的问题,同时经过大量试验最终发现在托伐普坦口服溶液中添加一定量的吐温80可以有效提高药物的生物利用度,吸收明显较快。
Description
技术领域
本发明属于医药制剂技术领域,具体涉及一种托伐普坦口服溶液及其制备方法。
背景技术
托伐普坦是由日本大冢制药公司(Otsuka Pharmaceutical Co.)研制开发,2009年分别在美国和欧洲上市,2010年在日本上市,商品名:Samsca®【中文为苏麦卡®】。托伐普坦为特异性拮抗精氨酸加压素,用于治疗高容或等容性低钠血症伴心力衰竭、肝硬化、抗利尿激素分泌异常综合征。其化学名称为:N-[4-[(5R)-7-氯-5-羟基-2,3,4,5-四氢-1-苯并氮杂卓-1-甲酰基]-3-甲基苯基]-2-甲基苯甲酰胺,其结构式如下:
多数口服固体制剂(片剂、胶囊等)从制剂内释放并溶解,经吸收进入血液循环,达到一定血药浓度后方能奏效。对于托伐普坦这种难溶性药物,其溶出是吸收的限速过程,常常为影响生物利用度的最主要因素。而目前的市售产品苏麦卡®即为片剂,因而存在生物利用度不高的问题。
另外,与口服固体制剂相比,口服液体制剂具有较好的服药顺应性,对于吞咽有困难的儿童和老人而言,口服液体制剂显然更为方便,然后稳定性则是影响口服液体制剂大规模使用的重要因素。
目前尚未发现托伐普坦口服溶液的有关报道。
发明内容
本发明的目的在于解决上述问题,提供一种生物利用度较高且稳定性较好的托伐普坦口服溶液及其制备方法。
实现本发明目的的技术方案是:一种托伐普坦口服溶液,它是由托伐普坦、吐温80以及药用辅料制成;所述药用辅料包括pH调节剂、矫味剂、抑菌剂以及水。
上述托伐普坦口服溶液中,所述托伐普坦的用量以1000mL口服溶液计为1.5g。
上述托伐普坦口服溶液中,所述吐温80的用量以1000mL口服溶液计为0.5~5.0g,优选为3.0g。
申请人经过大量试验发现:在托伐普坦口服溶液中添加一定量的吐温80可以有效提高药物的生物利用度,吸收明显较快。
上述托伐普坦口服溶液中,所述pH调节剂的用量为使口服溶液的pH值为5.5~6.5。
申请人经过大量试验发现:在该pH范围内,该托伐普坦口服溶液具有较好的稳定性。
而为了具有更好的稳定性,上述pH值优选为5.8~6.1。
所述pH调节剂选自枸橼酸、酒石酸、富马酸、苹果酸中的一种或者两种以上(含两种);优选为枸橼酸。
所述矫味剂选自甘露醇、木糖醇、糖精钠、香精中的一种或者两种以上(含两种)。
当上述托伐普坦口服溶液中含有甘露醇时,其用量以1000mL口服溶液计为5.0~10.0g,优选为6.0g。
当上述托伐普坦口服溶液中含有木糖醇时,其用量以1000mL口服溶液计为10.0~100.0g,优选为30.0~70.0g,更优选为50.0g。
当上述托伐普坦口服溶液中含有糖精钠时,其用量以1000mL口服溶液计为0.3~3.0g,优选为0.5~2.0g,更优选为1.0g。
当上述托伐普坦口服溶液中含有香精时,其用量以1000mL口服溶液计为0.03~0.3g,优选为0.05~0.2g,更优选为0.1g。
所述香精选自草莓香精、菠萝香精、桔子香精、苹果香精、柠檬香精、薄荷香精中的一种或者两种以上(含两种),优选为薄荷香精。
上述托伐普坦口服溶液中,所述抑菌剂的用量以1000mL口服溶液计为0.3~3.0g,优选为0.5~2.0g,更优选为1.0g。
所述抑菌剂选自苯甲酸盐或者依地酸盐中的一种或者两种以上(含两种);优选为苯甲酸钠和/或依地酸二钠;更优选为苯甲酸钠。
上述托伐普坦口服溶液的制备方法具有以下步骤:
①将pH调节剂以外的其它组分加入到80%处方量的纯化水中,搅拌溶解。
②向步骤①的溶液中加入pH调节剂并使pH值为5.5~6.5。
③补加纯化水至处方量,并保持溶液的pH值为5.5~6.5,过0.8μm滤膜,即得托伐普坦口服溶液。
本发明具有的积极效果:本发明经过大量试验最终发现一定pH范围内的托伐普坦口服溶液具有较好的稳定性,从而可以改善现有的托伐普坦片剂服药顺应性较差的问题,同时经过大量试验最终发现在托伐普坦口服溶液中添加一定量的吐温80可以有效提高药物的生物利用度,吸收明显较快。
附图说明
图1为实施例1制得的托伐普坦口服溶液以及市售商品苏麦卡®在Beagle犬体内的药代动力学实验结果图。
具体实施方式
(实施例1)
本实施例的托伐普坦口服溶液以1000mL计包括以下组分:1.5g托伐普坦;3.0g的吐温80;1.0g作为pH调节剂的枸橼酸;6.0g作为矫味剂的甘露醇;50g作为矫味剂的木糖醇;0.1g作为矫味剂的薄荷香精;1.0g作为抑菌剂的苯甲酸钠;余量为纯化水。
本实施例的托伐普坦口服溶液的pH值为6.0。
该托伐普坦口服溶液的制备方法具有以下步骤:
①将枸橼酸以外的其它组分加入到80%处方量的纯化水中,搅拌溶解。
②向步骤①的溶液中加入枸橼酸并使pH值为5.5~6.5(本实施例为6.0)。
③补加纯化水至处方量,并保持溶液的pH值为6.0,过0.8μm滤膜,即得托伐普坦口服溶液。
(实施例2~实施例8)
各实施例的托伐普坦口服溶液与实施例1基本相同,不同之处见表1。
表1
实施例1 | 实施例2 | 实施例3 | 实施例4 | 实施例5 | 实施例6 | 实施例7 | 实施例8 | |
托伐普坦 | 1.5g | 1.5g | 1.5g | 1.5g | 1.5g | 1.5g | 1.5g | 1.5g |
吐温80 | 3.0g | 3.0g | 3.0g | 0.5g | 2.0g | 5.0g | 4.0g | 3.0g |
枸橼酸 | 1.0g | 1.5g | 0.4g | 1.3g | 0.8g | 1.0g | 1.0g | 1.0g |
甘露醇 | 6.0g | 6.0g | 5.0g | 10.0g | 8.0g | 6.0g | 6.0g | 6.0g |
木糖醇 | 50.0g | 50.0g | 50.0g | 10.0g | 100.0g | 70.0g | / | 30.0g |
糖精钠 | / | 1.0g | 3.0g | / | / | 0.3g | / | / |
薄荷香精 | 0.1g | 0.1g | 0.03g | / | 0.2g | 0.05g | / | / |
苯甲酸钠 | 1.0g | 0.5g | 2.0g | / | / | / | 1.0g | 1.5g |
依地酸二钠 | / | / | / | 1.0g | 0.3g | 3.0g | / | / |
纯化水 | 余量 | 余量 | 余量 | 余量 | 余量 | 余量 | 余量 | 余量 |
pH值 | 6.0 | 5.5 | 6.5 | 5.8 | 6.1 | 6.0 | 6.0 | 6.0 |
(对比例1~对比例3)
各对比例的托伐普坦口服溶液与实施例1基本相同,不同之处见表2。
表2
实施例1 | 对比例1 | 对比例2 | 对比例3 | |
枸橼酸 | 1.0g | 1.9g | 2.5g | 0g |
pH值 | 6.0 | 5.0 | 4.5 | 7.0 |
(测试例)
分别对实施例1~实施例8以及对比例1~对比例3制得的托伐普坦口服溶液进行稳定性测试,结果见表3。
表3
0个月 | 常温放置3个月后 | 常温放置6个月后 | 常温放置9个月后 | 常温放置12个月后 | |
实施例1 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 |
实施例2 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 淡黄色澄清液体 |
实施例3 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 淡黄色澄清液体 |
实施例4 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 |
实施例5 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 |
实施例6 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 |
实施例7 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 |
实施例8 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 | 无色澄清液体 |
对比例1 | 淡黄色澄清液体 | 淡黄色澄清液体 | 有絮状沉淀 | 有晶体析出 | 有晶体析出 |
对比例2 | 淡黄色澄清液体 | 有絮状沉淀 | 有晶体析出 | 有晶体析出 | 有晶体析出 |
对比例3 | 无色澄清液体 | 无色澄清液体 | 淡黄色澄清液体 | 淡黄色澄清液体 | 有絮状沉淀 |
(实验例)
分别对实施例1制得的托伐普坦口服溶液以及市售产品苏麦卡®(规格为15mg)进行Beagle犬体内的药代动力学实验,结果见图1。
由图1可以看出,本发明的托伐普坦口服溶液相比于市售产品苏麦卡®吸收明显较快,生物利用度明显提高。
Claims (5)
1.一种托伐普坦口服溶液,其特征在于:它是由托伐普坦、吐温80以及药用辅料制成;所述药用辅料包括pH调节剂、矫味剂、抑菌剂以及水;所述pH调节剂为枸橼酸;所述pH调节剂的用量为使口服溶液的pH值为5.5~6.5;所述托伐普坦的用量以1000mL口服溶液计为1.5g;所述吐温80的用量以1000mL口服溶液计为0.5~5.0g。
2.根据权利要求1所述的托伐普坦口服溶液,其特征在于:所述pH调节剂的用量为使口服溶液的pH值为5.8~6.1。
3.根据权利要求1或2所述的托伐普坦口服溶液,其特征在于:所述矫味剂选自甘露醇、木糖醇、糖精钠、香精中的一种或者两种以上;
所述甘露醇的用量以1000mL口服溶液计为5.0~10.0g;
所述木糖醇的用量以1000mL口服溶液计为30.0~70.0g;
所述糖精钠的用量以1000mL口服溶液计为0.5~2.0g;
所述香精的用量以1000mL口服溶液计为0.05~0.2g。
4.根据权利要求1或2所述的托伐普坦口服溶液,其特征在于:所述抑菌剂的用量以1000mL口服溶液计为0.5~2.0g;所述抑菌剂选自苯甲酸盐或者依地酸盐中的一种或者两种。
5.一种权利要求1所述的托伐普坦口服溶液的制备方法,其特征在于具有以下步骤:
①将pH调节剂以外的其它组分加入到80%处方量的纯化水中,搅拌溶解;
②向步骤①的溶液中加入pH调节剂并使pH值为5.5~6.5;
③补加纯化水至处方量,并保持溶液的pH值为5.5~6.5,过0.8μm滤膜,即得托伐普坦口服溶液。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811565747.6A CN109528636B (zh) | 2018-12-20 | 2018-12-20 | 托伐普坦口服溶液及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201811565747.6A CN109528636B (zh) | 2018-12-20 | 2018-12-20 | 托伐普坦口服溶液及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN109528636A CN109528636A (zh) | 2019-03-29 |
CN109528636B true CN109528636B (zh) | 2022-05-03 |
Family
ID=65855866
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201811565747.6A Active CN109528636B (zh) | 2018-12-20 | 2018-12-20 | 托伐普坦口服溶液及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN109528636B (zh) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2894516A1 (en) * | 2012-12-28 | 2014-07-03 | Otsuka Pharmaceutical Co., Ltd. | Injectable depot formulation comprising optically active tolvaptan and process of producing the same |
TWI660748B (zh) * | 2013-03-01 | 2019-06-01 | 日商大塚製藥股份有限公司 | 用於口服投藥之包含非晶型托伐普坦(Tolvaptan)的懸浮液 |
TW201605488A (zh) * | 2013-10-15 | 2016-02-16 | 大塚製藥股份有限公司 | 用以預防及/或治療多囊腎病之藥物 |
CN108078933A (zh) * | 2017-12-06 | 2018-05-29 | 佛山市腾瑞医药科技有限公司 | 一种托伐普坦分散片及其制备方法 |
-
2018
- 2018-12-20 CN CN201811565747.6A patent/CN109528636B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN109528636A (zh) | 2019-03-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JPH07116029B2 (ja) | トラニラスト水溶液製剤 | |
US11957681B2 (en) | Liquid dosage forms of Imatinib | |
CN102924302A (zh) | 注射级盐酸氨溴索及其吸入用溶液 | |
CA2011063C (en) | Nicardipine pharmaceutical composition for parenteral administration | |
CN105193707A (zh) | 一种盐酸氨溴索口服溶液及其制备方法 | |
WO2019186515A1 (en) | Liquid pharmaceutical compositions of antiepileptic drugs | |
CN104784157A (zh) | 一种稳定的孟鲁司特口腔薄膜剂 | |
CN109010341A (zh) | 一种含有氢溴酸右美沙芬的复方口服溶液及其制备方法 | |
JPS62153220A (ja) | 胆汁酸内用水剤 | |
CN109528636B (zh) | 托伐普坦口服溶液及其制备方法 | |
CN102872462B (zh) | 一种盐酸氨溴索组合物及其制剂 | |
CN104840418A (zh) | 一种盐酸法舒地尔注射液组合物及其制备方法 | |
JP4959335B2 (ja) | メチルフェニデート溶液および関連する投与および製造方法 | |
CN106511264A (zh) | 一种盐酸哌甲酯口服溶液剂及其制备方法 | |
CN112168782A (zh) | 一种呼吸系统药物口服喷雾剂的制备方法 | |
EP2926816A1 (en) | Pharmaceutical composition comprising desloratadine and prednisolone and use thereof | |
CN112957481A (zh) | 一种难溶性药物包合物、包合方法及盐酸金霉素可溶性粉 | |
WO2019162756A2 (en) | Liquid pharmaceutical compositions of anticancer drugs | |
CN112022804A (zh) | 一种拉考沙胺口服溶液及制备方法 | |
CN112402392A (zh) | 一种甲磺酸达比加群酯缓释制剂及其制备方法 | |
CN112245388A (zh) | 含有帕拉米韦的氯化钠注射液及其制备方法 | |
CN110200905A (zh) | 一种盐酸氨溴索组合物及其注射液与应用 | |
CN101288645A (zh) | 替利定药物树脂口服混悬液及其制备方法 | |
CN103356478A (zh) | 一种布洛芬注射液组合物及其制备方法 | |
CN101427999B (zh) | 呋塞米口服溶液及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Tovastatin oral solution and its preparation method Effective date of registration: 20231225 Granted publication date: 20220503 Pledgee: Industrial and Commercial Bank of China Changzhou New Area Branch Pledgor: CHANGZHOU SUNLIGHT PHARMACEUTICAL Co.,Ltd. Registration number: Y2023980073845 |