CN109431996B - 一种含米诺地尔的外用剂组合物及其制备方法 - Google Patents
一种含米诺地尔的外用剂组合物及其制备方法 Download PDFInfo
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- ZFMITUMMTDLWHR-UHFFFAOYSA-N Minoxidil Chemical compound NC1=[N+]([O-])C(N)=CC(N2CCCCC2)=N1 ZFMITUMMTDLWHR-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960003632 minoxidil Drugs 0.000 title claims abstract description 39
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 title claims abstract description 19
- 239000008055 phosphate buffer solution Substances 0.000 claims abstract description 20
- 239000000243 solution Substances 0.000 claims abstract description 13
- 150000005846 sugar alcohols Polymers 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 229960004063 propylene glycol Drugs 0.000 claims description 5
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 claims description 4
- 229960005150 glycerol Drugs 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 238000003756 stirring Methods 0.000 claims description 3
- 239000004254 Ammonium phosphate Substances 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 229910000148 ammonium phosphate Inorganic materials 0.000 claims description 2
- 235000019289 ammonium phosphates Nutrition 0.000 claims description 2
- 239000007853 buffer solution Substances 0.000 claims description 2
- 235000019437 butane-1,3-diol Nutrition 0.000 claims description 2
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 2
- SZXQTJUDPRGNJN-UHFFFAOYSA-N dipropylene glycol Chemical compound OCCCOCCCO SZXQTJUDPRGNJN-UHFFFAOYSA-N 0.000 claims description 2
- 229940113120 dipropylene glycol Drugs 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- 229940068918 polyethylene glycol 400 Drugs 0.000 claims description 2
- 229940057847 polyethylene glycol 600 Drugs 0.000 claims description 2
- 239000008057 potassium phosphate buffer Substances 0.000 claims description 2
- 239000012064 sodium phosphate buffer Substances 0.000 claims description 2
- 230000000699 topical effect Effects 0.000 claims 3
- 238000003860 storage Methods 0.000 abstract description 2
- 238000005286 illumination Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 239000012535 impurity Substances 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 2
- 238000002845 discoloration Methods 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 201000004384 Alopecia Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 231100000360 alopecia Toxicity 0.000 description 1
- 208000004631 alopecia areata Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000003779 hair growth Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- YAAWASYJIRZXSZ-UHFFFAOYSA-N pyrimidine-2,4-diamine Chemical compound NC1=CC=NC(N)=N1 YAAWASYJIRZXSZ-UHFFFAOYSA-N 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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Abstract
本发明提供了一种米诺地尔外用剂组合物，其中含有米诺地尔、磷酸盐缓冲液和多元醇类溶剂。还提供了一种制备此米诺地尔外用剂组合物的方法，具体为在配制样品过程中加入磷酸盐缓冲液，可以阻止溶液在配制及存放过程中发生变色。该方法简单，稳定，重现性好，不易受光照及配样方式的影响。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种含米诺地尔的外用剂组合物及其配制方法。
背景技术
米诺地尔(minoxidil)，化学名称为(2，4-嘧啶二胺，6-(l-哌啶基)-3-氧化物(1)，最早是作为一种治疗高血压的药物在临床上使用。随后，发现其具有促进毛发生长的作用，1988年获FDA批准上市，适应症为治疗脂溢性脱发以及斑秃，剂型为外用溶液剂。米诺地尔是目前世界上唯一一个对脱发有明显疗效的外用化学药，可通过多种途径生发，疗效好而且安全，因此在临床广为推广。然而已有多篇文献报道了米诺地尔溶液剂不稳定，易出现变色现象。目前变色机理尚未明确，据假定是与光的作用有关，市场上有采用遮光容器来盛放，但尚未解决变色的问题，而且发现原辅料来源，配置罐材质均会对溶液性状造成影响，引起溶液变色。专利CN98811791.6报道其通过加入氨基酸可以防止在储存过程中变色，但实验证明配制过程中由于原辅料来源，配置罐材质导致的变色，通过加入氨基酸无法使其改变。
发明内容
为了解决现有技术问题，本发明人进行了大量研究，发现通过加入磷酸盐缓冲液可以意外地防止含米诺地尔的液体制剂变色，而且对已经变色的米诺地尔液体制剂通过加入磷酸盐缓冲液可以使颜色消失，从而解决现有米诺地尔液体制剂变色的问题，由此完成了本发明。
同时为了保证本方法的科学严谨，进行了影响因素考察，确保满足生产研发需求。因此，本发明的目的在于提供一种质量稳定、不易变色的米诺地尔外用制剂及其配制方法。
为实现上述发明目的，本发明采用如下技术方案：
一种米诺地尔外用剂组合物，包括有效量的米诺地尔、磷酸盐缓冲液和多元醇类溶剂以及乙醇。所述米诺地尔的含量为2％～5％(w/w)，磷酸盐缓冲液的含量为10％～30％(w/w)，多元醇类溶剂的含量为70％～90％(w/w)。
磷酸盐缓冲液选自磷酸钠缓冲液、磷酸钾缓冲液和磷酸铵缓冲液中的一种或多种。磷酸盐缓冲液中磷酸根的摩尔浓度为0.01mol/L～0.1mol/L。磷酸盐缓冲液pH范围要求在5-9之内。
多元醇选自1，3-丁二醇、丙二醇、甘油、二丙二醇、聚乙二醇400和聚乙二醇600中的一种或多种。
多元醇选自丙二醇和甘油中的一种或多种。
制备本申请所述的米诺地尔外用剂组合物的制备方法，其特征在于包括以下步骤:
(1)将多元醇类溶剂及乙醇与磷酸盐缓冲液充分混合均匀；
(2)将米诺地尔加至上述溶液中，搅拌使米诺地尔充分溶解；
(3)最后使用磷酸盐缓冲液定容至所需体积，即得米诺地尔外用剂组合物。
本发明的有益效果主要体现在：本发明制备的米诺地尔外用剂组合物稳定，未出现变色现象，能有效抑制杂质增长。且制备方法简单、稳定、重现性好。
具体实施方式
下面结合具体实施例对本发明进行进一步描述，但本发明的保护范围并不仅限于此。
实施例1：
配制pH5.8磷酸盐缓冲液：取磷酸二氢钾8.34g与磷酸氢二钾0.87g，加水使溶解成1000ml，即得。
取500ml丙二醇，300ml乙醇与100ml pH5.8磷酸盐缓冲液充分混合均匀，加入50g米诺地尔，搅拌2小时至完全溶解，最后加pH5.8磷酸盐缓冲液定容至1L，即得本发明的米诺地尔外用剂组合物。
对比实施例1：
将实施例1中的pH5.8磷酸盐缓冲液换成纯水，其他操作与实施例1相同，制备对比米诺地尔外用剂组合物。
实验1
将实施例1与对比实施例1所得米诺地尔外用制剂放置于不同影响因素条件下，检测杂质及性状的变化。结果见表1。
表1实施例1与比较实施例1的影响因素结果
实验2
往上述实验1中已经出现颜色的对比实施例1样品中加入实施例1中配置的磷酸盐缓冲液，颜色消失，变成无色。
上述实验1和实验2的测试结果说明，无论溶液颜色还是杂质增长情况，本发明的外用剂组合物都明显优于对比实施例，而且对于已经出现颜色变化的米诺地尔外用溶液剂，也可使颜色消失。因此本发明可有效控制米诺地尔颜色的变化，解决现有米诺地尔液体制剂溶液变色问题。
Claims (5)
1.一种米诺地尔外用剂组合物，其特征在于：包括有效量的米诺地尔、磷酸盐缓冲液、多元醇类溶剂和乙醇，其中，多元醇选自1，3-丁二醇、丙二醇、甘油、二丙二醇、聚乙二醇400和聚乙二醇600中的一种或多种；磷酸盐缓冲液pH范围在5-9；所述米诺地尔的含量为2％～5％(w/w)，磷酸盐缓冲液的含量为10％～30％(w/w)。
2.根据权利要求1所述的米诺地尔外用剂组合物，其特征在于：磷酸盐缓冲液选自磷酸钠缓冲液、磷酸钾缓冲液和磷酸铵缓冲液中的一种或多种。
3.根据权利要求2所述的米诺地尔外用剂组合物，其特征在于：磷酸盐缓冲液中磷酸根的摩尔浓度为0.01mol/L～0.1mol/L。
4.根据权利要求1所述的米诺地尔外用剂组合物，其特征在于：多元醇选自丙二醇和甘油中的一种或二种。
5.一种权利要求1所述的米诺地尔外用剂组合物的制备方法，包括以下步骤：(1)将多元醇类溶剂及乙醇与磷酸盐缓冲液充分混合均匀；(2)将米诺地尔加至上述溶液中，搅拌使米诺地尔充分溶解；(3)最后使用磷酸盐缓冲液定容至所需体积，即得米诺地尔外用剂组合物。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2311731A1 (en) * | 1997-12-03 | 1999-06-10 | Taisho Pharmaceutical Co., Ltd. | Minoxidil-containing liquid preparation composition |
| JP2000344668A (ja) * | 1999-03-30 | 2000-12-12 | Taisho Pharmaceut Co Ltd | ミノキシジル製剤 |
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| US8691518B2 (en) * | 2010-09-24 | 2014-04-08 | Global Life Science Partners Limited | Systems and methods for predicting response to minoxidil for the treatment of androgenetic alopecia |
| CN102349913B (zh) * | 2011-07-28 | 2013-03-13 | 刘国辉 | 高浓度甘油型米诺地尔酊剂及其制备方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CA2311731A1 (en) * | 1997-12-03 | 1999-06-10 | Taisho Pharmaceutical Co., Ltd. | Minoxidil-containing liquid preparation composition |
| JP2000344668A (ja) * | 1999-03-30 | 2000-12-12 | Taisho Pharmaceut Co Ltd | ミノキシジル製剤 |
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Effective date of registration: 20210616 Address after: 311305 No.1, Wangjiashan Road, Qingshanhu street, Lin'an District, Hangzhou City, Zhejiang Province Applicant after: ZHEJIANG WANSHENG PHARMACEUTICAL Co.,Ltd. Address before: 3 / F, block a, 1378 Wenyi West Road, Science Park, Hangzhou Normal University, Cangqian street, Yuhang District, Hangzhou City, Zhejiang Province, 310000 Applicant before: HANGZHOU SIMBOS PHARM Co.,Ltd. |
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Address after: 311305 No.1, Wangjiashan Road, Qingshanhu street, Lin'an District, Hangzhou City, Zhejiang Province Patentee after: Zhejiang Sansheng Mandi Pharmaceutical Co.,Ltd. Country or region after: China Address before: 311305 No.1, Wangjiashan Road, Qingshanhu street, Lin'an District, Hangzhou City, Zhejiang Province Patentee before: ZHEJIANG WANSHENG PHARMACEUTICAL Co.,Ltd. Country or region before: China |
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