CN1194685C - 硝酸毛果芸香碱眼用凝胶 - Google Patents
硝酸毛果芸香碱眼用凝胶 Download PDFInfo
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- CN1194685C CN1194685C CNB02117623XA CN02117623A CN1194685C CN 1194685 C CN1194685 C CN 1194685C CN B02117623X A CNB02117623X A CN B02117623XA CN 02117623 A CN02117623 A CN 02117623A CN 1194685 C CN1194685 C CN 1194685C
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- 229940100655 ophthalmic gel Drugs 0.000 title claims description 13
- OSASVXMJTNOKOY-UHFFFAOYSA-N chlorobutanol Chemical compound CC(C)(O)C(Cl)(Cl)Cl OSASVXMJTNOKOY-UHFFFAOYSA-N 0.000 claims abstract description 24
- YKFROQCFVXOUPW-UHFFFAOYSA-N 4-(methylthio) aniline Chemical compound CSC1=CC=C(N)C=C1 YKFROQCFVXOUPW-UHFFFAOYSA-N 0.000 claims abstract description 22
- 229960001963 pilocarpine nitrate Drugs 0.000 claims abstract description 22
- 229910021538 borax Inorganic materials 0.000 claims abstract description 12
- 229960004926 chlorobutanol Drugs 0.000 claims abstract description 12
- 235000010339 sodium tetraborate Nutrition 0.000 claims abstract description 12
- 239000004328 sodium tetraborate Substances 0.000 claims abstract description 12
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims abstract description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 33
- 239000004327 boric acid Substances 0.000 claims description 10
- 239000003814 drug Substances 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 4
- 239000006071 cream Substances 0.000 abstract description 3
- 239000003889 eye drop Substances 0.000 abstract description 3
- 230000002045 lasting effect Effects 0.000 abstract description 2
- 239000012528 membrane Substances 0.000 abstract description 2
- 230000001225 therapeutic effect Effects 0.000 abstract 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 abstract 1
- 208000010412 Glaucoma Diseases 0.000 abstract 1
- 229920002125 Sokalan® Polymers 0.000 abstract 1
- 235000010338 boric acid Nutrition 0.000 abstract 1
- 229960002645 boric acid Drugs 0.000 abstract 1
- 229960001631 carbomer Drugs 0.000 abstract 1
- 229940012356 eye drops Drugs 0.000 abstract 1
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical compound CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 abstract 1
- 238000002360 preparation method Methods 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 239000000758 substrate Substances 0.000 description 9
- 239000008215 water for injection Substances 0.000 description 9
- 239000004615 ingredient Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 6
- 239000013521 mastic Substances 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000008901 benefit Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 230000008961 swelling Effects 0.000 description 4
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 230000003020 moisturizing effect Effects 0.000 description 2
- QCHFTSOMWOSFHM-WPRPVWTQSA-N (+)-Pilocarpine Chemical compound C1OC(=O)[C@@H](CC)[C@H]1CC1=CN=CN1C QCHFTSOMWOSFHM-WPRPVWTQSA-N 0.000 description 1
- 206010009185 Ciliary muscle spasm Diseases 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 1
- 208000022873 Ocular disease Diseases 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 description 1
- 208000020992 contracted pupil Diseases 0.000 description 1
- KWGRBVOPPLSCSI-UHFFFAOYSA-N d-ephedrine Natural products CNC(C)C(O)C1=CC=CC=C1 KWGRBVOPPLSCSI-UHFFFAOYSA-N 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229960002179 ephedrine Drugs 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 239000003885 eye ointment Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 229960001416 pilocarpine Drugs 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 230000000007 visual effect Effects 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种药物有效成分-硝酸毛果芸香碱-首次制成眼用凝胶剂，应用于眼科角膜移植排斥反应、角膜结膜干燥症(KC)、春季卡他性结膜炎、眼部化学烧伤(2度至4度)等疾患的治疗，旨在提高药物有效成分的生物利用度，增加疗效和用药安全性；本发明首次将硝酸毛果芸香碱制成眼用凝胶，不仅解决了滴眼液易被泪液稀释、眼内停留时间短的问题；而且，解决了全身给药治疗效果不理想的问题；主要技术内容是：硝酸毛果芸香碱、卡泊姆、硼酸、硼砂与三氯叔丁醇制成稳定的水溶性透明乳膏体，使用后在眼表形成一层透气的网状膜，且用药方便，作用持久。
Description
所属技术领域
本发明涉及一种药物有效成分——硝酸毛果芸香碱——首次制成眼用凝胶，应用于眼科青光眼的治疗和眼科虹膜手术前缩瞳。
背景技术
硝酸毛果芸香碱20世纪70年代末开始用于眼部疾病的治疗，眼部用药比全身用硝酸毛果芸香碱安全可靠，但仍然可能出现一些毒副作用，可能出现刺痛及局部刺激症状，开始时的睫状肌痉挛及瞳孔缩小可使人烦恼。目前，硝酸毛果芸香碱眼科制剂在临床已有使用，但均为医院制剂，未见产品上市，国内未见申报其眼用凝胶者。
发明内容
为了克服给药量大，口服药物难以通过血眼屏障的不足，发明一种眼用凝胶，眼科局部给药，不仅解决了滴眼液易被泪液稀释，眼内停留时间短的问题，且使用量少，提高药物有效成分的生物利用度，增加疗效和用药安全性，是公认的长效制剂。
本发明的技术方案是：硝酸毛果芸香碱药物成分与卡泊姆膏体基质形成稳定的透明凝胶膏体，使用后在眼表形成一层透气的网状膜，作用持久。其具体特征如下：硝酸毛果芸香碱眼用凝胶单方制剂，其通用名：硝酸毛果芸香碱眼用凝胶；化学名为：4-[(1-甲基-1H咪唑-5-基)甲基]-3-乙基二氢-2(3H)呋喃酮硝酸盐；英文名：Pilocarpin NitrateOphthalmic Gel；汉语拼音：Xiaosuan Maoguoyunxiangiian Yanyong Ningjiao；硝酸毛果芸香碱药物与主要辅料成分及其按下列比例组成的应用于眼科疾患的制剂：其中含硝酸毛果芸香碱为1.0％(w/w)；含卡泊姆为0.8％(w/w)；含硼酸为0.5％(w/w)；含硼砂为1.0％(w/w)；含丙二醇0.3％(w/w)；含三氯叔丁醇1.0％(w/w)。硝酸毛果芸香碱药物有效成分，与适量注射用水混合溶解；卡泊姆溶涨成水溶液；加入丙二醇、硼酸、硼砂和三氯叔丁醇加热使全部溶解，制成透明乳膏；将硝酸毛果芸香碱水溶液加入到上述膏体基质中，搅拌均匀至膏体透明，过滤，分装，包装。另外，硝酸毛果芸香碱药物有效成分与羟丙甲基纤维素系列、甲基纤维素系列、聚乙烯醇系列等基质均可形成凝胶，卡泊姆系列基质效果最好。上述制备工艺中，其核心技术是：(1)硝酸毛果芸香碱药物成分充分溶解；(2)辅料成分混合后加热溶解(温度范围60-80℃)是保证膏体透明的关键；(3)卡泊姆溶涨(浓度范围1.5-3.0％)制成透明乳膏。
本发明还可采用如下的技术方案：
本发明的最终组合物中，以重量计含有硝酸毛果芸香碱0.1～5.0％，卡泊姆0.8～8.0％，硼酸0.3～3.0％，硼砂1.0～10.0％，丙二醇0.3～10.0％，三氯叔丁醇0.3～3.0％。
本发明的最终组合物中，每100g硝酸毛果芸香碱眼用凝胶含有硝酸毛果芸香碱1.0g，卡泊姆0.8g，硼酸0.5g，硼砂1.0g，丙二醇0.3g，三氯叔丁醇1.0g。
本发明的积极效果：硝酸毛果芸香碱眼用凝胶的研制与开发有以下优点：(1)、凝胶剂为水溶性基质组成，药物容易吸收，药品生物利用度高(2)、眼用凝胶直接作用于患处，能充分有效地发挥作用，可减少胃肠道刺激和其他副作用。(3)、相对于其它眼用制剂，凝胶剂具有无可比拟的优点。和滴眼液相比眼用凝胶不易被泪液稀释，在眼内停留时间长，有利于主药的充分吸收和利用；和凡士林基质的眼膏相比，眼用凝胶水溶性好，容易清洗，容易吸收，不污染衣物，使用方便。另一方面，眼用凝胶不造成视野模糊，昼夜都可使用。本产品的开发成功，不仅可填补国内眼科用药的一项空白，还可带来很好的社会效益和经济效益。(4)、我们企业是国内专业的眼科用药生产厂家，30多年来一直致力于眼药的生产、研制、开发，积极参加社会公益事业，眼科用药占总产值的90％以上。尤其是，我们有眼用凝胶剂的生产、开发经验。硝酸毛果芸香碱眼用凝胶一旦开发成功，必然会受到广大医生和患者的欢迎。
实施例
处方1：
硝酸毛果芸香碱 1.0g
硼酸 0.3g
硼砂 1.0g
卡泊姆 0.8g
丙二醇 1.0g
三氯叔丁醇 0.3g
注射用水 加至 全量
制成 100g
制备工艺：
①.卡泊姆加适量注射用水溶涨，备用；
②.三氯叔丁醇、硼酸、硼砂、丙二醇加适量注射用水，加热溶解；
③.冷却至室温，加入到卡泊姆膏中，搅拌制成透明凝胶基质；
④.硝酸毛果芸香碱加适量注射用水溶解，加入到基质中，搅拌均匀；
⑤.补水至全量，过滤，分装，即得。
处方2：
硝酸毛果芸香碱 0.1-5.0g
硼酸 0-3.0g
硼砂 0-10.0g
卡泊姆 0-8.0g
丙二醇 0-10.0g
三氯叔丁醇 0-3.0g
注射用水 加至 全量
制成 100g
制备工艺：
①.卡泊姆加适量注射用水溶涨，备用；
②.三氯叔丁醇、硼酸、硼砂、丙二醇加适量注射用水，加热溶解；
③.冷却至室温，加入到卡泊姆膏中，搅拌制成透明凝胶基质；
④.硝酸毛果芸香碱加适量注射用水溶解，加入到基质中，搅拌均匀；
⑤.补水至全量，过滤，分装，即得。
本发明的创造性，通过临床、毒理药理数据来实现，实质审查时一并提供。
图1为硝酸毛果芸香碱眼用凝胶制备工艺流程图。
Claims (3)
1.硝酸毛果芸香碱眼用凝胶，其特征在于：以重量计含有硝酸毛果芸香碱0.1～5.0％，卡泊姆0.8～8.0％，硼酸0.3～3.0％，硼砂1.0～10.0％，丙二醇0.3～10.0％，三氯叔丁醇0.3～3.0％。
2.根据权利要求1的硝酸毛果芸香碱眼用凝胶，其特征在于：每100g硝酸毛果芸香碱眼用凝胶含有硝酸毛果芸香碱1.0g，卡泊姆0.8g，硼酸0.5g，硼砂1.0g，丙二醇0.3g，三氯叔丁醇1.0g。
3.根据权利要求1的硝酸毛果芸香碱眼用凝胶，其特征在于：每100g硝酸毛果芸香碱眼用凝胶含有硝酸毛果芸香碱1.0g，卡泊姆0.8g，硼酸0.3g，硼砂1.0g，丙二醇1.0g，三氯叔丁醇0.3g。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB02117623XA CN1194685C (zh) | 2002-05-10 | 2002-05-10 | 硝酸毛果芸香碱眼用凝胶 |
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| Application Number | Priority Date | Filing Date | Title |
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| CNB02117623XA CN1194685C (zh) | 2002-05-10 | 2002-05-10 | 硝酸毛果芸香碱眼用凝胶 |
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| Publication Number | Publication Date |
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| CN1456156A CN1456156A (zh) | 2003-11-19 |
| CN1194685C true CN1194685C (zh) | 2005-03-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| CNB02117623XA Expired - Lifetime CN1194685C (zh) | 2002-05-10 | 2002-05-10 | 硝酸毛果芸香碱眼用凝胶 |
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| Country | Link |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113786380A (zh) * | 2021-09-18 | 2021-12-14 | 华北制药股份有限公司 | 一种硝酸毛果芸香碱眼用凝胶及其制备方法 |
| CN115089587B (zh) * | 2022-08-12 | 2023-03-31 | 南京恒道医药科技股份有限公司 | 一种复方毛果芸香碱组合物及其制备工艺和应用方法 |
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