CN105708788A - 一种盐酸氨基酮戊酸纳米乳膏的制备方法 - Google Patents
一种盐酸氨基酮戊酸纳米乳膏的制备方法 Download PDFInfo
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- CN105708788A CN105708788A CN201610099735.3A CN201610099735A CN105708788A CN 105708788 A CN105708788 A CN 105708788A CN 201610099735 A CN201610099735 A CN 201610099735A CN 105708788 A CN105708788 A CN 105708788A
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- emulsifiable paste
- valeric acid
- aminoguanidine hydrochloride
- ketone valeric
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- 229960002749 aminolevulinic acid Drugs 0.000 title claims abstract description 12
- 238000000034 method Methods 0.000 title claims description 12
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims abstract description 49
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- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 76
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- UBDZFAGVPPMTIT-UHFFFAOYSA-N 2-aminoguanidine;hydron;chloride Chemical compound [Cl-].NC(N)=N[NH3+] UBDZFAGVPPMTIT-UHFFFAOYSA-N 0.000 claims description 34
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- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0061—5-aminolevulinic acid-based PDT: 5-ALA-PDT involving porphyrins or precursors of protoporphyrins generated in vivo from 5-ALA
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Abstract
本发明公开了一种盐酸氨基酮戊酸纳米乳膏，是由以下重量份的原料制成的：盐酸氨基酮戊酸650～750份，纳米乳液750～850份，丙三醇80～100份，黄原胶45～55份，防腐剂50～120份，水1100～1600份。本发明的盐酸氨基酮戊酸纳米乳膏，可用于治疗尖锐湿疣、皮肤癌、光角化病、Bowen病；非肿瘤性疾病：病毒性疣、面部痤疮(粉刺)、银屑病等。本发明的盐酸氨基酮戊酸纳米乳膏，主要起保护、润滑和局部治疗作用，具有以下优点：①外观均匀、细腻、软滑、稠度适宜；②易涂布于皮肤和粘膜，使用方便；③性质稳定，效期内符合质量要求。④膏剂剂型附着力强，便于药物分散和吸收，提高生物利用度。
Description
技术领域
本发明涉及一种盐酸氨基酮戊酸纳米乳膏的制备方法，属于药物新剂型技术领域。
背景技术
光动力学疗法(PDT)是一种联合应用光敏剂及相应光源产生一系列光化学和光生物学反应，生成中间活性物质，与相应靶组织结合，选择性破坏病变组织的全新治疗技术。PDT是用于治疗皮肤或其它上皮器官或粘膜的各种病变或异常的有效方法，特别是癌症或癌症前期病变，以及某些非恶性皮肤感染(例如诸如银屑病、光化性角化病和痤疮等皮肤疾病)。PDT包括将光敏性试剂(光化学治疗剂)涂到身体的感染部分，然后为了活化光敏剂并将它们转变成细胞毒素形式而暴露在光敏化光下，从而杀死感染的细胞或减少它们的增殖潜力。光敏剂的范围是公知的，包括补骨脂素、卟啉、二氢卟酚和酞菁类染料。但是，本领域公知的临床最有用的光敏剂是5-氨基酮戊酸及其衍生物，例如，诸如5-ALA酯等。
5-盐酸氨酮戊酸(5-ALA)是近年来开发的第2代光敏剂，是一种体内血红蛋白合成过程的前体物。正常情况下，ALA在细胞内的量很小，本身不产生光敏性。外源性ALA进入体内后，可被增生活跃的细胞选择性吸收并积累，并在细胞内转化为原卟啉IX(PpIX)等卟啉类物质。细胞内的PpIX是一种很强的光敏剂，经过特定波长的红光照射后即发生光动力反应，产生活性氧如单线态氧等而杀死增生活跃的细胞，而邻近正常组织则不受任何影响。
现有技术中，5-盐酸氨酮戊酸的剂型为散剂，其用法为：浍疗时先在皮损害部位放置适当大小、能够完全覆盖皮损的脱脂棉球。然后用新鲜配制的20％5-氨基酮戊酸生理盐水溶液每30min在脱脂棉球上滴1次。使之完令浸透，并在尿道口外用塑料薄膜封包。整个敷药过程应处于避光环境中，在患处持续敷药3h。然后使用激光治疗仪垂直照射，病损部位激光照射的能量密度为100-150J/cm2。但是，盐酸氨酮戊酸外用散具有使用不便、分散性差、生物利用度低等不足之处，而本发明的纳米乳膏，性质稳定，生物利用度高，使用方便，克服了散剂的不足之处。
发明内容
针对上述现有技术，本发明提供了一种5-盐酸氨酮戊酸的新剂型——盐酸氨基酮戊酸纳米乳膏，本发明还提供了其制备方法。
本发明是通过以下技术方案实现的：
一种氨基酮戊酸纳米乳膏，是由有效剂量的主药盐酸氨基酮戊酸、磷酸氨基酮戊酸、氨基酮戊酸甲酯或其衍生物，纳米乳液以及其它药剂学上可接受的辅料制成的，剂型可以为乳膏、凝胶、乳液、栓剂等，其它药剂学上可接受的辅料选自但不限于丙三醇、黄原胶、防腐剂、水等。优选的，主药的浓度为20％(质量百分数)。
优选的，所述盐酸氨基酮戊酸纳米乳膏是由以下重量份的原料制成的：盐酸氨基酮戊酸650～750份，纳米乳液750～850份，丙三醇80～100份，黄原胶45～55份，防腐剂50～120份，水1100～1600份。
优选的，是由以下重量份的原料制成的：盐酸氨基酮戊酸700份，纳米乳液800份，丙三醇90份，黄原胶50份，防腐剂100份，水1200份。
所述纳米乳液是通过以下方法制备得到的：取大豆软磷脂15g±3g，溶于30g±5g异丙醇中；再加入吐温-8035g±3g，辛酸癸酸甘油三酯35g±5g，混合均匀；再加入900ml±50ml磷酸盐缓冲液，用高压均质机均质2～6次，即得。
所述磷酸盐缓冲液为现有技术中的常用试剂，通过常规方法即可制备得到，比如通过以下方法制备得到：取磷酸二氢钠30g，溶于1000ml水中，得磷酸二氢钠溶液；取磷酸氢二钠10g，溶于200ml水中，得磷酸氢二钠溶液；再分别取磷酸二氢钠溶液850ml和磷酸氢二钠溶液150ml，混合混匀，调pH值至6，即得。
所述防腐剂选自尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、三氯叔丁醇、硫柳汞、硝酸苯汞、苯甲醇、氯化苯甲烃铵、氯化十六烷基吡啶、溴化十六烷铵或度米芬中的任意一种或任意两种以上的组合。
优选的，所述防腐剂是通过以下方法制备得到的：取尼泊金甲酯2g，尼泊金丙酯1g，溶于50g丙二醇中，得溶液A；取咪唑烷基脲2g，溶于70g水中，得溶液B；将溶液A、溶液B两者混合均匀，即得。
所述盐酸氨基酮戊酸纳米乳膏的制备方法，步骤如下：
(1)制备A相：取盐酸氨基酮戊酸,加入到纳米乳液中，搅拌溶解，均质；
(2)制备B相：将水和丙三醇混合，升温至60℃±3℃，混匀；加黄原胶，升温至75℃±3℃并搅拌保持30±5分钟，然后降至室温，加入防腐剂，搅拌30分钟；
(3)将上述制备的A相加入B相中，真空条件下搅拌30±5分钟，即得。
本发明的盐酸氨基酮戊酸纳米乳膏，可用于治疗尖锐湿疣、皮肤癌(鳞状细胞癌、基底细胞癌)、光角化病、Bowen病；非肿瘤性疾病：病毒性疣、面部痤疮(粉刺)、银屑病等。使用时，可直接取膏剂涂抹于患处，给临床使用带来很大便利，避免了繁琐的操作，同时提高了生物利用度。
本发明的盐酸氨基酮戊酸纳米乳膏，主要起保护、润滑和局部治疗作用，具有以下优点：①外观均匀、细腻、软滑、稠度适宜；②易涂布于皮肤和粘膜，使用方便(直接涂抹即可，无需事先配制保存时间不超过4小时的新鲜药液)；③性质稳定(盐酸氨基酮戊酸被纳米乳液所包裹形成纳米粒，性质稳定)，有效期内符合质量要求。④膏剂剂型附着力强，便于药物分散和吸收，提高生物利用度。
具体实施方式
下面结合实施例对本发明作进一步的说明。
下述实施例中所涉及的仪器、试剂、材料等，若无特别说明，均为现有技术中已有的常规仪器、试剂、材料等，可通过正规商业途径获得。下述实施例中所涉及的实验方法，检测方法等，若无特别说明，均为现有技术中已有的常规实验方法，检测方法等。
实施例1制备盐酸氨基酮戊酸纳米乳膏
配方为：盐酸氨基酮戊酸700g，纳米乳液800g，丙三醇90g，黄原胶50g，防腐剂100g，水1200g。
制备方法为：
(1)制备纳米乳液：取大豆软磷脂15g，溶于30g异丙醇中；再加入吐温-8035g，辛酸癸酸甘油三酯35g，混合均匀；再加入900ml磷酸盐缓冲液，用高压均质机均质5次，即得。
所述磷酸盐缓冲液是通过以下方法制备得到的：取磷酸二氢钠30g，溶于1000ml水中，得磷酸二氢钠溶液；取磷酸氢二钠10g，溶于200ml水中，得磷酸氢二钠溶液；再分别取磷酸二氢钠溶液850ml和磷酸氢二钠溶液150ml，混合混匀，调pH值至6，即得。
(2)制备防腐剂：取尼泊金甲酯2g，尼泊金丙酯1g，溶于50g丙二醇中，得溶液A；取咪唑烷基脲2g，溶于70g水中，得溶液B；将溶液A、溶液B两者混合均匀，即得。
(3)制备A相：取盐酸氨基酮戊酸,加入到纳米乳液中，搅拌溶解，均质。
(4)制备B相：将水和丙三醇混合，升温至60℃，混匀；加黄原胶，升温至75℃并搅拌保持30分钟，然后降至室温，加入防腐剂，搅拌30分钟；
(5)将上述制备的A相加入B相中，真空条件下搅拌30分钟，即得。
稳定性考察：根据中国药典2005年版二部附录ⅪⅩC(药物稳定性试验指导原则)与《化学药品和治疗用生物制品研究指导原则》要求，对上述制备得到的盐酸氨基酮戊酸纳米乳膏进行了稳定性考察试验。
主要考察指标为性状、pH值、含量，分别在25℃±2℃/RH60％±5％条件下进行了6个月加速试验,结果各项指标未见明显变化(见表1)；在5℃±3℃/RH60％±5％条件下进行了12个月长期试验,结果各项指标未见明显变化(见表2)。
结果表明，本发明的盐酸氨基酮戊酸纳米乳膏使用方便，性质稳定，纳米制剂大大提高了生物利用度，临床使用更加便捷高效。
表1盐酸氨基酮戊酸纳米乳膏加速试验结果
| 时间(月) | 性状 | pH值 | 含量(％) |
| 0 | 淡黄色乳膏 | 5.89 | 99.57 |
| 1 | 淡黄色乳膏 | 5.78 | 99.82 |
| 2 | 淡黄色乳膏 | 5.91 | 99.41 |
| 3 | 淡黄色乳膏 | 5.82 | 99.59 |
| 6 | 淡黄色乳膏 | 5.85 | 99.12 |
表2盐酸氨基酮戊酸纳米乳膏长期试验结果
| 时间(月) | 性状 | pH值 | 含量(％) |
| 0 | 淡黄色乳膏 | 5.89 | 99.57 |
| 3 | 淡黄色乳膏 | 5.92 | 99.45 |
| 6 | 淡黄色乳膏 | 5.74 | 99.41 |
| 9 | 淡黄色乳膏 | 5.83 | 99.11 |
| 12 | 淡黄色乳膏 | 5.79 | 99.23 |
实施例2制备盐酸氨基酮戊酸纳米乳膏
配方为：盐酸氨基酮戊酸650g，纳米乳液850g，丙三醇100g，黄原胶50g，防腐剂100g，水1500g。
制备方法为：
(1)制备纳米乳液：取大豆软磷脂15g，溶于30g异丙醇中；再加入吐温-8035g，辛酸癸酸甘油三酯35g，混合均匀；再加入900ml磷酸盐缓冲液，用高压均质机均质5次，即得。
所述磷酸盐缓冲液是通过以下方法制备得到的：取磷酸二氢钠30g，溶于1000ml水中，得磷酸二氢钠溶液；取磷酸氢二钠10g，溶于200ml水中，得磷酸氢二钠溶液；再分别取磷酸二氢钠溶液850ml和磷酸氢二钠溶液150ml，混合混匀，调pH值至6，即得。
(2)制备防腐剂：取尼泊金甲酯2g，尼泊金丙酯1g，溶于50g丙二醇中，得溶液A；取咪唑烷基脲2g，溶于70g水中，得溶液B；将溶液A、溶液B两者混合均匀，即得。
(3)制备A相：取盐酸氨基酮戊酸,加入到纳米乳液中，搅拌溶解，均质。
(4)制备B相：将水和丙三醇混合，升温至60℃，混匀；加黄原胶，升温至75℃并搅拌保持30分钟，然后降至室温，加入防腐剂，搅拌30分钟；
(5)将上述制备的A相加入B相中，真空条件下搅拌30分钟，即得。
实施例3制备盐酸氨基酮戊酸纳米乳膏
配方为：盐酸氨基酮戊酸650g，纳米乳液850g，丙三醇100g，黄原胶50g，防腐剂(尼泊金乙酯)100g，水1500g。
其它同实施例1。
实施例4制备磷酸氨基酮戊酸纳米乳膏
配方为：磷酸氨基酮戊酸700g，纳米乳液800g，丙三醇90g，黄原胶50g，防腐剂100g，水1200g。
其它同实施例1。
实施例5制备氨基酮戊酸甲酯纳米乳膏
配方为：氨基酮戊酸甲酯650g，纳米乳液850g，丙三醇100g，黄原胶50g，防腐剂100g，水1500g。
其它同实施例1。
Claims (10)
1.一种盐酸氨基酮戊酸纳米乳膏，其特征在于：是由以下重量份的原料制成的：盐酸氨基酮戊酸650～750份，纳米乳液750～850份，丙三醇80～100份，黄原胶45～55份，防腐剂50～120份，水1100～1600份；
所述纳米乳液是通过以下方法制备得到的：取大豆软磷脂15g±3g，溶于30g±5g异丙醇中；再加入吐温-8035g±3g，辛酸癸酸甘油三酯35g±5g，混合均匀；再加入900ml±50ml磷酸盐缓冲液，用高压均质机均质2-6次，即得。
2.根据权利要求1所述的盐酸氨基酮戊酸纳米乳膏，其特征在于：所述防腐剂选自尼泊金甲酯、尼泊金乙酯、尼泊金丙酯、尼泊金丁酯、苯甲酸、苯甲酸钠、山梨酸、山梨酸钾、三氯叔丁醇、硫柳汞、硝酸苯汞、苯甲醇、氯化苯甲烃铵、氯化十六烷基吡啶、溴化十六烷铵或度米芬中的任意一种或任意两种以上的组合。
3.根据权利要求1或2所述的盐酸氨基酮戊酸纳米乳膏，其特征在于：所述防腐剂是通过以下方法制备得到的：取尼泊金甲酯2g，尼泊金丙酯1g，溶于50g丙二醇中，得溶液A；取咪唑烷基脲2g，溶于70g水中，得溶液B；将溶液A、溶液B两者混合均匀，即得。
4.根据权利要求1或2或3所述的盐酸氨基酮戊酸纳米乳膏，其特征在于：是由以下重量份的组分制成的：盐酸氨基酮戊酸700份，纳米乳液800份，丙三醇90份，黄原胶50份，防腐剂100份，水1200份。
5.权利要求1～4中任一项所述的盐酸氨基酮戊酸纳米乳膏的制备方法，其特征在于：步骤如下：
(1)制备A相：取盐酸氨基酮戊酸,加入到纳米乳液中，搅拌溶解，均质；
(2)制备B相：将水和丙三醇混合，升温至60℃±3℃，混匀；加黄原胶，升温至75℃±3℃并搅拌保持30±5分钟，然后降至室温，加入防腐剂，搅拌30分钟；
(3)将上述制备的A相加入B相中，真空条件下搅拌30±5分钟，即得。
6.权利要求1～4中任一项所述的盐酸氨基酮戊酸纳米乳膏在制备治疗尖锐湿疣、皮肤癌、光角化病、Bowen病、非肿瘤性疾病的药物中的应用。
7.一种氨基酮戊酸纳米乳膏，其特征在于：是由有效剂量的主药盐酸氨基酮戊酸、磷酸氨基酮戊酸、氨基酮戊酸甲酯或其衍生物，纳米乳液以及其它药剂学上可接受的辅料制成的，剂型为乳膏、凝胶、乳液或栓剂。
8.根据权利要求7所述的氨基酮戊酸纳米乳膏，其特征在于：是由以下重量份的原料制成的：主药650～750份，纳米乳液750～850份，丙三醇80～100份，黄原胶45～55份，防腐剂50～120份，水1100～1600份。
9.根据权利要求7或8所述的氨基酮戊酸纳米乳膏，其特征在于：所述纳米乳液是通过以下方法制备得到的：取大豆软磷脂15g±3g，溶于30g±5g异丙醇中；再加入吐温-8035g±3g，辛酸癸酸甘油三酯35g±5g，混合均匀；再加入900ml±50ml磷酸盐缓冲液，用高压均质机均质2-6次，即得。
10.权利要求7～9中任一项所述的氨基酮戊酸纳米乳膏在制备治疗尖锐湿疣、皮肤癌、光角化病、Bowen病、非肿瘤性疾病的药物中的应用。
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