CN108066332A - 一种凝胶制剂中阿达帕林的分散工艺 - Google Patents

一种凝胶制剂中阿达帕林的分散工艺 Download PDF

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CN108066332A
CN108066332A CN201711392438.9A CN201711392438A CN108066332A CN 108066332 A CN108066332 A CN 108066332A CN 201711392438 A CN201711392438 A CN 201711392438A CN 108066332 A CN108066332 A CN 108066332A
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adapalene
dispersing technology
technology according
water
propylene glycol
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刘婧
李刚
李小羿
戴向荣
殷雷
凌娟
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Mega Eye (guangzhou) Ophthalmic Drug Co Ltd
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ZHAOKE PHARMACEUTICAL (HONGKONG) CO Ltd
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Priority to CN202010529730.6A priority Critical patent/CN111759798A/zh
Priority to CN201711392438.9A priority patent/CN108066332A/zh
Publication of CN108066332A publication Critical patent/CN108066332A/zh
Priority to EP18214199.4A priority patent/EP3501497B1/en
Priority to ES18214199T priority patent/ES2955521T3/es
Priority to US16/228,808 priority patent/US11058636B2/en
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Abstract

本发明涉及医药领域，具体公开了一种凝胶制剂阿达帕林的分散工艺，包含以下步骤：阿达帕林原料粉碎后干法检测D50不大于10um，D90不大于30um；水中加入对羟基苯甲酸甲酯、1,2‑丙二醇、卡波姆980、乙二胺四乙酸二钠，持续加热并搅拌得到呈均匀胶冻状的基质；在水加入泊洛沙姆188、丙二醇、乙二醇苯醚搅拌并加热制备混合溶液；阿达帕林加入混合溶液中高速乳化后，加入基质中充分搅拌；再加入三乙醇胺水溶液均质搅拌。本发明所述工艺制备的制剂中阿达帕林的乳化分散效果好，可以规模化扩大生产，具有良好的工业应用前景。

Description

一种凝胶制剂中阿达帕林的分散工艺
技术领域
本发明涉及医药领域，具体涉及一种凝胶制剂中阿达帕林的分散工艺。
背景技术
阿达帕林(Adapalene)，是一种白色或类白色粉末的化学品。化学名称6-[3-(1-金刚烷基)-4-甲氧基苯基]-2-萘甲酸，分子式为C28H28O3，分子量为412.52000，不溶于水或乙醇，略溶于四氢呋喃。阿达帕林为皮肤科用药，临床上适用于以粉刺、丘疹和脓疱为主要表现的寻常型痤疮的皮肤治疗。亦可用于治疗面部、胸和背部的痤疮。
阿达帕林主要与RARβ、RARγ结合，与RARα的结合力很弱。在体外能抑制角质形成细胞的谷氨酰胺转化酶，对角化过程有抑制作用，并能调控细胞分化。动物实验发现阿达帕林有粉刺溶解作用，也有局部抗炎作用，其抗炎活性可能与其干扰多形核白细胞的功能和干扰花生四烯酸的代谢有关。
阿达帕林具有难溶性，因此水性凝胶中阿达帕林都是以混悬形式存在；对于混悬型凝胶，药典有严格的要求，2015版药典附录0114凝胶剂粒度项下要求：混悬型凝胶剂不得检出大于180μm的粒子。因此阿达帕林原料药粒径的大小对本品的吸收起到至关重要作用。粒度涉及制剂的均一性，生物利用度，制剂稳定性等。目前已经发表的相关专利以及文献，都没有对阿达帕林的粒度进行详细研究。由于是凝胶剂，乳化分散工艺也很重要，直接决定了制剂品质。目前的专利：
CN201510809500.4一种阿达帕林凝胶的制备方法、
CN201310393546.3一种阿达帕林凝胶剂及其制备方法、
CN201310350418.0一种阿达帕林凝胶剂及其制备方法、
CN201210378524.5阿达帕林凝胶
CN200510135286.5一种阿达帕林凝胶组合物及其制备方法。
这些专利规定了制剂的粒度小于50um，但是没有对阿达帕林粒度和粉碎工艺以及详细的粒度分布进行系统研究。且上述专利的公开的分散工艺均为小试的搅拌工艺，批量小，且都是制剂配制完毕后进行乳化分散，需要乳化分散的制剂体积大，因此乳化分散效果欠佳，造成制剂均匀性差，外观差，从而无法保证该粒度下所生产的制剂的均一性及稳定性。
发明内容
本发明的一个目的是提供一种凝胶制剂阿达帕林的分散工艺，包含以下步骤：
步骤1：阿达帕林原料粉碎后干法检测D50不大于10um，D90不大于30um；
步骤2：水中加入对羟基苯甲酸甲酯、1,2-丙二醇、卡波姆980、乙二胺四乙酸二钠，持续加热并搅拌得到呈均匀胶冻状的基质；
步骤3：在水中加入泊洛沙姆188、丙二醇、乙二醇苯醚搅拌并加热制备混合溶液；
步骤4：阿达帕林加入步骤3制备的混合溶液中高速乳化后，加入基质中充分搅拌；再加入三乙醇胺水溶液均质搅拌。
作为优选，步骤1使用气流粉碎机对阿达帕林原料进行粉碎。更优选地，粉碎参数为文丘里管压力8.0-11.0bar，环形压力8.0-10.0bar，进料速度50-150rpm。
作为优选，步骤2和步骤3所述加热为加热至50-60℃。
作为优选，步骤2所述水、对羟基苯甲酸甲酯、1,2-丙二醇、卡波姆980、乙二胺四乙酸二钠的质量比为480：2-4:80-100:5-7:1-2。
作为优选，步骤3水与泊洛沙姆188、丙二醇、乙二醇苯醚的质量比为1:30-40:1。
作为优选，步骤4阿达帕林：混合液的质量比为1：20-200。
更优选的，步骤4所述乳化为速度12-20m/s乳化20-40min。
作为优选，本发明所述方法还包含灭菌处理步骤。
更优选地，所述灭菌处理为121℃湿热灭菌。
本专利发明人对阿达帕林原料粒度控制和乳化分散工艺进行全面科学的研究，解决了阿达帕林凝胶制剂的乳化分散以及合理的粒度控制的问题。在具体实施方式中，本发明所述分散工艺制备的阿达帕林复方凝胶检测结果显示，符合粒度要求：D90≤50um；含量均匀度要求：2015版《中国药典》规定，A+2.2S＜15。本发明所述工艺制备的制剂中阿达帕林的乳化分散效果好，可以规模化扩大生产，具有良好的工业推广前景。
具体实施方式
本发明公开了一种凝胶制剂中阿达帕林的分散工艺，本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的工艺已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改动或适当变更与组合，来实现和应用本发明技术。
为了使本领域的技术人员更好地理解本发明的技术方案，下面结合具体实施例对本发明作进一步的详细说明。
实施例1：阿达帕林的分散工艺
1.阿达帕林的原料粉碎及粒径控制
(1)阿达帕林原料的粉碎
方法：使用气流粉碎机对阿达帕林进行粉碎，以期达到目标粒径。
粉碎参数：文丘里管压力8.0bar，环形压力8.0bar，进料速度50rpm
(2)粒径控制：
方法：取本品适量，采用马尔文MS3000激光粒度仪，干法检测，D50不得大于10um，D90不得大于30um。
2、阿达帕林的分散工艺
(1)基质配制
乳化罐中加入60Kg纯化水，启动加热55±5℃，启动均质、搅拌，加入250g对羟基苯甲酸甲酯，10Kg1,2-丙二醇，均质搅拌10min，加入700g卡波姆980，125g乙二胺四乙酸二钠，均质搅拌20min，呈均匀胶冻状基质。
(2)溶液配制
1)配液罐中加入5Kg纯化水，启动搅拌，加入1.125Kg三乙醇胺；
2)配液罐中加入5Kg纯化水，启动搅拌，加入200g泊洛沙姆188，启动加热55±5℃，搅拌15min，加入6Kg1,2-丙二醇和200g乙二醇苯醚搅拌5min。
(3)灭菌处理
将基质；三乙醇胺水溶液；泊洛沙姆188水溶液、1,2-丙二醇和乙二醇苯醚混合液；121℃湿热灭菌20分钟。
(4)制备工艺步骤
1)以7Kg纯化水溶解盐酸克林霉素，配制盐酸克林霉素溶液，并将该溶液无菌过滤后直接加入基质，充分搅拌混匀。
2)将125g的阿达帕林加入经灭菌过的2.5Kg的1,2－丙二醇、乙二醇苯醚和泊洛沙姆188混合液中，在乳化罐，高速乳化(速度15m/s)分散30min，然后加入基质中充分搅拌，缓慢加入三乙醇胺水溶液至乳化罐中，均质搅拌20min。
3)真空除去气泡。取样检测pH、黏度、盐酸克林霉素含量及阿达帕林含量均匀度。
实施例2：
1.阿达帕林的原料粉碎及粒径控制
(1)阿达帕林原料的粉碎
方法：使用气流粉碎机对阿达帕林进行粉碎，以期达到目标粒径。
粉碎参数：文丘里管压力9.0bar，环形压力9.0bar，进料速度100rpm
(2)粒径控制：
方法：取本品适量，采用马尔文MS3000激光粒度仪，干法检测，D50不得大于10um，D90不得大于30um。
2、阿达帕林的分散工艺
(1)基质配制
乳化罐中加入60Kg纯化水，启动加热55±5℃，启动均质、搅拌，加入500g对羟基苯甲酸甲酯12Kg1,2-丙二醇，均质搅拌10min，加入750g卡波姆980，200g乙二胺四乙酸二钠，均质搅拌20min，呈均匀胶冻状基质。
(2)溶液配制
1)配液罐中加入5.5Kg纯化水，启动搅拌，加入1.125Kg三乙醇胺；
2)配液罐中加入5Kg纯化水，启动搅拌，加入500g泊洛沙姆188，启动加热55±5℃，搅拌15min，加入15Kg1,2-丙二醇和500g乙二醇苯醚搅拌5min。
(3)灭菌处理
将基质；三乙醇胺水溶液；泊洛沙姆188水溶液、1,2-丙二醇和乙二醇苯醚混合液；121℃湿热灭菌20分钟。
(4)制备工艺步骤
1)以7Kg纯化水溶解盐酸克林霉素，配制盐酸克林霉素溶液，并将该溶液无菌过滤后直接加入基质，充分搅拌混匀。
2)将125g的阿达帕林加入经灭菌过的5Kg1,2－丙二醇、乙二醇苯醚和泊洛沙姆188混合液中，在乳化罐，高速乳化速度15m/s分散30min，然后加入基质中充分搅拌，缓慢加入三乙醇胺水溶液至乳化罐中，均质搅拌20min。
3)真空除去气泡。取样检测pH、黏度、盐酸克林霉素含量及阿达帕林含量均匀度。
实施例3：
(1)粉碎：阿达帕林原料粉碎后干法检测D50不大于10um，D90不大于30um；使用气流粉碎机对阿达帕林进行粉碎，以期达到目标粒径。
粉碎参数：文丘里管压力10.0bar，环形压力9.0bar，进料速度100rpm。
(2)基质配制：
纯化水中加入对羟基苯甲酸甲酯、1,2-丙二醇，搅拌均匀并持续加热，加入卡波姆980、乙二胺四乙酸二钠，搅拌至呈均匀胶冻状基质；
具体的，乳化罐中加入60Kg纯化水，启动加热55±5℃，启动均质、搅拌后加入250g对羟基苯甲酸甲酯10Kg1,2-丙二醇，加入750g卡波姆980，125g乙二胺四乙酸二钠，均质搅拌20min，呈均匀胶冻状基质。
(3)溶液配制：
在纯化水加入泊洛沙姆188、丙二醇、乙二醇苯醚搅拌并加热5min。配液罐中加入5Kg纯化水，启动搅拌，加入500g泊洛沙姆188，启动加热55±5℃，搅拌15min，加入15Kg1,2-丙二醇和500g乙二醇苯醚搅拌。
(4)分散步骤：
阿达帕林加入1,2－丙二醇、乙二醇苯醚和泊洛沙姆188混合液中，高速乳化后，加入基质中充分搅拌；再加入三乙醇胺水溶液均质搅拌。在乳化罐，高速乳化(速度15m/s)(12～20m/s)分散30min(20～40min)，然后加入基质中充分搅拌，缓慢加入三乙醇胺水溶液至乳化罐中，均质搅拌20min。
可以选择性加入盐酸克林霉素溶液，制备盐酸克林霉素阿达帕林复方凝胶。
5)真空除去气泡。取样检测pH、黏度、盐酸克林霉素含量及阿达帕林含量均匀度。
实施例4：
实施例1-3制备的阿达帕林盐酸克林霉素复方凝胶检测结果：
1、制剂均一性
注：粒度要求：D90≤50um；
含量均匀度要求：2015版《中国药典》规定，A+2.2S＜15符合规定。
制剂粒度检测方法：
取本品5-10g，用25ml水搅拌混匀后，用吐温-80的阿达帕林饱和溶液作为分散介质，转速为1500rpm，超声强度为20％。
2、制剂稳定性
由以上数据可知，制备的20150511、20150513和20150515批制剂，制剂的均一性和稳定性良好，长期24月样品与0月比较，各项检测指标均无明显变化。
3、制剂药代动力学研究和临床研究
通过人体药代动力学研究和临床研究，进行有效性和安全性评估。临床实验结果表明，本品的安全性良好，对寻常性痤疮由明显疗效。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

1.一种凝胶制剂阿达帕林的分散工艺，其特征在于，包含以下步骤：
步骤1：阿达帕林原料粉碎后干法检测D50不大于10um，D90不大于30um；
步骤2：水中加入对羟基苯甲酸甲酯、1,2-丙二醇、卡波姆980、乙二胺四乙酸二钠，持续加热并搅拌得到呈均匀胶冻状的基质；
步骤3：在水中加入泊洛沙姆188、丙二醇、乙二醇苯醚搅拌并加热制备混合溶液；
步骤4：阿达帕林加入步骤3制备的混合溶液高速乳化后，加入基质中充分搅拌；再加入三乙醇胺水溶液均质搅拌。
2.根据权利要求1所述的分散工艺，其特征在于，步骤1使用气流粉碎机对阿达帕林原料进行粉碎。
3.根据权利要求2所述的分散工艺，其特征在于，粉碎参数为文丘里管压力8.0-11.0bar，环形压力8.0-10.0bar，进料速度50-150rpm。
4.根据权利要求1所述的分散工艺，其特征在于步骤2和步骤3所述加热为加热至50-60℃。
5.根据权利要求1所述的分散工艺，其特征在于，步骤2所述水、对羟基苯甲酸甲酯、1,2-丙二醇、卡波姆980、乙二胺四乙酸二钠的质量比为480：2-4:80-100:5-7:1-2。
6.根据权利要求1所述的分散工艺，其特征在于，步骤3水与泊洛沙姆188、丙二醇、乙二醇苯醚的质量比为1:30-40:1。
7.根据权利要求1所述的分散工艺，其特征在于，步骤4阿达帕林：混合液的质量比为1：20-200。
8.根据权利要求1所述的分散工艺，其特征在于，步骤4所述乳化为速度12-20m/s乳化20-40min。
9.根据权利要求1所述的分散工艺，其特征在于，还包含灭菌处理步骤。
10.根据权利要求9所述的分散工艺，其特征在于，所述灭菌为121℃湿热灭菌。
CN201711392438.9A 2017-12-21 2017-12-21 一种凝胶制剂中阿达帕林的分散工艺 Pending CN108066332A (zh)

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