CN104523711B - 酮康他索乳膏及其制备方法 - Google Patents
酮康他索乳膏及其制备方法 Download PDFInfo
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- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
- A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
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Abstract
本发明公开了一种酮康他索乳膏，按重量百分比包括以下组分：酮康唑1～6％，醋酸氯己定0.1～2％，丙酸氯倍他索0.01～0.15％，水杨酸甲酯0.1～5％，油脂性基质20～28％，水溶性基质5～8％，乳化剂3～8％，助溶剂3～6％，抗氧剂0.01～0.4％，香精0.1～1％，以及余量的纯化水。本发明所述的酮康他索乳膏具有抗真菌、抗细菌和消炎作用，且透皮效果佳。
Description
技术领域
本发明涉及药物制剂技术领域，特别是涉及一种酮康他索乳膏及其制备方法。
背景技术
真菌感染根据感染层面分为：浅表、皮下和全身，浅表真菌感染在临床皮肤病中最常见。浅表真菌感染涉及表皮、毛发和甲的感染，通常由小孢子菌、发癣菌、念珠菌和马拉色菌感染引起。
酮康唑是合成的咪唑二烷衍生物，具有广谱的抗真菌作用，尤其对皮肤癣菌、念珠菌和马拉色菌具有明显的抑菌和杀菌作用。其作用机理是通过抑制真菌细胞膜麦角甾醇的生物合成，影响细胞膜的通透性而抑制其生长。
然而，真菌感染时常伴有炎症和细菌的存在，单用酮康唑等抗真菌药往往效果不佳，而单用激素类消炎药还容易诱发进一步的细菌或真菌感染。
此外，用于浅表真菌感染的抗真菌药物，通常采用软膏等外用剂型，具有不良反应轻、临床应用范围广等优点，但亦存在透皮效果不理想、生物利用度低等缺点。
发明内容
基于此，有必要针对上述抗真菌药物软膏所存在的问题，提供一种具有抗真菌、抗细菌和消炎作用，且透皮效果佳的酮康他索乳膏。
一种酮康他索乳膏，按重量百分比包括以下组分：酮康唑1～6％，醋酸氯己定0.1～2％，丙酸氯倍他索0.01～0.15％，水杨酸甲酯0.1～5％，油脂性基质20～28％，水溶性基质5～8％，乳化剂3～8％，助溶剂3～6％，抗氧剂0.01～0.4％，香精0.1～1％，以及余量的纯化水。
在其中一个实施例中，所述的油脂性基质选自白凡士林、液状石蜡、单(双)硬脂酸甘油酯、十八醇、十六十八醇、蜂蜡、甲基硅油中的一种或两种以上的组合。
在其中一个实施例中，所述的水溶性基质选自甘油、羧甲基纤维素钠、聚乙二醇、卡波姆中的一种或两种以上的组合。
在其中一个实施例中，所述的乳化剂选自十二烷基硫酸钠、聚山梨酯、脂肪醇聚氧乙烯醚、聚乙二醇辛基苯基醚中的一种或两种以上的组合。
在其中一个实施例中，所述的助溶剂选自乙醇、二甲基亚砜、丙二醇中的一种或两种以上的组合。
在其中一个实施例中，所述的抗氧剂选自二丁基羟基甲苯、亚硫酸氢钠、亚硫酸钠、生育酚、依地酸二钠、2,6-二叔丁基-4-甲基苯酚、没食子酸中的一种或两种以上的组合。
在其中一个实施例中，所述酮康他索乳膏的pH值为6～8。
本发明所述的酮康他索乳膏的制备方法，包括以下步骤：
1)取酮康唑和丙酸氯倍他索，加入助溶剂中，加热搅拌溶解；
2)取油脂性基质，加热搅拌熔化，然后加入步骤1)得到的溶液中，搅拌均匀，得到油相混合物；
3)取水溶性基质，加入醋酸氯己定、乳化剂、抗氧剂和纯化水，加热搅拌溶解，得到水相混合物；
4)将步骤3)得到的水相混合物加入步骤2)得到的油相混合物中，搅拌混合得到膏体，然后用均质机对膏体进行均质，再加入香精和水杨酸甲酯，继续搅拌均匀，得到所述的酮康他索乳膏。
本发明所述的酮康他索乳膏具有抗真菌、抗细菌和消炎作用，其中，酮康唑具有广谱的抗真菌作用；醋酸氯己定为双胍类高效广谱的细菌杀菌剂，对葡萄球菌、链球菌、白色念珠菌、大肠埃希菌、厌氧丙酸菌均高度敏感，其与酮康唑联用，能够扩大抗菌范围，增强抗菌疗效；而丙酸氯倍他索为强效的肾上腺皮质激索，具有较强的抗炎、抗过敏作用。此外，本发明所述的酮康他索乳膏还添加有水杨酸甲酯，其具有消炎止痛和杀菌的作用，还能够促进局部血液循环，改善病变部位的组织代谢和营养供给，从而减轻局部病理反应。透皮吸收结果显示，加了水杨酸甲酯后，产品的累计透皮渗透量比不加水杨酸甲酯的累计透皮渗透量高，说明水杨酸甲酯能够促进酮康唑、醋酸氯己定和丙酸氯倍他索在皮肤的吸收，增加药物透皮吸收的效果，从而进一步增强药效。
本发明所述的酮康他索乳膏中，酮康唑的用量比优选为1～6％，丙酸氯倍他素的用量比优选为0.01～0.15％，若酮康唑和丙酸氯倍他素的用量过低，临床效果不好；若酮康唑和丙酸氯倍他素的用量过高，动物实验结果显示AST、ALT、血糖、胆固醇均偏高，会导致肝功能损坏。水杨酸甲酯的用量比优选为0.1～5％，若水杨酸甲酯的用量过低，无法生产促进药物透皮吸收的效果；若水杨酸甲酯的用量过高，则会对皮肤造成刺激。
本发明所述的酮康他索乳膏，其pH值优选为6～8，若pH值过高，会使丙酸氯倍他索发生降解而降低药效；若pH值过低，会使酮康唑发生降解而降低药效。
具体实施方式
实施例一：本发明所述的酮康他索乳膏的制备
按照表1的配方分别称取各组分：
表1
分别取表1所示配方中的组分，按照以下步骤，制备本发明所述的酮康他索乳膏：
1)取酮康唑和丙酸氯倍他索，加入助溶剂中，加热至80±5℃，搅拌使之完全溶解；
2)取油脂性基质，加热至85±5℃，搅拌使之完全熔化，保温30分钟后冷却至80±2℃，然后加入步骤1)得到的溶液中，搅拌均匀，得到油相混合物；
3)取水溶性基质，加入醋酸氯己定、乳化剂、抗氧剂和纯化水，加热至90±5℃，搅拌使之完全溶解，保温15分钟后冷却至80±2℃，得到水相混合物；
4)将步骤3)得到的水相混合物加入步骤2)得到的油相混合物中，搅拌混合30分钟得到膏体，当膏体降温至60～65℃时，用均质机对膏体进行均质5分钟，继续搅拌至膏体温度下降至42℃以下，然后加入香精和水杨酸甲酯，继续搅拌至膏体温度下降至38℃以下，得到所述的酮康他索乳膏。
实施例二：透皮吸收效果测定
1、制备酮康他索乳膏对照例
1)取10g酮康唑和0.25g丙酸氯倍他索，加入40g二甲基亚砜中，加热至80±5℃，搅拌使之完全溶解；
2)取50g白凡士林、65g液状石蜡、70g单(双)硬脂酸甘油酯和50g十六十八醇，加热至85±5℃，搅拌使之完全熔化，保温30分钟后冷却至80±2℃，然后加入步骤1)得到的溶液中，搅拌均匀，得到油相混合物；
3)取50g聚乙二醇，加入5g醋酸氯己定、50g脂肪醇聚氧乙烯醚、0.1g二丁基羟基甲苯和602.65g纯化水，加热至90±5℃，搅拌使之完全溶解，保温15分钟后冷却至80±2℃，得到水相混合物；
4)将步骤3)得到的水相混合物加入步骤2)得到的油相混合物中，搅拌混合30分钟得到膏体，当膏体降温至60～65℃时，用均质机对膏体进行均质5分钟，继续搅拌至膏体温度下降至42℃以下，然后加入2g香精，继续搅拌至膏体温度下降至38℃以下，得到酮康他索乳膏对照例。
2、透皮吸收试验
采用体外透皮吸收试验法，以猪腹部皮作离体动物供试皮肤，用80％的乙醇生理盐水作为亲脂性渗透接收液，0.9％的生理盐水为亲水性渗透接收液，采用高效液相色谱法(HPLC)，检测接收液中的主成分含量，计算其累计透皮渗透量Q(μg/cm2)，结果如下表2所示。
表2酮康他索乳膏的透皮吸收试验结果
由表2的试验结果可见，实施例1的36小时透皮渗透量优于对照例，表明通过添加水杨酸甲酯，能够促进酮康他索乳膏的透皮吸收。
实施例三：治疗效果测定
1、病例选择：
取中山医科大学附属第三医院皮肤性病科门诊病例114例。
入选标准：确诊为体股癣、手足癣、花斑癣、湿疹、皮炎的皮肤病患者，性别、年龄不限。
下列病例者不列入观察对象：(1)妊娠及哺乳期妇女；(2)治疗前两周或近期接受过放疗，系统性免疫抑制剂或抗细菌、抗病毒以及抗蠕虫治疗药物者；(3)治疗前两周用过外用抗真菌药或治疗前1个月内服过抗真菌药者；(4)对咪唑类药物有过敏史者；(5)有肝、肾或血液病者。
2、治疗方法
洗净患处，将本发明的酮康他索乳膏均匀地涂抹于患处。
体股癣：一日2次，疗程3周；
手足癣：一日2次，疗程4周；
花斑癣：一日2次，疗程2周；
湿疹、皮炎：一日2次，疗程3周。
3、观察方法
(1)患者治疗用药前以及停药一周后，分别进行临床症状观察；
(2)真菌镜检和培养；
(3)记录用药后的不良反应。
4、疗效判断标准
(1)临床疗效判断标准
痊愈：皮疹完全消退，痒感消失，真菌培养阴性。
显效：皮疹消退60％以上，痒感明显减轻，真菌镜检阴性或可见少量破碎，变形的菌丝、孢子，培养阴性。
进步：皮疹消退20～60％，痒感减轻，真菌培养阳性。
无效：皮疹消退不足20％或继续加重，痒感同前或加剧，真菌培养阳性。
痊愈和显效合计为有效，计算有效率。
(2)真菌学疗效判断标准
真菌学疗效按照真菌清除(真菌镜检阴性)和未清除(真菌镜检阳性)统计。
真菌镜检阳性：显微镜下可见真菌；
真菌镜检阴性：显微镜下未见真菌。
5、治疗效果
114例患者中，完成规定疗程的112例，进入疗效评价的112例。其中，体股癣39例，手足癣28例，花斑癣8例，湿疹12例，脂溢性皮炎16例，接触性皮炎9例。
在临床试验过程中，均没有出现由本发明的酮康他索乳膏引起的毒副作用反应。
表3为本发明的酮康他索乳膏的临床疗效测试结果，其平均痊愈率为83.93％，平均有效率为91.96％。
表3酮康他索乳膏的临床疗效测试结果
| 病种 | 例数 | 痊愈 | 显效 | 进步 | 无效 | 有效例数 | 有效率 |
| 体股癣 | 39 | 36 | 2 | 1 | 0 | 38 | 97.44％ |
| 手足癣 | 28 | 22 | 4 | 2 | 0 | 26 | 92.86％ |
| 花斑癣 | 8 | 7 | 0 | 1 | 0 | 7 | 87.50％ |
| 湿疹 | 12 | 10 | 0 | 2 | 0 | 10 | 83.33％ |
| 脂溢性皮炎 | 16 | 12 | 2 | 1 | 1 | 14 | 87.50％ |
| 接触性皮炎 | 9 | 7 | 1 | 1 | 0 | 8 | 88.89％ |
| 合计 | 112 | 94 | 9 | 8 | 1 | 103 | 91.96％ |
*有效率＝有效例数÷例数；
平均痊愈率＝痊愈例数÷病例总数。
114例患者治疗前进行真菌培养(按药典标准方法)，其中67例呈真菌镜检阳性。表4为本发明的酮康他索乳膏的真菌学疗效测试结果，其治疗后的平均阴转率为88.06％。
表4酮康他索乳膏的真菌学疗效测试结果
| 菌种 | 治疗前阳性例数 | 治疗后阳性例数 | 阴转率 |
| 红色毛癣菌 | 17 | 1 | 94.12％ |
| 须癣毛癣菌 | 14 | 0 | 100.00％ |
| 紫发毛癣菌 | 11 | 2 | 81.82％ |
| 犬小孢子菌 | 10 | 2 | 80.00％ |
| 石膏样小孢子菌 | 7 | 3 | 57.14％ |
| 絮状表皮癣菌 | 6 | 0 | 100.00％ |
| 白念珠菌 | 2 | 0 | 100.00％ |
| 合计 | 67 | 8 | 88.06％ |
*转阴率＝(治疗前阳性例数-治疗后阳性例数)÷治疗前阳性例数。
6、结论
临床试验证明，本发明的酮康他索乳膏对治疗浅部真菌引起的体股癣、手足癣、花斑癣以及湿疹、皮炎均有良好的治疗效果，痊愈率为83.93％，有效率为91.96％，真菌阴转率为88.06％。在治疗过程中对皮肤均无刺激、过敏等副作用反应，可作为治疗癣病、湿疹、皮炎等浅部真菌感染的外用药物。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对本发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
Claims (5)
1.一种酮康他索乳膏，按重量百分比包括以下组分：酮康唑1～6％，丙酸氯倍他索0.01～0.15％，水杨酸甲酯0.1～5％，醋酸氯己定0.1～2％，油脂性基质20～28％，水溶性基质5～8％，乳化剂3～8％，助溶剂3～6％，抗氧剂0.01～0.4％，香精0.1～1％，以及余量的纯化水，所述酮康他索乳膏的pH值为6～8，所述的抗氧剂选自二丁基羟基甲苯、亚硫酸氢钠、亚硫酸钠、生育酚、依地酸二钠、2,6-二叔丁基-4-甲基苯酚、没食子酸中的一种或两种以上的组合，所述的助溶剂选自乙醇、二甲基亚砜、丙二醇中的一种或两种以上的组合。
2.根据权利要求1所述的酮康他索乳膏，其特征在于：所述的油脂性基质选自白凡士林、液状石蜡、单(双)硬脂酸甘油酯、十八醇、十六十八醇、蜂蜡、甲基硅油中的一种或两种以上的组合。
3.根据权利要求1所述的酮康他索乳膏，其特征在于：所述的水溶性基质选自甘油、羧甲基纤维素钠、聚乙二醇、卡波姆中的一种或两种以上的组合。
4.根据权利要求1所述的酮康他索乳膏，其特征在于：所述的乳化剂选自十二烷基硫酸钠、聚山梨酯、脂肪醇聚氧乙烯醚、聚乙二醇辛基苯基醚中的一种或两种以上的组合。
5.权利要求1所述的酮康他索乳膏的制备方法，包括以下步骤：
1)取酮康唑和丙酸氯倍他索，加入助溶剂中，加热搅拌溶解；
2)取油脂性基质，加热搅拌熔化，然后加入步骤1)得到的溶液中，搅拌均匀，得到油相混合物；
3)取水溶性基质，加入醋酸氯己定、乳化剂、抗氧剂和纯化水，加热搅拌溶解，得到水相混合物；
4)将步骤3)得到的水相混合物加入步骤2)得到的油相混合物中，搅拌混合得到膏体，然后用均质机对膏体进行均质，再加入香精和水杨酸甲酯，继续搅拌均匀，得到所述的酮康他索乳膏。
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