CN116270434A - 一种莫匹罗星软膏及其制备方法 - Google Patents
一种莫匹罗星软膏及其制备方法 Download PDFInfo
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- MINDHVHHQZYEEK-HBBNESRFSA-N mupirocin Chemical compound C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-HBBNESRFSA-N 0.000 description 1
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- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
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Abstract
本发明涉及一种莫匹罗星软膏及其制备方法,该软膏制剂具体包括莫匹罗星、聚乙二醇400、聚乙二醇3350、环糊精,所制得制剂可解决莫匹罗星软膏稳定性问题,有效控制效期内杂质增加,保障制剂质量和临床疗效,且该软膏制剂工艺过程简单,易于操作,适合产业化规模生产。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种莫匹罗星软膏及其制备方法。
背景技术
莫匹罗星,英文名称为Mupiroci,化学名称为9-[[(2E)-4-[(2S,3R,4R,5S)-3,4-二羟基-5-[[(2S,3S)-3-[(1S,2S)-2-羟基-1-甲基丙基]氧基]甲基]四氢-2H-吡喃-2-基]-3-甲基丁-2-酰基]氧基]-壬酸,分子式C26H44O9,分子量500.6,结构式如下:
莫匹罗星,又名假单胞菌酸A,是于1971年从荧光假单胞杆菌中分离得到的一种细菌代谢产物,于1985年由葛兰素史克以“百多邦”(Bactroban)为商品名推向市场。莫匹罗星主要用于预防和治疗革兰氏阳性球菌引起的皮肤感染,例如:脓疱病、疖肿、毛囊炎等原发性皮肤感染及湿疹合并感染,不超过10厘米×10厘米面积的浅表性创伤合并感染等继发性皮肤感染。莫匹罗星抗菌作用主要机理在于抑制细菌体内的蛋白质合成。具体而言,莫匹罗星作用在细菌体内的异亮氨酸-tRNA合成酶与异亮氨酸的结合点上,从而阻碍氨基酸的合成,也消耗了细胞内的tRNA,使RNA的合成及蛋白质的合成过程中止,是皮肤科局部抗菌治疗首选药物。《中国药典》2020年版尚未收载莫匹罗星软膏,但《国家药品标准》新药转正标准第23册、美国药典2021版(USP2021)、英国药典2022年版(BP2022)及日本药局16版(JP16)中均收载了莫匹罗星软膏(JP16收载为莫匹罗星钙软膏)。
莫匹罗星分子结构中含环氧键、烯键和酯键,其中环氧键极易开环,与邻近的羟基结合成环生成杂质。莫匹罗星在高温、酸性、碱性条件下有明显的降解,因此莫匹罗星软膏的稳定性成为需要解决的难点问题。北京协和药厂申请的专利CN102335122公开了一种莫匹罗星软膏及其制备方法,该方法制备的莫匹罗星软膏含有作为稳定剂的有机酸,提高软膏的稳定性,有关物质低。杭州朱养心药业有限公司申请的专利CN102885763公开了一种新颖的莫匹罗星软膏剂药物组合物,该含特定比率氨基酸的软膏剂药物组合物具有稳定性方面的优良药学特点。然而,莫匹罗星对酸不稳定,在酸性条件下易降解,通过在软膏中加入有机酸、氨基酸均无法良好解决莫匹罗星的稳定性问题。福元药业有限公司申请的专利CN113520994公开了一种莫匹罗星软膏制剂,该软膏中采用纤维素衍生物对莫匹罗星进行一定包裹,从而提高莫匹罗星软膏稳定性。该专利中选用的纤维素衍生物在局部外用制剂中一般用作增黏剂,对莫匹罗星的包裹作用有限,未很好解决莫匹罗星的稳定性问题。
现有技术通过在软膏中加入有机酸、氨基酸,或用纤维素衍生物对莫匹罗星进行一定包裹改善莫匹罗星稳定性,均未能有效解决莫匹罗星软膏稳定性问题,因此通过有效工艺手段,提高制剂稳定性,控制有关物质增加,仍是目前莫匹罗星软膏需解决问题。
发明内容
本发明提供一种莫匹罗星软膏及其制备方法,以解决莫匹罗星软膏稳定性问题,有效控制效期内杂质增加,保障制剂质量和临床疗效。该软膏制剂具体包括莫匹罗星、聚乙二醇400、聚乙二醇3350、环糊精。该软膏制剂工艺过程简单,易于操作,适合产业化规模生产。
为获得具有良好稳定性的莫匹罗星软膏,发明人经过深入研究,意外发现在现在软膏基质聚乙二醇400、聚乙二醇3350基础上加入环糊精,采用环糊精对莫匹罗星包合技术可以提高莫匹罗星软膏稳定性。且制得的软膏粘稠度适宜,细腻均匀、易凃展,患者顺应性良好。
本发明提供一种莫匹罗星软膏及其制备方法,该软膏制剂具体包括莫匹罗星、聚乙二醇400、聚乙二醇3350、环糊精。上述环糊精为α-环糊精、β-环糊精、γ-环糊精中的任意一种。进一步优选,环糊精为β-环糊精、γ-环糊精。
上述软膏中各组分重量份数如下:
原辅料名称 | 重量份数 |
莫匹罗星 | 2-5 |
聚乙二醇400 | 50-70 |
聚乙二醇3350 | 30-50 |
环糊精 | 1-10 |
进一步的,软膏中各组分重量份数优选为:
原辅料名称 | 重量份数 |
莫匹罗星 | 2-3 |
聚乙二醇400 | 50-60 |
聚乙二醇3350 | 30-40 |
环糊精 | 1-6 |
进一步的,一种莫匹罗星软膏的制备方法,包括以下步骤:
①将处方量50%~70%的聚乙二醇400加热至一定温度,得到溶液A;
②将处方量聚乙二醇3350加入溶液A中加热至一定温度,再保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B;
③将剩余处方量的聚乙二醇400加热至一定温度,再将环糊精加入其中搅拌均匀,再加入处方量莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C;④将含药药液C加入熔融的聚乙二醇混合液B中,在一定温度下搅拌使其混合均匀,冷却至室温,灌装即得。
进一步的,所述步骤①中的加热温度为53~55℃。
进一步的,所述步骤②中的加热温度为63~65℃。
进一步的,所述步骤③中的加热温度为55~60℃。
进一步的,所述步骤④中的搅拌温度为55~60℃。
有益效果
与现有技术相比,本发明通过环糊精对莫匹罗星包合技术可减少莫匹罗星的暴露,减少与软膏基质聚乙二醇400、聚乙二醇3350的接触,且该发明中未引入酸性成分,从而达到提高莫匹罗星稳定性的目的。
具体实施方式
通过以下实验进一步说明本发明的有益效果。但并不局限于下述实施例,本领域的技术人员在本发明基础上所作的,不脱离本发明实质内容的等同替换或变化,亦均在本发明的保护范围之内。
实施例1
原辅料名称 | 用量(g) |
莫匹罗星 | 2 |
聚乙二醇400 | 55.9 |
聚乙二醇3350 | 38.1 |
α-环糊精 | 4 |
工艺步骤如下:
①处方量50%的聚乙二醇400(27.95g)加热至55℃,得到溶液A;
②将处方量(38.1g)聚乙二醇3350加入溶液A中,搅拌待温度升至65℃,保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B,备用;
③将剩余量27.95g聚乙二醇400加热至57℃,加入4gα-环糊精搅拌均匀,再加入2g莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C,备用;
④将上述含药药液C加入已熔融的聚乙二醇混合液B中,57℃搅拌使其混合均匀,冷却至室温,灌装即得。
实施例2
原辅料名称 | 用量(g) |
莫匹罗星 | 4 |
聚乙二醇400 | 53 |
聚乙二醇3350 | 37 |
β-环糊精 | 6 |
工艺步骤如下:
①处方量65%的聚乙二醇400(34.45g)加热至55℃,得到溶液A;
②将处方量(37g)聚乙二醇3350加入溶液A中,搅拌待温度升至64℃,保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B,备用;
③将剩余量18.55g聚乙二醇400加热至60℃,加入6gβ-环糊精搅拌均匀,再加入4g莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C,备用;
④将上述含药药液C加入已熔融的聚乙二醇混合液B中,60℃搅拌使其混合均匀,冷却至室温,灌装即得。
实施例3
原辅料名称 | 用量(g) |
莫匹罗星 | 5 |
聚乙二醇400 | 53 |
聚乙二醇3350 | 36 |
γ-环糊精 | 6 |
工艺步骤如下:
①处方量70%的聚乙二醇400(37.1g)加热至55℃,得到溶液A;
②将处方量(36g)聚乙二醇3350加入溶液A中,搅拌待温度升至63℃,保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B,备用;
③将剩余量15.9g聚乙二醇400加热至55℃,加入6gγ-环糊精搅拌均匀,再加入5g莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C,备用;
④将上述含药药液C加入已熔融的聚乙二醇混合液B中,55℃搅拌使其混合均匀,冷却至室温,灌装即得。
实施例4
原辅料名称 | 用量(g) |
莫匹罗星 | 2 |
聚乙二醇400 | 57.7 |
聚乙二醇3350 | 38.1 |
β-环糊精 | 2.2 |
工艺步骤如下:
①处方量60%的聚乙二醇400(34.62g)加热至53℃,得到溶液A;
②将处方量(38.1g)聚乙二醇3350加入溶液A中,搅拌待温度升至65℃,保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B,备用;
③将剩余量23.08g聚乙二醇400加热至55℃,加入2.2gβ-环糊精搅拌均匀,再加入2g莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C,备用;
④将上述含药药液加入已熔融的聚乙二醇混合液B中,55℃搅拌使其混合均匀,冷却至室温,灌装即得。
实施例5
原辅料名称 | 用量(g) |
莫匹罗星 | 3 |
聚乙二醇400 | 54 |
聚乙二醇3350 | 37 |
β-环糊精 | 6 |
工艺步骤如下:
①处方量65%的聚乙二醇400(35.1g)加热至54℃,得到溶液A;
②将处方量(37g)聚乙二醇3350加入溶液A中,搅拌待温度升至63℃,保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B,备用;
③将剩余量18.9g聚乙二醇400加热至60℃,加入6gβ-环糊精搅拌均匀,再加入3g莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C,备用;
④将上述含药药液C加入已熔融的聚乙二醇混合液B中,60℃搅拌使混合均匀,冷却至室温,灌装即得。
实施例6
原辅料名称 | 用量(g) |
莫匹罗星 | 2.5 |
聚乙二醇400 | 56 |
聚乙二醇3350 | 38 |
β-环糊精 | 3.5 |
工艺步骤如下:
①处方量50%的聚乙二醇400(28g)加热至55℃,得到溶液A;
②将处方量(38g)聚乙二醇3350加入溶液A中,搅拌待温度升至64℃,保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B,备用;
③将剩余量28g聚乙二醇400加热至56℃,加入3.5gβ-环糊精搅拌均匀,再加入2.5g莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C,备用;
④将上述含药药液C加入已熔融的聚乙二醇混合液B中,56℃搅拌使混合均匀,冷却至室温,灌装即得。
对比例1
原辅料名称 | 用量(g) |
莫匹罗星 | 2 |
聚乙二醇400 | 58.9 |
聚乙二醇3350 | 39.1 |
制备工艺同实施例1.
对比例2
依据福元药业有限公司专利CN113520994中实施例1制备样品。
原辅料名称 | 用量(g) |
莫匹罗星 | 2 |
羧甲基纤维素钠 | 1 |
聚乙二醇400 | 58.6 |
聚乙二醇3350 | 38.4 |
工艺步骤如下:
①将处方量50%的聚乙二醇400(29.3g)加热至55℃时,加入聚乙二醇3350搅拌,继续升温至75℃,直至聚乙二醇400和聚乙二醇3350熔融得到混合溶液,备用;
②将莫匹罗星与羧甲基纤维素钠混合均匀,得混合物,并在55℃温度下,将混合物加入到29.3g聚乙二醇400中混匀,得到含药药液。
③在55℃温度下,将混合溶液与含药液体混合均匀,冷却到40℃,灌装。
对比例3
依据北京协和药厂专利CN102335122中实施例1(取各组分的十分之一)制备样品。
原辅料名称 | 用量(g) |
莫匹罗星 | 1 |
柠檬酸 | 0.1 |
聚乙二醇400 | 39.1 |
聚乙二醇4000 | 9.8 |
工艺步骤如下:
将0.1g的柠檬酸溶解于39.1g的聚乙二醇400中,再加入9.8g的聚乙二醇4000,在60℃的水浴中加热至熔融,再加入1g的莫匹罗星,在60℃的水浴中搅拌使莫匹罗星溶解,均匀混合,冷却至室温,即得莫匹罗星软膏。
对比例4
依据杭州朱养心药业有限公司专利CN102885763中实施例1制备样品。
原辅料名称 | 用量(g) |
莫匹罗星 | 1.5 |
精氨酸 | 1 |
聚乙二醇400 | 79.5 |
聚乙二醇4000 | 18 |
工艺步骤如下:
①将1g精氨酸溶于70%聚乙二醇400(55.65g)中得到混合物;
②向步骤①的混合物中加入1.5g莫匹罗星,搅拌溶解;
③将18g聚乙二醇4000加热至熔融,然后将其在搅拌下加入到步骤②所得物料中,搅拌均匀;
④补加剩余量的聚乙二醇400(23.85g),混合均匀,放冷至室温,即得莫匹罗星软膏。
关键质量属性评估:实施例1、2、3、4、5、6和对比例1、2、3、4制备的莫匹罗星软膏进行关键质量属性评估:性状、均匀性、黏度、稳定性(有关物质),测定方法及可接受标准如下:
性状、均匀度、粘度检测结果如下:
稳定性(有关物质)检测结果:
实施例1、2、3、4、5、6和对比例1、2、3、4制备的样品,在加速条件(30℃±2℃,相对湿度:65%±5%),考察时间6个月,上述各样品加速6月总杂(%)检测结果见下表:
由上述稳定性结果可知,本发明实施例中通过环糊精对莫匹罗星包合技术可减少莫匹罗星的暴露,减少与软膏基质聚乙二醇400、聚乙二醇3350的接触,从而提高莫匹罗星稳定性;相比对比例1未加入环糊精、对比例2加入纤维素类衍生物包裹莫匹罗星、对比例3加入柠檬酸、对比例4加入精氨酸所制备样品的稳定性,依据本发明制备的样品稳定性更优。
Claims (10)
1.一种莫匹罗星软膏,其特征在于,所述软膏含有莫匹罗星、聚乙二醇400、聚乙二醇3350、环糊精。
2.根据权利要求1所述的一种莫匹罗星软膏,其特征在于,环糊精为α-环糊精、β-环糊精、γ-环糊精中的任意一种。
3.根据权利要求2所述的一种莫匹罗星软膏,其特征在于,所述环糊精为β-环糊精或γ-环糊精。
4.根据权利要求1所述的一种莫匹罗星软膏,其特征在于,所述软膏中各组分重量份数如下:
5.根据权利要求4所述的一种莫匹罗星软膏,其特征在于,所述软膏中各组分重量份数为:
6.如权利要求1所述的一种莫匹罗星软膏的制备方法,其特征在于,包括如下工艺步骤:
①将处方量50%~70%的聚乙二醇400加热至一定温度,得到溶液A;
②将处方量聚乙二醇3350加入溶液A中加热至一定温度,再保温使聚乙二醇3350熔融,搅拌使两种聚乙二醇混合均匀,得到混合液B;
③将剩余处方量的聚乙二醇400加热至一定温度,再将环糊精加入其中搅拌均匀,再加入处方量莫匹罗星,搅拌使环糊精包合莫匹罗星,得到含药药液C;
④将含药药液C加入熔融的聚乙二醇混合液B中,在一定温度下搅拌使其混合均匀,冷却至室温,灌装即得。
7.根据权利要求6所述的一种莫匹罗星软膏的制备方法,其特征在于,所述步骤①中的加热温度为53~55℃。
8.根据权利要求6所述的一种莫匹罗星软膏的制备方法,其特征在于,所述步骤②中的加热温度为63~65℃。
9.根据权利要求6所述的一种莫匹罗星软膏的制备方法,其特征在于,所述步骤③中的加热温度为55~60℃。
10.根据权利要求6所述的一种莫匹罗星软膏的制备方法,其特征在于,所述步骤④中的搅拌温度为55~60℃。
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