CN1900077B - 利福昔明的新多晶型形式,它们的制备方法及其在药物制剂中的用途 - Google Patents

利福昔明的新多晶型形式,它们的制备方法及其在药物制剂中的用途 Download PDF

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CN1900077B
CN1900077B CN2005100851226A CN200510085122A CN1900077B CN 1900077 B CN1900077 B CN 1900077B CN 2005100851226 A CN2005100851226 A CN 2005100851226A CN 200510085122 A CN200510085122 A CN 200510085122A CN 1900077 B CN1900077 B CN 1900077B
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G·C·维斯科米
M·坎帕纳
D·孔福尔蒂尼
M·M·巴尔班蒂
D·布拉加
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Abstract

本发明的目的是抗菌剂利福昔明(INN)的结晶多晶型形式，它们被称为利福昔明δ和利福昔明ε，可用于制备用于口服和局部使用的包含利福昔明的药物制剂，并且可用如下进行的结晶方法获得：将利福昔明粗品热溶解在乙醇中，通过在规定温度下加入水而使产物结晶并持续规定的时间，然后在控制条件下进行干燥，直到达到终产品中规定的水含量。

Description

利福昔明的新多晶型形式,它们的制备方法及其在药物制剂中的用途
发明背景 
利福昔明(INN；参见The Merck Index，第13版，8304)是一种属于利福霉素类的抗生素，准确地说，是在意大利专利IT 1154655中描述和要求保护的吡啶并咪唑并利福霉素，而欧洲专利EP 0161534描述和要求保护了其从利福霉素O(The Merck Index，第13版，8301)起始的制备方法。 
这两篇专利均以概括的方式描述了利福昔明的纯化，披露称结晶可以在适宜的溶剂或溶剂系统中进行，并在一些实施例中概略地说明了反应所得的产物可以用乙醇/水7∶3的混合物结晶，并且在大气压力和真空下均可进行干燥，但没有以任何方式披露结晶和干燥的实验条件，也没有披露所获得的产物的任何特征性结晶学特性。 
由于先前没有注意到存在不同多晶型物，因此这两篇专利中所描述的实验条件均旨在得到从化学观点来看具有合适纯度的均匀产物，未涉及产物自身的结晶学方面。 
现在已经出乎意料地发现存在一些多晶型形式，它们的形成除溶剂外还取决于进行结晶和干燥的时间和温度条件。 
基于本发明中所报道的它们各自特殊的衍射图，这些有序的多晶型形式在下文中将被照例指定为利福昔明δ(图1)和利福昔明ε(图2)。 
利福昔明的多晶型形式通过粉末X-射线衍射技术来表征。 
对于一种作为用于人用和兽用的药物制剂出售的具有药理学活性的化合物如利福昔明而言，这些多晶型形式的鉴定和表征以及同时对获得它们的实验条件的确定均是非常重要的。实际上，已知能包含在药物制剂中用作活性成分的化合物的多晶现象能够影响药物的药理学-毒理学性质。作为口服或局部形式的药物被施用的活性成分的不同多晶型形式可以改变它们的许多性质，如生物利用度、 溶解度、稳定性、颜色、可压性、流动性和可加工性，从而改变毒理学安全性、临床有效性和生产效率特性。 
上述内容可以被如下事实权威地确证：即管理药品上市许可的批准授权的管理当局要求活性成分的生产方法要以就生产批次的多晶现象而言产生均匀和正确结果的方式进行标准化和控制(CPMP/QWP/96，2003-新活性物质的化学指导原则；CPMP/ICH/367/96-指导规范注解：新药成分和新药产品：化学成分的检测方法和验收标准；实施日期：2000年5月)。 
在利福霉素抗生素领域，对上述标准化的要求已经被Henwood S.Q.，deVilliers M.M，Liebenberg W.和 
Figure G05185122620050728D000021
A.P.，Drug Development and IndustrialPharmacy，26(4)，403-408，(2000)进一步加强，他们证实：由不同生产商制造的不同生产批次的利福平(INN)具有差异，因为它们具有不同的多晶型特性，并因此显示出不同的溶解特性和各自药理学性质的相应改变。 
通过使用在先专利IT 1154655和EP 0161534中所概括性披露的结晶和干燥方法，已经发现在一些实验条件下获得利福昔明的不充分结晶类型，而在其它实验条件下获得利福昔明的其它结晶多晶型形式。而且，还发现一些在上述专利中绝对没有被披露的参数如保存条件和周围环境的相对湿度对决定多晶型物的形式具有令人惊讶的影响。 
本专利申请的目的、即利福昔明的多晶型形式从未被发现或假设过，而是认为在所述的条件范围内，无论选择何种方法，总是可以获得单一的均匀产品，与用于结晶、干燥和保存的条件无关。 
现在已经发现：δ和ε形式的形成取决于结晶溶剂中水的存在、产物结晶的温度和干燥阶段结束时存在于产物中的水量。 
现合成了利福昔明的δ形式和ε形式，它们是本发明的目的。 
具体而言，δ形式的特征在于在干燥的固体物质中水的残留量为2.5％至6％(w/w)，更优选为3％至4.5％，而ε形式是在控制条件下从δ形式转变的多晶型转化的结果。在干燥物质中其水含量小于4.5％(w/w)。 
这些结果具有显著的重要性，因为它们确定了可能被认为不是决定产物多晶现象的关键的一些处理步骤的工业制备条件，例如将结晶产物的水量维持在严格 范围值内，或其中一种形式、即在继续干燥以获得ε形式之前获得δ形式的干燥终产物的方法，或终产物的保存条件，或保存产物的容器的性质。 
利福昔明在胃肠道中发挥其广谱抗菌活性，对抗包括厌氧菌菌株在内的引起感染性腹泻的集中于胃肠的细菌。据报道利福昔明的特征在于可以忽略的全身吸收，这是由其化学和物理性质造成的(Descombe J.J.等.口服施用于健康志愿者后利福昔明的药动学研究.Int J Clin.Pharmacol.Res.，14(2)，51-56，(1994))。 
现在我们已经发现在两种鉴定的利福昔明多晶型形式的基础上调整其全身吸收水平是可能的，并且这是本发明的一部分，实现的方法是施用利福昔明的不同的多晶型形式，即利福昔明δ和利福昔明ε。可能具有血中浓度为0.001-0.3μg/ml的几乎100倍的吸收差异。 
所证明的生物利用度差异是重要的，因为它能够区分利福昔明两种多晶型物δ和ε的药理学和毒理学性质。 
事实上，利福昔明ε通过口服途径的吸收可以忽略而利福昔明δ具有少量的吸收。 
利福昔明ε基本上不被吸收，可能仅通过包括胃肠道的情况在内的局部作用起作用，优点是毒性非常低。 
另一方面，可以发现被少量吸收的利福昔明δ具有对抗能隐藏它们自己并部分逃避局部抗生素作用的全身性微生物的有利应用。 
关于与利福昔明的治疗应用相关的可能不良事件，值得注意的相关是诱导细菌对抗生素的抗药性。一般而言，在用抗生素进行的治疗实践中，通过抗药性菌株的选择而诱导细菌对该种抗生素或其它抗生素产生抗药性一直是可能的。 
对于利福昔明，这一方面是尤其相关的，因为利福昔明属于利福霉素家族，该族的一个成员利福平在结核病的治疗中被大量使用。目前结核病的短疗程治疗是包括四种活性药物成分的组合疗法：利福平、异烟肼、乙胺丁醇和吡嗪酰胺，其中利福平起关键作用。因此，任何通过选择对利福平的抗药性而危害治疗有效性的药物都将是有害的。(Kremer L.等.“结核病再度出现：对策和治疗”，ExpertOpin.Investig.Drugs，11(2)，153-157，(2002))。 
原则上，看看利福昔明和利福平之间的结构相似性，就可能通过使用利福昔 明来选择结核分支杆菌的抗药性菌株和诱导对利福平的交叉抗药性。为了避免这一负性事件，关键是控制全身吸收的利福昔明量。 
在这一观点下，所发现的利福昔明的δ和ε形式在全身性吸收方面的差异是有意义的，因为还在低于利福昔明抑制浓度的浓度如0.1-1μg/ml下证实抗药性突变菌株的选择是可能的(Marchese A.等.利福昔明、甲硝唑和万古霉素抗难辨梭状芽孢杆菌的体外活性和包括产氨种类在内的代表性厌氧菌和需氧菌的自发抗药性突变菌株的选择速度。Chemotherapy，46(4)，253-266，(2000))。 
根据上述内容，清楚地强调了本发明的重要性，本发明给出了上述利福昔明多晶型形式存在的知识和用于制备具有不同药理学性质的纯单一形式的各种工业途径。 
上述δ和ε形式可以作为纯的和均质的产品被有利地用于制备包含利福昔明的药物制剂。 
如已经描述的那样，从所获得的产物的纯化和鉴定角度来看，EP 0161534中所公开的和要求保护的由利福霉素O制备利福昔明的方法是有缺陷的；从合成观点来看也具有一些局限，例如需要16-72小时的非常长的反应时间、很不适于工业应用，此外还因为其未提供可在反应混合物中形成的氧化利福昔明的原位还原。 
因此，本发明的另一目的是本文中以产物形式要求保护且可以如所述的那样使用的利福昔明的δ和ε形式的改进的工业制备方法以及用于制备包含这种活性成分的药物制剂的均质的活性成分。 
发明概述 
如已经描述的那样，称为利福昔明(INN)的抗菌剂的δ形式和ε形式、它们的制备方法以及它们在制备用于口服或局部途径的药物制剂中的用途是本发明的目的。 
本发明的方法目的包括使1摩尔当量的利福霉素O与过量的2-氨基-4-甲基吡啶、优选2.0至3.5摩尔当量在由水和乙醇以1∶1至2∶1的体积比组成的溶剂混合物中于40℃至60℃的温度下反应2至8小时。 
反应结束后，将反应物冷却至室温并在剧烈搅拌下加入抗坏血酸在水、乙醇和含水浓盐酸混合物中的溶液，以便将反应过程中形成的少量氧化的利福昔明还原，最后通过进一步加入浓盐酸水溶液将pH调至约2.0以便更好地除去反应中所使用的过量的2-氨基-4-甲基吡啶。过滤混悬液，用反应中所用的相同的溶剂混合物水/乙醇洗涤所得固体。所得的半成品被称为“利福昔明粗品”。 
利福昔明粗品可直接进行随后的纯化步骤。或者，如果希望长时间保存半成品，则可以将利福昔明粗品在低于65℃的温度下真空干燥6至24小时，这样制得的半成品被称为“干燥的利福昔明粗品”。 
如此获得的利福昔明粗品和/或干燥的利福昔明粗品可以通过以下方法纯化：在45℃至65℃的温度下将它们溶解在乙醇中，通过加入水使它们结晶，优选加入的水重量为用于溶解的乙醇重量的15％至70％，并在搅拌下将所得的混悬液保持在50℃至0℃的温度下4至36小时。 
过滤混悬液，将所得的固体用水洗涤并在真空或常压下、于室温至105℃的温度下、在存在或不存在干燥剂的情况下干燥2至72小时。 
δ和ε形式的获得取决于所选择的结晶条件。特别是已经证明用于进行结晶的溶剂混合物的组成、结晶后保持反应混合物的温度以及保持该温度的时间是至关重要的。 
更准确地说，在以下条件下获得利福昔明δ和ε形式：首先将温度调整至28℃至32℃以便使结晶开始，然后将混悬液温度调整至40℃至50℃并在该温度值下保持6至24小时，然后在15分钟至1小时内将混悬液快速冷却至0℃，过滤，用水洗涤固体，然后干燥。 
在利福昔明的δ和ε多晶型形式的获得中，干燥步骤具有重要作用，并且必须通过适于测定水含量的适宜方法来检测，例如Karl Fisher方法，以便检查干燥后产品中的残余水量。 
实际上在干燥过程中利福昔明δ的获得取决于水的最终残留量，其应该为2.5％(w/w)至6％(w/w)，更优选3％至4.5％，且水的最终残留量不是由达到这一关键的水百分比限度所用的压力和温度实验条件来确定的。 
为了获得吸收差的ε形式，必须从δ形式开始，并且必须在真空或大气压力 下、于室温或高温下、在存在或不存在干燥剂的情况下继续干燥，条件是干燥长达完成向ε形式转化所必需的时间。 
利福昔明的δ和ε形式均是吸湿性的，它们在周围环境中于适宜的压力和湿度条件下在一段时间中以可逆的方式吸收水并且易于转化成其它形式。 
在本发明的范围内，从一种形式向另一种形式的转化非常重要，因为它们可以成为用于获得药物制剂生产所需形式的可供选择的制备方法。因此，以有效的工业方式使利福昔明δ转化成利福昔明ε的方法是本发明的重要部分。 
关于利福昔明δ向利福昔明ε转化的方法包括在真空或在大气压力下、于室温或高温下、在存在或不存在干燥剂的情况下干燥利福昔明δ并将其保持一段时间，直至获得转变，该时间通常为6至36小时。 
从上述内容可以看出，这导致在产品的保存阶段必需特别小心以使周围环境条件不会改变产物的水含量，方法是将产物保存在不会使水与外部环境有显著交换的具有控制湿度的环境中或密闭容器中。 
被称作利福昔明δ的多晶型物的特征是水含量为2.5％至6％，优选3.0％至4.5％，其粉末X-射线衍射图(参见图1)显示在值为5.7°±0.2，6.7°±0.2，7.1°±0.2，8.0°±0.2，8.7°±0.2，10.4°±0.2，10.8°±0.2，11.3°±0.2，12.1°±0.2，17.0°±0.2，17.3°±0.2，17.5°±0.2，18.5°±0.2，18.8°±0.2，19.1°±0.2，21.0°±0.2，21.5°±0.2的2θ衍射角处有峰。被称为利福昔明ε的多晶型物的特征是其粉末X-射线衍射图(参见图2)显示在值为7.0°±0.2，7.3°±0.2，8.2°±0.2，8.7°±0.2，10.3°±0.2，11.1°±0.2，11.7°±0.2，12.4°±0.2，14.5°±0.2，16.3°±0.2，17.2°±0.2，18.0°±0.2，19.4°±0.2的2θ衍射角处有峰。 
衍射图用能进行Bragg-Brentano几何学处理的Philips X’Pert仪器并在以下工作条件下完成： 
X-射线管：铜 
使用的放射物：K(α1)，K(α2) 
发生器的电压和电流：KV40，mA40 
单色仪：石墨 
步长：0.02 
每步时间：1.25秒 
起始和最终角2θ值：3.0°÷30.0° 
总是通过Karl Fisher方法评估所分析的样品中存在的水含量。 
利福昔明δ和利福昔明ε彼此不同也因为它们在生物利用度方面显示出重大差异。 
已经用Beagle雌性犬进行了两种多晶型物的生物利用度研究，通过口服途径用多晶型物中的一种的胶囊剂以100mg/kg的剂量对它们进行处理，在每次给药前和每次给药后1、2、4、6、8和24小时从每只动物的颈静脉采集血样，将血样转移入含有肝素的试管中，通过离心分离血浆。 
用经过验证的LC-MS/MS方法分析血浆中的利福昔明含量，计算出最大实测血浆浓度(Cmax)、达到Cmax的时间(tmax)和浓度-时间曲线下面积(AUC)。 
在以下表1中报告的实验数据清楚地显示利福昔明ε吸收非常少，而利福昔明δ以0.1至1.0μg/ml的值(Cmax＝0.308μg/ml)被吸收。 
表1 
用胶囊剂单次口服给予雌性犬100mg/kg后利福昔明多晶型物的药动学参数。 
    Cmax   ng/ml   Tmax   小时   AUC0-24   ng·小时/ml
    均值   均值   均值
  多晶型物δ   308.31   2   801
  多晶型物ε   6.86   4   42
上述实验结果进一步指出了两种利福昔明多晶型物之间存在的差异。 
附图简要说明 
图1表示根据上述方法所记录的多晶型物δ的粉末X-射线衍射图； 
图2表示根据上述方法所记录的多晶型物ε的粉末X-射线衍射图。 
δ和ε形式能有利地用于制备口服和局部使用的包含利福昔明的具有抗菌活性的药物制剂。用于口服使用的药物制剂包含利福昔明δ和ε以及常规赋形剂如稀释剂例如甘露醇、乳糖和山梨醇；粘合剂例如淀粉、明胶、蔗糖、纤维素衍生物、天然树胶和聚乙烯吡咯烷酮；润滑剂例如滑石粉、硬脂酸盐、氢化植物油、聚 乙二醇和胶态二氧化硅；崩解剂例如淀粉、纤维素、藻酸盐、树胶和网状聚合物；着色剂、矫味剂和甜味剂。 
在本发明的范围内，可以使用可通过口服途径施用的所有固体制剂，例如包衣和未包衣的片剂、软和硬明胶制得的胶囊剂、糖衣丸剂、锭剂、糯米纸囊剂、小丸和在密封袋中的散剂。 
用于局部使用的药物制剂包含利福昔明δ和ε以及常规赋形剂例如白凡士林、白蜡、羊毛脂及其衍生物、硬脂醇、丙二醇、十二烷基硫酸钠、脂族聚氧乙烯醇的醚、脂族聚氧乙烯酸的酯、失水山梨糖醇单硬脂酸酯、甘油单硬脂酸酯、丙二醇单硬脂酸酯、聚乙二醇、甲基纤维素、羟甲基丙基纤维素、羧甲基纤维素钠、胶态硅酸铝和硅酸镁、藻酸钠。 
在本发明的范围内，可以使用所有局部用制剂，例如软膏剂、香膏剂、乳膏剂、凝胶剂和洗剂。 
下文将通过一些不应认为是限制本发明的实施例进行举例说明：从实际上描述的结果可明显看出δ和ε形式能通过在合适地组合上述结晶和干燥条件而获得。 
实施例1 
利福昔明粗品和干燥的利福昔明粗品的制备 
在室温下，在装配有机械搅拌器、温度计和回流冷凝器的三颈瓶中，按顺序加入120ml软化水、96ml乙醇、63.5g利福霉素O和27.2g 2-氨基-4-甲基吡啶。加料结束后，将混合物在47±3℃下加热，保持在该温度下搅拌5小时，然后冷却至20±3℃，在30分钟内加入另外制备的由9ml软化水、12.6ml乙醇、1.68g抗坏血酸和9.28g含水浓盐酸组成的混合物。加料结束后，在内部温度20±3℃下持续搅拌混合物30分钟，然后在同样的温度下，滴加7.72g浓盐酸直至pH等于2.0。 
加料结束后，将混合物一直处于内部温度20℃下搅拌30分钟，然后过滤沉淀物并用由32ml软化水和25ml乙醇组成的混合物洗涤。将如此得到的“利福昔明粗品”(89.2g)在室温下真空干燥12小时，得到64.4g“干燥的利福昔明粗品”，其具有等于5.6％的水含量。将该产物通过进一步真空干燥得到62.2g重量的干燥的 利福昔明粗品，其具有等于3.3％的水含量，它的衍射图相应于多晶型形式δ，特征是粉末X-线衍射图显示在值为5.7°±0.2，6.7°±0.2，7.1°±0.2，8.0°±0.2，8.7°±0.2，10.4°±0.2，10.8°±0.2，11.3°±0.2，12.1°±0.2，17.0°±0.2，17.3°±0.2，17.5°±0.2，18.5°±0.2，18.8°±0.2，19.1°±0.2，21.0°±0.2，21.5°±0.2的2θ角处有峰。该产物是吸湿性的。 
实施例2 
利福昔明ε的制备 
重复实施例1的操作并在获得δ形式后，将固体粉末在65℃的温度下进一步真空干燥24小时。获得的产物是利福昔明ε，其特征是粉末X-射线衍射图显示在值为7.0°±0.2，7.3°±0.2，8.2°±0.2，8.7°±0.2，10.3°±0.2，11.1°±0.2，11.7°±0.2，12.4°±0.2，14.5°±0.2，16.3°±0.2，17.2°±0.2，18.0°±0.2，19.4°±0.2的2θ角处有峰。 
实施例3 
通过口服途径施用在犬中的生物利用度 
将8只20周龄且体重5.0-7.5kg的纯种Beagle雌性犬分成2组，每组4只。 
按照下述方法用利福昔明δ处理第一组，用利福昔明ε处理第二组。 
对每只犬通过口服途径施用在明胶胶囊中的利福昔明多晶型物中的一种，并在每次给药前和给药后1、2、4、6、8和24小时从每只动物的颈静脉各采集2ml血样。 
将每个血样转移入含有肝素作为抗凝剂的试管中并离心；将血浆分成2等份，每份500μl，在-20℃下冷冻。 
用经过验证的LC-MS/MS方法分析血浆中包含的利福昔明，并按照标准非隔室分析计算下述参数： 
Cmax＝血浆中利福昔明的最大实测血浆浓度 
Tmax＝达到Cmax的时间 
AUC＝通过线性梯形法则计算的浓度-时间曲线下面积 
[0090] 在以下表1中报告的结果清楚地显示利福昔明δ是的吸收非常多，比利福昔明ε多40倍，后者基本上不被吸收。 
表1 
用胶囊剂单次口服给予雌性犬100mg/kg后利福昔明多晶型物的药动学参数
 
    Cmax   ng/ml   Tmax   小时   AUC0-24   ng·小时/ml
    均值   均值   均值
  多晶型物δ   308.31   2   801
  多晶型物ε   6.86   4   42

Claims (12)

1.称作利福昔明δ的抗菌剂利福昔明的多晶型物，其特征在于水含量为2.5％(w/w)至6％(w/w)，并且特征在于粉末X-射线衍射图显示在值为5.7°±0.2，6.7°±0.2，7.1°±0.2，8.0°±0.2，8.7°±0.2，10.4°±0.2，10.8°±0.2，11.3°±0.2，12.1°±0.2，17.0°±0.2，17.3°±0.2，17.5°±0.2，18.5°±0.2，18.8°±0.2，19.1°±0.2，21.0°±0.2，21.5°±0.2的2θ衍射角处有峰。
2.权利要求1的利福昔明的多晶型物，其特征在于水含量为3.0％(w/w)至4.5％(w/w)。
3.称作利福昔明ε的抗菌剂利福昔明的多晶型物，其特征在于粉末X-射线衍射图显示在值为7.0°±0.2，7.3°±0.2，8.2°±0.2，8.7°±0.2，10.3°±0.2，11.1°±0.2，11.7°±0.2，12.4°±0.2，14.5°±0.2，16.3°±0.2，17.2°±0.2，18.0°±0.2，19.4°±0.2的2θ衍射角处有峰。
4.制备利福昔明δ的方法，其特征在于使1摩尔当量的利福霉素O与过量的2-氨基-4-甲基吡啶在由水和乙醇以1∶1至2∶1的体积比组成的溶剂混合物中于40℃至60℃的温度下反应2至8小时；将反应物在室温下用抗坏血酸在水、乙醇和含水浓盐酸混合物中的溶液处理，然后用浓盐酸水溶液调至pH 2.0，过滤混悬液，用反应中所用的相同的水/乙醇溶剂混合物洗涤固体；将如此获得的利福昔明粗品进行纯化，方法是在45℃至65℃的温度下将利福昔明粗品溶解在乙醇中，通过加入水使其沉淀，将温度降低至28℃至32℃以引发结晶；在搅拌下将获得的混悬液保持在40℃至50℃下6至24小时，然后将其在15分钟至1小时内冷却至0℃，然后过滤，将固体干燥直至水含量为2.5％(w/w)至6％(w/w)，优选3％(w/w)至4.5％(w/w)。
5.权利要求4的方法，其特征在于利福霉素O与2.0至3.5摩尔当量的2-氨基-4-甲基吡啶反应。
6.权利要求5的方法，其用于制备利福昔明ε，其特征在于在真空或大气压力下、于室温或高温下、在存在或不存在干燥剂的情况下干燥利福昔明δ，条件是干燥长达获得ε形式所必需的时间。
7.利福昔明δ与常规赋形剂一起在制备用于口服使用的药物制剂中的用途，所述的制剂具有抗菌活性，所述的常规赋形剂选自稀释剂、粘合剂、润滑剂、崩解剂、着色剂、矫味剂和甜味剂。
8.利福昔明ε与常规赋形剂一起在制备用于口服使用的药物制剂中的用途，所述的制剂具有抗菌活性，所述的常规赋形剂选自稀释剂、粘合剂、润滑剂、崩解剂、着色剂、矫味剂和甜味剂。
9.权利要求6和7中任一项的用途，其特征在于用于口服使用的制剂选自包衣和未包衣的片剂、硬和软明胶胶囊剂、糖衣丸剂、锭剂、糯米纸囊剂、小丸和在密封袋中的散剂。
10.利福昔明δ在制备具有抗菌活性的用于局部使用的药物制剂中的用途。
11.利福昔明ε在制备具有抗菌活性的用于局部使用的药物制剂中的用途。
12.权利要求10和11中任一项的用途，其特征在于用于局部使用的制剂选自软膏剂、香膏剂、乳膏剂、凝胶剂和洗剂。
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