CN112294754A - 一种曲安奈德益康唑乳膏剂及其制备方法 - Google Patents
一种曲安奈德益康唑乳膏剂及其制备方法 Download PDFInfo
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- triamcinolone acetonide
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- econazole
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Abstract
本发明公开了一种曲安奈德益康唑微乳乳膏剂及其制备方法,该微乳乳膏剂由曲安奈德益康唑微乳、乳膏基质和保湿剂混匀而得。本发明通过将微粒传递系统‑微乳加入到传统的乳膏剂中,增加了曲安奈德和硝酸益康唑两种药物的皮肤滞留性,提高了局部药物浓度,使药物发挥疗效的时间延长,并且还能减轻皮肤刺激性和副作用,对健康豚鼠皮肤无致敏性。
Description
技术领域
本发明属于医药制剂技术领域,具体而言,涉及一种曲安奈德益康唑乳膏及其制备方法。
背景技术
真菌在自然界在大量存在,致病真菌分为深部真菌和浅部真菌两类。容易引起皮肤真菌感染的病原菌有许多种,针对异性抗原,机体常对侵入皮肤的病原真菌产生较明显的变态反应。临床上可表现为湿疹皮炎样外观、瘙痒、癣菌疹,严重的可继发细菌感染。
曲安奈德益康唑乳膏剂为0.1%曲安奈德与1.0%硝酸益康唑的复方制剂,硝酸益康唑是一种广谱抗真菌药,对皮肤癣菌、霉菌和酵母菌均有很好的抗菌活性,对部分革兰氏阳性细菌也有较好作用;曲安奈德为一种含氟的中效皮质类固醇激素,有明显的消炎、抗过敏、止痒作用。曲安奈德益康唑乳膏既有抗菌的作用,也有抗炎的作用,临床主要用于湿疹患者的治疗,也用于治疗皮炎患者。
曲安奈德益康唑乳膏剂虽然对致病真菌治疗有效,但也存在全身作用的肝脏毒性、局部刺激及生物利用度低等副作用。所以有必要开发一种疗效确切、安全性高的新型曲安奈德益康唑乳膏剂。
发明内容
本发明的目的是开发一种经皮给药的高效、副作用小、生物利用度高的曲安奈德益康唑外用乳膏剂和提供其制备方法。为了实现本发明的目的,发明人进行大量文献研究,研究结果表明,药物被包封于微粒(如脂质体、微乳、脂质纳米粒及磷脂复合物)后,可促进药物透过角质层进入皮肤内,并具有较好的皮肤贮留性,能长时间发挥疗效,同时减少体内吸收。另外,药物被包封于微粒载体之中有利于药物稳定性,并减少由于药物带来的皮肤刺激性。根据这个思路,发明人将含药物的微乳加入到乳膏基质中,以期改善普通乳膏剂的不足。
为达到本发明的目的,采用的技术方案是由下列质量百分比制成的曲安奈德益康唑微乳乳膏剂:
曲安奈德益康唑微乳 40%-70%
乳膏基质 20%-60%
保湿剂 4%-10%
曲安奈德在微乳乳膏剂中的质量百分比含量为0.1%
硝酸益康唑在微乳乳膏剂中的质量百分比含量为1%
所述的曲安奈德益康唑微乳组分的质量百分比为:0.3%曲安奈德、3%硝酸益康唑、20-40%油相、30~60%表面活性剂和10~30%助表面活性剂。水相和油相的质量比为0.3-1.2:1。
制备曲安奈德益康唑微乳的油相采用丙二醇单辛酸酯、辛酸/癸酸甘油三酯、丙二醇单月桂酸酯中的任意一种;表面活性剂采用聚山梨酯80、聚氧乙烯40氢化蓖麻油、聚乙二醇8辛酸/癸酸甘油酯中的任意一种;助表面活性剂采用乙醇、聚乙二醇、二乙二醇单乙醚中的任意一种;
所述的乳膏基质组分的质量百分比为:硬脂酸15%、白凡士林10%、十六十八醇8%、单硬脂酸甘油酯9%、聚山梨酯80 3%、纯化水55%。
所述的保湿剂为丙二醇或甘油中的任意一种。
本发明的目的还可以这样实现:如上所述的曲安奈德益康唑乳膏剂,优选如下质量百分比的组分制备而成:
曲安奈德益康唑微乳 45%-55%
乳膏基质 40%-50%
保湿剂 5%-7%
所述的曲安奈德益康唑微乳组分的质量百分比为:0.3%曲安奈德、3%硝酸益康唑、25-35%油相、40~50%表面活性剂和15~20%助表面活性剂。水相和油相的质量比为0.4-0.6:1。
制备曲安奈德益康唑微乳的油相采用丙二醇单辛酸酯;表面活性剂采用聚氧乙烯40氢化蓖麻油;助表面活性剂采用二乙二醇单乙醚;
所述的保湿剂为甘油;
本发明还提供了上述曲安奈德益康唑乳膏剂的其制备方法,该方法包括如下步骤:
A、曲安奈德益康唑微乳的制备
称取油相、表面活性剂和助表面活性剂搅拌均匀制备成浓缩乳,在浓缩乳中加入曲安奈德、硝酸益康唑搅拌使其溶解,然后在搅拌下加入蒸馏水,制得曲安奈德益康唑微乳。
B、乳膏剂基质的制备
称取硬脂酸、十六十八醇,白凡士林、单硬脂酸甘油酯在70℃水浴下熔融制成油相;称取聚山梨酯80作为乳化剂,将油相加入到水相中,搅拌均匀,即得乳膏基质;
C、曲安奈德益康唑微乳乳膏剂的制备
称取曲安奈德益康唑微乳、乳膏基质和保湿剂,将曲安奈德益康唑微乳及保湿剂加入到乳膏基质中,同方向搅拌混匀,并通过抽真空除去气泡,即得曲安奈德益康唑微乳乳膏剂;
本发明的优点:1、本发明的产品能促进曲安奈德益康唑的皮肤透过能力,增加皮肤滞留性,提高皮肤局部药物浓度,延长发挥疗效的时间。2、本产品副作用小,能产生有效的局部效应,同时避免全身作用,降低不良反应发生率。3、本发明能提高药物的稳定性,并减少由于药物带来的皮肤刺激性和过敏反应。
具体实施例
下面通过实施例进一步阐述本发明的技术方案和进步。
实施例1
A、曲安奈德益康唑微乳的制备
称取曲安奈德0.3g、硝酸益康唑3g,丙二醇单辛酸酯30g,聚氧乙烯40氢化蓖麻油46.7g,聚氧乙烯40氢化蓖麻油20g及纯化水35g,在室温下将丙二醇单辛酸酯、聚氧乙烯40氢化蓖麻油、聚氧乙烯40氢化蓖麻油混合搅拌均匀,得到浓缩乳,再在浓缩乳中加入曲安奈德和硝酸益康唑,搅拌使曲安奈德、硝酸益康唑完全溶于浓缩乳,然后在搅拌的条件下缓慢滴入纯化水,即得曲安奈德益康唑微乳。微乳经透射电镜观察为近球体,经激光粒度分析微乳的粒径为35.5±2.5nm;
B、乳膏剂基质的制备
称取硬脂酸30g,十六十八醇16g,单硬脂酸甘油酯18g及白凡士林20g,在70℃水浴上加热使熔化成为油相。另称取聚山梨酯80 6g及水110g,在70℃水浴上加热使成为水相。然后将油相缓缓加入水相中,边加边搅拌直至乳化完全,放冷即得;
C、曲安奈德益康唑微乳乳膏剂的制备
将微乳135g、空白乳膏基质150g和甘油15g经过均质机混匀混匀,抽真空除去气泡,即得曲安奈德益康唑微乳软膏剂。
实施例2
A曲安奈德益康唑微乳的制备
称取曲安奈德0.3g、硝酸益康唑3g,丙二醇单辛酸酯30g,聚氧乙烯40氢化蓖麻油46.7g,聚氧乙烯40氢化蓖麻油20g及纯化水50g,在室温下将丙二醇单辛酸酯、聚氧乙烯40氢化蓖麻油、聚氧乙烯40氢化蓖麻油混合搅拌均匀,得到浓缩乳,再在浓缩乳中加入曲安奈德和硝酸益康唑,搅拌使曲安奈德、硝酸益康唑完全溶于浓缩乳,然后在搅拌的条件下缓慢滴入纯化水,即得曲安奈德益康唑微乳。微乳经透射电镜观察为近球体,经激光粒度分析微乳的粒径为30.5±2.5nm;
B、乳膏剂基质的制备
称取硬脂酸30g,十六十八醇16g,单硬脂酸甘油酯18g及凡士林20g,在70℃水浴上加热使熔化成为油相。另称取聚山梨酯80 6g及水110g,在70℃水浴上加热使成为水相。然后将油相缓缓加入水相中,边加边搅拌直至乳化完全,放冷即得;
C、曲安奈德益康唑微乳乳膏剂的制备
将微乳150g、空白乳膏基质130g和甘油20g经过均质机混匀混匀,抽真空除去气泡,即得曲安奈德益康唑微乳乳膏剂。
实施例3
A曲安奈德益康唑微乳的制备
称取曲安奈德0.3g、硝酸益康唑3g,丙二醇单辛酸酯30g,聚氧乙烯40氢化蓖麻油46.7g,聚氧乙烯40氢化蓖麻油20g及纯化水100g,在室温下将丙二醇单辛酸酯、聚氧乙烯40氢化蓖麻油、聚氧乙烯40氢化蓖麻油混合搅拌均匀,得到浓缩乳,再在浓缩乳中加入曲安奈德和硝酸益康唑,搅拌使曲安奈德、硝酸益康唑完全溶于浓缩乳,然后在搅拌的条件下缓慢滴入纯化水,即得曲安奈德益康唑微乳。微乳经透射电镜观察为近球体,经激光粒度分析微乳的粒径为32.5±2.5nm;
B、乳膏剂基质的制备
称取硬脂酸15g,十六十八醇8g,单硬脂酸甘油酯9g及凡士林10g,在70℃水浴上加热使熔化成为油相。另称取聚山梨酯80 3g及水55g,在70℃水浴上加热使成为水相。然后将油相缓缓加入水相中,边加边搅拌直至乳化完全,放冷即得;
C、曲安奈德益康唑微乳乳膏剂的制备
将微乳200g、空白乳膏基质85g和甘油15g经过均质机混匀混匀,抽真空除去气泡,即得曲安奈德益康唑微乳乳膏剂。
试验例1:曲安奈德益康唑的普通乳膏剂与曲安奈德益康唑微乳乳膏剂的经皮渗透对比试验
曲安奈德益康唑普通乳膏剂的制备:称取曲安奈德1g、硝酸益康唑10g,然后加入到1000g乳膏剂基质中,混匀制得0.1%曲安奈德、1%硝酸益康唑普通乳膏剂。
将本发明实施例2中的微乳乳膏剂与普通乳膏剂进行经皮渗透比较试验。
试验方法:鼠皮肤离体透过实验(雄性SD大鼠断颈处死后,立即剃毛,剥离腹部皮肤,去除皮下脂肪组织,用生理盐水冲洗干净,冷冻保存,备用。临用前自然解冻,用生理盐水洗涤,再用纯水冲洗,即可。每次试验前检查鼠皮的完整性。利用透皮仪,将处理好的大鼠腹部皮肤固定于供给池与接受池之间,角质层面向供给池,有效透皮面积为1.77cm2。供给池中为含50mg曲安奈德益康唑的微乳软膏剂和普通乳膏剂;接受液为20%乙醇/pH7.4磷酸缓冲液,于1,2,4,6,8,10,12,24h取样,并补充相应体积的接受液。所取样品用0.22μm的微孔滤膜过滤,测定接受液中曲安奈德益康唑的含量,按公式计算各处方的累积渗透量;
其中Cn表示第n个取样点测得的浓度,Ci表示第i个取样点测得的浓度,V0表示接受池的体积,V表示每次取样的体积,A表示释药面积,Qn(μg·cm-2)为累积渗透量。体外透皮试验终止后,从扩散池中取出大鼠皮肤,用水洗涤表面,棉花擦干,剪碎,加pH7.4磷酸缓冲液5mL,匀浆,5000r·min-1离心5min,取上清液,用0.22μm滤膜过滤,取续滤液,采用高效液相色谱法测定皮肤中曲安奈德益康唑的含量即皮肤滞留量。试验结果如下:
表1曲安奈德益康唑普通制剂与微乳制剂的经皮渗透比较
结论:曲安奈德益康唑微乳乳膏剂透过皮肤的量约是普通乳膏剂的3倍,在皮肤中的滞留量是普通乳膏剂的2-3倍。表明曲安奈德益康唑制备成微乳后能促进曲安奈德益康唑的皮肤透过能力,增加皮肤滞留量,特别是能提高皮肤局部药物浓度,有利于药物治疗局部疾患发挥疗效。
试验例2:皮肤刺激性试验
以生理盐水为阴性对照,以曲安奈德益康唑普通乳膏剂和曲安奈德益康唑微乳乳膏剂为受试药物经家兔完整皮肤和破损皮肤刺激性试验。
完整皮肤刺激性试验方法:取日本大耳白兔18只,雌雄各半,随机分为阴性对照组、曲安奈德益康唑普通乳膏剂组、曲安奈德益康唑微乳乳膏剂组共3组,每组6只。试验前24小时在背部中间褪毛,褪毛范围每只约6cm×6cm。给药前检查去毛皮肤无损伤者进行试验。将生理盐水,曲安奈德益康唑普通乳膏,曲安奈德益康唑微乳乳膏分别涂敷在已分组的家兔脱毛皮肤上,单次给药,连续涂敷给药8小时。多次给药分组及涂敷方法同单次给药,但每天涂敷1次,每次持续8小时,连续涂敷14d。
样品:生理盐水,曲安奈德益康唑普通乳膏,曲安奈德益康唑微乳乳膏。
结果:在自然光线下观察皮肤反应,曲安奈德益康唑普通乳膏剂组d2时有1/6的动物出现轻度红斑,d9时3/6的动物出现中度红斑,5d后逐渐减轻,实验中4/6的动物出现皮肤粗糙、脱屑的现象,至末次给药后7d,所有动物红斑消退;曲安奈德益康唑微乳乳膏剂组d4时有2/6的动物出现轻度红斑,4d后逐渐减轻,至末次给药后3d红斑消退;阴性对照组未见红斑和水肿。
破损皮肤刺激性试验方法:取日本大耳白兔18只,雌雄各半,随机分为阴性对照组、曲安奈德益康唑普通乳膏剂、曲安奈德益康唑微乳乳膏剂组共3组,每组6只。试验前24小时在背部中间褪毛,褪毛范围每只约6cm×6cm。再用消毒处理的400号细砂纸在褪毛处造成擦伤,使皮肤出现密集出血点,以渗血为度,立即将生理盐水,曲安奈德益康唑普通乳膏,曲安奈德益康唑微乳乳膏分别涂敷在已分组的家兔皮肤擦伤部位上。单次给药,连续涂敷给药8小时。多次给药分组及涂敷方法同单次给药,但每天涂敷1次,每次持续8小时,连续涂敷14天。
样品:生理盐水,曲安奈德益康唑普通乳膏,曲安奈德益康唑微乳乳膏。
结果:在自然光线下观察皮肤反应,曲安奈德益康唑普通乳膏剂组d4时有2/6的动物出现轻度红斑;d5时有4/6的动物出现中度红斑;d9时3/6的动物出现中度红斑,5d后逐渐减轻;实验中6/6的动物出现结痂,6/6的动物出现皮肤粗糙、脱屑的现象,至末次给药后7d,所有动物红斑消退;微乳乳膏剂组d4时有2/6的动物出现轻度红斑;d6时有4/6的动物出现轻度红斑,并分别在5d后逐渐减轻,至末次给药后7d红斑消退;阴性对照组未见红斑和水肿。
结论:曲安奈德益康唑微乳乳膏剂对家兔完整皮肤及破损皮肤有轻度的刺激性,但刺激性要小于曲安奈德益康唑普通乳膏剂。
试验例3皮肤过敏性反应试验
试验方法:将50只清洁级健康白色豚鼠随机分为4组,受试药物曲安奈德益康唑微乳乳膏20只,其余阳性组、赋型剂对照组和生理盐水阴性对照组各10只。试验前24小时,先在背部左侧皮肤上褪毛3cm×3cm,给药前检查去毛皮肤无损伤者进行试验。第2天开始致敏接触给药:阳性组涂敷1%2,4二硝基氯苯于脱毛皮肤上,其余各组涂敷相应样品,涂敷6小时后,除去受试药物并用温水清洁给药部位。在致敏期间每隔7天,即在0天,7天和14天,在同一部位各涂敷一次。休息2周后,即在28天,所有豚鼠做激发致敏,在未给药的肋腹部涂敷6小时以局部激发。除去后24小时观察局部皮肤有无红斑和水肿。致敏率=出现皮肤红斑和水肿动物受试动物数/受试动物数×100%。
样品:生理盐水(阴性对照),乳膏基质(赋型剂),曲安奈德益康唑微乳乳膏(受试药物),1%2,4二硝基氯苯(阳性对照)。
结果:在激发去除药物后24小时,48小时分别观察皮肤红斑、水肿和其他异常反应,对红斑和水肿进行评分,计算过敏发生率。结果见表2。
表2豚鼠皮肤过敏反应结果
结论:以生理盐水为阴性对照、以乳膏基质为赋形剂对照,以2,4二硝基氯苯为阳性对照,经健康豚鼠皮肤过敏性反应试验,结果表明曲安奈德益康唑微乳乳膏对豚鼠皮肤无致敏性。
Claims (10)
1.一种曲安奈德益康唑乳膏剂,其特征在于:曲安奈德益康唑乳膏剂为微乳乳膏剂,按下列质量百分比的组分制备曲安奈德益康唑微乳乳膏剂:
曲安奈德益康唑微乳 40-70%,
乳膏基质 20-50%,
保湿剂 4-10%,
曲安奈德在微乳乳膏剂中的含量为0.1%,
硝酸益康唑在微乳乳膏剂中的含量为1%。
2.根据权利要求1所述的曲安奈德益康唑乳膏剂,其特征在于:所述的曲安奈德益康唑微乳组分的质量百分比为:0.3%曲安奈德、3%硝酸益康唑、20-40%油相、30~60%表面活性剂和10~30%助表面活性剂,水相和油相的质量比为0.3-1.2:1。
3.根据权利要求2所述的曲安奈德益康唑乳膏剂,其特征在于:曲安奈德益康唑微乳的油相采用丙二醇单辛酸酯、辛酸/癸酸甘油三酯、丙二醇单月桂酸酯中的任意一种;表面活性剂采用聚山梨酯80、聚氧乙烯40氢化蓖麻油、聚乙二醇8辛酸/癸酸甘油酯中的任意一种;助表面活性剂采用乙醇、聚乙二醇、二乙二醇单乙醚中的任意一种。
4.根据权利要求1所述的曲安奈德益康唑乳膏剂,其特征在于:所述的乳膏基质组分的质量百分比为:硬脂酸15%、白凡士林10%、十六十八醇8%、单硬脂酸甘油酯9%、聚山梨酯80 3%、纯化水55%;所述的保湿剂为丙二醇或甘油中的任意一种。
5.根据权利要求1所述的曲安奈德益康唑乳膏剂,其特征在于:按下列质量百分比的组分制备曲安奈德益康唑微乳乳膏剂:
曲安奈德益康唑微乳 45%-55%,
乳膏基质 40%~50%,
保湿剂 5~7%,
曲安奈德在微乳乳膏剂中的含量为0.1%,
硝酸益康唑在微乳乳膏剂中的含量为1%。
6.根据权利要求5所述的曲安奈德益康唑乳膏剂,其特征在于:所述的曲安奈德益康唑微乳组分的质量百分比为:0.3%曲安奈德、3%硝酸益康唑、25-35%油相、40~50%表面活性剂和15~20%助表面活性剂。水相和油相的质量比为0.4-0.6:1。
7.根据权利要求6所述的曲安奈德益康唑乳膏剂,其特征在于:曲安奈德益康唑微乳的油相采用丙二醇单辛酸酯;表面活性剂采用聚氧乙烯40氢化蓖麻油;助表面活性剂采用二乙二醇单乙醚。
8.根据权利要求2所述的曲安奈德益康唑乳膏剂,其特征在于,曲安奈德益康唑微乳的制备方法包括如下步骤:称取油相、表面活性剂和助表面活性剂搅拌均匀制备成浓缩乳,在浓缩乳中加入曲安奈德、硝酸益康唑搅拌使其溶解,然后在搅拌下加入蒸馏水,制得曲安奈德益康唑微乳。
9.根据权利要求4所述的曲安奈德益康唑乳膏剂,其特征在于,乳膏剂基质的制备方法包括如下步骤:称取硬脂酸、十六十八醇,白凡士林、单硬脂酸甘油酯在70℃水浴下熔融制成油相;称取聚山梨酯80作为乳化剂,将油相加入到水相中,搅拌均匀,即得乳膏基质。
10.根据权利要求1所述的曲安奈德益康唑乳膏剂,其特征在于,制备方法包括如下步骤:称取曲安奈德益康唑微乳、乳膏基质和保湿剂,将曲安奈德益康唑微乳及保湿剂加入到乳膏基质中,同方向搅拌混匀,并通过抽真空除去气泡,即得曲安奈德益康唑乳膏剂。
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