CN111588691B - 一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法 - Google Patents
一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法 Download PDFInfo
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Abstract
一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法,属于阴道炎治疗药物技术领域。由700~800mg的载药基质脂质材料、5~10mg的药物伊曲康唑和200~300mg的共溶剂制成。伊曲康唑在酸性条件下是离子状态,而在中性条件下很难溶于水,难以制成凝胶剂,因此,本发明使用共溶剂来增加亲脂性药物伊曲康唑的溶解性,以提高制剂的稳定性。伊曲康唑原位液晶凝胶制剂,是药物伊曲康唑的一种新的制剂类型。具有给药方便,滴入腔道后迅速胶凝的特点,能够延长药物在阴道的保留时间,减少用药频率,降低伊曲康唑的副作用,且采用的载药基质生物相容性高,对阴道黏膜无刺激,使用舒适,提高患者依从性。
Description
技术领域
本发明属于阴道炎治疗药物技术领域,具体是涉及一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂及其制备方法。
背景技术
相关研究表明,在女性的阴道中均存在一定的细菌,并形成菌群,这部分细菌之间具有一定的平衡状态,在平衡的状态下维持女性阴道的健康,主要是对外来的病原体能起到一定程度的抵抗作用。如果女性阴道环境的酸碱值处在均衡的状态也会对外来的病原菌的侵蚀起到阻碍的作用。因此一旦由于各种因素导致女性阴道内菌群的平衡状态失衡或者酸碱值失衡就会使外界的病原菌对患者的阴道产生影响,进而引发阴道炎疾病。
阴道炎是女性生殖系统的炎性疾病,如不能及时采取相应治疗,将会导致宫颈炎、宫颈糜烂等病症的出现。阴道炎病原菌普非常广泛,包含滴虫、真菌、病毒、支原体、衣原体等,对根治造成一定难度。一般临床针对阴道炎主要是确诊病原菌的菌群,然后进行针对性治疗,混合病原菌感染的治疗比较复杂,常规药物治疗并不能产生理想的效果,但是疾病如果没有得到及时有效的控制,将对患者身心带来很大的伤害,甚至无法正常工作或生活。据相关数据显示,我国已婚女性中约有70%有不同程度的阴道炎,严重影响患者身心健康。由于医疗条件限制和部分义务工作者对阴道炎缺乏足够的认识,从而滥用药物导致阴道菌群失调,阴道耐药菌的形成及繁殖,最终形成阴道炎症的致病菌,若不及时治疗,会继发宫颈炎、子宫内膜炎等,甚至发生恶变。
伊曲康唑是一种合成的亲脂性三氮唑衍生物,为三氮唑类广谱抗真菌药,临床主要用于治疗浅部和深部真菌感染。目前临床应用的伊曲康唑剂型主要有胶囊剂、口服溶液剂和静脉注射剂,未见有凝胶剂产品。为了患者用药的方便,更好地发挥药效,本发明采用脂质材料和共溶剂作为基质,制备伊曲康唑原位液晶凝胶,用于治疗真菌性阴道炎。目前未见报道。
发明内容
本发明要解决的技术问题为提供一种利用伊曲康唑原位液晶凝胶制剂作为治疗阴道炎的新的给药方式,使患者用药更为方便。同时本发明提供该伊曲康唑原位液晶凝胶的制备方法。
为了实现上述目的,本发明所采用的技术方案为:一种用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂,由700~800mg的载药基质脂质材料、5~10mg的药物伊曲康唑和200~300mg的共溶剂制成。
作为优选技术方案,伊曲康唑原位液晶凝胶制剂由700mg的载药基质脂质材料、8mg的药物伊曲康唑和300mg的共溶剂制成。
作为优选技术方案,所述载药基质脂质材料采用植烷三醇(PHYT)、单油酸甘油酯(GMO)、单甘酯(MO)和山梨糖醇单油酸酯(SMO)中的一种或多种。
作为优选技术方案,所述共溶剂采用二甲基乙酰胺(DMAC)、卵磷脂、聚山梨酯-80(Tween-80)、泊洛沙姆188(F-68)、羟丙基-β-环糊精(HP-β-CD)、N-甲基吡咯烷酮(NMP)和水中的一种或多种。
一种伊曲康唑原位液晶凝胶制剂的制备方法,步骤如下:
(1)将载药基质脂质材料于对应熔化温度下水浴加热成熔融状态;
(2)将药物伊曲康唑(ITZ)溶解于共溶剂中,水浴条件下加热至脂质材料熔化温度备用;
(3)将熔融状态下的脂质材料置于涡旋震荡仪中,边涡旋边加入伊曲康唑的共溶剂溶液,加入之后继续涡旋震荡充分混匀,从而得到无色透明的伊曲康唑原位液晶凝胶制剂。
伊曲康唑在酸性条件下是离子状态,而在中性条件下很难溶于水,难以制成凝胶剂,因此,本发明使用共溶剂来增加亲脂性药物伊曲康唑的溶解性,以提高制剂的稳定性。与现有技术相比,本发明的有益效果还表现在:
(1)本发明的伊曲康唑原位液晶凝胶制剂,是药物伊曲康唑的一种新的制剂类型。具有给药方便,滴入腔道后迅速胶凝的特点,能够延长药物在阴道的保留时间,减少用药频率,降低伊曲康唑的副作用。
(2)液晶凝胶具有与生物膜类似的微观结构,能够增强阴道渗透效率。采用的载药基质生物相容性高,提高药物生物利用度。对阴道黏膜无刺激,使用舒适,提高患者依从性。
(3)伊曲康唑原位液晶凝胶制剂所采用的凝胶脂质材料和共溶剂材料均具有安全、无毒、生物相容性好的特点,故本制剂具有舒适度高、安全、无刺激的优点。
(4)伊曲康唑阴道用原位液晶凝胶制剂的制备工艺简单,且长期稳定性较高。
附图说明
图1是伊曲康唑液晶凝胶原位(相转变)前(A)、后(B)外观照片。
图2是伊曲康唑液晶凝胶原位(相转变)前(A)、后(B)偏光显微镜照片。
图3是伊曲康唑液晶凝胶的小角X射线散射曲线。
图4是白色念珠菌标准菌株接种的培养基照片。
图5是阴道炎症造模小鼠照片(A:正常小鼠,B:模型小鼠,C:模型小鼠阴道分泌物)。
图6是小鼠阴道灌洗液显微镜照片(A:正常小鼠,B:模型小鼠)。
图7是造模成功的小鼠阴道分泌物培养结果照片(A)和显微镜照片(B)。
图8是小鼠阴道灌洗液显微观察照片(A:空白对照组,B:阴性对照组,C:伊曲康唑原位液晶凝胶给药组,D:达克宁硝酸咪康唑乳膏给药组)。
图9是原位液晶凝胶在小鼠体内的相转化情况照片(左:F1,右:F2)。
图10是小鼠阴道组织切片显微观察结果(×200)(A:生理盐水组,B:空白原位液晶凝胶组,C:伊曲康唑原位液晶凝胶组,D:达克宁硝酸咪康唑乳膏组)。
具体实施方式
以下结合附图和实施例对本发明作出进一步的详述。
实施例1
伊曲康唑原位液晶凝胶制剂,制备组分由700mg的植烷三醇、8mg的伊曲康唑和300mg的二甲基乙酰胺组成。制备步骤如下:
(1)称取700mg的植烷三醇,于60℃水浴加热成熔融状态。
(2)称取8mg的伊曲康唑和300mg的二甲基乙酰胺,将伊曲康唑溶解于共溶剂中,水浴条件下加热至60℃备用。
(3)将熔融状态下的植烷三醇置于涡旋震荡仪中,边涡旋边加入伊曲康唑的二甲基乙酰胺溶液,加入之后继续涡旋震荡充分混匀,从而得到伊曲康唑原位液晶凝胶制剂。外观照片如图1所示,立方相液晶凝胶原位(相转变)前后均呈无色透明状,原位前后分别呈液态、半固态凝胶。
实施例2
伊曲康唑原位液晶凝胶的偏光显微镜观察
取实施例1所制得的伊曲康唑原位液晶凝胶进行偏光显微镜观察。为了考察凝胶的内部形态,将少量样品置于载玻片上并盖上盖玻片,然后在室温下以100倍的放大率进行偏光显微镜观察,结果如图2所示,伊曲康唑液晶凝胶原位(相转变)前后均为暗视野。
实施例3
伊曲康唑液晶凝胶的小角X射线散射曲线绘制
取实施例1所制得的伊曲康唑液晶凝胶原位后进行小角X射线衍射观察。当X射线照射到样品上时,样品内部存在的不均匀纳米尺度的电子密度区导致入射光束周围的小角度范围内会出现散射X射线,根据样品的各散射峰对应的散射矢量比值,可以确定晶格类型为反相立方相液晶。
实施例4
伊曲康唑原位液晶凝胶的药效学考察:
1、小鼠阴道炎症模型的建立
将白色念珠菌标准菌株连续几次用接种环接种至沙氏培养基上,37℃培养48h(如图4所示),挑取新培养活化的菌落溶于液体培养基中,充分混匀后用血细胞计数板调节菌悬液浓度至5×104个孢子/mL。现配现用。
每只小鼠在接种菌液之前6天开始皮下注射2mg/mL的苯甲酸雌二醇溶液0.1mL。之后隔天注射一次。处理后第7天开始接种菌悬液,取上述配置好的菌悬液10μL,注入小鼠阴道内,注射后保持小鼠呈仰卧位10min,以防止菌液流出。每天接种一次,连续接种5天。以小鼠阴道外观及阴道灌洗物镜检和小鼠阴道分泌物观察菌种是否接种成功,作为造模评价指标。造模结果如图5~7所示,显示小鼠阴道炎模型构建成功。
2、给药方式
随机选取10只健康雌性昆明小鼠作为A组,选取20只阴道炎模型构建成功的雌性昆明小鼠,随机分为B、C、D组,每组10只。每组给药方式如下:
A:空白对照组
每20g体重正常小鼠给与40mg空白立方液晶前体(不含伊曲康唑)。
B:阴性对照组
每20g体重模型小鼠给与40mg空白立方液晶前体(不含伊曲康唑)。
C:伊曲康唑原位液晶凝胶给药组
每20g体重模型小鼠给与40mg伊曲康唑原位液晶凝胶(实施例1制备,有效成分伊曲康唑含量为0.32mg)。
D:达克宁硝酸咪康唑乳膏给药组
每20g体重模型小鼠给与40mg达克宁硝酸咪康唑乳膏(有效成分硝酸咪康唑含量为0.32mg)。
每组连续给药7天,每天给药1次。
3、考察结果
(1)外观:伊曲康唑原位液晶凝胶给药组小鼠阴道口豆腐渣样分泌物减少或消失,阴道充血及红肿等现象也逐步减轻,随着每日连续给药症状逐步减轻至消失。
(2)涂片镜检:磷酸缓冲盐溶液(PBS)反复冲洗小鼠阴道后,显微镜观察灌洗液中孢子及菌丝生长情况。如图8所示,对比造模成功小鼠的阴道灌洗液(图8B),伊曲康唑原位液晶凝胶给药组中孢子和菌丝数量显著减少。对比正常小鼠仍存在少量孢子。说明伊曲康唑原位液晶凝胶药物均对念珠菌性小鼠阴道炎有较好的疗效,且孢子和菌丝数量明显少于达克宁硝酸咪康唑乳膏给药组。
实施例5
伊曲康唑原位液晶凝胶相转化性质
一、体外相转化最少吸水量(Vm)和相转化时间(Tg)测定
1、体外相转化最少吸水量(Vm)测定
由于女性阴道粘液分泌量较少,正常女性的阴道中储存的阴道粘液量仅为1~4mL,其中水的含量更低。立方液晶前体在阴道注射给药后需吸水才能发生相转变形成立方液晶,因此立方液晶前体溶液相转化最少吸水量Vm是评价其质量的重要指标。采用转子法测定Vm。精密称取100mg立方液晶前体至5mL离心管中,加入搅拌子(10mm×6mm),37.0±0.5℃水浴,转速设置为30r/min,每次加20μL水并观察1min,直至搅拌子停止转动,记录加水总量即为Vm。
2、体外相转化时间(Tg)测定
立方液晶前体溶液的相转化时间的长短也是评价其质量的重要指标。采用转子法测定相转化时间(Tg)。精密称取100mg立方液晶前体溶液至5mL离心管中,加入搅拌子(10mm×6mm),37.0±0.5℃水浴平衡5min,转速设置为30r/min,加入过量的水(500μL),记录搅拌子停止转动的时间记为Tg。
3、实验结果:
Vm及Tg的测定结果如表1所示,F1为空白原位立方液晶(不含伊曲康唑),F2是实施例1中制备的伊曲康唑原位液晶凝胶。实验结果表明伊曲康唑原位液晶凝胶能在较短时间内仅需少量水分就可以相转化形成液晶凝胶,具有良好的体外相转化能力。
表1 Vm及Tg测定结果(x±s,n=3)
编号 | V<sub>m</sub>/μL | T<sub>g</sub>/s |
F1 | 62.28±4.05 | 11.65±2.95 |
F2 | 60.42±2.11 | 11.82±1.23 |
二、体内相转化能力的考察
选择健康成年雌性小鼠18只,随机分为2组,每组9只。将小鼠麻醉后,阴道注入空白原位液晶凝胶F1和实施例1制备的伊曲康唑原位液晶凝胶F2,给药后使小鼠保持仰卧位防止阴道内制剂流出。分别于给药后5、10和15min处死小鼠,解剖并分离阴道组织,观察并记录原位液晶在小鼠体内的相转化情况,分别如表2和图9所示。
表2立方液晶前体在小鼠体内的相转化情况
实施例6
小鼠阴道刺激性考察
通过阴道组织的刺激性评分及组织病理学研究制剂的阴道刺激性。选择24只健康雌性小鼠(体重20±2g),随机分为四组,分别为:生理盐水(A)、空白原位液晶凝胶(B)、伊曲康唑原位液晶凝胶(C)和达克宁硝酸咪康唑乳膏(D),连续7天每24小时通过小鼠阴道给药(40mg/20g),每天详细记录小鼠外阴变化如充血,水肿的程度和范围及分泌物的多少等,同时观察小鼠的活跃状态等。最后一次给药后24小时,处死所有小鼠并分离阴道组织,将组织固定在组织固定液(4%多聚甲醛溶液)中,固定后脱钙,脱水,石蜡包埋,切片,HE染色,光学显微镜观察。
1、阴道外观刺激性评分标准
参考Eckstein评价标准,以阴道充血、水肿和分泌物三项为指标进行评分。每项指标的刺激程度按照轻重分别判定为0~4分,刺激性严重程度随分数增大而增高,具体情况如表3所示。三项指标评分的平均值小于3分为刺激性较小范围。3.75~6分为轻度刺激范围。6.75~9分为中度刺激范围。9.75~12分为重度刺激范围。评分总分在0~6分范围内表示刺激性较小或无刺激,6.75~7.5分范围内表示出现轻度或中度刺激,总分等于或大于8.25分表示产生重度刺激。
每只小鼠阴道的充血、水肿和分泌物的刺激性评分相加,可得阴道刺激性总分值,将所有小鼠的阴道刺激性总分相加除以动物数即可得到小鼠阴道刺激性最终得分。按表4所示测评价标准定受试动物的阴道刺激程度。
表3阴道刺激性评分细则
表4刺激性评价标准
刺激程度 | 分值 |
无刺激 | 0~3 |
轻度刺激 | 3.75~6 |
中度刺激 | 6.75~9 |
重度刺激 | 9.75~12 |
2、阴道刺激性评分结果
表5阴道刺激性评分结果
肉眼观察四组小鼠的阴道壁组织均未出现明显损伤,且总分分值均在0~6分范围内(表5所示),且无统计学差异,说明四组实验均对小鼠阴道组织产生轻微刺激性。由此表明,伊曲康唑原位液晶凝胶对小鼠阴道仅产生轻微刺激性,符合阴道用药要求。
3、阴道组织HE染色切片观察结果
图10是小鼠阴道组织切片显微观察结果。由图可知,生理盐水组的小鼠阴道黏膜上皮完好无损,个别黏膜上皮细胞显示出轻微的肿胀,偶见阴道黏膜下毛细血管充血和少量炎症细胞浸润(图10A)。空白原位液晶凝胶组的小鼠阴道黏膜正常,可观察到轻微的黏膜下毛细血管充血和炎性细胞浸润(图10B)。伊曲康唑原位液晶凝胶组,小鼠阴道黏膜结构完整,出现轻微黏膜下毛细血管充血和炎性细胞浸润(图10C)。炎症情况略大于A组,但弱于B组。与A、B、C三组相比,达克宁硝酸咪康唑乳膏组的阴道黏膜下毛细血管充血明显,炎性细胞浸润更为严重,可以看到部分上皮细胞肿胀呈气球状(图10D)。由小鼠阴道组织切片结果可知四组小鼠均保持完整的阴道黏膜结构,未见明显黏膜及黏膜下组织损伤。各组仅出现轻微的黏膜水肿和炎症细胞浸润。表明四组实验对阴道黏膜均具有较小的刺激性,与阴道刺激性评分结果一致。
理想的阴道药物和制剂不仅需要良好的治疗效果,还要求对阴道黏膜的低毒性或无毒。在有效性和安全性之间找到平衡时,阴道药物和制剂才能够具有实际应用价值而发挥最大的作用。虽然本发明选用的植烷三醇等基质材料具有良好的生物相容性和安全性,但在制备原位液晶凝胶的过程中,加入了二甲基乙酰胺等共溶剂以及药物伊曲康唑。考虑到二甲基乙酰胺和伊曲康唑以及各组分相互作用所组成的新制剂均有可能对制剂作用部位产生刺激性。所以考察空白原位液晶凝胶和装载伊曲康唑的载药原位液晶凝胶对给药部位即阴道黏膜的刺激性就较为必要。本发明采用了目前实验研究中较为常用的阴道刺激性评分以及阴道组织切片观察来评估对比不同制剂对小鼠阴道黏膜的刺激性,实验结果表明空白原位液晶凝胶和伊曲康唑原位液晶凝胶均对阴道黏膜有较小的刺激性。符合临床试验要求。
实施例7
伊曲康唑原位液晶凝胶制剂,制备组分由800mg的山梨糖醇单油酸酯、5mg的伊曲康唑和200mg的1%(重量百分比)的羟丙基-β-环糊精溶液组成。制备步骤如下:
(1)称取800mg的山梨糖醇单油酸酯,放置室温下。
(2)称取5mg的伊曲康唑和200mg的1%的羟丙基-β-环糊精溶液,室温下将伊曲康唑溶解于羟丙基-β-环糊精溶液中,备用。
(3)将山梨糖醇单油酸酯置于涡旋震荡仪中,边涡旋边加入伊曲康唑的羟丙基-β-环糊精溶液,加入之后继续涡旋震荡充分混匀,从而得到无色透明的伊曲康唑原位液晶凝胶制剂。
实施例8
伊曲康唑原位液晶凝胶制剂,制备组分由760mg的单油酸甘油酯、10mg的伊曲康唑和240mg的20%(体积百分比)聚山梨酯-80溶液组成。制备步骤如下:
(1)称取760mg的单油酸甘油酯,于45℃水浴加热成熔融状态。
(2)称取10mg的伊曲康唑和240mg的20%的聚山梨酯-80溶液,将伊曲康唑溶解于聚山梨酯-80溶液中,水浴条件下加热至45℃备用。
(3)将熔融状态下的单油酸甘油酯置于涡旋震荡仪中,边涡旋边加入伊曲康唑的聚山梨酯-80水溶液,加入之后继续涡旋震荡充分混匀,从而得到无色透明的伊曲康唑原位液晶凝胶制剂。
以上内容仅仅是对本发明的构思所作的举例和说明,所属本技术领域的技术人员对所描述的具体实施例做各种各样的修改或补充或采用类似的方式替代,只要不偏离发明的构思或者超越本权利要求书所定义的范围,均应属于本发明的保护范围。
Claims (2)
1.一种制备用于治疗阴道炎的伊曲康唑原位液晶凝胶制剂的方法,其特征在于:制备组分由700 mg的植烷三醇、8 mg的伊曲康唑和300 mg的二甲基乙酰胺组成,制备方法步骤如下:
(1)称取700 mg的植烷三醇,于60℃水浴加热成熔融状态;
(2)称取8 mg的伊曲康唑和300 mg的二甲基乙酰胺,将伊曲康唑溶解于二甲基乙酰胺中,水浴条件下加热至60℃备用;
(3)将熔融状态下的植烷三醇置于涡旋震荡仪中,边涡旋边加入伊曲康唑的二甲基乙酰胺溶液,加入之后继续涡旋震荡充分混匀,从而得到伊曲康唑原位液晶凝胶制剂。
2.如权利要求1所述方法制备的伊曲康唑原位液晶凝胶制剂在制备治疗阴道炎药物中的应用。
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