CN113995715A - 一种黄体酮凝胶制剂以及制备工艺 - Google Patents
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Abstract
本发明涉及一种黄体酮凝胶制剂及其制备工艺,提供了黄体酮凝胶制剂的配方,含有黄体酮、液体石蜡、甘油、温敏材料、氮酮、聚山梨酯、羟苯乙酯、无水乙醇以及纯化水。制备工艺如下:(1)黄体酮粉末制备(2)黄体酮乳液制备(3)黄体酮乳液加入温敏基质中制备凝胶制剂。本发明的黄体酮制成凝胶剂,能够有效地利用凝胶剂的特点,避免黄体酮的首过效应,利用首过子宫效应,提高黄体酮在子宫内的浓度,更好地发挥黄体酮的治疗作用。
Description
技术领域
本发明涉及医药科技技术领域,具体涉及一种黄体酮凝胶制剂及其制备工艺。
背景技术
目前,在女性中常见妇科内分泌疾患和功能失调是由于孕激素不足或是由于雌激素缺乏,导致内环境的不平衡,使生理活动失调,从而引发潮热、出汗、烦躁、焦虑、失眠、抑郁、记忆力减退、骨质疏松、泌尿生殖道萎缩和心血管疾病等一系列症状。黄体酮在妇科疾病中应用广泛,特别在激素补充疗法(HRT)中与雌激素合用,可有效避免雌激素带来的不良反应。天然黄体酮在HRT中,与雌激素合用,能防止长期应用雌激素所引起的子宫内膜增生,降低因单用雌激素所引起的子宫内膜癌的危险,与合成孕激素相比,不良反应更小,但天然黄体酮口服吸收差,且存在强的首过效应,在临床上常用剂型为黄体酮肌肉注射剂,而黄体酮注射剂是油溶液,注射后疼痛,且黄体酮在HRT中需要长期给药,所以提高黄体酮的生物利用度,已成为黄体酮应用中的关键问题。
发明内容
为了克服上述不足,本发明提供了一种天然黄体酮凝胶制剂及其制备工艺,本发明的黄体酮制成凝胶剂,能够有效地利用凝胶剂的特点,避免黄体酮的首过效应,利用首过子宫效应,提高黄体酮在子宫内的浓度,更好地发挥黄体酮的治疗作用。
本发明的技术方案如下:
一种黄体酮凝胶制剂,黄体酮凝胶制剂的配方的重量比如下:
上述份数为质量份数。
上述温敏材料由卡波姆和聚异丙基丙烯肽胺组成,其质量份数比为:1:0.3-0.5。优选为:1:0.5。
上述温敏材料由泊洛沙姆和聚异丙基丙烯肽胺组成,其质量份数比为:1:0.6-0.8。优选为:1:0.6。
进一步地,本发明提供一种黄体酮凝胶制剂的制备工艺,适用于工业化生产,利用上述的配方,包括如下步骤:
(1)黄体酮粉末制备
将黄体酮原料药研磨成粉末状,进行微粉化处理;
(2)黄体酮乳液制备
将液体石蜡、聚山梨酯按照比例加热熔融后,加入黄体酮粉末进行搅拌,制成油相;同时将甘油、无水乙醇、纯化水、氮酮混合溶解,形成水相,将水相加热至60℃-65℃时,加入油相;
(3)黄体酮乳液加入温敏基质中制备凝胶制剂
将步骤(2)制得的乳液加入温敏基质中,充分搅拌后加入适量的三乙醇胺调节至PH6-7,然后加入羟苯乙酯搅拌均匀制得黄体酮凝胶制剂。
黄体酮和大多数激素药物一样,均难溶于水,因此,对于黄体酮的微粉化是本发明的前提,通过研磨和机械粉碎达到较小的粒度,从而增加了药物和吸收介质的接触面积,增加了药物溶解到介质的速度,增加药物吸收的效果,本发明的缓释凝胶中,黄体酮的粒径控制在5-15um大小范围内。
为了将黄体酮分散均匀到给药部位,并且能够不聚集,本发明采用了油相和水相结合的方式做成乳化剂。
本发明采用的液体石蜡,作为乳膏的基质,在此不进行阐述。
本发明提供的温敏材料的基质,采用了卡波姆/泊洛沙姆和聚异丙基丙烯肽胺的组合,卡波姆和泊洛沙姆是常用的温敏材料的基质,但是作为阴道内用的温敏缓释凝胶来说,温敏材料的影响是非常大的,聚异丙基丙烯肽胺一种热敏性高分子材料,但是其在阴道药物控释中还没有得到广泛应用,本发明将其与卡波姆和泊洛沙姆组合,能够达到更加的温敏效果。
具体实施方式
下面结合实施例对本发明作进一步描述。以下实施例仅用于更加清楚地说明本发明的技术方案,而不能以此来限制本发明的保护范围。
实施例1:
一种黄体酮凝胶制剂,黄体酮凝胶制剂的配方的重量比如下:
工艺:
(1)黄体酮粉末制备
将黄体酮原料药研磨成粉末状,进行微粉化处理;
(2)黄体酮乳液制备
将液体石蜡、聚山梨酯按照比例加热熔融后,加入黄体酮粉末进行搅拌,制成油相;同时将甘油、无水乙醇、纯化水、氮酮混合溶解,形成水相,将水相加热至60℃-65℃时,加入油相;
(3)黄体酮乳液加入温敏基质中制备凝胶制剂
将制得的乳液加入卡波姆和聚异丙基丙烯肽胺形成的温敏基质中,充分搅拌后加入适量的三乙醇胺调节至PH,然后加入羟苯乙酯搅拌均匀制得黄体酮凝胶制剂。
实施例2:
一种黄体酮凝胶制剂,黄体酮凝胶制剂的配方的重量比如下:
工艺:
(1)黄体酮粉末制备
将黄体酮原料药研磨成粉末状,进行微粉化处理;
(2)黄体酮乳液制备
将液体石蜡、聚山梨酯按照比例加热熔融后,加入黄体酮粉末进行搅拌,制成油相;同时将甘油、无水乙醇、纯化水、氮酮混合溶解,形成水相,将水相加热至60℃-65℃时,加入油相;
(3)黄体酮乳液加入温敏基质中制备凝胶制剂
将步骤(2)制得的乳液加入泊洛沙姆和聚异丙基丙烯肽胺形成的温敏基质中,充分搅拌后加入适量的三乙醇胺调节至PH7,然后加入羟苯乙酯搅拌均匀制得黄体酮凝胶制剂。
实施例3:
一种黄体酮凝胶制剂,黄体酮凝胶制剂的配方的重量比如下:
工艺:
(1)黄体酮粉末制备
将黄体酮原料药研磨成粉末状,进行微粉化处理;
(2)黄体酮乳液制备
将液体石蜡、聚山梨酯按照比例加热熔融后,加入黄体酮粉末进行搅拌,制成油相;同时将甘油、无水乙醇、纯化水、氮酮混合溶解,形成水相,将水相加热至60℃-65℃时,加入油相;
(3)黄体酮乳液加入温敏基质中制备凝胶制剂
将步骤(2)制得的乳液加入卡波姆形成的温敏基质中,充分搅拌后加入适量的三乙醇胺调节至PH7,然后加入羟苯乙酯搅拌均匀制得黄体酮凝胶制剂。
实施例1-3所制成的凝胶制剂,试验证明均可以在35℃以上凝胶的粘度发生急剧增加,凝胶失去流动性,从而在粘附在给药部位释放发挥药效。
并且在给药部位由于乳液中药物的分散性较好,能够在给药部位形成较大面积的给药区,从而促进黄体酮在体内的吸收,为了更好地验证给药效果,本发明提供了一系列的给药实验。
实施例4:
选用黄体酮注射液1组作为阳性对照,按照15mg.kg-1肌肉注射给药,选用空白基质组,选用实施例1所制得的凝胶制剂,选用3中剂量,选用高中低三种剂量,分别为1.5mg.kg-1,5mg.kg-1,7.5mg.kg-1。
动物实验采用兔子宫内膜转化试验,测定兔子宫内膜腺体增生程度。将雌性新西兰未成熟白兔40只,随机分为空白基质组、阳性对照组、低剂量组、中剂量组和高剂量组,每组各8只阳性对照组以黄体酮注射液作为阳性对照,按15mg.kg-1肌肉注射给药,空白基质组、低剂量组、中剂量组和高剂量组连阴道给药23d,第1天、23天分别称重,第24天处死。阳性对照组连续给药10d,第11天称重后处死。兔处死后,取部分子宫组织(自子宫与阴道连接处向卵巢方向用直尺量2cm处),将取下的子宫称重,然后剪开平铺于滤纸上,吸干水分,置于10%甲醇溶液中固定24h,做病理切片检查。按兔子宫分级标准对各组兔病理切片结果进行分级。用子宫重量除以每只兔体质量,计算子宫指数。
结果:
表1兔子宫指数、子宫分级和腺体数
注:与阳性对照组相比,*P<0.05,**P<0.01。
随着黄体酮凝胶剂量的增加,兔子宫指数、子宫分级指数均呈增加趋势,子宫腺体数目低、中、高剂量组较空白组增加。
空白基质组与阳性对照组之间有显著性差异,而低剂量组、中剂量组、高剂量组与阳性对照组之间无显著性差异。这说明给予黄体酮凝胶剂后,随着给药剂量的增加,子宫内膜厚度增加,兔的孕酮反应增强;而且与阳性对照组相比,黄体酮凝胶剂的黄体酮的含量要明显减少,说明低、中、高剂量组对兔子宫内膜的增生、子宫腺体的增多、子宫由增生期转化为分泌期具有一定的作用,相对于阳性对照组,黄体酮凝胶剂的所达到的药效所需的药量要明显减少,说明凝胶制剂的药物的吸收作用更佳。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明技术原理的前提下,还可以做出若干改进和变形,这些改进和变形也应视为本发明的保护范围。
Claims (6)
2.根据权利要求1所述的一种黄体酮凝胶制剂,其特征在于所述温敏材料由卡波姆和聚异丙基丙烯肽胺组成,其质量份数比为:1:0.3-0.5。
3.根据权利要求2所述的一种黄体酮凝胶制剂,其特征在于所述卡波姆和聚异丙基丙烯肽胺质量份数比优选为:1:0.5。
4.根据权利要求1所述的一种黄体酮凝胶制剂,其特征在于所述温敏材料由泊洛沙姆和聚异丙基丙烯肽胺组成,其质量份数比为:1:0.6-0.8。
5.根据权利要求4所述的一种黄体酮凝胶制剂,其特征在于所述泊洛沙姆和聚异丙基丙烯肽胺质量份数比优选为:1:0.6。
6.一种黄体酮凝胶制剂的制备工艺,其特征在于利用权利要求1-3任一权利要求所述的配方,包括如下步骤:
(1)黄体酮粉末制备
将黄体酮原料药研磨成粉末状,进行微粉化处理;
(2)黄体酮乳液制备
将液体石蜡、聚山梨酯按照比例加热熔融后,加入黄体酮粉末进行搅拌,制成油相;同时将甘油、无水乙醇、纯化水、氮酮混合溶解,形成水相,将水相加热至60℃-65℃时,加入油相;
(3)黄体酮乳液加入温敏基质中制备凝胶制剂
将步骤(2)制得的乳液加入温敏基质中,充分搅拌后加入适量的三乙醇胺调节至PH6-7,然后加入羟苯乙酯搅拌均匀制得黄体酮凝胶制剂。
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