CN113730355A - 一种盐酸艾司氯胺酮鼻喷剂及其制备方法 - Google Patents
一种盐酸艾司氯胺酮鼻喷剂及其制备方法 Download PDFInfo
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Abstract
本发明属于药物制剂领域,具体涉及一种盐酸艾司氯胺酮鼻喷剂及其制备方法。本发明制剂制备过程中使用盐酸艾司氯胺酮,螯合剂,pH调节剂,渗透压调节剂,并将得到的无菌溶液灌装至鼻喷剂装置中。本发明制剂不含防腐剂,减少了对鼻粘膜的损伤以及对鼻纤毛的刺激,保护了患者的鼻腔环境及鼻粘膜纤毛清除功能。本制剂处方简单,易于操作,使用也比较方便,是一种安全有效的制剂。
Description
技术领域
本发明属于药物制剂领域,涉及一种盐酸艾司氯胺酮鼻喷剂及其制备方法。
背景技术
氯胺酮(对应的S-和R-对映体的外消旋混合物)是一种NMDA受体拮抗剂,对人体有广泛的影响,包括镇痛、麻醉、幻觉、解离效应、高血压和支气管扩张。氯胺酮主要用于全麻的诱导和维持。其他用途包括重症监护镇静、镇痛(特别是在急诊和支气管痉挛的治疗中)。氯胺酮在治疗抑郁症方面也被证明是有效的(尤其是那些对目前的抗抑郁药物治疗没有反应的人)。在患有严重抑郁障碍的患者中,氯胺酮还能在几个小时内产生快速的抗抑郁作用。氯胺酮和氯胺酮的药物组合物已通过多种给健康受试者和病人,包括静脉注射,鼻内和口服。Clements等人(1982年)记录到口服氯胺酮的相对生物利用度为17%,肌内氯胺酮的相对生物利用度为93%。自那篇文章以来,其他一些研究记录了氯胺酮的相对口服生物利用度在17%至24%之间。Malinovsky等人(1996年)记录了鼻内氯胺酮的相对生物利用度为50%,直肠氯胺酮的相对生物利用度为30%。Yanagihara等人(2003年)记录了直肠和舌下氯胺酮的相对生物利用度为30%,而他们发现鼻腔生物利用度为45%。
抑郁症是所有疾病中致残最严重的疾病之一,终生患病率约为17%[1]。它经常出现在生命早期,可以运行一个慢性过程,并对其他医疗疾病的预后产生不利影响,如冠心病、糖尿病和骨质疏松症。
抑郁症在女性中比在男性中更常见。据估计,男性和女性单极抑郁发作的点患病率分别为1.9%和3.2%,5.8%的男性和9.5%的女性将在12个月内经历抑郁症。这些流行率数字因人口而异,在某些人口中可能更高。世界卫生组织(WorldHealthOrganization)的一项研究报告称,抑郁症是全球导致多年残疾生活的主要原因,也是调整残疾寿命的第四大原因。经残疾调整的寿命年指的是个人生产寿命的减少,是一种考虑到过早死亡的衡量标准。
抑郁症的治疗在大约半个世纪前由于偶然发现单胺氧化酶抑制剂和三环抗抑郁药而发生了革命性的变化。从那时起,一系列新的药物的提供,具有更好的副作用配置,极大地提高了我们的能力,安全地治疗了相当大比例的病人。然而,较新的药物主要是通过增加单胺类物质的突触内水平来增强或增强现有药物的主要生化效应的药物。
不幸的是,目前用于治疗抑郁症的药物需要几周到几个月才能充分发挥作用,同时,患者仍会出现症状,并继续面临自我伤害以及个人和职业生活受损的风险。事实上,传统抗抑郁药几周起效的滞后期被认为是一个主要的限制因素,导致相当多的发病率和自杀行为的高风险,特别是在开始使用抗抑郁药的前9天。因此,在几个小时或几天内迅速产生抗抑郁作用的药理学战略将对公众健康产生巨大影响。
发明内容
本发明提供了一种盐酸艾司氯胺酮鼻喷剂及其制备方法,其主要组分有盐酸艾司氯酮,包括以下辅料:渗透压调节剂,pH调节剂,螯合剂和注射用水,得到的药用制剂pH值为4-6制剂稳定性较好,不含防腐剂,能够减少防腐剂对鼻纤毛的毒性,以及长时间使用带有防腐剂药物对身体带来的伤害,同时使用鼻喷剂的药物制剂的形式可以准确计量,使用也比较方便,制备工艺简单。本发明主要技术方案如下:
一种盐酸艾司氯胺酮鼻喷剂,其特征在于,原料药浓度150mg/ml-240mg/ml,以重量百分比计包括以下辅料:1 .5%~5%的渗透压调节剂,适量的pH调节剂,0 .005%~0 .9%的螯合剂,加注射用水至100%。除此之外发明人还提供了本发明所述盐酸艾司氯胺酮鼻喷剂的制备方法如下:
1) 用注射用水将处方量的渗透压调节剂、螯合剂及原料药依次溶解,搅拌混合均匀,过0 .22μm的除菌过滤器除菌;
2)将步骤1)的无菌溶液加入无菌的pH调节剂调节至4-6,加灭菌注射用水定容至100%,得到的溶液灌装至鼻喷雾剂瓶中。
综上所述,采用本发明所提供的配方和工艺制备的盐酸艾司氯胺酮鼻喷剂,是一种适于鼻内给药,不含防腐剂的药用制剂,且药效持续时间长。本发明公开的药用制剂不含有防腐剂,经灭菌之后,使用可以遮光、避免微生物污染的瓶子配合鼻喷雾器装置获得。本发明提供的方法避免因为过量使用防腐剂、使用廉价且有毒副作用等的防腐剂对身体的伤害,减少防腐剂对鼻纤毛的毒性。本专利制剂操作简单,使用也比较方便,制备工艺简单。
实施例1
一种盐酸艾司氯酮鼻喷剂,其组成如下:
名称 | 处方(g) |
盐酸艾司氯酮 | 140.00 |
乙二胺四乙酸二钠 | 0 .8 |
甘油 | 30.0 |
氢氧化钠 | 适量 |
注射用水 | 加至1000 |
(1)用注射用水将处方量的渗透压调节剂、螯合剂及原料药依次溶解,搅拌混合均匀,过0 .22μm的除菌过滤器除菌;
(2)将步骤1)的无菌溶液加入无菌的pH调节剂调节至4,加灭菌注射用水定容至100%,得到的溶液灌装至鼻喷雾剂瓶中。
实施例2
一种盐酸艾司氯酮鼻喷剂,其组成如下:
名称 | 处方(g) |
盐酸艾司氯酮 | 148.00 |
乙二胺四乙酸二钠 | 0. 9 |
甘油 | 25.0 |
氢氧化钠 | 适量 |
注射用水 | 加至1000 |
(1)用注射用水将处方量的渗透压调节剂、螯合剂及原料药依次溶解,搅拌混合均匀,过0 .22μm的除菌过滤器除菌;
(2)将步骤1)的无菌溶液加入无菌的pH调节剂调节至5,加灭菌注射用水定容至100%,得到的溶液灌装至鼻喷雾剂瓶中。
实施例3
一种盐酸艾司氯酮鼻喷剂,其组成如下:
名称 | 处方(g) |
盐酸艾司氯酮 | 148.00 |
乙二胺四乙酸二钠 | 0. 9 |
甘油 | 30.0 |
氢氧化钠 | 适量 |
注射用水 | 加至1000 |
(1)用注射用水将处方量的渗透压调节剂、螯合剂及原料药依次溶解,搅拌混合均匀,过0 .22μm的除菌过滤器除菌;
(2)将步骤1)的无菌溶液加入无菌的pH调节剂调节至6,加灭菌注射用水定容至100%,得到的溶液灌装至鼻喷雾剂瓶中。
对比实施例1
一种盐酸艾司氯酮鼻喷剂,其组成如下:
名称 | 处方(g) |
盐酸艾司氯酮 | 140.00 |
乙二胺四乙酸二钠 | 0. 8 |
甘油 | 30.0 |
氢氧化钠 | 适量 |
注射用水 | 加至1000 |
(1)用注射用水将处方量的渗透压调节剂、螯合剂及原料药依次溶解,搅拌混合均匀,过0 .22μm的除菌过滤器除菌;
(2)将步骤1)的无菌溶液加入无菌的pH调节剂调节至3.5,加灭菌注射用水定容至100%,得到的溶液灌装至鼻喷雾剂瓶中。
分别取本发明实施例 1 ~ 3 制备的盐酸艾司氯酮鼻喷剂和对比例样品放置于温度40℃ ±2℃、RH75%±5% 条件下进行考察,分别于 1 月、2 月、3 月和6月末取样并进行溶出度、有关物质和含量的变化,试验结果见表5。
从表5 可以看出,本发明实施例样品在 40℃ ±2℃,75%±5% 条件下放置 6 个月,与 0 月比较,有关物质略有增加,其他各项指标均无显著变化,说明本品经 40℃±2℃,75%±5% 条件下放置 6 个月较稳定,而样品PH小于4后稳定性较差。即在相同条件下,本发明实施例样品有关物质优于对比例样品。
通过上述试验结果可知,采用本发明的处方制备的盐酸艾司氯酮鼻喷剂在含量及有关方面均优于对比实施例。且采用处方简单,省时节能。采用本发明的技术方案制得的鼻喷剂质量更加可控,较现有技术具有明显进步,更适用于工业化大生产。
Claims (6)
1.一种盐酸艾司氯胺酮鼻喷剂,其特征在于,原料药浓度为150mg/ml-240mg/ml,以重量百分比计包括以下辅料:1 .5%~5%的渗透压调节剂,适量的pH调节剂,0 .005%~0.1%的螯合剂,加注射用水至100%。
2.根据权利要求1所述的一种盐酸艾司氯胺酮鼻喷剂,其特征在于所述的鼻喷剂pH值为4-6。
3.根据权利要求1所述的一种盐酸艾司氯胺酮鼻喷剂,其特征在于:所述的渗透压调节剂选自氯化钠、甘油、无水葡萄糖、丙二醇、氯化钾、山梨糖醇、甘露醇中的一种或几种。
4.根据权利要求1所述的一种盐酸艾司氯胺酮鼻喷剂,其特征在于:所述 pH调节剂选柠檬酸,磷酸二氢钠,磷酸氢二钠,乙酸,硼酸,硼酸钠,琥珀酸,酒石酸,苹果酸,乳酸和呋喃甲酸中的一种或者两种。
5.根据权利要求1所述的一种盐酸艾司氯胺酮鼻喷剂,其特征在于:所述
的螯合剂选自乙二胺四乙酸二钠。
6.权利要求1所述的一种盐酸艾司氯胺酮鼻喷剂的制备方法,其特征在于:具体的制备步骤如下:
1) 用注射用水将处方量的渗透压调节剂、原料药及螯合剂依次溶解,搅拌混合均匀,过0 .22μm的除菌过滤器除菌;
2)将步骤1)的无菌溶液加入无菌的pH调节剂调节至4-6,加灭菌注射用水定容至100%,得到的溶液灌装至鼻喷雾剂瓶中。
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