CN111588696A - 一种阿法骨化醇口服脂质体药物及其制备方法与应用 - Google Patents
一种阿法骨化醇口服脂质体药物及其制备方法与应用 Download PDFInfo
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- CN111588696A CN111588696A CN202010349467.2A CN202010349467A CN111588696A CN 111588696 A CN111588696 A CN 111588696A CN 202010349467 A CN202010349467 A CN 202010349467A CN 111588696 A CN111588696 A CN 111588696A
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- Prior art keywords
- alfacalcidol
- liposome
- sodium
- round
- phospholipid
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Abstract
本发明公开了一种阿法骨化醇口服脂质体药物及其制备方法与应用，所述的阿法骨化醇口服脂质体药物，由以下原料按重量份数制成：阿法骨化醇1份，磷脂5～50份，胆固醇1～10份，抗氧剂1～5份。本发明用脂质体包封阿法骨化醇以提高其化学稳定性。脂质体可以保护阿法骨化醇免受胃液、胆汁及消化酶等的破坏，提高其在胃肠道的稳定性，进而增加阿法骨化醇在小肠的吸收和生物利用度。口服给予阿法骨化醇脂质体和市售阿法骨化醇片剂，前者血药浓度增高，生物利用度提高，对骨质疏松的治疗效果增加。
Description
技术领域
本发明属于药物制剂领域，具体涉及一种阿法骨化醇口服脂质体药物及其制备方法与应用，该方法可以适用于工业放大生产。
背景技术
阿法骨化醇在调节钙、磷平衡和骨骼代谢中起重要作用，其可通过肝脏中的25-羟化酶激活成为具有活性的1α,25-(OH)2D3，并在全身和成骨细胞中发挥作用。它可以增加小肠和肾小管对钙的重吸收，抑制甲状旁腺的增生，减少甲状旁腺素合成与释放，抑制骨吸收；还可增加转化生长因子和胰岛素样生长因子合成，促进胶原和骨基质蛋白合成；另外，该药物还能调节肌肉钙代谢，促进肌细胞分化，增强肌肉力量，增加神经肌肉协调性，减少跌倒倾向。阿法骨化醇在临床上适用于骨质疏松症及各种原因造成的佝偻病、骨软化症，以及用于改善妇女绝经和使用激素类药物引起骨质疏松。
现有的阿法骨化醇口服制剂存在稳定性差、吸收有限、释放可控性差、生物利用度相对较低的问题，影响其在临床上的治疗效果。现有口服制剂化学稳定性差和释放可控性差也是造成其不良反应的主要原因。
脂质体是由磷脂双分子层所组成的封闭囊泡，可以包封药物形成超微球形结构，具有黏膜亲和性、缓释性和靶向性等优点。为提高脂质体中阿法骨化醇在存储过程中的稳定性，我们将油溶性抗氧剂与阿法骨化醇同时包裹于脂质体中，以抵抗光线、氧气等环境因素对阿法骨化醇的降解。除此之外，脂质体形成的封闭囊泡结构可以在一定程度上保护阿法骨化醇在胃肠道环境中的稳定性，且磷脂天然的黏膜亲和性可增加阿法骨化醇的吸收，提高生物利用度。而脂质体的缓释性能可有效调控阿法骨化醇的释放速度。因此，开发阿法骨化醇的口服脂质体新剂型可解决口服阿法骨化醇稳定性差、不良反应多、生物利用度不佳等问题，进而有效提高阿法骨化醇抗骨质疏松的治疗效果。
发明内容
发明目的：本发明公开的是一种阿法骨化醇口服脂质体药物及制备工艺与应用，采用脂质体包封阿法骨化醇，可以提高其化学稳定性。脂质体保护阿法骨化醇免受胃液、胆汁及消化酶等的破坏，提高其在胃肠道的稳定性，进而增加阿法骨化醇在小肠的吸收，提高生物利用率，增加治疗效果。
技术方案：一种阿法骨化醇口服脂质体药物，由以下原料按重量份数制成：阿法骨化醇1份，磷脂5～50份，胆固醇1～10份，抗氧剂1～5份所述的阿法骨化醇所示的结构如下：
作为优化：所述的磷脂选自大豆磷脂、蛋黄磷脂、氢化大豆磷脂以及二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二油酰磷脂酰胆碱、磷脂酰乙醇胺、磷脂酸、磷脂酰甘油、磷脂酰肌醇、磷脂酰丝氨酸及其混合物。
所述的阿法骨化醇口服脂质体药物的制备方法，制备过程避光操作，包括步骤如下：
(1)称取处方量的阿法骨化醇、磷脂、胆固醇和油溶性抗氧剂置于圆底烧瓶中，加入5ml～20ml二氯甲烷短时超声使其溶解；
(2)将圆底烧瓶置于旋转蒸发仪上，在40℃条件下减压蒸发除去二氯甲烷，直至圆底烧瓶内壁形成脂质薄膜，随后，将圆底烧瓶置于干燥器中抽真空24h；
(3)将5ml～20ml溶有水溶性抗氧剂的0.01M pH7.4磷酸盐缓冲液加入圆底烧瓶中，水合洗脱脂质薄膜，水浴超声30min使其分散均匀，制备得到脂质体粗混悬液；
(4)采用探头超声200w，30s，得到粒径较小并均匀分散的脂质体混悬液；
(5)将上述的脂质体混悬液在冷冻保护剂作用下进行冷冻干燥，进一步除去溶剂，得到阿法骨化醇脂质体冻干粉。
作为优化：所述的油溶性抗氧剂选自维生素E、二丁基羟基甲苯(BHT)、叔丁基-4-羟基茴香醚(BHA)、没食子酸丙酯(PG)、叔丁基对苯二酚(TBHQ)及其混合物。
作为优化：所述的水溶性抗氧剂选自维生素C、亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、EDTA-2Na及其混合物。
作为优化：所述的冷冻保护剂选自乳糖、蔗糖、麦芽糖、甘露糖、海藻糖、右旋糖酐、白蛋白、羟丙甲基纤维素及其混合物。
所述的阿法骨化醇口服脂质体药物的应用，将本发明制得的脂质体冻干粉，通过加入适宜的辅料：填充剂、粘合剂、崩解剂、润滑剂和包囊材料制成口服剂型。
作为优化：所述的填充剂包括淀粉、蔗糖、糊精、乳糖、预胶化淀粉、微晶纤维素、二水硫酸钙和磷酸氢钙；
所述的粘合剂包括淀粉、预胶化淀粉、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚维酮、明胶、阿拉伯胶、西黄蓍胶、聚乙二醇类、聚乙烯醇、蔗糖、葡萄糖；
所述的崩解剂包括干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、海藻酸、海藻酸钠、泡腾崩解剂；
所述的润滑剂包括硬脂酸镁和硬脂酸钙等硬脂酸盐、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、十二烷基硫酸钠；
所述的包囊材料包括明胶、阿拉伯胶、纤维素类、聚乙烯醇、聚乳酸。
作为优化：所述的口服剂型为：片剂、胶囊剂。
有益效果：本发明制备出的阿法骨化醇进行脂质体包封后，不仅提高了阿法骨化醇的存储稳定性，增强其对消化系统的酸性及酶环境的抵抗能力，增加了阿法骨化醇的口服吸收和生物利用度，进而提高了骨质疏松的治疗效果。
本发明公开的阿法骨化醇口服脂质体的制备工艺，主体药物为阿法骨化醇，膜材包括磷脂和胆固醇，关键添加剂为抗氧剂。
附图说明
图1是本发明的小鼠股骨骨密度示意图。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，以使本领域的技术人员能够更好的理解本发明的优点和特征，从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例，基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
称取阿法骨化醇1mg，大豆卵磷脂20mg，胆固醇5mg，维生素E 2mg置于圆底烧瓶中，加入20ml二氯甲烷短时水浴超声使其溶解。将圆底烧瓶置于旋转蒸发仪上，在40℃条件下减压蒸发除去二氯甲烷直至圆底烧瓶内壁形成脂质薄膜，将圆底烧瓶置于干燥器中抽真空24h。称取2mg维生素C和1mg EDTA-2Na溶解于20ml 0.01M pH7.4磷酸盐缓冲液中，将缓冲液加入圆底烧瓶中水合洗脱脂质薄膜，水浴超声30min使其分散均匀，制备得到脂质体粗混悬液。随后，将脂质体粗混悬液探头超声200w，30s，得到粒径较小并均匀分散的脂质体混悬液。将10mg海藻糖加入脂质体混悬液中进行冷冻干燥，得到阿法骨化醇脂质体冻干粉。以上制备过程全程避光。
实施例2
称取阿法骨化醇1mg，蛋黄卵磷脂50mg，胆固醇10mg，二丁基羟基甲苯1mg置于圆底烧瓶中，加入20ml二氯甲烷短时水浴超声使其溶解。将圆底烧瓶置于旋转蒸发仪上，在40℃条件下减压蒸发除去二氯甲烷直至圆底烧瓶内壁形成脂质薄膜，将圆底烧瓶置于干燥器中抽真空24h。称取2mg亚硫酸钠和1mg EDTA-2Na溶解于20ml 0.01M pH7.4磷酸盐缓冲液中，将缓冲液加入圆底烧瓶中水合洗脱脂质薄膜，水浴超声30min使其分散均匀，制备得到脂质体粗混悬液。随后，将脂质体粗混悬液探头超声200w，30s，得到粒径较小并均匀分散的脂质体混悬液。将10mg甘露糖加入脂质体混悬液中进行冷冻干燥，得到阿法骨化醇脂质体冻干粉。以上制备过程全程避光。
实施例3
称取阿法骨化醇1mg，氢化大豆卵磷脂10mg，胆固醇1mg，叔丁基-4-羟基茴香醚1mg置于圆底烧瓶中，加入20ml二氯甲烷短时水浴超声使其溶解。将圆底烧瓶置于旋转蒸发仪上，在40℃条件下减压蒸发除去二氯甲烷直至圆底烧瓶内壁形成脂质薄膜，将圆底烧瓶置于干燥器中抽真空24h。称取2mg硫代硫酸钠和1mg EDTA-2Na溶解于20ml 0.01M pH7.4磷酸盐缓冲液中，将缓冲液加入圆底烧瓶中水合洗脱脂质薄膜，水浴超声30min使其分散均匀，制备得到脂质体粗混悬液。随后，将脂质体粗混悬液探头超声200w，30s，得到粒径较小并均匀分散的脂质体混悬液。将10mg海藻糖加入脂质体混悬液中进行冷冻干燥，得到阿法骨化醇脂质体冻干粉。以上制备过程全程避光。
实施例4
称取阿法骨化醇1mg，二肉豆蔻酰磷脂酰胆碱20mg，胆固醇5mg，没食子酸丙酯1mg置于圆底烧瓶中，加入20ml二氯甲烷短时水浴超声使其溶解。将圆底烧瓶置于旋转蒸发仪上，在40℃条件下减压蒸发除去二氯甲烷直至圆底烧瓶内壁形成脂质薄膜，将圆底烧瓶置于干燥器中抽真空24h。称取2mg亚硫酸氢钠和1mg EDTA-2Na溶解于20ml 0.01M pH7.4磷酸盐缓冲液中，将缓冲液加入圆底烧瓶中水合洗脱脂质薄膜，水浴超声30min使其分散均匀，制备得到脂质体粗混悬液。随后，将脂质体粗混悬液探头超声200w，30s，得到粒径较小并均匀分散的脂质体混悬液。将10mg海藻糖加入脂质体混悬液中进行冷冻干燥，得到阿法骨化醇脂质体冻干粉。以上制备过程全程避光。
实施例5
将阿法骨化醇口服脂质体与原料药和市售片剂相比，考察本发明阿法骨化醇口服脂质体对阿法骨化醇化学稳定性、口服生物利用度和抗骨质疏松效果的提高作用。
对比实验例1：稳定性试验
试验样品：实施例1-4制备的样品、原料药与市售片剂。
试验方法：将试验样品在温度25℃、相对湿度60％下避光放置6个月，分别于0、1、2、3和6个月时取样，按照《中国药典》2015版要求，采用HPLC法进行含量测定。HPLC条件：硅胶为填充剂，流动相：石油醚(60-90℃)-乙酸乙酯-三氯甲烷＝44:42:14；检测波长：265nm；柱温：室温。理论塔板数按阿法骨化醇峰计算不应低于2000；采用外标法计算含量。含量测定结果(测得量与标示量的百分比)见表1稳定性试验含量测定结果(％)。
表1稳定性实验结果(n＝6)
根据表1可知，实施例1-4制备的样品的稳定性明显优于原料药和市售制剂，其中实施例1的稳定性最佳。
对比实验例2：生物利用度实验。
实验动物：6只雄性比格犬；试验样品：实施例1和市售片剂。
试验方法：将6只比格犬(均为雄性)分成两组进行口服给药，一组给予实施例1的脂质体冻干粉，另一组给予市售片剂，剂量均为50.0μg/只(以阿法骨化醇计)。口服后0、0.5、1、2、4、6、8、12、24、32、48h采集血样，计算阿法骨化醇的最大血药浓度(Cmax)、达峰时间(tmax)和生物利用度(AUC0→48h)。
表2生物利用度实验结果(n＝3)
根据表2可知，实施例1的脂质体冻干粉在比格犬体内的生物利用度高于市售片剂，阿法骨化醇经脂质体包封后，吸收增加，生物利用度提高。
对比实验例3：实验鼠骨质疏松治疗效果评价
实验动物：90只5周龄Wistar健康雌性大鼠；实验样品：实施例1-4与市售片剂。
实验方法：70只大鼠行双侧卵巢摘除术，20只做假手术。8周后各处死10只证实骨质疏松造模成功。剩余60只骨质疏松模型鼠随机分为6个治疗组，每组10只，其它10只假手术组作对照。脂质体治疗组：50μg/kg，每日口服1次；市售片剂对照组：50μg/kg，每日口服1次；安慰剂组：生理盐水，每日口服1次；假手术对照组：生理盐水，每日口服1次。治疗4个月后，测定并比较股骨骨密度及匀浆后股骨组织中碱性磷酸酶(ALP)活性。
各组动物于治疗后16周断颈处死，取右侧股骨中段，尽量剔除周围软组织，采用法国DMS公司CHALLENGER双能X线吸收仪进行扫描测定，DMS公司CHALLENGER分析动物软件进行分析。使用SPSS 11.0软件进行统计，结果以Mean±SD表示，组间比较采用单因素方差分析。
实验结果：大鼠双侧卵巢摘除8周后，其左侧股骨密度试验显示骨密度为(0.245±0.037)g/mm2，假手术组骨密度为(0.296±0.082)g/mm2(P<0.05)，提示骨质疏松模型造模成功。脂质体治疗组、市售片剂对照组、安慰剂组及假手术组的股骨骨密度结果如图1所示，结果表明脂质体治疗组的股骨骨密度高于市售片剂治疗组，显著高于安慰剂组(P<0.05)，与假手术组没有显著差异。结果表明，口服阿法骨化醇脂质体在小鼠骨质疏松的治疗上优于市售片剂。
Claims (9)
1.一种阿法骨化醇口服脂质体药物，其特征在于：由以下原料按重量份数制成：阿法骨化醇1份，磷脂5～50份，胆固醇1～10份，抗氧剂1～5份；所述的阿法骨化醇所示的结构如下：
2.根据权利要求1所述的阿法骨化醇口服脂质体药物，其特征在于：所述的磷脂选自大豆磷脂、蛋黄磷脂、氢化大豆磷脂以及二棕榈酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、二肉豆蔻酰磷脂酰胆碱、二油酰磷脂酰胆碱、磷脂酰乙醇胺、磷脂酸、磷脂酰甘油、磷脂酰肌醇、磷脂酰丝氨酸及其混合物。
3.一种根据权利要求1所述的阿法骨化醇口服脂质体药物的制备方法，其特征在于：制备过程避光操作，包括步骤如下：
(1)称取处方量的阿法骨化醇、磷脂、胆固醇和油溶性抗氧剂置于圆底烧瓶中，加入5ml～20ml二氯甲烷短时超声使其溶解；
(2)将圆底烧瓶置于旋转蒸发仪上，在40℃条件下减压蒸发除去二氯甲烷，直至圆底烧瓶内壁形成脂质薄膜，随后，将圆底烧瓶置于干燥器中抽真空24h；
(3)将5ml～20ml溶有水溶性抗氧剂的0.01M pH7.4磷酸盐缓冲液加入圆底烧瓶中，水合洗脱脂质薄膜，水浴超声30min使其分散均匀，制备得到脂质体粗混悬液；
(4)采用探头超声200w，30s，得到粒径较小并均匀分散的脂质体混悬液；
(5)将上述的脂质体混悬液在冷冻保护剂作用下进行冷冻干燥，进一步除去溶剂，得到阿法骨化醇脂质体冻干粉。
4.根据权利要求3所述的阿法骨化醇口服脂质体药物的制备方法，其特征在于：所述的油溶性抗氧剂选自维生素E、二丁基羟基甲苯(BHT)、叔丁基-4-羟基茴香醚(BHA)、没食子酸丙酯(PG)、叔丁基对苯二酚(TBHQ)及其混合物。
5.根据权利要求3所述的阿法骨化醇口服脂质体药物的制备方法，其特征在于：所述的水溶性抗氧剂选自维生素C、亚硫酸钠、焦亚硫酸钠、亚硫酸氢钠、硫代硫酸钠、EDTA-2Na及其混合物。
6.根据权利要求3所述的阿法骨化醇口服脂质体药物的制备方法，其特征在于：所述的冷冻保护剂选自乳糖、蔗糖、麦芽糖、甘露糖、海藻糖、右旋糖酐、白蛋白、羟丙甲基纤维素及其混合物。
7.一种根据权利要求1所述的阿法骨化醇口服脂质体药物的应用，其特征在于：将本发明制得的脂质体冻干粉，通过加入适宜的辅料：填充剂、粘合剂、崩解剂、润滑剂和包囊材料制成口服剂型。
8.根据权利要求7所述的阿法骨化醇口服脂质体药物的应用，其特征在于：所述的填充剂包括淀粉、蔗糖、糊精、乳糖、预胶化淀粉、微晶纤维素、二水硫酸钙和磷酸氢钙；
所述的粘合剂包括淀粉、预胶化淀粉、甲基纤维素、羟丙基纤维素、羟丙基甲基纤维素、羧甲基纤维素钠、乙基纤维素、聚维酮、明胶、阿拉伯胶、西黄蓍胶、聚乙二醇类、聚乙烯醇、蔗糖、葡萄糖；
所述的崩解剂包括干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联聚维酮、交联羧甲基纤维素钠、海藻酸、海藻酸钠、泡腾崩解剂；
所述的润滑剂包括硬脂酸镁和硬脂酸钙等硬脂酸盐、微粉硅胶、滑石粉、氢化植物油、聚乙二醇类、十二烷基硫酸钠；
所述的包囊材料包括明胶、阿拉伯胶、纤维素类、聚乙烯醇、聚乳酸。
9.根据权利要求7所述的阿法骨化醇口服脂质体药物的应用，其特征在于：所述的口服剂型为：片剂、胶囊剂。
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Application publication date: 20200828 |