CN108175746A - 一种n-乙酰半胱氨酸纳米乳液药物制剂及其制备方法 - Google Patents
一种n-乙酰半胱氨酸纳米乳液药物制剂及其制备方法 Download PDFInfo
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Abstract
本发明涉及一种N‑乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法。该N‑乙酰半胱氨酸纳米乳液由下列重量百分比的物料组成：5‑40％的NAC、1‑30%的乳化剂、8‑35％植物油、0.5%‑5%的表面活性剂、2%‑20%的表面活性助剂，余下为纯化或注射用水。将NAC药物制剂研发成纳米乳液剂型，一方面满足老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者的临床需求；另一方面，将NAC研发成纳米乳液后，既提高了NAC与粘痰的有效作用强度和时间，又提高了药效。
Description
技术领域
本发明属于药物制剂技术及其应用领域。
背景技术
N-乙酰半胱氨酸(NAC)为谷胱甘肽的前体,是一种含有巯基的抗氧化剂。NAC在呼吸、心血管、神经系统和抗AIDS的临床应用广泛,说明NAC为一具有研究价值的用途广泛的药物。NAC可以作为粘液溶解剂，其分子式中含有巯基(-SH)，可使多肽链中的双硫键(-S-S-)断裂，降低痰的粘度，痰易排出，不仅能溶解白痰也能溶解脓性痰，适用于大量粘痰阻引起呼吸困难，及咯痰困难的疾患。用于术后咯痰困难，急、慢性支气管炎，支气管扩张，肺炎，肺结核，肺气肿等引起痰液粘稠和咯痰困难者。
纳米技术是指在纳米尺度上研究利用原子、分子结构的特性及其相互作用原理，并按人类的需要，在纳米尺度上直接操纵物质表面的分子、原子乃至电子来制造特定产品或创造纳米级加工工艺的一门新兴学科技术。纳米技术主要包括：纳米材料学、纳米电子学、纳米动力学、纳米生物学和纳米药物学。纳米技术加深了人们对于物质构成和性能的认识，使人们在物质的微观空间内研究电子、原子和分子运动的规律和特性，运用纳米技术我们可以在原子、分子的水平上设计并制造出具有全新性质和各种功能的材料。由于纳米材料表现出的新特性和新功效，纳米技术的迅速发展将引发一场新的工业革命。继信息科技、材料科学等高精尖应用领域之后，纳米技术的应用深入到生命科技和传统产业方面，逐步影响着人们的衣、食、住、行。如医药方面，广泛的应用载药纳米微粒溶解、包裹或者吸附活性组分，达到缓释药物、延长药物的作用时间、靶向运输、增强药物效应、减轻毒副反应、提高药物的稳定性的目的。
N-乙酰半胱氨酸(NAC)为一含有巯基的化合物,以往多将其作为黏液溶解剂,是一种疗效良好而且安全的呼吸道感染用药中的祛痰剂。其作用机理是其分子中的巯基能将痰液中粘蛋白的二硫键(-S-S-)断裂,使黏蛋白分解,从而降低痰的粘滞性,使之容易咳出而改善症状。目前，国内外大多数批准上市的剂型为颗粒剂、片剂、胶囊、注射剂。但对于老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者在临床使用时方便，需要将固体制剂溶解，且溶解的水量不一，导致药物作用浓度不一，治疗效果也存在差异。而注射剂不是普遍推荐使用的剂型，且不太适用于婴幼儿和儿童。
因此，临床上需要科学、合理、方便于老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者的NAC药物制剂剂型。我们经大量研究实验，创新地将NAC药物制剂研发成纳米乳液剂型，一方面满足了上述老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者的临床需求；另一方面，将NAC研发成纳米乳液后，既提高了NAC与粘痰的有效作用强度和时间，提高了药效。
发明内容
本发明涉及一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法。该N-乙酰半胱氨酸纳米乳液由下列重量百分比的物料组成：N-乙酰半胱氨酸纳米乳液由5-40％的NAC、1-30%的乳化剂、20-30％植物油、0.5%-5%的表面活性剂、2%-20%的表面活性助剂、纯化水或注射用水组成。将NAC药物制剂研发成纳米乳液剂型，一方面满足老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者临床需求；另一方面，将NAC研发成纳米乳液后，既提高了NAC与粘痰的有效作用强度和时间，提高了药效。
本发明的技术方案是这样实现的：
（1）称量脂质材料加热至75～85℃，得到液态油相；
（2）称取乳化剂、表面活性剂、蒸馏水，加热至75～85℃，混合均匀得液态水相；（3）按比例称取NAC加入上述液态水相中混合均匀；
（4）将液态油相和液态水相混合，在8000-12000rpm条件下高速剪切；
（5）在80～200MPa压力、60～85℃温度条件下，通过高压均质机循环均质6～12次，保持高压均质机出口段混合液温度不超过85℃；
（6）冷却至室温，添加适量防腐剂，得NAC纳米粒乳液。
本发明的优点：
1、 将NAC药物制剂研发成纳米乳液剂型，临床上，更适用于老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者，提高了患者的用药依从性；
2、 将NAC研发成纳米乳液后，提高了NAC与粘痰的有效作用强度和时间，提高了药效。
本发明有益效果：
1、该NAC纳米乳液滞留于咽喉食道的时间，比其它如：片剂、胶囊、颗粒剂等制剂滞留时间长，见附表1；
2、该NAC纳米乳液化痰时间快于其它如：片剂、胶囊、颗粒剂等制剂的化痰时间，见附表2;
3、该NAC纳米乳液在药代动力学方面优于其它如：片剂、胶囊、颗粒剂等制剂，见附表3。
具体实施方式
下面将描述本发明的实施例，但本发明的内容完全不限于此。
从下列实施例中中可以更好地理解本发明。这些实施例并不用来作 为对本发明范围的限定。
实施例1
处方组成：
NAC 10％
辛酸/癸酸甘油酯20％
卵磷脂2％
甘油10.％
胆固醇2％
水平衡至达到总计100％ 。
NAC纳米乳液制备方法：
称量脂质材料加热至75～85℃，得到液态油相；称取乳化剂、表面活性剂、蒸馏水，加热至75～85℃，混合均匀得液态水相；按比例称取NAC加入上述液态水相中混合均匀；将液态油相和液态水相混合，在8000-12000rpm条件下高速剪切；在80～200MPa压力、60～85℃温度条件下，通过高压均质机循环均质6～12次，保持高压均质机出口段混合液温度不超过85℃；冷却至室温，添加适量防腐剂，得NAC纳米粒乳液。
实施例2
NAC纳米乳液制备方法：
通过与实施例1中所述相同的操作制备NAC纳米乳液， 但应用下列纳米乳液组合物中的组分结构组成。
处方组成：
NAC 10％
辛酸/癸酸甘油酯20％
卵磷脂2％
甘油10％
胆固醇2％
聚山梨酯20(聚氧乙烯20山梨醇酐单月桂酸酯)3％
水平衡至达到总计100％。
实施例3
NAC纳米乳液组合物的制备
通过与实施例1中所述相同的操作制备NAC纳米乳液， 但应用下列纳米乳液组合物中的组分结构组成。
处方组成：
NAC 20％
辛酸/癸酸甘油酯25％
卵磷脂3％
甘油15％
吐温80 1％
水平衡至达到总计100％
实施例4
NAC纳米乳液组合物的制备
通过与实施例1中所述相同的操作制备NAC纳米乳液， 但应用下列纳米乳液组合物中的组分结构组成。
处方组成：
NAC 10％
辛酸/癸酸甘油酯25％
卵磷脂3％
甘油15％
吐温80 2％
大豆油 10%
水平衡至达到总计100％
实施例5
NAC纳米乳液组合物的制备
通过与实施例1中所述相同的操作制备NAC纳米乳液， 但应用下列纳米乳液组合物中的组分结构组成。
处方组成：
NAC 20％
聚甘油油酸酯20％
卵磷脂2％
甘油15％
吐温80 2％
花生油10%
水平衡至达到总计100％
实施例6
NAC纳米乳液组合物的制备
通过与实施例1中所述相同的操作制备NAC纳米乳液， 但应用下列纳米乳液组合物中的组分结构组成。
处方组成：
NAC 20％
聚甘油油酸酯20％
卵磷脂2％
1,2丙二醇5％
Span80 2％
花生油 15%
水平衡至达到总计100％
实施例7
NAC纳米乳液组合物的制备
通过与实施例1中所述相同的操作制备NAC纳米乳液， 但应用下列纳米乳液组合物中的组分结构组成。
处方组成：
NAC 10％
辛酸/癸酸甘油酯20％
甘油1％
TEA椰油基谷氨酸盐3％
葵花子油 20％
水平衡至达到总计100wt.％
附表：
1、NAC纳米乳液与其它剂型产品在咽喉食道滞留于时间检测结果对比表1；
2、NAC纳米乳液与其它剂型产品化痰时间对比表2;
3、NAC纳米乳液与其它剂型产品药代动力学对比表3
Claims (9)
1.一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于，由下列重量百分比的物料组成：5-40％的NAC、1-30%的乳化剂、20-30％植物油、0.5%-5%的表面活性剂、2%-20%的表面活性助剂，余下为纯化或注射用水。
2.根据权利要求1所述的N-乙酰半胱氨酸(NAC)纳米乳液及其制备方法，其特征在于，所述乳液是由下述方法制备得到的：（1）称量脂质材料加热至75～85℃，得到液态油相；（2）称取乳化剂、表面活性剂、纯化或注射用水，加热至75～85℃，混合均匀得液态水相；（3）按比例称取NAC加入上述液态水相中混合均匀；（4）将液态油相和液态水相混合，在8000-12000rpm高速剪切条件下搅拌混合；（5）在80～200MPa压力、60～85℃温度条件下，通过高压均质机循环均质6～12次，保持高压均质机出口段混合液温度不超过85℃；（6）冷却至室温，添加适量防腐剂，得NAC纳米粒乳液。
3.权利要求1或2所述一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于：所述的NAC用量（重量百分比）为5-40％，优选10%、20%。
4.权利要求1或2所述一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于：所述的乳化剂为选自如下中的至少一种：聚氧乙烯20山梨醇酐单月桂酸酯、聚氧乙烯20山梨醇酐单油酸酯、聚甘油脂肪酸酯、甘油脂肪酸酯、丙二醇脂肪酸酯、胆固醇、TEA椰油基谷氨酸盐、谷氨酸钠、椰油基谷氨酸钠、椰油基谷氨酸镁、月桂酰谷氨酸钠、辛酸/癸酸甘油酯、聚甘油油酸酯、卵磷脂，优选卵磷脂、辛酸/癸酸甘油酯、聚甘油油酸酯。
5.权利要求1或2所述一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于：所述的植物油为花生油、大豆油、澳洲坚果油、葵花子油、橄榄油、植物角鲨烷的一种或一种以上，优选大豆油、花生油。
6.权利要求1或2所述一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于：所述的表面活性剂Span80、Tween80或其混合物，所述的表面活性助剂为甘油或1,2-丙二醇，优选甘油。
7.权利要求1或2所述一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于：所述的防腐剂为苯甲酸钠、苯甲酸、山梨酸钾、尼泊金酯，以上的一种或一种以上组合，优选苯甲酸钠、山梨酸钾。
8.权利要求1或2所述一种N-乙酰半胱氨酸(NAC)纳米乳液药物制剂及其制备方法，其特征在于：所述乳液为纳米乳药液，其乳滴粒径为10-100纳米。
9.根据权利要求1或2所述的N-乙酰半胱氨酸(NAC)纳米乳液，其特征在于：所述的NAC纳米乳液用于治疗咳嗽袪痰，尤其应用于老年人咯痰困难、婴幼儿和儿童咯痰困难或不会咯痰患者临床需求。
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