CN107441090A - 一种托匹司他微球制剂及其制备方法 - Google Patents
一种托匹司他微球制剂及其制备方法 Download PDFInfo
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- CN107441090A CN107441090A CN201710736677.5A CN201710736677A CN107441090A CN 107441090 A CN107441090 A CN 107441090A CN 201710736677 A CN201710736677 A CN 201710736677A CN 107441090 A CN107441090 A CN 107441090A
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Classifications
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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Abstract
本发明涉及医药技术领域，具体涉及一种托匹司他微球制剂及其制备方法。本发明采取的技术方案是一种托匹司他微球制剂，其特征在于，含有以下重量份的组分：托匹司他10‑20份，高分子载体30‑100份，乳化剂0‑5份，冻干支撑剂0‑10份。本发明制得的托匹司他微球包封率高，粒径大小均匀，质量稳定，制备工艺简单，增加了托匹司他的给药途径，提高患者顺应性；并且还具有托匹司他的长效释放效果，具有预料不到的技术效果。
Description
技术领域
本发明涉及医药技术领域，具体涉及一种托匹司他微球制剂及其制备方法。
背景技术
痛风及高尿酸血症是由于体内尿酸合成过多或尿酸排泄过少而导致体内血尿酸水平过高，尿酸盐结晶在关节肾脏中沉积，进而诱导引发一系列炎症反应的代谢性疾病。该病严重威胁人类健康，是仅次于糖尿病的第二大代谢疾病。通过药物降低血尿酸水平是预防和治疗痛风以及高尿酸血症的有效方法，临床常用的药物包括黄嘌呤氧化酶(xanthineoxidase，XO)抑制剂别嘌呤醇(allopurinol)、非布索坦(febuxostat)和托匹司他(topiroxostat)，以及尿酸排泄促进剂丙磺舒(probenecid)和苯溴马隆(benzbromarone)。
托匹司他是一个不含嘌呤结构的选择性黄嘌呤氧化还原酶抑制剂，是由日本富士制药和三和化学共同研发的新一代抗高尿酸血症和痛风的药物。与以黄嘌呤氧化酶为结构基础设计的抑制剂如非布索坦和别嘌呤醇相比，托匹司他表现出对黄嘌呤氧化酶更为有效和安全的抑制作用，特别是针对有肾损伤的患者。
托匹司他的原研制剂是托匹司他片，于2013年6月以适应症(痛风、高尿酸血症)被批准在日本上市，规格有20mg、40mg、60mg三种。目前还公开了其他多种托匹司他制剂，包括托匹司他普通片剂、托匹司他固体分散片剂、托匹司他包衣片剂、托匹司他缓释片剂、托匹司他普通胶囊制剂、托匹司他缓释胶囊制剂、托匹司他复方缓释制剂和托匹司他环糊精包合物等。
但上述开发的制剂都属于口服制剂，临床应用具有局限性。尤其是对于吞咽困难的患者来说，上述口服制剂的服用极不方便。
微球(microsphere)是指药物溶解或分散在高分子材料基质中形成的粒径为1～1000μm的微小球状实体；粒径在10～1000n m之间的微球也被称为纳米球(又称毫微球)。微球技术作为一种新型给药技术,首先通过调节和控制药物的释放速度实现长效的目的，同时又能保护药物免遭破坏，掩盖药物的不良口味，减少给药次数和药物刺激，降低毒性和副作用，提高疗效。此外，微球还与某些细胞组织有特殊亲和性，能被器官组织的网状内皮系统所内吞或被细胞融合，集中于靶区逐步扩散释出药物或被溶酶体中的酶降解而释出药物。
微球可以供注射(静注、肌注)、口服、滴鼻、皮下埋植或是关节腔给药使用，能够开发出更为广泛的给药途径。除现有技术报道的口服缓控释制剂外，微球制剂也可作为托匹司他长效制剂的一种选择。
发明内容
为解决上述技术问题，增加托匹司他的给药途径，提高患者顺应性，本发明提供了一种托匹司他微球制剂。该托匹司他微球包封率高，粒径大小均匀，质量稳定，制备工艺简单；还具有托匹司他的长效释放效果，具有预料不到的技术效果。
为实现上述目的，本发明采取的技术方案是：
一种托匹司他微球制剂，其特征在于，含有以下重量份的组分：托匹司他10-20份，高分子载体30-100份，乳化剂0-5份，冻干支撑剂0-10份。
进一步地，所述高分子载体选自聚乳酸、聚羟基乳酸、聚乳酸羟基乳酸、壳聚糖、几丁质、淀粉、胶原、明胶、透明质酸、海藻酸盐、白蛋白、丝素蛋白、酪蛋白和玉米醇溶蛋白的一种或多种的混合物。
进一步地，所述乳化剂选自硬脂酸钠、十二烷基硫酸钠、十二烷基苯磺酸钙、聚氧乙烯醚类、聚氧丙烯醚类、Span和Tween中的一种或多种的混合物。
进一步地，所述冻干支撑剂选自甘露醇、山梨醇、乳糖、蔗糖、海藻糖、右旋糖酐、明胶、葡萄糖、果糖、甘氨酸、丙氨酸、组氨酸和精氨酸中的一种或多种的混合物。
本发明进一步提供了上述托匹司他微球制剂的制备方法，其特征在于，包括以下步骤：称取处方量的托匹司他，溶入10-20mL有机溶剂中作为分散相；称取处方量的高分子载体和乳化剂，溶入100-200mL乙醇水溶液中作为连续相，将分散相缓慢滴加至有机相中，在30-50℃、1000-2000r/min搅拌条件下乳化20-40min，将所得的乳剂倒入200-500ml丙酮中固化；沉降物用丙酮洗涤至无油滴，加入冻干支撑剂溶液，真空冷冻干燥即得。
本发明进一步提供了上述托匹司他微球制剂的制备方法，其特征在于，包括以下步骤：称取处方量的托匹司他，溶入10-20mL有机溶剂中作为分散相；称取处方量的高分子载体和乳化剂，溶入100-200mL乙醇水溶液中作为连续相，将分散相缓慢滴加至有机相中，超声乳化20-40min，形成水包油型乳化液；30-50℃旋转蒸发去除有机溶剂，加入冻干支撑剂溶液，真空冷冻干燥即得。
本发明进一步提供了上述托匹司他微球制剂的制备方法，其特征在于，包括以下步骤：称取处方量的托匹司他，溶入10-20mL有机溶剂中；称取处方量的高分子载体，溶入100-200mL乙醇水溶液中，将两种溶液混合后通过喷雾干燥制得托匹司他微球制剂。
进一步地，所述有机溶剂选自乙醇、乙醚、氯仿、二氯甲烷、二甲基亚砜中的一种或多种的混合物。
进一步地，所述真空冷冻干燥过程包括：-40～-25℃预冻2～6h，缓慢升温至-5～5℃真空干燥10-12h，缓慢升温至10～20℃真空干燥4-8h，继续升温至30～35℃真空干燥1-3h。
进一步地，所述喷雾干燥条件为：雾化压力10-20MPa，料液温度为40-60℃，喷雾干燥塔内热风温度为100-120℃，进料泵速为4-6r/min。
本发明制得的托匹司他微球包封率高，粒径大小均匀，质量稳定，制备工艺简单，增加了托匹司他的给药途径，提高患者顺应性；并且还具有托匹司他的长效释放效果，具有预料不到的技术效果。
具体实施方式
下面结合实施例对本发明的具体实施方式作进一步描述，但这些实施例仅是范例性的，并不对本发明的范围构成任何限制。本领域技术人员应该理解的是，在不偏离本发明的精神和范围下可以对本发明技术方案的细节和形式进行修改或替换，但这些修改和替换均落入本发明的保护范围内。
实施例1
称取10g托匹司他，溶入20mL二氯甲烷中作为分散相；称取40g聚乳酸羟基乳酸和3g Span 80，溶入100mL乙醇水溶液中作为连续相，将分散相缓慢滴加至有机相中，在30℃、2000r/min搅拌条件下乳化20min，将所得的乳剂倒入400ml丙酮中固化，沉降物用丙酮洗涤至无油滴；配制5％的甘露醇溶液，取100mL加入至沉降物中，搅拌均匀，真空冷冻干燥即得。所述真空冷冻干燥工艺为-40℃预冻2h，缓慢升温至-5℃真空干燥10h，缓慢升温至10℃真空干燥8h，继续升温至30℃真空干燥1h。微球中托匹司他的包封率为88.2±4.1％，粒径大小为0.73±0.02μm。
实施例2
称取20g托匹司他，溶入20mL氯仿中作为分散相；称取80g壳聚糖和2g十二烷基硫酸钠，溶入200mL乙醇水溶液中作为连续相，将分散相缓慢滴加至有机相中，超声乳化30min，形成水包油型乳化液；40℃旋转蒸发去除有机溶剂，加入3％的葡萄糖溶液100mL，真空冷冻干燥即得。所述真空冷冻干燥工艺为-30℃预冻4h，缓慢升温至3℃真空干燥12h，缓慢升温至15℃真空干燥6h，继续升温至32℃真空干燥2h。微球中托匹司他的包封率为92.5±3.7％，粒径大小为0.54±0.04μm。
实施例3
称取15g托匹司他，溶入20mL二氯甲烷中；称取100g聚乳酸，溶入200mL乙醇水溶液中，将两种溶液混合后通过喷雾干燥制得托匹司他微球制剂。所述喷雾干燥条件为：雾化压力15MPa，料液温度为50℃，喷雾干燥塔内热风温度为110℃，进料泵速为5r/min。微球中托匹司他的包封率为80.8±2.9％，粒径大小为0.96±0.07μm。
试验例1微球包封率测定方法
实施例1-3的微球包封率的测定方法为：取微球分散溶液适量，置于高速塑料离心管中，称重配对后放入离心机中离心，转速为25000r/min，离心30min。取离心后的上清液适量，测定单位体积上清液中托匹司他的浓度。计算重量包封率(n＝6)：
Qw％＝(W总-W游)/W总×100％，其中W总、W游分别表示投料量、未包入微球(游离)
的药量。
根据上述结果可知，实施例2制得的托匹司他微球的包封率最高，粒径也最小。
试验例2实施例1-3的微球释放度测定
根据《中华人民共和国药典2015年版》四部通则“缓释、控释和迟释制剂指导原则”，以0.25％十二烷基硫酸钠为释放介质，分别精密称取实施例1-3所得的托匹司他微球适量(约100mg)，按照《中华人民共和国药典2015年版》四部通则第一法测定，用HPLC法测定峰面积，计算药物浓度及累积释放百分率。测定结果见表1。
表1实施例1-3的微球释放度测定结果(n＝6)
根据上述结果可知，实施例2制得的微球托匹司他长效释放的效果最佳。
试验例3对比例1-5的微球释放度测定
分别采用等量的聚乳酸、聚乳酸羟基乳酸、淀粉、海藻酸盐和白蛋白替代实施例2中的壳聚糖作为高分子载体材料，其他条件同实施例2制得托匹司他微球(分别作为对比例1-5)。按照试验例2的方法测定微球释放度。测定结果见表2。
表2对比例1-5的微球释放度测定结果(n＝6)
根据上述结果可知，对比例1-5中采用聚乳酸、聚乳酸羟基乳酸、淀粉、海藻酸盐和白蛋白替代实施例2中的壳聚糖作为高分子载体材料后，所制得的微球中托匹司他的长效释放的效果明显降低；说明采用实施例2的制备方法、并采用壳聚糖作为高分子载体材料制得的微球在延长托匹司他释放方面具有预料不到的技术效果。
试验例4对比例6-10的微球包封率的测定
分别采用等量的硬脂酸钠、Span20、Span80、Tween20和Tween80替代实施例2中的十二烷基硫酸钠作为乳化剂，其他条件同实施例2制得托匹司他微球(分别作为对比例6-10)。按照试验例1的方法测定微球释放度。测定结果见表3。
表3对比例6-10的微球包封率测定结果(n＝6)
根据上述结果可知，对比例6-10中采用硬脂酸钠、Span20、Span80、Tween20和Tween80替代实施例2中的十二烷基硫酸钠作为乳化剂后，所制得的微球中托匹司他的包封率明显降低；说明采用实施例2的制备方法、并采用十二烷基硫酸钠作为乳化剂制得的微球的包封效果具有预料不到的技术效果。
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。
Claims (10)
1.一种托匹司他微球制剂，其特征在于，含有以下重量份的组分：托匹司他10-20份，高分子载体30-100份，乳化剂0-5份，冻干支撑剂0-10份。
2.根据权利要求1所述的一种托匹司他微球制剂，其特征在于，所述高分子载体选自聚乳酸、聚羟基乳酸、聚乳酸羟基乳酸、壳聚糖、几丁质、淀粉、胶原、明胶、透明质酸、海藻酸盐、白蛋白、丝素蛋白、酪蛋白和玉米醇溶蛋白的一种或多种的混合物。
3.根据权利要求1所述的一种托匹司他微球制剂，其特征在于，所述乳化剂选自硬脂酸钠、十二烷基硫酸钠、十二烷基苯磺酸钙、聚氧乙烯醚类、聚氧丙烯醚类、Span和Tween中的一种或多种的混合物。
4.根据权利要求1所述的一种托匹司他微球制剂，其特征在于，所述冻干支撑剂选自甘露醇、山梨醇、乳糖、蔗糖、海藻糖、右旋糖酐、明胶、葡萄糖、果糖、甘氨酸、丙氨酸、组氨酸和精氨酸中的一种或多种的混合物。
5.权利要求1所述的一种托匹司他微球制剂的制备方法，其特征在于，包括以下步骤：称取处方量的托匹司他，溶入10-20mL有机溶剂中作为分散相；称取处方量的高分子载体和乳化剂，溶入100-200mL乙醇水溶液中作为连续相，将分散相缓慢滴加至有机相中，在30-50℃、1000-2000r/min搅拌条件下乳化20-40min，将所得的乳剂倒入200-500ml丙酮中固化；沉降物用丙酮洗涤至无油滴，加入冻干支撑剂溶液，真空冷冻干燥即得。
6.权利要求1所述的一种托匹司他微球制剂的制备方法，其特征在于，包括以下步骤：称取处方量的托匹司他，溶入10-20mL有机溶剂中作为分散相；称取处方量的高分子载体和乳化剂，溶入100-200mL乙醇水溶液中作为连续相，将分散相缓慢滴加至有机相中，超声乳化20-40min，形成水包油型乳化液；30-50℃旋转蒸发去除有机溶剂，加入冻干支撑剂溶液，真空冷冻干燥即得。
7.权利要求1所述的一种托匹司他微球制剂的制备方法，其特征在于，包括以下步骤：称取处方量的托匹司他，溶入10-20mL有机溶剂中；称取处方量的高分子载体，溶入100-200mL乙醇水溶液中，将两种溶液混合后通过喷雾干燥制得托匹司他微球制剂。
8.根据权利要求5-7任意一项所述的一种托匹司他脂质体制剂的制备方法，其特征在于，所述有机溶剂选自乙醇、乙醚、氯仿、二氯甲烷、二甲基亚砜中的一种或多种的混合物。
9.根据权利要求5-6任意一项所述的一种托匹司他脂质体制剂的制备方法，其特征在于，所述真空冷冻干燥过程包括：-40～-25℃预冻2～6h，缓慢升温至-5～5℃真空干燥10-12h，缓慢升温至10～20℃真空干燥4-8h，继续升温至30～35℃真空干燥1-3h。
10.根据权利要求7所述的一种托匹司他脂质体制剂的制备方法，其特征在于，所述喷雾干燥条件为：雾化压力10-20MPa，料液温度为40-60℃，喷雾干燥塔内热风温度为100-120℃，进料泵速为4-6r/min。。
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