CN114191386B - 一种波生坦口服溶液的制备方法 - Google Patents
一种波生坦口服溶液的制备方法 Download PDFInfo
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- CN114191386B CN114191386B CN202111606463.9A CN202111606463A CN114191386B CN 114191386 B CN114191386 B CN 114191386B CN 202111606463 A CN202111606463 A CN 202111606463A CN 114191386 B CN114191386 B CN 114191386B
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Abstract
本发明涉及一种口服制剂的制备，具体表述为一种含内皮素受体抑制剂的口服给药制剂，它含有：内皮素受体抑制剂，包合物环糊精及其衍生物，作为混合液体载体的水性碱性介质和醇性共溶剂或碱性溶剂。附加一种或多种药用甜味剂和/或一种或多种药用调味剂能得到适口性较好的口服制剂。本发明还涉及所述制剂及含所述制剂的药物剂型的制备方法。本发明制备的波生坦口服溶液，工艺稳定，与参比制剂相比，具有更高的口服生物利用度。
Description
技术领域
本发明涉及药物制剂技术领域，具体为波生坦口服溶液，其包合化合物N-[6-(2-羟基乙氧基)-5-(2-甲氧基苯氧基)-2-嘧啶-2-基-嘧啶-4-基]-4-叔丁基苯磺酰胺，所述的化合物在下文中称为化合物I。
化合物I具有如下结构式：
化合物I是一种内皮素受体抑制剂，可用于肺动脉高压(PAH)的治疗。
背景技术
波生坦是2001年由强生旗下杨森医药公司爱可泰隆(Actelion)开发的一种内皮素受体抑制剂，用于治疗3岁及以上特发性或先天性肺动脉高压(PAH)儿科患者，改善肺血管阻力(PVR)。波生坦是一种对于内皮素ETA和ETB受体均具有亲和性的双重内皮素受体拮抗剂，在起到治疗作用的同时，能够避免ET1的毒副作用。
目前波生坦仅有普通片、薄膜衣片、分散片等片剂产品上市，且均为进口产品，暂无国内企业生产产品上市。
发明内容
由化合物I治疗PAH的片剂目前已经上市，但儿童用药存在顺应性问题，因而目前上市的片剂对儿童用药是不方便的。溶液型的药物产品更适合儿童。本发明通过对产品处方工艺进行改进，使其可以制成溶液剂型。
儿科配方的进一步的优点如下：
1)特别的儿科配方具有更好依从性；
2)液体制剂，吸收快，起效迅速；
3)服用剂量可控，根据儿童体重进行剂量优化和个体化给药。
本发明涉及口服溶液剂，该制剂含有：作为活性成分的波生坦、增溶剂或包合剂环糊精或其衍生物(CD)、水性碱性介质、醇性共溶剂或碱性溶剂。通过加入一种或多种药用的甜味剂和一种或多种药用调味剂可以得到适口性更好的优选配方。
波生坦的临床推荐剂量如下(详见表1)。
表1：儿童患者(年龄≤12岁)的剂量推荐
| 患者(年龄≤12岁) | 初始4周和维持剂量(4周后) |
| ≥4-8kg | 16mg/次，每日两次 |
| ＞8-16kg | 32mg/次，每日两次 |
| ＞16-24kg | 48mg/次，每日两次 |
| ＞24-40kg | 64mg/次，每日两次 |
| ＞40kg | 64mg/次，每日两次 |
根据波生坦的临床推荐剂量，考虑临床用量，适用的口服制剂应含有0.2％～2.0％ (W/V)的活性成分。
本发明中足够量的环糊精衍生物是指结构上进行取代了的环糊精衍生物。环糊精分子结构由6个以上葡萄糖通过α-1,4-糖苷键链接而成，呈桶状。桶内形成疏水性空腔，能吸收一定大小和形状的疏水性小分子物质或基团，形成稳定的非共价复合物。分别由六，七，八个葡萄糖单体通过α-1,4-糖苷键链接而成的环糊精为α-CD，β-CD，γ-CD。β-CD是已知效果最好的包合材料之一，在三种类型中应用最为广泛。根据本发明，优选10％～40％ (W/V)的羟丙基-β-环糊精或磺丁基-β-环糊精，其中最优选为20％(W/V)。
本发明为提高难溶性药物波生坦溶解速度，在制剂中加入了一种醇性共溶剂或碱性溶剂。为达此目的，应选择对波生坦具有良好溶解性能的醇性共溶剂或碱性溶剂，可选用的溶剂包括乙醇，丙二醇、丙三醇、氢氧化钠溶液、氢氧化钾溶液等，优选为乙醇。
同时，加入大量的碱性调节剂促进波生坦在羟丙基-β-环糊精或磺丁基-β-环糊精存在的介质环境中的溶解速度。加入醇性共溶剂优选在5％～20％(V/V)，其中最优选为10％ (V/V)，其中最优选条件下波生坦在羟丙基-β-环糊精或磺丁基-β-环糊精介质中的溶解速度增加至少5倍，极大地缩短和简化了制备过程。
如上所述，碱性调节剂优选强性碱，如氢氧化钠、氢氧化钾等，优选为氢氧化钠。因碱性影响波生坦的生物利用度及顺应性，须控制pH，优选的pH：7.0±1.0。
药用甜味剂优选的含有至少一种强甜味剂和任选的普通甜味剂，强甜味剂包括：糖精、糖精钠或糖精钙、阿力甜、甘茶素、甜蜜素、三氯蔗糖、安赛蜜、甜菊苷、阿斯巴甜、索马甜、甘草甜、天冬酰苯丙氨酸甲酯、双氧噻嗪钾、环已氨磺酸钠，优选糖精、糖精钠和糖精钙的一种或多种混合物。普通甜味剂包括：山梨糖醇、甘露糖醇、果糖、蔗糖、麦芽糖、异麦芽糖、葡萄糖、氢化葡萄糖浆、木糖醇、焦糖和蜂蜜的一种或多种混合物。
强甜味剂以糖精钠为例，使用的浓度范围：0.05％～0.1％(V/V)。普通甜味剂以山梨醇(70％)溶液为例，用量范围为：10％～35％(V/V)，优选为：20％(V/V)。
在制剂组成中，使用药用调味剂掩盖苦味，调味剂包括樱桃、橘子或草莓口味，优选用量范围为0.05％～1.0％(V/V)。
在制剂组成中，使用药用防腐剂抑制微生物的生长，防腐剂包括对羟基苯甲酸酯类或其钠盐，优选用量范围为0％～1.0％(V/V)。
综上所述，根据本发明，波生坦口服溶液制剂含有以下成分(以重量/体积或体积/体积百分比计，以制剂总体积为分母)：
i.0.2％～2.0％(W/V)波生坦；
ii.10％～40％(W/V)羟丙基-β-环糊精；
iii.5％～20％(V/V)乙醇或溶解API的10％氢氧化钠溶液；
iv.调节组合物的pH在7.0±1.0范围内；
v.0.05％～0.1％(W/V)糖精钠；
vi.10％～35％(V/V)山梨糖醇(70％)溶液；
vii.最大为1％(W/V)的一种或多种调味剂；
viii.0％～1.0％(W/V)一种或多种防腐剂；
ix.水。
上述制剂的制备过程包含以下步骤：
i.将活性成分溶于醇性共溶剂或碱性溶剂中；
ii.将环糊精衍生物溶于水中，并在搅拌下加入(i)步骤溶液至均相；
iii.加入甜味剂、调味剂、防腐剂，调节pH至7.0±1.0；
iv.加水稀释制剂至所需体积。
v.经0.22μm微孔滤膜过滤，分装，即得。
附图说明
图1波生坦口服溶液(Homemade Fomulation)和波生坦片(Tracleer)Beagle犬体内药时曲线(n＝3)
具体实例如下：
实例1：
| 组分 | 浓度(mg/mL) |
| 波生坦 | 4 |
| 羟丙基-β-环糊精 | 200 |
| 山梨糖醇 | 140 |
| 乙醇 | 100 |
| 糖精钠 | 0.6 |
| 10％氢氧化钠溶液 | 适量 |
| 10％盐酸溶液 | 适量 |
| 对羟基苯甲酸乙酯钠 | 0.6 |
| 草莓香精 | 2 |
| 纯化水 | 加至1mL |
量取100mL乙醇，加入1.7mL的10％的氢氧化钠溶液，混匀。加入4g波生坦，并搅拌至溶解。在另一容器中，将200g羟丙基-β-环糊精溶于400mL纯化水中，将API溶液在搅拌下缓慢加入到环糊精溶液中。再加入200mL山梨糖醇(70％)溶液并搅拌至均相。 0.6g糖精钠溶于50mL纯化水中，然后再加入混合物中。加入调味剂、防腐剂，并用氢氧化钠溶液或盐酸溶液调节混合物的pH至约7.0，得到的溶液用纯化水稀释至终1L。用 0.22μm滤膜过滤上述溶液，分装上述溶液至10mL玻璃瓶中，充氮气，加塞，轧盖，25℃以下保存。
实例2：
| 组分 | 浓度(mg/mL) |
| 波生坦 | 8 |
| 羟丙基-β-环糊精 | 300 |
| 山梨糖醇 | 140 |
| 乙醇 | 150 |
| 糖精钠 | 1.0 |
| 10％氢氧化钠溶液 | 适量 |
| 10％盐酸溶液 | 适量 |
| 对羟基苯甲酸乙酯钠 | 0.6 |
| 草莓香精 | 2 |
| 纯化水 | 加至1mL |
量取150mL乙醇，加入4mL的10％的氢氧化钠溶液，混匀。加入8g波生坦，并搅拌至溶解。在另一容器中，将300g羟丙基-β-环糊精溶于400mL纯化水中，将API溶液在搅拌下缓慢加入到环糊精溶液中。再加入200mL山梨糖醇(70％)溶液并搅拌至均相。 1.0g糖精钠溶于50mL纯化水中，然后再加入混合物中。加入调味剂、防腐剂，并用氢氧化钠溶液或盐酸溶液调节混合物的pH至约7.0，得到的溶液用纯化水稀释至终1L。用 0.22μm滤膜过滤上述溶液，分装上述溶液至10mL玻璃瓶中，充氮气，加塞，轧盖，25℃以下保存。
实例3：
| 组分 | 浓度(mg/mL) |
| 波生坦 | 10 |
| 羟丙基-β-环糊精 | 400 |
| 山梨糖醇 | 140 |
| 乙醇 | 200 |
| 糖精钠 | 1.0 |
| 10％氢氧化钠溶液 | 适量 |
| 10％盐酸溶液 | 适量 |
| 对羟基苯甲酸乙酯钠 | 0.6 |
| 草莓香精 | 4 |
| 纯化水 | 加至1mL |
量取200mL乙醇，加入6mL的10％的氢氧化钠溶液，混匀。加入10g波生坦，并搅拌至溶解。在另一容器中，将400g羟丙基-β-环糊精溶于400mL纯化水中，将API溶液在搅拌下缓慢加入到环糊精溶液中。再加入200mL山梨糖醇(70％)溶液并搅拌至均相。 1.0g糖精钠溶于50mL纯化水中，然后再加入混合物中。加入调味剂、防腐剂，并用氢氧化钠溶液或盐酸溶液调节混合物的pH至约7.0，得到的溶液用纯化水稀释至终1L。用 0.22μm滤膜过滤上述溶液，分装上述溶液至10mL玻璃瓶中，充氮气，加塞，轧盖，25℃以下保存。
实例4：
| 组分 | 浓度(mg/mL) |
| 波生坦 | 4 |
| 羟丙基-β-环糊精 | 200 |
| 山梨糖醇 | 140 |
| 糖精钠 | 0.8 |
| 10％氢氧化钠溶液 | 适量 |
| 10％盐酸溶液 | 适量 |
| 对羟基苯甲酸乙酯钠 | 0.6 |
| 草莓香精 | 2 |
| 纯化水 | 加至1mL |
量取100mL纯化水，加入5mL的10％的氢氧化钠溶液，混匀。加入4g波生坦，50℃水浴加热，并搅拌至溶解。在另一容器中，将200g羟丙基-β-环糊精溶于400mL纯化水中，将API溶液在搅拌下缓慢加入到环糊精溶液中。再加入200mL山梨糖醇(70％)溶液并搅拌至均相。1.0g糖精钠溶于50mL纯化水中，然后再加入混合物中。加入调味剂、防腐剂，并用氢氧化钠溶液或盐酸溶液调节混合物的pH至约7.0，得到的溶液用纯化水稀释至终1L。用0.22μm滤膜过滤上述溶液，分装上述溶液至10mL玻璃瓶中，充氮气，加塞，轧盖，25℃以下保存。
实例5：
将实例1制备的波生坦口服溶液至于高温(60℃)条件下，放置30天，其变化如下：
表2：波生坦口服溶液高温样品检测结果
| 项目 | 0天 | 5天 | 10天 | 30天 |
| 含量(％) | 100.6 | 100.2 | 100.4 | 100.5 |
| 有关物质(％) | 0.12 | 0.23 | 0.17 | 0.26 |
| pH值 | 6.94 | 6.99 | 6.97 | 6.94 |
| 性状 | 无色透明溶液 | 无色透明溶液 | 无色透明溶液 | 无色透明溶液 |
实例6：
本实施例比较了波生坦口服溶液(Homemade Fomulation)和市售波生坦片(商品名 Tracleer)在雄性Beagle犬体内的相对生物利用度。受试Beagle犬6只，体重7～8kg，随机分为两组，每组3只。实验采用交叉给药方式，给药剂量为16mg。给药前禁食过夜，给药当天先给予饲料100g，从开始进食30分钟后灌胃给药并给予100m1自来水。分别于给药后0.5、1、2、3、4、6、8、12、24、36、48和72小时立即抽取血浆样品，收集到肝素管中。血浆经处理后进HPLC分析。药动学参数如下表所示。
表3：波生坦口服溶液和Tracleer在Beagle犬体内药动学参数
药动学实验结果表明，波生坦口服溶液的相对生物利用度为106.8％，与参比制剂相比，具有更高的口服生物利用度。
Claims (1)
1.一种波生坦口服液制备方法：
i.量取100mL乙醇，加入1.7mL的10％的氢氧化钠溶液，混匀；加入4g波生坦，并搅拌至溶解；
ii.在另一容器中，将200g羟丙基-β-环糊精溶于400mL纯化水中，将步骤ⅰ得到的溶液在搅拌下缓慢加入到羟丙基-β-环糊精溶液中；
iii.再加入200mL的70％的山梨糖醇溶液并搅拌至均相；0.6g糖精钠溶于50mL纯化水中，然后再加入上述均相溶液中；
iv.加入对羟基苯甲酸乙酯钠、草莓香精，并用10％的氢氧化钠溶液或10％的盐酸溶液调节混合物的pH至7.0，得到的溶液用纯化水稀释至1L；
v.用0.22μm的滤膜过滤步骤ⅳ得到的溶液，分装至10mL玻璃瓶中，充氮气，加塞，
轧盖，25℃以下保存。
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| Sanaz Sajedi-Amin et al..Solubilization of bosentan using ethanol as a pharmaceutical cosolvent.《Journal of Molecular Liquids》.2017,第232卷第152-158页. * |
| 杨红梅 等.《药剂学》.天津科学技术出版社,2020,(第1版),第29-30页. * |
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