CN101856345A - 适合吸入式给药的药粉制造方法 - Google Patents
适合吸入式给药的药粉制造方法 Download PDFInfo
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- CN101856345A CN101856345A CN201010206264A CN201010206264A CN101856345A CN 101856345 A CN101856345 A CN 101856345A CN 201010206264 A CN201010206264 A CN 201010206264A CN 201010206264 A CN201010206264 A CN 201010206264A CN 101856345 A CN101856345 A CN 101856345A
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Abstract
本发明涉及可精确控制药粉颗粒气动力尺寸的药粉制造方法，适合于吸入式给药。本方法将3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物溶于碱性溶液后，将药物直接加入该溶液或将该碱性溶液与酸性溶液在高剪力环境下混合后形成混悬液后再将药物加入，并将该溶液或混悬液干燥，制成合适气动力尺寸(0.5-10微米)的药物颗粒。将药粉颗粒通过干粉吸入器输送到患者鼻腔、支气管和肺部等部位，利用药物颗粒在pH值于6.4-8之间的人体环境下快速溶解，在pH值小于等于6.4或者大于8的环境下稳定的特性，实现药物的快速有效吸收。
Description
技术领域
本发明涉及适合吸入式给药的药粉制造方法，尤其是利用3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪及其盐取代物作为药物载体的药粉制造方法。
背景技术
由于人体鼻腔、支气管和肺部的粘膜表面积很大，同时药物颗粒可以快速透过粘膜组织被人体吸收，并且可以避免肝脏的首过效应，因此相对于口服和皮下注射等给药方式，吸入式给药具有给药更迅速的治疗优势。目前有很多吸入式给药系统可以通过干粉吸入器或者是雾化器将化学药物成份或者生物药物成份送达患者鼻腔、支气管和肺部等部位，直接治疗鼻腔、支气管和肺部等部位的病变或者是透过鼻腔、支气管和肺部等部位的粘膜组织直接被人体吸收，实现全身性给药，治疗其他部位的病变。
吸入式给药对药物颗粒的气动力尺寸要求较高，只有气动力直径0.5-10微米之间的药物颗粒才可以有效沉积到人体鼻腔、支气管和肺部等处，从而被人体有效吸收。大于10微米的颗粒将沉积到口腔或者喉管，无法达到鼻腔、支气管和肺部等有效吸收部位，而小于0.5微米的颗粒将随患者呼气而呼出体外。但是通常气动力直径0.5-10微米之间的药物粉末颗粒通常很容易结团，这进一步增加了精确控制药物颗粒的气动力尺寸，从而实现精确给药的难度。目前市场上绝大多数的吸入式给药系统无法精确控制药物颗粒的气动力尺寸，在患者吸入这些药物以后，通常只有少量颗粒具有合适的气动力尺寸(0.5-10微米之间)并可以沉积到粘膜表面进而被人体吸收，因此通常吸入式给药需要较大剂量，并且无法做到精确给药。
此外，目前很多吸入式药物颗粒在pH值于6.4-8之间的人体环境下无法达到快速溶解，其所携带的有效药物成份无法通过粘膜组织被人体快速吸收，没有发挥呼吸系统给药给药迅速的优势；并且在粘膜表面残存的固体颗粒会带来呼吸系统病变等副作用。
因此本专利的目标是发明一种可以精确控制药粉颗粒气动力尺寸从而精确控制给药剂量的药粉制造方法，适合于吸入式给药。本专利使用在一定的pH值和温度下保持稳定、同时在另一特定的pH值和温度环境下能够迅速溶解并被人体吸收进而快速送达指定部位的化学物质如3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物等，采用特定工艺制成具有适宜性质(如颗粒大小、形状、表面特性、密度、颗粒间粘结力、结构强度、溶解度等以及低毒性)的药物载体颗粒，将有效药物成份加载到这种药物载体颗粒上后形成具有适宜气动力尺寸的药物颗粒。这种具有适宜气动力尺寸的药物颗粒可以通过吸入式给药的方式被有效地输送到患者鼻腔、支气管和肺部等部位，沉积到患者鼻腔、支气管和肺部等部位的药物颗粒可以在pH值于6.4-8之间的人体环境下快速溶解，并透过人体粘膜组织快速被人体吸收，从而实现给药剂量的精确控制进而达到预期的治疗效果。
发明内容
3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪及其盐取代物的分子通式
是：
其中当X为氢时，为3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪；当X为金属离子如锂、钠、钾等或铵根离子时，则为相应的3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪盐取代物。
药粉颗粒的一种制造方法是将3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物溶于碱性溶液(如氨水溶液等)，与酸性溶液(如冰醋酸等)在高剪力环境下(如高速搅拌器)进行快速混合，溶解的3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物成份将沉淀成合适大小的固体颗粒，形成混悬液。将混悬液用水或有机溶剂进行漂洗，以去除残留的酸或者碱成份。将有效药物成份加入混悬液中，使之加载到混悬液中的固体3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物颗粒上，调节混悬液的pH值后，喷雾干燥制成药物粉末或者将混悬液滴入液氮中形成冷冻固体颗粒，将冷冻固体颗粒冷冻干燥成药物粉末。
药粉颗粒的另一种制造方法实例是将3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物溶于碱性溶液(如氨水溶液等)，将有效药物成份加入混合溶液中，调节混合溶液的pH值后再将混合液通过冷冻干燥或者喷雾干燥直接制成药物粉末。
作为一个通用的可以通过呼吸系统如鼻腔、支气管和肺部等部位进行有效的全身性给药的药物颗粒载体平台，基本上所有药物都可以加载到本专利的3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物药物载体颗粒上，实现药物成份的吸入式给药输送。可加载药物包括合成的无机或者有机化学物质、蛋白质和多肽、多糖和其他糖、类脂、具有治疗作用的核酸序列、具有预防和诊断意义的物质等。例如蛋白质(多于100个氨基酸)，多肽(少于100个氨基酸)，如胰岛素和其他荷尔蒙如生长荷尔蒙，多糖如肝磷脂，核酸，脂质，脂多糖类，以及其他具有生物活性的物质如抗生素，抗发炎药物，抗病毒药物，刺激血管与神经系统的药物等等。具体例子包括荷尔蒙，抗凝药物，免疫调节剂，细胞毒素类药物，抗生素，抗病毒素，反义核酸，抗原，抗体等等。这些适用药物的生物反应也可以有很大不同，比如神经调节剂、荷尔蒙、抗原、抗体、血管扩张剂、血管收缩剂、抗生素、抗病毒剂、抗凝剂、免疫调节剂、细胞毒素剂、麻醉剂等等。具体药物包括非氨酯、美拉诺坦、重组人粒细胞集落刺激因子、胰高糖素样肽、肝素、副甲状腺荷尔蒙、甲状旁腺激素、生长荷尔蒙、皮质激素、促红细胞生成素、叠氮胸苷、β-干扰素、α-干扰素、γ-干扰素、双脱氧胞苷、粒细胞集落刺激因子、胰岛素、肝磷脂、降血钙素、拉莫三嗪、促性腺激素释放激素、绒毛膜促性腺激素、黄体生成激素释放因子、促肾上腺皮质激素、阿加曲班、β-D-半乳糖苷酶、西特那非、双氢麦角胺、硝酸甘油、溴化异丙托溴铵、丙酸氟替卡松氢氟烷、糖皮质激素、硫酸沙丁胺醇、利血平、心得安、利多卡因、美多心安、舒喘灵、利他灵、吗啡、度冷丁、阿司匹林、可的松、丙咪臻、二氧丙嗪、替培啶、依普拉酮、苯丙哌啉、右美沙芬、喘必灵、舒弗美、伐地那非、他达那非、威猛、阿布马、达泊西汀、布洛芬、消炎痛、扑热息痛、保泰松、罗非昔布、塞来昔布、曲马多、格列苯脲、格列波脲、格列吡嗪、格列齐特、格列喹酮、格列美脲、罗格列酮、吡格列酮、二甲双胍、苯乙双胍、α-葡萄糖苷酶抑制剂等等。每摩尔可以加载1到1百万克的药物成份。
药物成份的加载可以使用以下方法：可以将药物成份与3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物等载体成份溶于溶液后直接干燥成粉，或者将药物成份直接加载到含有3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物载体微颗粒的混悬液中再干燥成粉，或者将药物成份先溶于溶剂中再加载到制备好的含有3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物载体微颗粒的混悬液中然后干燥成粉，或者是将药物成份直接加载到已干燥的3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物载体微颗粒粉末中搅拌或干燥后制成药粉，或者是将药物成份溶于溶液后喷洒到已干燥的3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物载体微颗粒粉末中搅拌或干燥后制成药粉。
这里所描述的药物成份加载方法只是代表性的方法，本专利申请的加载方法不仅仅局限于上述方法，凡是与本发明性质相似的方法均应纳入本专利保护范围。
可以使用多种方法传送使用本专利的方法制造的药物颗粒，如使用喷雾器通过鼻腔给药，或者是使用干粉吸入器通过口腔给药。干粉吸入器包括使用推进剂的类型和通过病人主动呼吸的类型等多种类型。
具体实施方式
实施例1：将10克3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪粉末溶于3升3％的氨水溶液中，形成溶液A。并配好3升的5％冰醋酸溶液，形成溶液B。将溶液A和B在容器中使用高速搅拌器快速充分混合，形成含有微米级微颗粒的悬浮液C。将悬浮液C用50升高纯水过滤漂洗浓缩后，得到500毫升浓缩的混悬液D。将6克胰岛素粉末溶于50毫升3％的冰醋酸溶液中，形成溶液E。将浓缩混悬液D和含有药物成份胰岛素的冰醋酸溶液E混合后，并用氨水调节悬浮液的pH值到4.0-5.0，得到550毫升的混悬液F。将混悬液F滴入液氮中形成冷冻固体颗粒510克，将冷冻固体颗粒冷冻干燥48小时，得到含有胰岛素成份的适于吸入式给药的药粉12.8克。
实施例2：将10克3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪粉末溶于3升3％的氨水溶液中，形成溶液A。并配好3升的5％冰醋酸溶液，形成溶液B。溶液A和B在容器中使用高速搅拌器快速充分混合，形成含有微米级微颗粒的悬浮液C。将悬浮液C用50升高纯水过滤漂洗浓缩后，得到500毫升浓缩的混悬液D。将6克胰岛素粉末溶于50毫升3％的冰醋酸溶液中，形成溶液E。将浓缩混悬液D和含有药物成份胰岛素的冰醋酸溶液E混合后，并用氨水调节悬浮液的pH值为4-5之间，得到550毫升的混悬液F。用喷雾干燥器将悬浮液F干燥，形成含有胰岛素成份的适于吸入式给药的药粉11.3克。
实施例3：直接将10克3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪粉末和6克胰岛素粉末直接溶于5升3％的氨水溶液中，形成溶液A，用氨水调节溶液的pH值为7.5-8.5之间，用喷雾干燥器直接将溶液A干燥，得到含有胰岛素成份的适于吸入式给药的药粉9.5克。
实施例4：将1.7克氢氧化钠溶于3升水中，加入10克3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪形成含有双钠-3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪(一种3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪的盐取代物)的溶液A，加入6克胰岛素粉末后充分搅拌形成溶液B，用氨水调节溶液B的pH值为7.5-8.5之间，用喷雾干燥器干燥，得到含有胰岛素成份的适于吸入式给药的药粉8.1克。
实施例5：将10克3，6-双(反式丁烯二酰基-4-氨丁基)-2，5-二酮哌嗪粉末溶于3升3％的氨水溶液中，形成溶液A。将溶液A和3升的5％冰醋酸溶液B在容器中使用高速搅拌器快速充分混合，形成含有微米级微颗粒的悬浮液C。将悬浮液C用50升高纯水过滤漂洗浓缩后，得到浓缩的2升混悬液D。将6克胰岛素粉末溶于100毫升3％的冰醋酸溶液中，形成溶液E。将混悬液D和含有药物成份胰岛素的冰醋酸溶液E混合后，并用氨水调节悬浮液的pH值为4-5之间，得到2100毫升的混悬液F。用喷雾干燥器将悬浮液F干燥，得到含有胰岛素成份的适于吸入式给药的药粉7.0克。
Claims (10)
1.适合吸入式给药的药粉制造方法，包括如下步骤：
(1)将3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物溶于碱性溶液，形成溶液；
(2)将有效药物成份加入溶液中；
(3)调节该溶液的PH值后，将含有药物成份的溶液干燥成药物粉末。
2.如权利要求1所述的药粉制造方法，在步骤(1)中将3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物溶于碱性溶液后，再与酸性溶液在高剪力环境下进行快速混合，形成混悬液，并用水或有机溶剂进行漂洗，去除残留的酸或者碱成份；步骤(2)为将有效药物成份加入混悬液中；步骤(3)为调节该混悬液的PH值后，将含有药物成份的混悬液干燥成药物粉末。
3.如权利要求1或2所述的药粉制造方法，其特征在于所述步骤(3)的干燥方法为将溶液或者混悬液滴入液氮中形成冷冻固体颗粒，再将冷冻固体颗粒冷冻干燥成药物粉末。
4.如权利要求1或2所述的药粉制造方法，其特征在于所述步骤(3)的干燥方法为喷雾干燥制成药物粉末。
5.如权利要求1所述的药粉制造方法，其特征在于所述步骤(3)的干燥方法为调节溶液的pH值为7.5-8.5后，冷冻干燥或者喷雾干燥制成药物粉末。
6.如权利要求2所述的药粉制造方法，其特征在于所述步骤(3)的干燥方法为调节混悬液的pH值为4.0-5.0后，冷冻干燥或者喷雾干燥制成药物粉末。
7.如权利要求1所述药粉制造方法，其特征在于所述碱性溶液为氨水。
8.如权利要求2所述药粉制造方法，其特征在于所述碱性溶液为氨水，所述酸性溶液为冰醋酸溶液。
9.如上述任意一项权利要求，其特征在于所述的药物成分包括合成的无机或者有机化学物质、蛋白质和多肽、多糖和其他糖、类脂、具有治疗作用的核酸序列、具有预防和诊断意义的物质等。
10.如权利要求1或2所述药粉制造方法，在完成步骤(1)后，直接将混悬液或溶液干燥，再将药物成份加载到或喷洒到已干燥的3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪或其盐取代物载体微颗粒粉末中搅拌或干燥后制成药粉。
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958752A (zh) * | 2011-10-10 | 2015-10-07 | 安皮奥制药股份有限公司 | 退行性关节病的治疗 |
| US9925300B2 (en) | 2011-10-10 | 2018-03-27 | Ampio Pharmaceuticals, Inc. | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
| CN111544420A (zh) * | 2020-05-22 | 2020-08-18 | 中国药科大学 | 可吸入泡腾粉雾剂及其在制备感染性肺炎药物中的应用 |
| US11389512B2 (en) | 2015-06-22 | 2022-07-19 | Ampio Pharmaceuticals, Inc. | Use of low molecular weight fractions of human serum albumin in treating diseases |
| CN116687888A (zh) * | 2023-06-02 | 2023-09-05 | 苏州易合医药有限公司 | 伐地那非和达泊西汀复方干粉吸入制剂及其制备方法 |
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2010
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Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104958752A (zh) * | 2011-10-10 | 2015-10-07 | 安皮奥制药股份有限公司 | 退行性关节病的治疗 |
| US9925300B2 (en) | 2011-10-10 | 2018-03-27 | Ampio Pharmaceuticals, Inc. | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
| CN104958752B (zh) * | 2011-10-10 | 2019-01-18 | 安皮奥制药股份有限公司 | 退行性关节病的治疗 |
| US10251930B2 (en) | 2011-10-10 | 2019-04-09 | Ampio Pharmaceuticals, Inc. | Treatment of degenerative joint disease |
| US10471178B2 (en) | 2011-10-10 | 2019-11-12 | Ampio Pharmaceuticals, Inc. | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
| US10842847B2 (en) | 2011-10-10 | 2020-11-24 | Ampio Pharmaceuticals, Inc. | Treatment of degenerative joint disease |
| US11058798B2 (en) | 2011-10-10 | 2021-07-13 | Ampio Pharmaceuticals, Inc. | Implantable medical devices with increased immune tolerance, and methods for making and implanting |
| US11389512B2 (en) | 2015-06-22 | 2022-07-19 | Ampio Pharmaceuticals, Inc. | Use of low molecular weight fractions of human serum albumin in treating diseases |
| CN111544420A (zh) * | 2020-05-22 | 2020-08-18 | 中国药科大学 | 可吸入泡腾粉雾剂及其在制备感染性肺炎药物中的应用 |
| CN111544420B (zh) * | 2020-05-22 | 2022-04-29 | 中国药科大学 | 可吸入泡腾粉雾剂及其在制备感染性肺炎药物中的应用 |
| CN116687888A (zh) * | 2023-06-02 | 2023-09-05 | 苏州易合医药有限公司 | 伐地那非和达泊西汀复方干粉吸入制剂及其制备方法 |
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