CN112569211A - 一种吸入用加替沙星溶液及其制备方法 - Google Patents
一种吸入用加替沙星溶液及其制备方法 Download PDFInfo
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- XUBOMFCQGDBHNK-JTQLQIEISA-N (S)-gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCN[C@@H](C)C1 XUBOMFCQGDBHNK-JTQLQIEISA-N 0.000 title claims abstract description 44
- 229960003923 gatifloxacin Drugs 0.000 title claims abstract description 44
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- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 27
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 26
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- UNXNGGMLCSMSLH-UHFFFAOYSA-N dihydrogen phosphate;triethylazanium Chemical group OP(O)(O)=O.CCN(CC)CC UNXNGGMLCSMSLH-UHFFFAOYSA-N 0.000 description 1
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- XUBOMFCQGDBHNK-UHFFFAOYSA-N gatifloxacin Chemical compound FC1=CC(C(C(C(O)=O)=CN2C3CC3)=O)=C2C(OC)=C1N1CCNC(C)C1 XUBOMFCQGDBHNK-UHFFFAOYSA-N 0.000 description 1
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- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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Abstract
本发明涉及一种吸入用加替沙星溶液及其制备方法,该吸入溶液包含活性成分加替沙星、增溶剂、稳定剂、pH调节剂、渗透压调节剂和溶剂;采用本发明所述的吸入用加替沙星溶液制剂不含抛射剂,借助雾化泵或压缩空气压力将药物释出的吸入溶液剂,剂量规格为1ml~5ml;具有计量准确、疗效好;不含防腐剂、质量稳定、副反应少等优点。
Description
技术领域
本发明属于医药领域,具体涉及一种吸入用加替沙星溶液及其制备方法。
背景技术
加替沙星是第四代氟喹诺酮类抗菌药物,属于8-甲氧氟喹诺酮类外消旋化合物,具有广谱的抗革兰氏阴性和阳性微生物和活性,由Kyorin Pharmaceutical(日本杏林制药株式会社)首次研制成功,其R-和S-对映体抗菌活性相同,通过抑制细菌的DNA旋转酶和拓扑异构酶IV,从而抑制细菌DNA复制、转录和修复过程而起作用,对多种细菌都有强大的抗菌作用,对于呼吸系统感染和生殖系统感染有较好的疗效,是近年来增长迅速的“呼吸氟喹诺酮”类药物的代表之一。临床主要用于治疗由敏感病原体所致的各种轻、中度感染性疾病,包括:呼吸道感染疾病、单纯性尿路感染和复杂性尿路感染、膀胱炎、急性肾盂肾炎以及由奈瑟淋球菌引起的尿道、宫颈、直肠感染。在用于呼吸道感染疾病方面,在治疗慢性支气管炎急性发作、急性支气管炎、社区获得性肺炎等呼吸系统疾病中,均可起到显著疗效。
加替沙星用于治疗敏感菌株引起的中度以上的感染性疾病。其化学名称:(±)-1-环丙基-6-氟-1,4-二氢-8-甲氧基-7-(3-甲基-1-哌嗪基)-4-氧代-3-喹啉羧酸;化学式:C19H22FN3O4,分子量:375.40,结构式:
目前国内外市场上所售加替沙星剂型为片剂、胶囊剂、粉针、滴眼液、注射液、分散片、眼用凝胶剂,但无吸入制剂,已上市剂型均不能直达病变部位用于治疗呼吸道感染疾病。
本发明克服上述缺点,提供一种起效迅速、使用范围更广的药物。本发明的吸入溶液制剂,可通过特殊装置将药物和溶剂驱散成雾滴或微粒、气溶胶,让病人吸入,使药物沉降在鼻咽喉、各级支气管及肺泡内,从而达到局部或全身治疗作用。吸入治疗尤其适用于哮喘、COPD、呼吸道感染、囊性纤维化、肺心病、肺动脉高压等呼吸系统疾病的治疗,并且方便儿童、老年人、重患病人等特殊人群用药。本发明的液体制剂符合高质量标准,具有吸收快、疗效高、生物利用度高、无胃肠毒副作用及刺激性的特点,可将药物直接作用于病变部位,雾化吸入溶液起效快,且更适合低龄儿童、术后病人和老年人。
发明内容
本发明目的在于提供一种不含抛射剂,借助雾化泵或压缩空气压力将药物释出的吸入溶液剂,剂量规格为1ml~5ml。具有计量准确、疗效好;不含防腐剂、质量稳定、副反应少等优点。
本发明目的在于提供一种吸入溶液,用于治疗由肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌、卡他莫拉菌或金黄色葡萄球菌等所致的慢性支气管炎急性发作和社区获得性肺炎。
在上述吸入溶液中,其特征在于所述吸入溶液为吸入用加替沙星溶液。
在上述吸入溶液中,其特征在于所述吸入溶液包括活性成分加替沙星、增溶剂、稳定剂、pH调节剂、渗透压调节剂和溶剂。
在上述吸入溶液中,其特征在于所述吸入溶液中活性成分加替沙星浓度为20~100mg/ml。
在上述吸入溶液中,其特征在于所述增溶剂选自乙醇、氨丁三醇中的一种或两种组合物,其用量为0.001~25%w/v。
在上述吸入溶液中,其特征在于所述稳定剂选自丙二醇、依地酸二钠、焦亚硫酸钠、亚硫酸氢钠中的一种或几种组合物,其用量为0.003~25%w/v。
在上述吸入溶液中,其特征在于所述pH调节剂为药学上可接受的酸或者碱,具体选自柠檬酸、柠檬酸钠、乳酸、盐酸、磷酸二氢钠、磷酸氢二钠、甘氨酸、氢氧化钠中的一种或几种组合物。
在上述吸入溶液中,其特征在于所述渗透压调节剂选自无机盐类渗透压调节剂,具体选自氯化钠、氯化钾、氯化镁、氯化钙中的一种或多种,优选为氯化钠,其用量为0.60~0.85%w/v。
在上述吸入溶液中,其特征在于所述溶剂选用纯化水、注射用水或无菌注射用水。
在上述吸入溶液中,其特征在于所述吸入溶液的pH值为3.0~10.0,更优为3.0~6.0;
本发明的另一目的在于提供一种加替沙星吸入溶液的制备方法。所述制备流程简单,重现性好,产品稳定性好,易于大规模工业化生产。
具体包括以下步骤:
步骤一:向配液器中加入总体积50~80%的溶剂,水温控制在20℃~60℃;
步骤二:将处方量的增溶剂、稳定剂、渗透压调节剂加入步骤一的溶剂中,搅拌使溶解;
步骤三:将pH调节剂加入至步骤二的溶液中,搅拌使溶解,使pH值为3.0~10.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
与现有技术相比,本发明技术方案具有如下有益效果:
1、本发明提供一种用于治疗由肺炎链球菌、流感嗜血杆菌、副流感嗜血杆菌、卡他莫拉菌或金黄色葡萄球菌等所致的慢性支气管炎急性发作和社区获得性肺炎的吸入溶液剂。
2、本发明提供一种不含抛射剂,借助雾化泵或压缩空气压力将药物释出的加替沙星吸入溶液剂,剂量规格为1ml-5ml,计量准确、疗效好。
3、本发明提供了一种通过加入增溶剂和控制pH值范围,以提高加替沙星溶解度的方法。
4、本发明提供了一种不含防腐剂,且质量稳定、副反应少的吸入溶液。
5、本发明的吸入溶液制备工艺简单,重现性好,产品稳定性好,易于大规模工业化生产。
具体实施方式
下面将结合实施例对本发明的实施方案进行详细描述,但本领域技术人员将会理解,下列实施例仅用于说明本发明,而不应视为限定本发明的范围。实施例中的实验方法,如无特殊说明,均为常规方法;所用的原料、试剂材料等,如无特殊说明,均为市售购买产品。
实施例1
处方组成
制备方法:
步骤一:向配液器中加入500ml的溶剂,水温控制在25℃;
步骤二:将处方量氨丁三醇、焦亚硫酸钠、氯化钠加入步骤一的溶剂中,搅拌使溶解;
步骤三:将柠檬酸、柠檬酸钠加入至步骤二的溶液中,搅拌使溶解,使pH值为3.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例2
处方组成
名称 | 组成 |
加替沙星 | 50g |
乙醇 | 100g |
柠檬酸 | 0.25g |
柠檬酸钠 | 0.20g |
焦亚硫酸钠 | 5g |
氯化钠 | 8.2g |
加溶剂至 | 1000ml |
制备方法:
步骤一:向配液器中加入800ml的溶剂,水温控制在30℃;
步骤二:将处方量乙醇、焦亚硫酸钠、氯化钠加入步骤一的溶剂中,搅拌使溶解;
步骤三:将柠檬酸、柠檬酸钠加入至步骤二的溶液中,搅拌使溶解,使pH值为4.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例3
处方组成
名称 | 组成 |
加替沙星 | 100g |
乙醇 | 100g |
氨丁三醇 | 0.10g |
柠檬酸 | 0.30g |
柠檬酸钠 | 0.25g |
亚硫酸氢钠 | 10g |
氯化钠 | 7.0g |
加溶剂至 | 1000ml |
制备方法:
步骤一:向配液器中加入600ml的溶剂,水温控制在60℃;
步骤二:将处方量乙醇、氨丁三醇、亚硫酸氢钠、氯化钠加入步骤一的溶剂中,搅拌使溶解;
步骤三:将柠檬酸、柠檬酸钠加入至步骤二的溶液中,搅拌使溶解,使pH值为4.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例4
处方组成
名称 | 组成 |
加替沙星 | 50g |
氨丁三醇 | 0.01g |
柠檬酸 | 0.17g |
柠檬酸钠 | 0.35g |
依地酸二钠 | 0.03g |
氯化钠 | 8.0g |
加溶剂至 | 1000ml |
制备方法:
步骤一:向配液器中加入800ml的溶剂,水温控制在20℃;
步骤二:将处方量氨丁三醇、依地酸二钠、氯化钠加入步骤一的溶剂中,搅拌使溶解;
步骤三:将柠檬酸、柠檬酸钠加入至步骤二的溶液中,搅拌使溶解,使pH值为6.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例5
处方组成
名称 | 组成 |
加替沙星 | 50g |
乙醇 | 50g |
磷酸氢二钠 | 1.7g |
磷酸二氢钠 | 0.04g |
丙二醇 | 50g |
氯化钙 | 6.5g |
加溶剂至 | 1000ml |
制备方法:
步骤一:向配液器中加入800ml的溶剂,水温控制在30℃;
步骤二:将处方量乙醇、丙二醇、氯化钙加入步骤一的溶剂中,搅拌使溶解;
步骤三:将磷酸氢二钠、磷酸二氢钠加入至步骤二的溶液中,搅拌使溶解,使pH值为8.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例6
处方组成
名称 | 组成 |
加替沙星 | 50g |
氨丁三醇 | 0.01g |
甘氨酸 | 0.75g |
氢氧化钠 | 0.07g |
焦亚硫酸钠 | 5.0g |
氯化钠 | 6.5g |
加溶剂至 | 1000ml |
制备方法:
步骤一:向配液器中加入700ml的溶剂,水温控制在30℃;
步骤二:将处方量氨丁三醇、焦亚硫酸钠、氯化钠加入步骤一的溶剂中,搅拌使溶解;
步骤三:将甘氨酸、氢氧化钠加入至步骤二的溶液中,搅拌使溶解,使pH值为10.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例7
处方组成
名称 | 组成 |
加替沙星 | 80g |
乙醇 | 150g |
乳酸 | 适量 |
丙二醇 | 80g |
氯化镁 | 8.5g |
加溶剂至 | 1000ml |
制备方法:
步骤一:向配液器中加入800ml的溶剂,水温控制在30℃;
步骤二:将处方量乙醇、丙二醇、氯化镁加入步骤一的溶剂中,搅拌使溶解;
步骤三:将乳酸加入至步骤二的溶液中,搅拌使溶解,使pH值为4.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
实施例8
处方组成
制备方法:
步骤一:向配液器中加入800ml的溶剂,水温控制在30℃;
步骤二:将处方量氨丁三醇、焦亚硫酸钠、氯化钾加入步骤一的溶剂中,搅拌使溶解;
步骤三:将稀盐酸加入至步骤二的溶液中,搅拌使溶解,使pH值为4.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
试验例稳定性试验
取实施例1-8制备的加替沙星吸入溶液剂,于60℃条件下放置10天;采用HPLC测试实施例1-8制备的加替沙星吸入溶液剂第0天加替沙星的含量,及加速实验后实施例1-8的加替沙星吸入溶液剂中加替沙星含量;检测条件:采用HPLC法,色谱柱为Agilent HC-C18(250mm×4.6mm,5μm);流动相为三乙胺磷酸溶液[三乙胺溶液(1→100),用磷酸调节pH值至4.3]-乙腈(87∶13),梯度洗脱;检测波长为325nm,柱温为30℃
检测结果见表1。
表1加速试验前后加替沙星吸入溶液剂中加替沙星的含量变化
由表1可知,在本发明保护范围内的加替沙星吸入溶液剂中经加速试验后杂质含量低于1.2%。在步骤三中,药学上可接受的碱的碱性过强会破坏加替沙星;另外,本发明的吸入溶液质量稳定、副反应少。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这些仅是举例说明,在不背离本发明的原理和实质的前提下,可以对这些实施方式做成多种变更或修改。因此,本发明的保护范围由所属权利要求书限定。
Claims (9)
1.一种吸入用加替沙星溶液制剂,其特征在于:包含加替沙星、增溶剂、稳定剂、pH调节剂、渗透压调节剂和溶剂。
2.根据权利要求1所述的制剂,其特征在于:所述加替沙星的含量为20~100mg/ml。
3.根据权利要求1所述的制剂,其特征在于:所述增溶剂选自乙醇、氨丁三醇中的一种或两种组合物,其用量为0.001~25%w/v。
4.根据权利要求1所述的制剂,其特征在于:所述稳定剂选自丙二醇、依地酸二钠、焦亚硫酸钠、亚硫酸氢钠中的一种或几种组合物,其用量为0.003~25%w/v。
5.根据权利要求1所述的制剂,其特征在于:所述pH调节剂为药学上可接受的酸或者碱,选自柠檬酸、柠檬酸钠、乳酸、盐酸、磷酸二氢钠、磷酸氢二钠、甘氨酸、氢氧化钠中的一种或几种组合物。
6.根据权利要求1所述的制剂,其特征在于:所述渗透压调节剂选自无机盐类渗透压调节剂,具体选自氯化钠、氯化钾、氯化镁、氯化钙中的一种或多种,优选为氯化钠,其用量为0.60~0.85%w/v。
7.根据权利要求1所述的制剂,其特征在于:所述溶剂选自纯化水、注射用水或无菌注射用水。
8.根据权利要求1所述的制剂,其特征在于:所述吸入溶液的pH值为3.0~10.0,更优为3.0~6.0。
9.根据权利要求1-8任一所述制剂的制备方法:其特征在于,包括如下步骤:
步骤一:向配液器中加入总体积50~80%的溶剂,水温控制在25℃~60℃;
步骤二:将处方量的增溶剂、稳定剂、渗透压调节剂加入步骤一的溶剂中,搅拌使溶解;
步骤三:将pH调节剂加入至步骤二的溶液中,搅拌使溶解,使pH值为3.0~10.0;
步骤四:加入处方量的加替沙星至步骤三的溶液中,搅拌使溶解;
步骤五:加溶剂至全量,搅拌均匀,用0.22μm滤膜或滤芯过滤;
步骤六:灌装,密封。
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