CN116115589A - 一种吸入用西维来司他钠药物组合物及其制备方法 - Google Patents
一种吸入用西维来司他钠药物组合物及其制备方法 Download PDFInfo
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- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 title claims abstract description 56
- 229910052708 sodium Inorganic materials 0.000 title claims abstract description 56
- 239000011734 sodium Substances 0.000 title claims abstract description 56
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- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
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- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 4
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
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- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 4
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- 206010051379 Systemic Inflammatory Response Syndrome Diseases 0.000 description 3
- NCNFDKWULDWJDS-OAHLLOKOSA-N cilansetron Chemical compound CC1=NC=CN1C[C@@H]1C(=O)C(C=2C=3N4CCCC=3C=CC=2)=C4CC1 NCNFDKWULDWJDS-OAHLLOKOSA-N 0.000 description 3
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- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
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- 229940098458 powder spray Drugs 0.000 description 1
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- 210000002345 respiratory system Anatomy 0.000 description 1
- 229950009343 sivelestat Drugs 0.000 description 1
- BTGNGJJLZOIYID-UHFFFAOYSA-N sivelestat Chemical compound C1=CC(OC(=O)C(C)(C)C)=CC=C1S(=O)(=O)NC1=CC=CC=C1C(=O)NCC(O)=O BTGNGJJLZOIYID-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/007—Pulmonary tract; Aromatherapy
- A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
- A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
本发明公开了一种吸入用西维来司他钠的药物组合物及其制备方法,包括:治疗有效量的西维来司他钠和药学上可接受的辅料。将西维来司他钠和两亲性材料二硬脂酰基磷脂酰乙醇胺‑聚乙二醇分别溶于有机溶剂中,二者按比例混合,采用减压蒸发法除去有机溶剂,得含药脂膜,用水溶解后加入一定量的甘露醇,冻干,得药物组合物。本发明制备的西维来司他钠的药物组合物使用时先用水复溶后,通过吸入给药器雾化后吸入。该工艺方法简单,适合产业化规模,且用药方便、解决了西维来司他钠溶解度低、稳定性差的问题。
Description
技术领域
本发明涉及药物制剂领域,具体涉及一种治疗治疗伴有全身性炎症反应综合征(SIRS)的急性肺损伤(ALI)和急性呼吸窘迫综合征(ARDS)的药物西维来司他钠的药物组合物及其制备方法。
背景技术
急性肺损伤/急性呼吸窘迫综合征是一种临床常见危重症,病死率极高,严重威胁重症患者的生命。据统计,有超过10%的ALI患者需进入重症监护病房治疗,病死率高达32%-55%,近年来还有逐步增高的趋势。ALS/ARDS的基本病理生理改变是肺泡上皮细胞和肺毛细血管内皮通透性增加所致的非心源性肺水肿,由于肺泡水肿、肺泡塌陷导致严重通气/血流比例失调,特别是肺内分流明显增加,从而产生严重的低氧血症,导致急性低氧性呼吸功能不全或衰竭。临床上表现为进行性低氧血症和呼吸窘迫,肺部影像学表现为非均一性的渗出性病变。目前仍缺乏有效的治疗急性肺损伤的药物和方法。
肺部给药系统是指药物经特殊给药系统直接进入呼吸道发挥局部或全身治疗作用的给药系统,目前肺部给药系统有气雾剂、喷雾剂、粉雾剂或干粉吸入剂。
西维来司他钠(sivelestat sodium),化学名称:N-{2-[4-(2,2-二甲基丙酰氧基)苯磺酰氨基]苯甲酰基}氨基乙酸钠盐四水合物。分子式:C20H21N2NaO7S·4H2O,结构式如下:
西维来司他钠在水中的溶解度不到0.4mg/mL,用于注射剂或吸入剂,该溶解度都无法达到用药需求。同时,西维来司他钠在水溶液中易发生水解。
研究发现,水溶液的pH越高,西维来司钠在水溶液中的溶解度越好,但随着pH的升高,西维来司钠水解程度明显增加。随着西维来司他钠或其水合物在吸入药物组合物中的重量比增加,将对吸入药物组合物的稳定性产生显著影响,如杂质含量增加,且雾化后雾滴的均匀性差,难以控制雾滴粒径。
西维来司钠产品最早由日本小野制药株式会社研制,为冻干粉针剂,每瓶100mg,2002年在日本上市。临床适应症为治疗伴有SIRS的急性肺损伤。
CN114681435A公开了西维来司他钠吸入用冻干粉,含赋形剂甘露醇,pH调节剂,渗透压调节剂和表面活性剂,使用时将该冻干粉溶于水或载体,采用常规吸入装置雾化吸入。该冻干粉在前期溶液配制过程中,需要低温配制,制备条件苛刻,且存在杂质增长的问题。
CN107913261A公开了西维来司他钠干粉吸入剂,通过口腔或鼻腔吸入。吸入剂中由分散剂、助流剂和稀释剂组成。并加入抗静电剂及表面活性剂。干粉吸入剂需将物料置于球磨机中研磨1h,最终粒径可达0.5um-50μm。干粉吸入剂对颗粒的粒径要求比较严格,《中华人民共和国药典》2005版规定肺部吸入的雾滴或药物粒度应控制在10μm以下,其中大多数应在5μm以下,对工艺要求较高。
CN104107172A公开了西维来司他钠注射用冻干粉的制备方法,其非活性成分含有由磷酸二氢钠和氢氧化钠组成的pH调节剂以及赋形剂甘露醇。
CN1263736C公开的注射用西维来司他钠冻干制剂,含有选自磷酸三钠及其水合物、氢氧化钠或氢氧化钾的pH调节剂。
US7638556 B2公开了注射用西维来司他钠冻干制剂含有pH调节剂无水碳酸钠,以及氯化钠。
综上所述,西维来司他钠目前仅上市了注射制剂,现有文献报道公开的西维来司他钠剂型有注射用冻干粉、吸入用冻干粉及干粉吸入剂。因此,亟需一种能够免于注射的西维来司他钠制剂,而且工艺简单、用药方便、并能克服西维来司他钠溶解度低、不稳定的问题。
发明内容
为了克服现有技术的不足,本发明提供了一种吸入用西维来司他钠药物组合物,以及制备该药物组合物的方法。本发明所得的药物组合物制备工艺简单、用药方便、并能克服西维来司他钠溶解度低、不稳定性的问题。
为了解决上述现有技术存在的问题,本发明采取的技术解决方案为:
一种吸入用西维来司他钠药物组合物,包含:治疗有效量的西维来司他钠与药学上可接受的辅料。
所述的西维来司他钠,是指西维来司他钠的四水合物。
所述的辅料,包括两亲性材料和赋形剂。
所述的两亲性材料为二硬脂酰基磷脂酰乙醇胺-聚乙二醇,其中聚乙二醇的分子量为1000~4000Da,优选聚乙二醇的分子量为2000Da。
所述的赋形剂为乳糖或甘露醇,优选赋形剂为甘露醇。
详言之,其特征在于,西维来司他钠和两亲性材料的比例为1:10-1:40。
所述的吸入用西维来司他钠药物组合物,其制备方法如下:
(1)将西维来司他钠与二硬脂酰基磷脂酰乙醇胺-聚乙二醇分别溶于有机溶剂;所述易挥发有机溶剂选自:甲醇、乙醇、氯仿、丙酮、四氢呋喃;优选有机溶剂为甲醇;将西维来司他钠溶液和二硬脂酰基磷脂酰乙醇胺-聚乙二醇溶液在容器中按照比例混合均匀;
(2)采用减压蒸发法去除混合溶液中的有机溶剂,去除有机溶剂过程中,以惰性气体对容器中的蒸发体系进行填充,最终在容器中形成含药脂膜;优选惰性气体为N2;
(3)用水复溶含药脂膜,按比例加入一定量的甘露醇,至含药溶液完全溶解成澄明溶液,优选水为预充N2的饱和水;
(4)将复溶后的液体进行冻干,得药物组合物;
所述的吸入用西维来司他钠药物组合物使用时与水混合后,通过吸入给药器雾化后吸入。
有益效果:
1.吸入用西维来司他钠药物组合物,其复溶时间小于40秒。
2.吸入用西维来司他钠药物组合物经雾化器雾化后,粒径为0.5~7.0μm。
3.该药物组合物性质稳定,高温、高湿光照条件下,稳定性较好。
具体实施方式
以下结合实施例对本发明作进一步的详细说明。
实施例1-4制备的药物组合物中,各原料、两亲性材料和赋形剂如表1所示:
表1
实施例1
制备工艺:
(1)将西维来司他钠0.3g与二硬脂酰基磷脂酰乙醇胺-聚乙二醇9.6g分别溶于10ml甲醇中;将西维来司他钠甲醇溶液和二硬脂酰基磷脂酰乙醇胺-聚乙二醇甲醇溶液混合均匀;
(2)采用减压蒸发法去除混合溶液中的甲醇,去除过程中,以N2保护,最终在容器中形成含药脂膜;
(3)用5ml水复溶含药脂膜,加入4.5g甘露醇,至含药溶液完全溶解至澄清状态;
(4)将复溶后的液体进行冻干,得到药物组合物,冻干步骤如下:
①预冻:将隔板温度降至-40℃,放入样品,预冻温度为-40℃,预冻1h,保存3h。
②升华:升华温度:-30℃,真空度:0.2MPa,升华为630min。
③解析干燥:30min内将温度由-30℃升至0℃,随后1h内将温度由0℃升至15℃,保持0.5h。
实施例2
制备工艺:
(1)将西维来司他钠0.5g与二硬脂酰基磷脂酰乙醇胺-聚乙二醇9.4g分别溶于10ml甲醇中;将西维来司他钠甲醇溶液和二硬脂酰基磷脂酰乙醇胺-聚乙二醇甲醇溶液混合均匀;
(2)采用减压蒸发法去除混合溶液中的甲醇,去除过程中,以N2保护,最终在容器中形成含药脂膜;
(3)用5ml水复溶含药脂膜,加入4.5g甘露醇,至含药溶液完全溶解至澄清状态;
(4)将复溶后的液体进行冻干,得到药物组合物,冻干步骤如下:
①预冻:将隔板温度降至-40℃,放入样品,预冻温度为-40℃,预冻1h,保存3h。
②升华:升华温度:-30℃,真空度:0.2MPa,升华为630min。
③解析干燥:30min内将温度由-30℃升至0℃,随后1h内将温度由0℃升至15℃,保持0.5h。
实施例3
制备工艺:
(1)将西维来司他钠0.7g与二硬脂酰基磷脂酰乙醇胺-聚乙二醇9.2g分别溶于10ml甲醇中;将西维来司他钠甲醇溶液和二硬脂酰基磷脂酰乙醇胺-聚乙二醇甲醇溶液混合均匀;
(2)采用减压蒸发法去除混合溶液中的甲醇,去除过程中,以N2保护,最终在容器中形成含药脂膜;
(3)用5ml水复溶含药脂膜,加入4.5g甘露醇,至含药溶液完全溶解至澄清状态;
(4)将复溶后的液体进行冻干,得到药物组合物,冻干步骤如下:
①预冻:将隔板温度降至-40℃,放入样品,预冻温度为-40℃,预冻1h,保存3h。
②升华:升华温度:-30℃,真空度:0.2MPa,升华为630min。
③解析干燥:30min内将温度由-30℃升至0℃,随后1h内将温度由0℃升至15℃,保持0.5h。
实施例4
制备工艺:
(1)将西维来司他钠0.9g与二硬脂酰基磷脂酰乙醇胺-聚乙二醇9.0g分别溶于10ml甲醇中;将西维来司他钠甲醇溶液和二硬脂酰基磷脂酰乙醇胺-聚乙二醇甲醇溶液混合均匀;
(2)采用减压蒸发法去除混合溶液中的甲醇,去除过程中,以N2保护,最终在容器中形成含药脂膜;
(3)用5ml水复溶含药脂膜,加入4.5g甘露醇,至含药溶液完全溶解至澄清状态;
(4)将复溶后的液体进行冻干,得到药物组合物,冻干步骤如下:
①预冻:将隔板温度降至-40℃,放入样品,预冻温度为-40℃,预冻1h,保存3h。
②升华:升华温度:-30℃,真空度:0.2MPa,升华为630min。
③解析干燥:30min内将温度由-30℃升至0℃,随后1h内将温度由0℃升至15℃,保持0.5h。
外观:实施例1-4所制备的药物组合物为白色或类白色冻干粉。
复溶时间:将冻干样品以水复溶,复溶时间指将冻干制剂复溶于5mL水溶液中的所用的时间。本发明记录实施例1、实施例2、实施例3、实施例4的冻干样品的复溶时间,分别为30秒、40秒、35秒、37秒。
雾化后粒径:本发明的粒径测定方法采用将实施例1、实施例2、实施例3、实施例4的冻干样品以水复溶,将药液以PARI eflow雾化器进行雾化,采用新一代药用级联撞击器(NGI)测定其空气动力学直径(MMAD),设置流速为15L/min,结果显示,MMAD结果分别为6.045μm、4.843μm、3.242μm、5.073μm,表明本发明吸入用药物组合物能够获得符合药用需求的粒径。
实施例5
实施例3所制备的西维来司他钠药物组合物进行稳定性考察,具体试验条件、考察时间、考察项目及试验结果如表2和表3:
表2实验条件
表3试验结果
Claims (9)
1.一种吸入用西维来司他钠药物组合物,其特征在于,包含:治疗有效量的西维来司他钠与药学上可接受的辅料。
2.根据权利要求1所述的吸入用西维来司他钠药物组合物,其特征在于,所述的西维来司他钠,是指西维来司他钠的四水合物。
3.根据权利要求1所述的吸入用西维来司他钠药物组合物,其特征在于,所述的辅料包括,两亲性材料和赋形剂。
4.根据权利要求3所述的吸入用西维来司他钠药物组合物,其特征在于,所述的两亲性材料为二硬脂酰基磷脂酰乙醇胺-聚乙二醇。
5.根据权利要求3所述的吸入用西维来司他钠药物组合物,其特征在于,所述的赋形剂为乳糖或甘露醇,优选赋形剂为甘露醇。
6.根据权利要求4所述的吸入用西维来司他钠药物组合物,其特征在于,所述的两亲性材料为二硬脂酰基磷脂酰乙醇胺-聚乙二醇中的聚乙二醇的分子量为1000~4000Da,优选聚乙二醇的分子量为2000Da。
7.根据权利要求2所述的吸入用西维来司他钠药物组合物,其特征在于,西维来司他钠和两亲性材料的比例为1:10-1:40。
8.权利要求1所述的吸入用西维来司他钠药物组合物的制备方法,其特征在于,步骤如下:
(1)将西维来司他钠与二硬脂酰基磷脂酰乙醇胺-聚乙二醇分别溶于有机溶剂;所述易挥发有机溶剂选自:甲醇、乙醇、氯仿、丙酮、四氢呋喃;优选有机溶剂为甲醇;将西维来司他钠溶液和二硬脂酰基磷脂酰乙醇胺-聚乙二醇溶液在容器中按照比例混合均匀;
(2)采用减压蒸发法去除混合溶液中的有机溶剂,去除有机溶剂过程中,以惰性气体对容器中的蒸发体系进行填充,最终在容器中形成含药脂膜;优选惰性气体为N2;
(3)用水溶解含药脂膜,按比例加入一定量的甘露醇,至含药溶液完全溶解成澄明溶液,优选水为预充N2的饱和水;
(4)将溶解后的液体进行冻干得药物组合物。
9.权利要求1所述的吸入用西维来司他钠药物组合物,其特征在于,使用时将所述吸入用药物组合物与水混合后,通过吸入给药器雾化后吸入。
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