CN113116866A - 适合于吸入的盐酸丙卡特罗的药物组合物 - Google Patents
适合于吸入的盐酸丙卡特罗的药物组合物 Download PDFInfo
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- CN113116866A CN113116866A CN202110280057.1A CN202110280057A CN113116866A CN 113116866 A CN113116866 A CN 113116866A CN 202110280057 A CN202110280057 A CN 202110280057A CN 113116866 A CN113116866 A CN 113116866A
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- procaterol hydrochloride
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- LZULAZTXJLWELL-UHFFFAOYSA-N methyl hex-5-ynoate Chemical group COC(=O)CCCC#C LZULAZTXJLWELL-UHFFFAOYSA-N 0.000 title claims abstract description 39
- 229960002789 procaterol hydrochloride Drugs 0.000 title claims abstract description 39
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- 239000003814 drug Substances 0.000 claims abstract description 25
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 32
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 29
- 230000003204 osmotic effect Effects 0.000 claims description 20
- 238000002347 injection Methods 0.000 claims description 19
- 239000007924 injection Substances 0.000 claims description 19
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 18
- 239000000443 aerosol Substances 0.000 claims description 16
- 229940041682 inhalant solution Drugs 0.000 claims description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 15
- 238000003825 pressing Methods 0.000 claims description 14
- 239000003381 stabilizer Substances 0.000 claims description 14
- 239000008215 water for injection Substances 0.000 claims description 14
- 239000007788 liquid Substances 0.000 claims description 13
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 claims description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 12
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 10
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 8
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 8
- 238000005303 weighing Methods 0.000 claims description 8
- 239000003380 propellant Substances 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 235000001727 glucose Nutrition 0.000 claims description 6
- UKACHOXRXFQJFN-UHFFFAOYSA-N heptafluoropropane Chemical compound FC(F)C(F)(F)C(F)(F)F UKACHOXRXFQJFN-UHFFFAOYSA-N 0.000 claims description 6
- NNPPMTNAJDCUHE-UHFFFAOYSA-N isobutane Chemical compound CC(C)C NNPPMTNAJDCUHE-UHFFFAOYSA-N 0.000 claims description 6
- 229940124531 pharmaceutical excipient Drugs 0.000 claims description 6
- 239000001103 potassium chloride Substances 0.000 claims description 6
- 235000011164 potassium chloride Nutrition 0.000 claims description 6
- 239000011780 sodium chloride Substances 0.000 claims description 6
- 239000004471 Glycine Substances 0.000 claims description 5
- 238000005096 rolling process Methods 0.000 claims description 5
- 239000001509 sodium citrate Substances 0.000 claims description 5
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 5
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 claims description 4
- LVGUZGTVOIAKKC-UHFFFAOYSA-N 1,1,1,2-tetrafluoroethane Chemical compound FCC(F)(F)F LVGUZGTVOIAKKC-UHFFFAOYSA-N 0.000 claims description 4
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 claims description 4
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 239000005642 Oleic acid Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000654 additive Substances 0.000 claims description 4
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 4
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 claims description 4
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 229960003966 nicotinamide Drugs 0.000 claims description 4
- 235000005152 nicotinamide Nutrition 0.000 claims description 4
- 239000011570 nicotinamide Substances 0.000 claims description 4
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 235000002639 sodium chloride Nutrition 0.000 claims description 4
- 230000001502 supplementing effect Effects 0.000 claims description 4
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 claims description 4
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 3
- 239000001282 iso-butane Substances 0.000 claims description 3
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 claims description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 claims description 3
- 229940001584 sodium metabisulfite Drugs 0.000 claims description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 claims description 3
- LQZZUXJYWNFBMV-UHFFFAOYSA-N 1-dodecanol group Chemical group C(CCCCCCCCCCC)O LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 claims description 2
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 229960002449 glycine Drugs 0.000 claims description 2
- 239000001294 propane Substances 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- 229960005480 sodium caprylate Drugs 0.000 claims description 2
- BYKRNSHANADUFY-UHFFFAOYSA-M sodium octanoate Chemical compound [Na+].CCCCCCCC([O-])=O BYKRNSHANADUFY-UHFFFAOYSA-M 0.000 claims description 2
- 239000001488 sodium phosphate Substances 0.000 claims description 2
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- CYRMSUTZVYGINF-UHFFFAOYSA-N trichlorofluoromethane Chemical group FC(Cl)(Cl)Cl CYRMSUTZVYGINF-UHFFFAOYSA-N 0.000 claims description 2
- 229940029284 trichlorofluoromethane Drugs 0.000 claims description 2
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 3
- 238000004519 manufacturing process Methods 0.000 claims 2
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- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 abstract description 3
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- 239000012535 impurity Substances 0.000 description 12
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- 239000000018 receptor agonist Substances 0.000 description 3
- 229940044601 receptor agonist Drugs 0.000 description 3
- 208000023504 respiratory system disease Diseases 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 208000024716 acute asthma Diseases 0.000 description 2
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- 230000008901 benefit Effects 0.000 description 2
- 230000003182 bronchodilatating effect Effects 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 230000008021 deposition Effects 0.000 description 2
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- 210000004185 liver Anatomy 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- YFMFNYKEUDLDTL-UHFFFAOYSA-N 1,1,1,2,3,3,3-heptafluoropropane Chemical compound FC(F)(F)C(F)C(F)(F)F YFMFNYKEUDLDTL-UHFFFAOYSA-N 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- 208000000059 Dyspnea Diseases 0.000 description 1
- 206010013975 Dyspnoeas Diseases 0.000 description 1
- 241000282414 Homo sapiens Species 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- AEQDBKHAAWUCMT-UHFFFAOYSA-N Procaterol hydrochloride Chemical compound Cl.N1C(=O)C=CC2=C1C(O)=CC=C2C(O)C(NC(C)C)CC AEQDBKHAAWUCMT-UHFFFAOYSA-N 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 102000016966 beta-2 Adrenergic Receptors Human genes 0.000 description 1
- 108010014499 beta-2 Adrenergic Receptors Proteins 0.000 description 1
- 210000000621 bronchi Anatomy 0.000 description 1
- 230000007883 bronchodilation Effects 0.000 description 1
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- 239000007974 sodium acetate buffer Substances 0.000 description 1
- BHZOKUMUHVTPBX-UHFFFAOYSA-M sodium acetic acid acetate Chemical compound [Na+].CC(O)=O.CC([O-])=O BHZOKUMUHVTPBX-UHFFFAOYSA-M 0.000 description 1
- 239000012064 sodium phosphate buffer Substances 0.000 description 1
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- 208000024891 symptom Diseases 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000003437 trachea Anatomy 0.000 description 1
- XPFJYKARVSSRHE-UHFFFAOYSA-K trisodium;2-hydroxypropane-1,2,3-tricarboxylate;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound [Na+].[Na+].[Na+].OC(=O)CC(O)(C(O)=O)CC(O)=O.[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O XPFJYKARVSSRHE-UHFFFAOYSA-K 0.000 description 1
- LEAHFJQFYSDGGP-UHFFFAOYSA-K trisodium;dihydrogen phosphate;hydrogen phosphate Chemical compound [Na+].[Na+].[Na+].OP(O)([O-])=O.OP([O-])([O-])=O LEAHFJQFYSDGGP-UHFFFAOYSA-K 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4704—2-Quinolinones, e.g. carbostyril
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- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
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- 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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- 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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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
本发明属于医药技术领域，涉及含有盐酸丙卡特罗的可吸入药物组合物，包含盐酸丙卡特罗及一种或几种适用于吸入给药的药用辅料；可用于支气管哮喘、喘息性支气管炎、伴有支气管反应性增高的急性支气管炎、慢性阻塞性肺部疾病(COPD)等疾病的治疗。
Description
技术领域
本发明属于医药技术领域，具体涉及适合于吸入的盐酸丙卡特罗的药物组合物。
背景技术
随着现代科学技术的高速发展，工业化进程加快，环境污染问题日益突出，空气质量逐步恶化，呼吸道疾病已成为全球主要疾病之一。常见的呼吸道疾病包括支气管哮喘、支气管炎、慢性阻塞性肺部疾病(COPD)等疾病，近年来发病率呈上升趋势，严重威胁人类健康和生命安全。
β2受体激动剂为该类呼吸系统疾病的治疗药物之一，是一类能够激动分布在气道平滑肌上的β2受体产生支气管扩张作用的支气管扩张药，尤其是哮喘急性发作(气道痉挛)的首选药物，能够迅速改善哮喘急性发作时的呼吸困难、咳嗽等的症状。
盐酸丙卡特罗为第三代β2受体激动剂，化学名为5-(1-羟基-2-异丙胺基丁基)-8-羟基-2(1H)-喹诺酮盐酸盐半水合物。盐酸丙卡特罗对支气管平滑肌的β2肾上腺素受体具有较高的选择性，支气管扩张作用较为明显，且作用时间长，大大降低药物副作用发生几率，临床优势明显。广泛用于支气管哮喘、喘息性支气管炎、伴有支气管反应性增高的急性支气管炎、慢性阻塞性肺部疾病(COPD)等疾病的治疗。
β2受体激动剂作为气管扩张药物有着一定的特殊性，口服起效较慢而且生物利用度较低，有恶心、呕吐、消化不良等胃肠道不良反应。吸入给药是β2受体激动剂最常见的给药方式，包括气雾剂、喷雾剂和干粉吸入剂等，也可以将药物溶液经雾化泵雾化后再雾化吸入。药物经吸入后，能迅速到达气管内扩张支气管，用量小，吸入率高，局部有较高药物浓度，患者治疗过程耐受性好，适合临床使用。
发明内容
本发明目的在于提供一种可吸入药物组合物，可以通过肺部吸收，能直接达到病变部位，作用直接，起效快，能有效避免口服给药由肝脏引起的首过效应，大大提高生物利用度。治疗过程患者均能很好耐受，质量稳定，安全性高。
一种可吸入药物组合物，包含盐酸丙卡特罗及一种或几种适用于吸入给药的药用辅料。
所述药物组合物为吸入溶液剂或气雾剂。
药物组合物为吸入溶液剂时，所述吸入溶液剂为盐酸丙卡特罗作为活性成分及一种或几种适用于吸入给药的药用辅料组成的吸入溶液剂；所述的吸入溶液的药用辅料包括稳定剂、pH调节剂、渗透压调节剂中的一种或几种。所述稳定剂为L-酒石酸、枸橼酸、焦亚硫酸钠中的一种或几种混合。所述渗透压调节剂为氯化钠、氯化钾、葡萄糖、甘露醇、山梨醇中的一种或几种混合，供吸入溶液使用的药液为等渗溶液。所述pH调节剂为盐酸、枸橼酸钠、氢氧化钠中的一种或几种混合，药液pH值为3.0～4.0。
进一步的，所述药物组合物为吸入溶液剂时，每升药物组合物包括：盐酸丙卡特罗0.05～0.2g，稳定剂0.2～3g、pH调节剂0.2～1g，渗透压调节剂5～50g，余量为注射用水。
药物组合物为气雾剂时，所述的气雾剂的药用辅料包括适用于气雾剂药用的抛射剂和其它可选附加剂。所述其他可选附加剂包含稳定剂、pH调节剂、渗透压调节剂、潜溶剂中的一种或几种。所述抛射剂为三氯一氟甲烷、四氟乙烷(HFA134a)、七氟丙烷(HFA227)、二甲醚、丙烷、二氟甲烷、三氯四氟乙烷、正丁烷、异丁烷等，优选四氟乙烷(HFA134a)、七氟丙烷(HFA227)、二甲醚、正丁烷、异丁烷。所述稳定剂为月桂醇、油酸、硫脲、甘氨酸、烟酰胺、辛酸钠等，优选油酸、甘氨酸、烟酰胺。所述渗透压调节剂为氯化钠、氯化钾、葡萄糖、甘露醇，供气雾使用的药液为等渗溶液。所述pH调节剂为醋酸、醋酸钠、磷酸、磷酸钠、枸橼酸、枸橼酸钠、盐酸、氢氧化钠一种或几种，药液pH值为3.0～4.0。所述潜溶剂为乙醇或丙二醇，优选乙醇。
所述吸入溶液制备方法为取主药加入到适量注射用水中预溶，搅拌使溶解，再加入稳定剂、渗透压调节剂，搅拌使溶解，补充注射用水至总量的80％，并用pH调节剂调节溶液pH值为3.0-4.0，加注射用至全量，继续搅拌15min，既得。
进一步的，所述药物组合物为气雾剂时，每升药物组合物包括：盐酸丙卡特罗0.05～0.2g，稳定剂0.2～3g、pH调节剂0.2～1g，渗透压调节剂5～50g，潜溶剂0.2～2g，余量为注射用水。抛射剂与药液按重量比8～12：1～2加入。
所述气雾剂制备方法为取主药加入到适量注射用水中，预溶，搅拌使溶解，再加入稳定剂使溶解。称取潜溶剂加入到上述溶液中，搅拌5min使充分混匀后，加入渗透压调节剂，补充注射用水至总量的80％，并用pH调节剂调节溶液pH值为3.0～4.0，加注射用水至全量，继续搅拌15min。每60mL药液灌装到60mL气雾瓶中，装上阀门并轧紧，再压入定量的抛射剂，即得。
本发明的有益效果：
1、本发明的主成分盐酸丙卡特罗属于微量给药药物，浓度仅为0.05～0.2mg/mL，每日给药一次，儿童每次10～30μg，成人每次30～50μg，用药剂量少会导致缺乏药效，过量给药会造成诸多不良反应。吸入溶液和气雾剂克服了口服药物的含量均一性问题，保证剂量准确，提高了用药的安全性和有效性。
2、本发明的提供的适合吸入的药物组合物在pH值范围内，能有效减少有关物质的产生。所述吸入溶液经雾化后，其质量中质空气流动力学直径(MMAD)在3～4μm之间，细微粒子有效沉积率(FPF)在60％～80％之间，有利于药物沉积在肺组织，效果较好。而气雾剂具有可随身携带，使用简单方便的优点。
3、本发明提供的适合吸入的药物组合物能够在吸入后1～5min即产生支气管扩张作用，疗效可持续10～12小时。起效较现有的盐酸丙卡特罗片、盐酸丙卡特罗颗粒及盐酸丙卡特罗口服溶液要快。
4、本发明直接通过肺部吸入产生效用，避免的口服给药由肝脏引起首过效应，生物利用度较低，且有严重胃肠道不良反应等缺点，是一种较为合理的给药方式。
具体实施方式
以下结合实施例对本发明做详细的说明，实施例旨在解释而非限定本发明的技术方案。
实施例1：
称取盐酸丙卡特罗0.2g，加入含1L注射用水的2L容器中预溶，搅拌使溶解，再加入L-酒石酸5g、氯化钠15g，搅拌使溶解，将上述制备好的盐酸丙卡特罗溶液加注射用水至1.6L，并用氢氧化钠溶液调节溶液pH值为3.5，加入注射用水定容至2L，继续搅拌15min，既得。取样检测，性状：无色澄明液体；pH：3.5；渗透压为289mOsmol/kg；含量：100.2％；有关物质：最大单杂0.02％，总杂0.04％。
实施例2：
称取盐酸丙卡特罗0.2g，加入含1L注射用水的2L容器中预溶，搅拌使溶解，再加入枸橼酸5g、氯化钾15g，搅拌使溶解，将上述制备好的盐酸丙卡特罗溶液加注射用水至1.6L，并用枸橼酸钠钠溶液调节溶液pH值为3.5，加入注射用水定容至2L，继续搅拌15min，既得。取样检测，性状：无色澄明液体；pH：3.5；渗透压为284mOsmol/kg；含量：99.8％；有关物质：最大单杂0.02％，总杂0.04％。
实施例3：
称取盐酸丙卡特罗0.2g，加入含1L注射用水的2L容器中预溶，搅拌使溶解，再加入焦亚硫酸钠1.5g、葡萄糖89g，搅拌使溶解，将上述制备好的盐酸丙卡特罗溶液加注射用水至1.6L，并用盐酸溶液调节溶液pH值为3.4，加入注射用水定容至2L，继续搅拌15min，既得。取样检测，性状：无色澄明液体；pH：3.4；渗透压为291mOsmol/kg；含量：99.5％；有关物质：最大单杂0.02％，总杂0.04％。
实施例4：
称取盐酸丙卡特罗0.2g，加入含1L注射用水的2L容器中预溶，搅拌使溶解，再称取0.7g烟酰胺到该容器中搅拌使溶解。称取1.6g丙二醇加入到上述溶液中，搅拌5min使充分混匀，加入氯化钠15g，将上述制备好的盐酸丙卡特罗溶液加注射用水至1.6L，并用磷酸-磷酸钠缓冲溶液调节配液罐中溶液pH值为3.5，加入注射用水定容至2L，继续搅拌15min。测试渗透压为288mOsmol/kg，含量为99.7％，有关物质：最大单杂0.02％，总杂0.04％。灌装60mL药液至已经清洗干净的气雾玻璃瓶中，装上阀门并轧紧，再压入定量的四氟乙烷(HFA134a)，即得。每瓶总揿次不少于30次，平均每揿主要含量为标示量的99.2％，雾粒中药物含量为每揿主要含量的54％。
实施例5：
称取盐酸丙卡特罗0.2g，加入含1L注射用水的2L容器中预溶，搅拌使溶解，再称取0.7g烟酰胺到该容器中搅拌使溶解。称取1.6g乙醇加入到上述溶液中，搅拌5min使充分混匀，加入氯化钾15g，将上述制备好的盐酸丙卡特罗溶液加注射用水至1.6L，并用枸橼酸-枸橼酸钠缓冲溶液调节配液罐中溶液pH值为3.5，加入注射用水定容至2L，继续搅拌15min。测试渗透压为286mOsmol/kg，含量为99.5％，有关物质：最大单杂0.02％，总杂0.04％。灌装60mL药液至已经清洗干净的气雾玻璃瓶中，装上阀门并轧紧，再压入定量的七氟丙烷(HFA227)，即得。每瓶总揿次不少于30次，平均每揿主要含量为标示量的99.6％，雾粒中药物含量为每揿主要含量的53％。
实施例6：
称取盐酸丙卡特罗0.2g，加入含1L注射用水的2L容器中预溶，搅拌使溶解，再称取0.8g甘氨酸到该容器中搅拌使溶解。称取1.5g丙二醇加入到上述溶液中，搅拌5min使充分混匀，加入葡萄糖89g，将上述制备好的盐酸丙卡特罗溶液加注射用水至1.6L，并用醋酸-醋酸钠缓冲溶液调节配液罐中溶液pH值为3.5，加入注射用水定容至2L，继续搅拌15min。测试渗透压为278mOsmol/kg，含量为99.9％，有关物质：最大单杂0.02％，总杂0.04％。灌装60mL药液至已经清洗干净的气雾玻璃瓶中，装上阀门并轧紧，再压入定量的二甲醚，即得。每瓶总揿次不少于30次，平均每揿主要含量为标示量的100.1％，雾粒中药物含量为每揿主要含量的55％。
Claims (10)
1.一种可吸入药物组合物，其特征在于，包含盐酸丙卡特罗及一种或几种适用于吸入给药的药用辅料。
2.如权利要求1所述的药物组合物，其特征在于，所述药物组合物为吸入溶液剂或气雾剂。
3.如权利要求2所述的药物组合物，其特征在于，所述吸入溶液剂为盐酸丙卡特罗作为活性成分及一种或几种适用于吸入给药的药用辅料组成的吸入溶液剂；所述药用辅料包含稳定剂、pH调节剂、渗透压调节剂中的一种或几种。
4.如权利要求2所述的药物组合物，其特征在于，所述稳定剂为L-酒石酸、枸橼酸、焦亚硫酸钠中的一种或几种；所述渗透压调节剂为氯化钠、氯化钾、葡萄糖、甘露醇、山梨醇中的一种或几种；所述pH调节剂为盐酸、枸橼酸钠、氢氧化钠中的一种或几种。
5.如权利要求2所述的药物组合物，其特征在于，所述的气雾剂的药用辅料包括适用于气雾剂的可药用抛射剂和其他可选附加剂；所述其他可选附加剂包含稳定剂、pH调节剂、渗透压调节剂、潜溶剂中的一种或几种。
6.如权利要求2所述的药物组合物，其特征在于，所述抛射剂为三氯一氟甲烷、四氟乙烷、七氟丙烷、二甲醚、丙烷、二氟甲烷、三氯四氟乙烷、正丁烷或异丁烷；所述稳定剂为月桂醇、油酸、硫脲、甘氨酸、烟酰胺、辛酸钠等，优选油酸、甘氨酸或烟酰胺；所述渗透压调节剂为氯化钠、氯化钾、葡萄糖或甘露醇；所述pH调节剂为醋酸、醋酸钠、磷酸、磷酸钠、枸橼酸、枸橼酸钠、盐酸、氢氧化钠中的一种或几种；所述潜溶剂为乙醇或丙二醇。
7.如权利要求1所述的药物组合物，其特征在于，所述盐酸丙卡特罗药物浓度为0.05～0.2mg/mL。
8.如权利要求1所述的药物组合物，其特征在于，所述药物组合物pH值为3.0～4.0。
9.如权利要求2所述的药物组合物制备方法，其特征在于，所述吸入溶液制备方法为：取盐酸丙卡特罗加入到适量注射用水中预溶，搅拌使溶解，再加入稳定剂、渗透压调节剂，搅拌使溶解，补充注射用水至总量的80％，并用pH调节剂调节溶液pH值为3.0-4.0，加注射用至全量，继续搅拌15min，得到吸入溶液。
10.如权利要求2所述的药物组合物制备方法，其特征在于，所述气雾剂制备方法为：取盐酸丙卡特罗加入到注射用水中，预溶，搅拌使溶解，再加入稳定剂使溶解；称取潜溶剂加入到上述溶液中，搅拌5min使充分混匀后，加入渗透压调节剂，补充注射用水至总量的80％，并用pH调节剂调节溶液pH值为3.0～4.0，加注射用水至全量，继续搅拌15min；将药液灌装到气雾瓶中，装上阀门并轧紧，再压入定量的抛射剂，得到气雾剂。
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