CN107106515A - 可吸入的配制剂 - Google Patents
可吸入的配制剂 Download PDFInfo
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- CN107106515A CN107106515A CN201580055461.1A CN201580055461A CN107106515A CN 107106515 A CN107106515 A CN 107106515A CN 201580055461 A CN201580055461 A CN 201580055461A CN 107106515 A CN107106515 A CN 107106515A
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- preparaton
- inhalable
- propellant
- heating
- pharmaceutical ingredient
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- 239000008186 active pharmaceutical agent Substances 0.000 claims abstract description 11
- 239000000725 suspension Substances 0.000 claims abstract description 9
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- 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 claims description 3
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- IHOXNOQMRZISPV-YJYMSZOUSA-N 5-[(1r)-1-hydroxy-2-[[(2r)-1-(4-methoxyphenyl)propan-2-yl]azaniumyl]ethyl]-2-oxo-1h-quinolin-8-olate Chemical compound C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C2=C1C=CC(=O)N2 IHOXNOQMRZISPV-YJYMSZOUSA-N 0.000 description 1
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- 241000282470 Canis latrans Species 0.000 description 1
- XIQVNETUBQGFHX-UHFFFAOYSA-N Ditropan Chemical compound C=1C=CC=CC=1C(O)(C(=O)OCC#CCN(CC)CC)C1CCCCC1 XIQVNETUBQGFHX-UHFFFAOYSA-N 0.000 description 1
- 238000001159 Fisher's combined probability test Methods 0.000 description 1
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- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
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- 229920000538 Poly[(phenyl isocyanate)-co-formaldehyde] Polymers 0.000 description 1
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- ANGKOCUUWGHLCE-HKUYNNGSSA-N [(3s)-1,1-dimethylpyrrolidin-1-ium-3-yl] (2r)-2-cyclopentyl-2-hydroxy-2-phenylacetate Chemical compound C1[N+](C)(C)CC[C@@H]1OC(=O)[C@](O)(C=1C=CC=CC=1)C1CCCC1 ANGKOCUUWGHLCE-HKUYNNGSSA-N 0.000 description 1
- OIPILFWXSMYKGL-UHFFFAOYSA-N acetylcholine Chemical compound CC(=O)OCC[N+](C)(C)C OIPILFWXSMYKGL-UHFFFAOYSA-N 0.000 description 1
- 229960004373 acetylcholine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
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- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 1
- OBRNDARFFFHCGE-QDSVTUBZSA-N arformoterol fumarate Chemical compound OC(=O)\C=C\C(O)=O.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1.C1=CC(OC)=CC=C1C[C@@H](C)NC[C@H](O)C1=CC=C(O)C(NC=O)=C1 OBRNDARFFFHCGE-QDSVTUBZSA-N 0.000 description 1
- 238000000149 argon plasma sintering Methods 0.000 description 1
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 1
- 229940092705 beclomethasone Drugs 0.000 description 1
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- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 229940125389 long-acting beta agonist Drugs 0.000 description 1
- 229940125386 long-acting bronchodilator Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 1
- 229940071648 metered dose inhaler Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 239000003149 muscarinic antagonist Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229960005434 oxybutynin Drugs 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- SSOLNOMRVKKSON-UHFFFAOYSA-N proguanil Chemical compound CC(C)\N=C(/N)N=C(N)NC1=CC=C(Cl)C=C1 SSOLNOMRVKKSON-UHFFFAOYSA-N 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 229960002052 salbutamol Drugs 0.000 description 1
- 229940127211 short-acting beta 2 agonist Drugs 0.000 description 1
- 229940125387 short-acting bronchodilator Drugs 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000003270 steroid hormone Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 229960000195 terbutaline Drugs 0.000 description 1
- 229960000257 tiotropium bromide Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 229960004026 vilanterol Drugs 0.000 description 1
- DAFYYTQWSAWIGS-DEOSSOPVSA-N vilanterol Chemical compound C1=C(O)C(CO)=CC([C@@H](O)CNCCCCCCOCCOCC=2C(=CC=CC=2Cl)Cl)=C1 DAFYYTQWSAWIGS-DEOSSOPVSA-N 0.000 description 1
- 229950000339 xinafoate Drugs 0.000 description 1
Classifications
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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
- A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/12—Aerosols; Foams
- A61K9/124—Aerosols; Foams characterised by the propellant
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/44—Glucocorticosteroids; Drugs increasing or potentiating the activity of glucocorticosteroids
Landscapes
- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pulmonology (AREA)
- Otolaryngology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
Abstract
本发明提供制备可吸入的活性药物成分的方法，包括下述步骤：在容器中加热活性药物成分在液化推进剂中的悬浮液，蒸发推进剂和收集所得粉末。
Description
与相关申请的交叉引用
本申请要求2014年10月16日提交的美国临时申请No.62/064,684的优先权，通过援引将其全部公开并入本文用于全部意图。
发明领域
本发明涉及制备活性药物成分的方法。更特别地，本发明涉及可吸入的配制剂和特别涉及制备可吸入配制剂的方法，所述配制剂具有活性药物成分(API)中减少的无定形含量。
背景技术
本发明涉及提供可吸入配制剂，其含有一种或多种用于治疗呼吸系统障碍比如哮喘或COPD的API。已开发各种类别的药物来治疗呼吸系统障碍，并且各类别具有不同的靶标和效果。可吸入药物的共同特征是它们必须深入穿透至肺以达到其作用位点。
为此将API例如通过喷射研磨微粒化以获得具有所需尺寸的颗粒，一般来说为1-5μm的质量中位数空气动力学直径(MMAD)。然而，微粒化技术赋予API颗粒的能量常常导致向否则为结晶的API颗粒材料引入无定形特征。无定形特征区域一般在本领域中被视为不希望的，主要是因为它们具有吸水倾向、导致API颗粒聚结。这种不可预料性有害地影响API的颗粒尺寸分布(PSD)，其又影响达到肺的API细颗粒的量，所述量通过用冲击器确定的细颗粒级分(FPF)来定量。
已提出各种技术来从微粒化的API颗粒除去这些无定形特征区域。它们一般牵涉通过将微粒化的颗粒暴露至潮湿环境来重结晶无定形区域。参见例如ParticulateInteractions in Dry Powder Formulations for Inhalation,X.M.Zeng et al.,Taylor&Francis,London,2000中关于该途径的讨论。
然而，本领域存在对备择和改善的途径的需要。
发明概要
相应地，本发明提供制备可吸入的活性药物成分的方法，包括下述步骤：在容器中加热活性药物成分在液化推进剂中的悬浮液，蒸发推进剂和收集所得粉末。
附图说明
图1和2显示调理前(各图中的第一幅图)和调理后(各图中的第二幅图)的丙醋氟替卡松的扫描电子显微镜图像。
本发明某些实施方式的详述
本文描述的方法将可用于制备需要降低结晶API中的无定形含量的任何活性药物成分(API)，例如用于改善化学稳定性。
本发明提供制备吸入产品的方法。已发现进行将API悬浮在液化推进剂中的调理步骤导致令人惊讶地快速的调理和更稳定的PSD。这将通过测量API在成品中的稳定性即空气动力学颗粒尺寸分布(APSD)来测定，正如本领域技术人员的理解。
在调理步骤期间可以存在一种或多种API。
API优选是支气管扩张药和/或吸入的糖皮质类固醇。支气管扩张药用来扩大支气管和细支气管，降低呼吸道中的阻力，由此增加通向肺的气流。支气管扩张药可以短效或长效药。短效支气管扩张药提供急性支气管狭窄的快速缓解，而长效支气管扩张药帮助控制和预防更长期的症状。不同类别的支气管扩张药靶向呼吸道中的不同的受体。一般使用的两种类别是β2-激动剂和抗胆碱能药。
β2-肾上腺素能激动剂(或"β2-激动剂")作用于诱导平滑肌松弛的β2-肾上腺素受体，引起支气管通道的扩张。长效β2-激动剂(LABAs)的实例包括福莫特罗(富马酸盐)，沙美特罗(昔萘酸盐)，茚达特罗(马来酸盐)，卡莫特罗(盐酸盐)和维兰特罗(vilanterol)(trifenatate)。短效β2-激动剂(SABAs)的实例包括沙丁胺醇(硫酸盐)，特布他林(硫酸盐)，吡布特罗(乙酸盐)和奥西那林(硫酸盐)。
抗胆碱能药(也称为抗毒蕈碱药)阻断神经递质乙酰胆碱：选择性阻断其在神经细胞中的受体。在局部施用时，抗胆碱能药主要作用于位于呼吸道中的M3毒蕈碱受体以产生平滑肌松弛，从而产生支气管扩张效果。长效毒蕈碱拮抗剂(LAMAs)的实例包括噻托溴铵(溴化物)，阿地铵(aclidinium)(溴化物)，格隆铵(溴化物)，芜地溴铵(umeclidinium)(溴化物)，奥昔布宁(盐酸盐或氢溴酸盐)和达非那新(氢溴酸盐)。
用于治疗呼吸系统障碍中的又一类药物是吸入的皮质类固醇(ICSs)。ICS是用于长期控制呼吸系统障碍的类固醇激素类。它们通过降低呼吸道炎症起效。实例包括布地奈德，倍氯米松(二丙酸盐)，莫米松(糠酸盐)和氟替卡松(丙酸盐或糠酸盐)。
API优选是氟替卡松，包括其药学上可接受的盐或溶剂化物。
API在容器中悬浮在液化推进剂中。容器优选是药物添加容器。液化推进剂可以是一般用于配制加压的定量吸入器(pMDI)配制剂的任何推进剂，比如氢氟烷烃(HFA)推进剂，例如HFA134a或HFA227，更优选HFA134a。
容器优选具有1-50L的体积。API优选于1-30％重量存在，基于API和推进剂的组合重量。10至1000g API的批量是优选的。
加热在30-50℃的温度，更优选35-45℃的温度，和最优选38-42℃的温度进行。在推进剂存在下的加热步骤是用于API的调理步骤，其目的在于减少API的无定形含量而不影响PSD。无定形含量可以通过溶液微量热法确定。
加热步骤进行6小时至5天，更优选24-84小时，最优选48-72小时。在又一实施方式中，加热步骤进行12-72小时。
不需要其它调理步骤。可以施加初始的常规调理步骤，但是其不是必须的。优选，本发明基于推进剂的加热步骤是唯一是微粒化后的处理步骤。
推进剂可以如供给的那样使用，但是能够加水。水并不是调理过程的关键，但如果加水，则推进剂的含水量一般是0.01-3％重量，基于推进剂总重量。一般地，水在HFA 134a中不超过0.05％。含水量可以通过Karl Fisher方法来确定。
加热步骤的外部湿度较不相关。优选，相对湿度小于70％(也即0-70％)，更优选30-55％和最优选40-50％。
优选在加热步骤期间搅动悬浮液。搅动悬浮液需要的能量可以外部地或内部地提供。外部能量来源的非限制性实例包括振摇板，轨道摇床，涡旋搅拌器，振动振荡器，波动振荡器或摇床。内部能量来源的非限制性实例包括推进器，高剪切匀化器，高剪切制粒机，桨式共混，带式共混，鼓式共混或喷射混合。
本发明也提供可通过本发明过程获得的可吸入的活性药物成分。产品的区别之处尤其是更光滑的表面和随时间更稳定的PSD。
可吸入API可以以任何常规方式配制，包括配制为干燥粉末配制剂，用于pMDI的配制剂，或含水的可雾化配制剂。在后两种配制剂类型中，API应优选是悬浮液以便获得本发明所提供的改善的固态形式的益处。
干燥粉末配制剂一般含有API和粗粒载体。API需要呈微粒化形式(质量中位数空气动力学直径一般为1-5μm、更一般为2-4μm)。该颗粒尺寸能够在吸入时穿透肺。然而，所述颗粒具有高表面能量并且需要粗载体以便能够计量配制剂。粒状载体的实例包括乳糖、葡萄糖或羟乙酸淀粉钠，优选乳糖和最优选α-乳糖一水合物。粗载体颗粒的尺寸是在吸入之后其绝大多数保留在吸入器中或沉积在口腔和上呼吸道中。相应地，载体优选具有40微米或更大的体积平均直径(VMD)，更优选载体颗粒具有50-250微米的VMD。颗粒尺寸可以用激光散射来确定，采用激光衍射系统例如来自Sympatec GmbH,Claasthal-Zellerfeld，德国。
配制剂可以在吸入器或胶囊中提供。
干燥粉末配制剂可以存在于吸入器中，例如在多剂量干燥粉末吸入器(MDPI)的储库中，例如以商品名销售的吸入器。适宜的MDPI也描述于WO 92/10229和WO2011/054527。所述吸入剂包含底盘(chassis)，剂量给药室，接口管和药物。配制剂还可以在吸入器内以单元剂量泡罩条提供，比如MicroDose Therapeutx Inc.的干燥粉末雾化器和描述于WO 2005/081833和WO 2008/106616的吸入剂。
干燥粉末配制剂可以另选地计量并且充入胶囊，例如明胶或羟丙基甲基纤维素胶囊，从而胶囊含有单元剂量的活性成分。在干燥粉末位于含有单元剂量活性成分的胶囊中的情况下，组合物总量取决于胶囊尺寸和胶囊所使用的吸入装置的特征。
pMDI配制剂含有API和液化的HFA推进剂。用于制备气雾配制剂的推进剂气体的实例包括HFA134a，HFA227或其混合物，最优选HFA134a。在优选的实施方式中，配制剂中所用的HFA推进剂是方法中所用的相同推进剂，和最优选方法和配制剂均使用HFA134a。配制剂还可以含有共溶剂(例如乙醇和/或甘油)，表面活性剂(例如油酸)和/或酸(例如柠檬酸)。气雾配制剂的进一步细节参见EP 0 372 777，EP 0 616 525和WO 98/05302。该类型的加压的计量吸入剂一般包含底盘、接口管和包含药物的罐，如前述文献的描述。
可雾化的配制剂含有API和水。配制剂还可以含有共溶剂(例如乙醇)和/或酸(例如柠檬酸)。
参照所附实施例现描述本发明，但并非意在限制。
实施例
丙醋氟替卡松在药物添加容器中调理。在温和的摇摆移动下，将HFA134a中5％浓度的丙醋氟替卡松在40℃处理48-72小时。将HFA134a通气，评价剩余物质的无定形含量。结果如表1所示。
表1、调理研究，未处理vs处理。
结果显示，在HFA134a悬浮液中于40℃进行调理48-72小时，无定形丙醋氟替卡松颗粒被调理为更稳定的低能量结晶状态。调理过程适应一系列颗粒尺寸分布。经调理的丙醋氟替卡松颗粒用于制备过程当中以在长期贮藏期间稳定化药物产品。经由本发明方法减少或除去无定形含量是有益的，原因在于降解产品的形成被最小化并且实现储存产品的一致药物效能。本发明的其它益处是实现调理而不影响PSD。这提供通过空气动力学颗粒尺寸分布(APSD)测得的改善的API稳定性。这也提供改善的化学稳定性。
图1和2拍摄自表1的实验1和2并且显示调理前(各图中的第一幅图)和调理后(各图中的第二幅图)的丙醋氟替卡松的扫描电子微观图像。各图像展示，作为本发明调理的结果，API具有增加的结晶度(即减少的无定形含量)。
Claims (20)
1.制备可吸入的活性药物成分的方法，包括下述步骤：在容器中加热活性药物成分在液化推进剂中的悬浮液，蒸发推进剂和收集所得粉末。
2.权利要求1中所要求保护的方法，其中所述推进剂是氢氟烷烃(HFA)推进剂。
3.权利要求2中所要求保护的方法，其中所述推进剂是HFA134a或HFA227。
4.前述权利要求任一项中所要求保护的方法，其中在加热步骤期间搅动悬浮液。
5.前述权利要求任一项中所要求保护的方法，其中加热在30-50℃的温度进行。
6.权利要求5中所要求保护的方法，其中加热在35-45℃的温度进行。
7.权利要求6中所要求保护的方法，其中加热在38-42℃的温度进行。
8.前述权利要求任一项中所要求保护的方法，其中加热进行6小时至5天。
9.前述权利要求任一项中所要求保护的方法，其中加热进行24-84小时。
10.权利要求1-8任一项中所要求保护的方法，其中加热进行12-72小时。
11.前述权利要求任一项中所要求保护的方法，其中所述可吸入的活性药物成分是吸入的糖皮质类固醇，β2-激动剂，抗胆碱能药或其组合。
12.前述权利要求任一项中所要求保护的方法，其中所述可吸入的活性药物成分具有1-5μm的质量中位数空气动力学直径。
13.权利要求12中所要求保护的方法，其中所述可吸入的活性药物成分是氟替卡松，包括其药学上可接受的盐或溶剂化物。
14.前述权利要求任一项中所要求保护的方法，其中所述悬浮液含有1-30％的活性药物成分，按活性药物成分和推进剂的组合重量计。
15.前述权利要求任一项中所要求保护的方法，其中所述方法有效地降低活性药物成分的无定形含量。
16.可通过前述权利要求任一项中所要求保护的方法获得的可吸入的活性药物成分。
17.可吸入的药物配制剂，包含权利要求16所要求保护的可吸入的活性药物成分和一种或多种药学上可接受的赋形剂。
18.权利要求17所要求保护的可吸入的药物配制剂，其中所述配制剂是干燥粉末配制剂而赋形剂是粗粒载体。
19.权利要求17所要求保护的可吸入的药物配制剂，其中所述配制剂是加压的定量吸入器粉末配制剂而赋形剂是HFA推进剂。
20.权利要求19所要求保护的可吸入的药物配制剂，其中配制剂中所用的HFA推进剂是方法中所用的相同推进剂。
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| CO2017004789A2 (es) | 2017-09-20 |
| KR20170070151A (ko) | 2017-06-21 |
| EA201790832A1 (ru) | 2017-09-29 |
| US20170239269A1 (en) | 2017-08-24 |
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