CN100337614C - 医用气溶胶制剂 - Google Patents
医用气溶胶制剂 Download PDFInfo
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Abstract
本发明涉及一种医用气溶胶制剂,具体而言涉及一种含有特定药物、抛射剂和选择氨基酸、氨基酸衍生物和其混合物的稳定剂的医用气溶胶制剂。
Description
发明背景
发明领域
本发明涉及一种医用气溶胶制剂,并且更具体涉及一种含有选自氨基酸、其衍生物或其混合物的稳定剂的医用气溶胶制剂。
相关现有技术
通过吸入将药物释放至肺部是一种治疗多种病症的重要方式,所述病症包括普通的局部疾病如支气管哮喘和慢性阻塞性肺部疾病,和某些全身性疾病,包括疼痛控制、囊性纤维变性等。甾族化合物、β2激动剂、抗胆碱能药、蛋白质和多肽是符合肺部给药目的的药物。上述药物一般是以可呼吸大小(直径小于约10μm)的颗粒的气溶胶形式给药至肺部。为了确保气溶胶中的适当粒度,可将颗粒制备为为可呼吸大小并且随后混合在含有抛射剂的混悬液制剂中。此外,可将制剂配制成溶液形式以回避对制剂内适当粒度的担忧。然而,溶液型制剂必须以可呼吸大小的产物颗粒或液滴的方式分配。
一旦制成,气溶胶制剂被填充在装配有计量剂量阀的气溶胶罐内。在患者手中制剂经传动器分配,该传动器适合将剂量药物由阀门定向分配给患者。
至关重要的是气溶胶制剂应稳定以使从计量剂量阀排放出的加压剂量可重现。在混悬液制剂中搅动后的快速(乳状液)分层、沉淀或絮凝是剂量无法重现的常见原因。当二元气溶胶制剂仅仅含有药物并且采用例如1,1,1,2-四氟乙烷抛射剂时或当此类制剂还含有少量表面活性剂时,上述问题尤为确定。阀门粘着也可引起剂量无法重现。为了克服这些问题,气溶胶制剂常常含有表面活性剂,表面活性剂的作用是作为助悬剂使混悬液在一定时间内保持稳定以便可重复给药。某些表面活性剂还具有乳化剂的作用,用于润滑阀门以确保阀门开动顺畅。多数原料已知并且公开应用在气溶胶制剂中作为分散助剂。然而,原料的适应性取决于制剂中所用的特定药物和抛射剂或抛射剂种类。
有时难以使足够量的常规表面活性剂溶解在含氢氟烃(HFC)抛射剂,例如HFC-134a和HFC-227。共溶剂如乙醇用来克服这种问题,如美国专利号5225183所述。另一条避免使用共溶剂的途径是含有那些可溶于含氢氟烃抛射剂中并且在气溶胶制剂中是有效表面活性剂或分散助剂的材料。某些符合表面活性剂和某些聚乙氧基表面活性剂属于此类材料。
发明概述
令人惊奇地发现,无需向二元气溶胶制剂中加入共溶剂如乙醇,或表面活性剂如脱水山梨糖醇三油酸酯就可以获得新的医用气溶胶制剂。通过应用氨基酸、其衍生物或上述物质的混合物可以获得稳定的医用气溶胶制剂。
发明详述
本发明涉及一种适合加压释放的稳定的混悬液气溶胶制剂,其中含有(1)颗粒药剂或药物,(2)适当的抛射剂,和(3)适当稳定剂。
适当的药剂或药物是适合吸入给药的药剂或药物,所述吸入被应用于经口和经鼻吸入疗法中。治疗类的药物或药剂包括:心血管药物、抗变态反应药、镇痛剂、支气管扩张药、抗组胺药、镇咳药、杀真菌剂、抗病毒药、抗生素、痛觉药物、抗炎药、肽、蛋白质和甾类化合物。
特别适用的药剂或药物包括:沙丁胺醇(也称作舒喘宁),阿托品,倍氯米松;倍氯米松的酯,例如其一丙酸酯和二丙酸酯;布地奈德、色甘酸、肾上腺素、麻黄素、芬太尼、9-去氟肤轻松、福莫特罗、异丙托溴铵、异丙肾上腺素、吡布特罗、泼尼松龙、沙美特罗、阿米洛利;氟地松酯,例如磷酸酯、一水合物和糠酸酯;(-)4-氨基-3,5-二氯-α-[[[6(2-吡啶基)乙氧基]己基]氨基]甲基]苯-甲醇。还包括上述药物的适当酸加成盐、其水合物及其其他溶剂化物。因此,所述适当酸加成盐包括由无机酸获得的盐,例如盐酸、氢溴酸、硫酸、硝酸、磷酸和高氯酸;以及由有机酸或的盐,例如酒石酸、柠檬酸、乙酸、琥珀酸、马来酸、富马酸和草酸。适当的药学可接受溶剂化物包括与乙酸乙酯、烷烃、醚、醇和水形成的溶剂化物。
鉴于本发明制剂的目的,为了经肺部吸入给药,优选将药剂或药物微粉化,由此使有效量或部分(例如等于或大于90%)的药物成为颗粒。通常,颗粒的直径小于约10微米,并且优选小于约5微米,目的是使颗粒能够洗涤到呼吸道和/或肺部内。
颗粒状药剂或药物以治疗有效量存在于本发明制剂中,所述有效量也就是指药物可作为气溶胶(例如局部)或经口或鼻吸入给药并且引起其预期治疗功效时的用量,通常优选施用一个剂量或数个剂量引起预期的治疗效应。颗粒状药物作为气溶胶由常规阀门如计量剂量阀给药。
此处所用的术语“用量”是指适合本发明的量或浓度。构成治疗有效量的药物的用量根据多种因素变化,例如特定药物的效价,制剂的给药途径和施用制剂所采用的机械系统。所属领域普通技术人员鉴于这些因素可以选择特定药物的治疗有效量。一般地,治疗有效量应为约0.005重量份-约2重量份,基于100重量份抛射剂计。
选择适用的抛射剂。适用的抛射剂是任何氟烃化合物,例如含有1-4氢的氟烃化合物(如CHF2CHF2、CF3CH2F、CHF2CH3和CF3CHFCF3),全氟烃,例如含有1-4个碳原子的全氟烃(例如CF3CF3、CF3CF2CF3);或上述抛射剂的任何混合物,其具有足以有效成为抛射剂的蒸汽压。一些典型的适用抛射剂包括常规的氯氟烃(CFC)类抛射剂,如抛射剂11、12和114的混合物。优选非CFC抛射剂,例如1,1,1,2-四氟乙烷(抛射剂134a)、1,1,1,2,3,3,3-七氟丙烷(抛射剂227)或它们的混合物。抛射剂优选以足以将多个选定剂量的药物由气溶胶罐内抛射出的量存在。
选择适当的稳定剂。适用的稳定剂包括(1)氨基酸,选自(a)式HN2-R-COOH(I)的一氨基羧酸,(b)式H2N-R(COOH)2(II)的一氨基二元羧酸,和(c)式(H2N)2-R COOH(III)的二氨基一元羧酸,其中R是含有1-22个碳原子的直链或支链烷基,其可以被一个或多个例如硫(-S-)、氧(-O-)、羟基(_OH)、氨基(-NH)、硫酸根(_SO4)的基团取代;下式的芳基:
其中X是氢,卤素(F、Cl、BR、I),1-6个碳原子的烷基,1-6个碳原子的烷氧基,羟基和硝基;和杂环,例如噻吩基、呋喃基、吡喃基、咪唑基、吡咯基、噻唑基、唑基、吡啶基和嘧啶基类混合物;(2)氨基酸的衍生物,选自(a)由无机酸和有机酸得到的氨基的酸加成盐,所述无机酸例如盐酸、氢溴酸、硫酸、硝酸、磷酸和高氯酸,所述有机酸例如是酒石酸、柠檬酸、乙酸、琥珀酸、马来酸、富马酸、草酸;(b)羧酸基团的酰胺类化合物,例如谷酰胺,(c)由1-6个碳原子的脂族直链或支链醇获得的羧酸基的酯,例如L-门冬氨酰基-L-苯基丙氨酸甲酯(Aspartame),和(3)氨基酸和氨基酸衍生物的混合物。
适当的式I的氨基酸类化合物包括:对羟苯甘氨酸(glycin)、甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、苏氨酸、异缬氨酸、苯丙氨酸、酪氨酸、丝氨酸、半胱氨酸、N-乙酰基-L-半胱氨酸、组氨酸、色氨酸、脯氨酸和羟基脯氨酸,例如反式-4-羟基脯氨酸。式II的化合物包括天门冬氨酸和谷氨酸;式(III)的化合物包括精氨酸、赖氨酸、羟赖氨酸、鸟氨酸、天冬酰胺和瓜氨酸。
气溶胶制剂适宜含有有效量的稳定剂以使该制剂比不含稳定剂的相同制剂更加稳定,致使搅动后药物不会迅速沉淀、分层或絮凝达到妨碍药物的可重现给药。如果制剂在搅动后约2或3秒内保持药物浓度基本均匀,则可以获得可重现给药。
稳定剂的特定有效量的具体用量取决于特定稳定剂、特定抛射剂和制剂中所用的特有药物。因此,实际上无法例举适用于本发明特殊制剂的特定有效量,但是所属领域普通技术人员依据上述因素可很容易地测定出该用量。然而一般地,稳定剂在制剂中的含量是约0.000002%(重量)-约20%(重量),更优选约0.0002%(重量)-约10%(重量),基于制剂的重量计。
令人惊奇地发现,本发明的制剂不需要采用共溶剂如乙醇或表面活性剂就可保持稳定。然而,本发明的气溶胶制剂中也可以存在适量的其他组分,例如常规润滑剂或表面活性剂、共溶剂、乙醇等,所属领域普通技术人员易于测定出其用量。因此,参见美国专利号5225183,该文献在此全文引入作为参考。
通常,可以通过混合(i)足够提供多个治疗有效剂量的量的药物;(ii)可稳定制剂中各组分的有效量的稳定剂;(iii)足以由气溶胶罐抛射出多个剂量的量的抛射剂;和(iv)任何其他选择性组分,例如乙醇作为共溶剂;并且分散上述组分来制备本发明的制剂。利用普通混合器或均化器通过振摇或通过超声能量分散上述组分。采用阀对阀方法、加压填充或采用常规冷冻填充法可以将批量制剂转移到较小的独立气溶胶瓶中,不要求混悬液气溶胶制剂中所用的稳定剂可溶于抛射剂中。那些无法充分溶解的稳定剂可能以适当的量涂层在药物颗粒上,进而可将经涂层颗粒混合在上述制剂中。
可以采用装配有普通阀门,优选计量剂量阀门的气溶胶罐来释放本发明的制剂。然而已经发现,对气溶胶制剂装配使用的适当阀门的选择取决于特定的稳定剂和所用的其他辅剂(如果使用),取决于抛射剂和所用的特定药物。当制剂含有HFC-134a或HFC-227时,释放常规CFC制剂的计量剂量阀门中所采用的氯丁(二烯)橡胶丁钠橡胶常常具有劣于最佳阀门释放的特征和操作容易性。所以,某些本发明的制剂适宜经一种阀门组件分配,该阀门组件中的隔膜是由丁腈橡胶如DB-218(American Gasket & Rubber,Schiller Park,I11.)或EPDM橡胶如VistalonTM(Exxon)、RoyaleneTM(Uniroyal)、bunaEP(Bayer)制成。由热塑弹性材料如FLEXOMERTM GERS 1085 NT聚烯烃(Union Carbide)通过挤出、注射模制或压缩模制成形的隔膜也适用。
因此,本发明还涉及一种含有医用气溶胶制剂的计量剂量吸入器,该制剂含有:
(a)治疗有效量的颗粒形式的药剂;
(b)抛射剂;和
(c)适当稳定剂,其选自氨基酸、氨基酸衍生物、或氨基酸和氨基酸衍生物的混合物,所述氨基酸衍生物选自(1)氨基的酸加成盐、(2)羧酸基的酰胺和(3)羧酸基的酯,所述稳定剂是以可在足够长的时间内有效防止该制剂沉淀、分层或絮凝以使在搅动制剂后药物可重现给药的量存在。
也可以利用常规的涂层或未涂层、阳极化或非阳极化的气溶胶罐如铝制、玻璃、不锈钢、聚对一酸乙二酯的那些,以及用环氧类树脂、环氧化合物等涂层的罐或容器来装纳本发明的制剂。
本发明的制剂可以经吸入释放至呼吸道和/或肺部,目的是引起支气管扩张或治疗对吸入治疗敏感的病症,例如哮喘、某些阻塞性肺部疾病。也可以经鼻吸入释放本发明的制剂,目的是治疗例如过敏性鼻炎、鼻炎(定位)或糖尿病(全身性);或经局部(例如颊)给药释放本发明的制剂用量治疗如心绞痛或局部感染。
Claims (20)
1.一种医用气溶胶制剂,其中含有:
(a)治疗有效量的颗粒药剂;
(b)抛射剂;和
(c)稳定剂,其选自氨基酸、氨基酸衍生物、或氨基酸和氨基酸衍生物的混合物,所述氨基酸衍生物选自(1)氨基的酸加成盐、(2)羧酸基的酰胺和(3)羧酸基的酯。
2.如权利要求1所述的制剂,其中所述稳定剂选自:对羟苯甘氨酸、甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、苏氨酸、异缬氨酸、苯丙氨酸、酪氨酸、丝氨酸、组氨酸、色氨酸、脯氨酸、羟基脯氨酸、精氨酸、鸟氨酸、天冬酰胺、瓜氨酸、天门冬氨酸、半胱氨酸、谷氨酸、赖氨酸、羟赖氨酸、N-乙酰基-L-半胱氨酸、苯丙氨酸、反式-4-羟基-L-脯氨酸、酪氨酸、L-门冬氨酰基-L-苯丙氨酸甲酯和上述化合物的任意混合物。
3.如权利要求1的制剂,其中所述药剂选自:沙丁胺醇、阿托品、倍氯米松、倍氯米松一丙酸酯、倍氯米松二丙酸酯、布地奈德、色甘酸、肾上腺素、麻黄素、芬太尼、9-去氟肤轻松、福莫特罗、异丙托溴铵、异丙肾上腺素、吡布特罗、泼尼松龙、沙美特罗、阿米洛利、氟地松、氟地松酯、(-)4-氨基-3,5-二氯-α-[[[6(2-吡啶基)乙氧基]己基]氨基]甲基]苯-甲醇及上述物质的药学上可接受的盐、酯、水合物和溶剂化物。
4.如权利要求1的制剂,其中所述抛射剂选自1,1,1,2-四氟乙烷,1,1,1,2,3,3,3-七氟丙烷或其混合物。
5.如权利要求1的制剂,其中进一步含有共溶剂。
6.如权利要求5的制剂,其中所述共溶剂包括乙醇。
7.如权利要求2的制剂,其中所述稳定剂是以可在足够长的时间内防止该制剂沉淀、分层或絮凝以便搅动制剂后药物可重现给药的有效量存在。
8.如权利要求7的制剂,其中所述稳定剂的含量基于该制剂重量计是0.000002%(重量)-20%(重量)。
9.一种制备权利要求1所述气溶胶制剂的方法,其中包括:
(a)混合(i)足够提供多个治疗有效剂量的量的颗粒药剂;(ii)可稳定制剂中各组分的有效量的稳定剂;(iii)足以由气溶胶罐抛射出多个治疗有效剂量的量的抛射剂;和
(b)分散组分(i)、(ii)和(iii)。
10.如权利要求9的方法,其中所述医用气溶胶制剂进一步包括,在步骤(a)中混合共溶剂并且在步骤(b)中用所述共溶剂分散组分(i)、(ii)、(iii)。
11.权利要求1的制剂,用于通过口腔或鼻吸入治疗动物疾病。
12.如权利要求1的制剂,存在于装配有计量剂量阀的气溶胶罐中。
13.一种稳定含有抛射剂和特定药物的混悬液气溶胶制剂的方法,其中包括:
向该制剂中混入选自氨基酸、氨基酸衍生物、或氨基酸和氨基酸衍生物的混合物的稳定剂,所述氨基酸衍生物选自(1)氨基的酸加成盐、(2)羧酸基的酰胺和(3)羧酸基的酯的氨基酸衍生物,所述稳定剂的用量能够在足够长的时间内有效防止该制剂沉淀、分层或絮凝以使在搅动制剂后药物可重现给药。
14.一种含有医用气溶胶制剂的计量剂量吸入器,该制剂含有:
(a)治疗有效量的颗粒形式的药剂;
(b)抛射剂;和
(c)适当的稳定剂,其选自氨基酸、氨基酸衍生物、或氨基酸和氨基酸衍生物的混合物,所述氨基酸衍生物选自(a)氨基的酸加成盐、(b)羧酸基的酰胺和(c)羧酸基的酯,所述稳定剂是以可在足够长的时间内有效防止该制剂沉淀、分层或絮凝以使在搅动制剂后药物可重现给药的量存在。
15.如权利要求14所述的计量剂量吸入器,其中所述稳定剂选自:对羟苯甘氨酸、甘氨酸、丙氨酸、缬氨酸、亮氨酸、异亮氨酸、甲硫氨酸、苏氨酸、异缬氨酸、苯丙氨酸、酪氨酸、丝氨酸、组氨酸、色氨酸、脯氨酸、羟基脯氨酸、精氨酸、鸟氨酸、天冬酰胺、瓜氨酸、天门冬氨酸、半胱氨酸、谷氨酸、赖氨酸、羟赖氨酸、N-乙酰基-L-半胱氨酸、苯丙氨酸、反式-4-羟基-L-脯氨酸、酪氨酸、L-门冬氨酰基-L-苯丙氨酸甲酯和上述化合物的任意混合物。
16.如权利要求15所述的计量剂量吸入器,其中所述稳定剂的含量基于该制剂重量计为0.000002%(重量)-20%(重量)。
17.如权利要求14的计量剂量吸入器,其中所述药剂选自:沙丁胺醇(也称作舒喘宁),阿托品,倍氯米松、倍氯米松一丙酸酯、倍氯米松二丙酸酯、布地奈德、色甘酸、肾上腺素、麻黄素、芬太尼、9-去氟肤轻松、福莫特罗、异丙托溴铵、异丙肾上腺素、吡布特罗、泼尼松龙、沙美特罗、阿米洛利、氟地松、氟地松酯、(-)4-氨基-3,5-二氯-α-[[[6(2-吡啶基)乙氧基]己基]氨基]甲基]苯-甲醇及上述物质的药学上可接受的盐、酯、水合物和溶剂化物。
18.如权利要求14的计量剂量吸入器,其中所述抛射剂选自1,1,1,2-四氟乙烷,1,1,1,2,3,3,3-七氟丙烷或其混合物。
19.如权利要求14的计量剂量吸入器,其中所述医用气溶胶制剂进一步含有共溶剂。
20.如权利要求19的计量剂量吸入器,其中所述共溶剂包括乙醇。
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-
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- 1998-09-22 US US09158369 patent/US6136294C1/en not_active Expired - Lifetime
-
1999
- 1999-09-17 AU AU59267/99A patent/AU745554B2/en not_active Ceased
- 1999-09-17 JP JP2000573775A patent/JP2002526459A/ja active Pending
- 1999-09-17 MX MXPA01002894A patent/MXPA01002894A/es active IP Right Grant
- 1999-09-17 AT AT99946974T patent/ATE336268T1/de active
- 1999-09-17 ES ES99946974T patent/ES2267288T3/es not_active Expired - Lifetime
- 1999-09-17 AT AT06016853T patent/ATE505184T1/de not_active IP Right Cessation
- 1999-09-17 EP EP06016853A patent/EP1731140B1/en not_active Expired - Lifetime
- 1999-09-17 DE DE69932835T patent/DE69932835T2/de not_active Expired - Lifetime
- 1999-09-17 WO PCT/US1999/021510 patent/WO2000016814A1/en active IP Right Grant
- 1999-09-17 CA CA2344816A patent/CA2344816C/en not_active Expired - Fee Related
- 1999-09-17 DK DK99946974T patent/DK1123120T3/da active
- 1999-09-17 PT PT99946974T patent/PT1123120E/pt unknown
- 1999-09-17 EP EP99946974A patent/EP1123120B1/en not_active Expired - Lifetime
- 1999-09-17 DE DE69943360T patent/DE69943360D1/de not_active Expired - Lifetime
- 1999-09-17 CN CNB998135674A patent/CN100337614C/zh not_active Expired - Fee Related
-
2002
- 2002-05-08 HK HK02103508A patent/HK1041835A1/xx not_active IP Right Cessation
-
2006
- 2006-09-12 CY CY20061101291T patent/CY1105538T1/el unknown
-
2007
- 2007-05-23 HK HK07105448.0A patent/HK1097777A1/xx unknown
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Also Published As
Publication number | Publication date |
---|---|
MXPA01002894A (es) | 2002-06-04 |
DE69932835T2 (de) | 2007-02-01 |
EP1123120B1 (en) | 2006-08-16 |
EP1731140A2 (en) | 2006-12-13 |
AU745554B2 (en) | 2002-03-21 |
ATE336268T1 (de) | 2006-09-15 |
WO2000016814A1 (en) | 2000-03-30 |
US6136294A (en) | 2000-10-24 |
CA2344816C (en) | 2011-05-24 |
ATE505184T1 (de) | 2011-04-15 |
HK1097777A1 (en) | 2007-07-06 |
EP1731140B1 (en) | 2011-04-13 |
DK1123120T3 (da) | 2006-10-02 |
EP1123120A4 (en) | 2003-07-23 |
HK1041835A1 (en) | 2002-07-26 |
ES2267288T3 (es) | 2007-03-01 |
EP1123120A1 (en) | 2001-08-16 |
DE69943360D1 (de) | 2011-05-26 |
AU5926799A (en) | 2000-04-10 |
US6136294C1 (en) | 2002-09-24 |
JP2002526459A (ja) | 2002-08-20 |
DE69932835D1 (de) | 2006-09-28 |
CN1328473A (zh) | 2001-12-26 |
EP1731140A3 (en) | 2007-06-27 |
CA2344816A1 (en) | 2000-03-30 |
PT1123120E (pt) | 2006-10-31 |
CY1105538T1 (el) | 2010-07-28 |
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