CN1638731A - 用于经肺给药以产生全身效应的气溶胶制剂 - Google Patents
用于经肺给药以产生全身效应的气溶胶制剂 Download PDFInfo
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- CN1638731A CN1638731A CNA038049775A CN03804977A CN1638731A CN 1638731 A CN1638731 A CN 1638731A CN A038049775 A CNA038049775 A CN A038049775A CN 03804977 A CN03804977 A CN 03804977A CN 1638731 A CN1638731 A CN 1638731A
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Abstract
本发明公开了一种气溶胶药用组合物，它包括一在氢氟烷烃推进剂和一种或多种助溶剂的混合溶液中的药物，其中促动吸入器时递送的气溶胶液滴的颗粒大小为0.5μm－2.5μm，其中质量中值空气动力学直径是约1－2μm，并且其中细粒分数是至少30％。
Description
发明领域
本发明涉及气溶胶溶液制剂，它包括药物、推进剂、一种或多种助溶剂和任选常用于这种制剂的其它添加剂。
发明背景
为了获得全身效应，目前通过口、非肠道或透皮给药用于临床实践并呈现给药和/或吸收问题的许多药用活性化合物可以通过肺递送获益。
使用加压计量吸入器(pMDIs)可以将药用活性化合物给药到呼吸道。PMDIs使用一推进剂将含有药品的液滴以气溶胶排放到呼吸道。
制剂可以是溶液或悬浮液形式。相对悬浮液，溶液制剂不存在悬浮颗粒的物理稳定性的问题并且这样可以保证更高剂量的均匀性和再现性。
至于提到的推进剂，氢氟链烷[(HFAs)，也称之为氢-氟-碳(HFCs)]将是必不可少的推进剂如氟氯化碳(还称之为氟利昂或CFCs)，多年来它们都是药用优选的气溶胶推进剂，由于其对环境有害而已被禁止。
具体地说，1，1，1，2-四氟乙烷(HFA 134a)和1，1，1，2，3，3，3-七氟丙烷(HFA 227)已知是非-CFC推进剂的最佳候选并且已公开了许多使用这种HFA推进剂的药用气溶胶制剂。
发明概述
为了气溶胶递送药物而提供在HFA推进剂中的溶液制剂的目的在于经呼吸道提供快速全身活性剂量的所述药物。
本文后面使用术语药物定义可以经肺递送以便产生全身治疗效应而获益的任意药用活性化合物。
为了提供治疗有用的血浆水平，应获得治疗浓度的药物和有效的气溶胶递送。
有效的气溶胶递送以产生全身治疗效应的一个重要参数是气溶胶云状物的颗粒大小分布。当制剂为悬浮液形式时，云状物的颗粒大小由悬浮药物的颗粒大小决定，通过磨碎/微粉化法限定。
当制剂为溶液形式时，没有悬浮药物颗粒的体积分布，并且产生主要由溶液中的药物浓度限定的细得多的液滴云状物。
由pMDI提供的颗粒大小通常是以质量中值空气动力学直径(MMAD)表示的。选择用于治疗支气管肺病的气溶胶药物的颗粒大小通常约为3μm。这些气溶胶或小滴的优选直径在0.5-5μm之间。
当将药物经气溶胶计量吸入器递送到肺以产生全身效应时，这些颗粒应足够小以递送到肺中并经吸入吸收到血流中，即颗粒大小有益地在约0.5μm-2.5μm之间(MMAD为约1-2μm)。小于0.5μm的颗粒由于它们被呼出因而事实上没有治疗效果。
这些气溶胶溶液制剂具有均匀的完全溶解在推进剂载体或其与合适助溶剂如乙醇的混合物中的活性成分和赋形剂的优点。溶液制剂也避免了与悬浮液制剂有关的物理稳定性的问题，因此确保了可再现的剂量。
而且，当需要全身效应时，在本发明的情况下，气溶胶溶液制剂具有产生主要由溶液中药物浓度限定的细得多的云状物的优点，并且这些较细云状物更广泛地沉积在肺周围。
当药物微溶于HFA推进剂如HFA 134a和HFA 227或其混合物中时，必须使用溶剂，通常是乙醇。
当药物在推进剂中的溶解度非常小时，需要大量乙醇。大量的乙醇，又会与其浓度成比例地使留在促动器孔口的气溶胶小滴的直径增加。尺寸较打的小滴过度沉积在口咽道，从而降低渗透到下部气道的药物剂量分数(可呼吸分数)。差的可呼吸分数不可能提供产生治疗效果所需的药物血清水平。
而且，制剂中增加量的乙醇还意味着剩余水的量增加。而量至多10％w/w，优选在0.5-8％w/w之间并更优选在0.5-6％的水在一些情况下可能对提高药物在推进剂/助溶剂体系中的溶解度是有益的，在其它情况下水的存在可能加快了药物的降解并且对产生不均匀体系的制剂的物理稳定性可能是有害的。
提供用加压计量吸入器经肺递送的制剂将是有益的，它在化学和物理上稳定，并且在促动时能够提供合适的细粒剂量(FPD)和细小的可呼吸分数(FPF)，从而提供药物的早期治疗血浆水平。细粒剂量或可呼吸剂量是颗粒大小小于4.7μm的活性颗粒的量，并且细粒分数或可呼吸分数是可呼吸剂量与促动吸入器时递送的剂量之比。可呼吸分数应为递送剂量的至少30％，优选大于40％，甚至更优选大于50％。
提供在从pMDI重复给药之后递送的剂量可高度再现的制剂也是非常有益的。
由于在这种情况下气溶胶颗粒的高的全身接触将是有益的，因此提供这样的制剂甚至更有益：其中整个溶剂体系的组成经过调整以便能够产生之后可以深入渗透到肺中的气溶胶颗粒，同时使将呼出的非常小的颗粒(≤0.5μm)最小化。
本发明提供了一种解决所述问题的方法，它使用了包括药物、HFA推进剂和任选一种或多种助溶剂的溶液制剂。所述溶液化学上稳定适当时间，并且促动时能够提供开始快速产生药物的治疗血浆水平的可呼吸分数。
优选的助溶剂是低级烷基(C1-C4)醇、多元醇、聚亚烷基二醇及其组合。
特别优选乙醇。
其它合适的助溶剂是(多)烷氧基衍生物，包括聚烷氧基醇类，特别是2-(2-乙氧基乙氧基)乙醇(可以商标Transcutol获得)。
其它(多)烷氧基衍生物包括聚氧链烷基醚和酯类，例如聚氧乙烯醚或酯类。优选的聚氧乙烯醚和酯类是聚氧乙烯烷基醚类、聚氧乙烯山梨糖醇酐脂肪酸酯类和聚氧乙烯硬脂酸酯。
作为助溶剂，也可以使用脂肪酸烷基酯类。优选的脂肪酸烷基酯是油酸乙酯、肉豆蔻酸异丙酯和棕榈酸异丙酯。
根据一个优选实施方式，本发明提供了一种药用组合物，它包括一药物、HFA推进剂、量至多30％，优选至多20％，更优选至多10％w/w的乙醇和极性比乙醇高且量为0.2％-10％w/w，优选0.5-10％w/w，更优选0.5-6％w/w，甚至更优选1-2％w/w的助溶剂。
根据介电常数，或者使用介电常数与折光率的平方的关系的Maxwell等式，将该极性定量化，并且因此可以比较，材料的折光率可以容易地测定或者可以从文献中获得。或者，可以使用评价溶剂力的Kauri-丁醇值测定助溶剂的极性。该方案描述在ASTM Standard：Designation 1133-86。
加入极性高于乙醇的助溶剂可以降低用于调节制得的气溶胶小滴的颗粒大小的乙醇量。
极性高于乙醇的助溶剂可以优选选自低级烷基(C1-C4)醇、多元醇或聚亚烷基二醇。
优选的多元醇包括丙二醇和甘油，优选的聚亚烷基二醇是聚乙二醇。
在极性高于乙醇的助溶剂中，考虑包括水。水，如果有时，其量至多10％w/w，优选在0.5-8％w/w之间，更优选在0.5-6％之间。
根据甚至更优选的实施方式，本发明提供了一种药用组合物，它主要由如下物质组成：药物、HFA推进剂、任选量为2-30％w/w，优选5％-20％w/w，更优选至多10％w/w的乙醇，和任选的助溶剂。有益地，活性成分的量是至少0.01％w/v，优选在0.1-1.0％w/v之间。
当药物完全溶解在推进剂中时，少量的乙醇和助溶剂是有用的。
事实上已发现，尽管不需要溶剂来将药物溶解在推进剂中，但是少量乙醇(优选约5-8％w/w，更优选约5％w/w)影响沉积特性，可能使全身递送更容易，这是由于乙醇有助于降低因在肺中停留时间短而呼出的非常小的颗粒(＜0.5μm)的量。而且，乙醇降低了排放的物料在吸入器促动器孔口上的沉积，这样通过保持促动器孔口“清洁”而提高了重复给药之后的剂量再现性。
由于乙醇的“清洁”效果，因此通常没有必要使用表面活性剂作为阀润滑剂。
然而，在某些情况下，制剂可以任选含有少量的其它组分如表面活性剂或其它添加剂，这些添加剂有防腐剂、缓冲剂、抗氧化剂、自由基猝灭剂、甜味剂和异味掩蔽剂。
优选的有机表面活性剂选自油醇、脱水山梨糖醇三油酸酯、脱水山梨糖醇一油酸酯、脱水山梨糖醇一月桂酸酯、聚氧乙烯(20)脱水山梨糖醇一月桂酸酯、聚氧乙烯(20)脱水山梨糖醇一油酸酯、天然卵磷脂、油酰基聚氧乙烯(2)醚、硬脂酰基聚氧乙烯(2)醚、月桂酰基聚氧乙烯(4)醚、氧乙烯和氧丙烯的嵌段共聚物、油酸、合成卵磷脂、二乙二醇二油酸酯、四氢糠基油酸酯、油酸乙酯、肉豆蔻酸异丙酯、甘油一油酸酯、甘油一硬脂酸酯、甘油一蓖麻酸酯、鲸蜡醇、硬脂醇、氯化十六烷基吡啶鎓、橄榄油、甘油一月桂酸酯、玉米油、棉籽油或向日葵籽油。
根据另一方面，本发明提供了一种将本发明的组合物装入气溶胶吸入器的方法，该方法包括：
(a)将所需量的活性成分称重到罐或小瓶中；
(b)如果需要的话，加入适当体积的乙醇和其它助溶剂；
(c)卷曲阀，并充气；
(d)加入一种含有氢氟烷烃(HFA)的推进剂。
可以气溶胶吸入给药、能够溶解在HFA/乙醇/助溶剂体系并且经肺吸收到血流中的任意药物，都可用于本发明的气溶胶组合物中。所述药物的实例是环氧合酶-、肥大细胞-、脂肪氧合酶-和蛋白水解酶-抑制剂、花生四烯酸-、白细胞三烯-、促凝血素-、钠/钾通道-、神经激肽-、速激肽-、缓激肽-、蕈毒碱-、组胺-、磷酸二酯酶-和选择蛋白-拮抗剂、钾通道阻断剂、抗感染剂、抗生素、戊双脒、细胞抑制剂、抑制真菌剂、自由基清除剂、维生素、激素、免疫兴奋剂、免疫抑制剂、肝素、抗糖尿病剂、镇痛剂、安眠药等，例如：
-白细胞三烯拮抗剂如伊拉司特、扎鲁司特和普仑司特，
-脂氧合酶抑制剂如弃白通，
-钠通道拮抗剂如盐酸阿米洛利、钾通道拮抗剂、比卡林，
-花生四烯酸拮抗剂如2-苯并噁唑胺，
-组胺受体拮抗剂如依匹那丁、氮卓斯汀、肉桂苯哌嗪、塞替利嗪、咪唑斯汀、mequitamium、氯苯那敏、阿司咪唑、特非那定和fenoxfenadine，
-抗偏头痛剂如麦角生物碱类methisergide、麦角胺、血清素、舒马曲坦、佐米曲坦、偏扁桃酯等，
-止痛剂如芬太尼、吗啡、丁丙诺啡、鸦片、海洛因、纳布啡、镇痛新、羟氢可待酮、曲马朵、哌替啶、胺苯环己乙酯、美沙酮、平痛新、右丙氧芬、哌腈米特等，
-止吐药如溴必利、多潘立酮、甲氧氯普胺、三乙膦、三氟丙嗪、美克洛嗪、氯苯氧胺、乘晕宁等，
-抗生素类如青霉素类(例如阿洛西林)、先锋霉素类(例如头孢替安或头孢三嗪)、碳青霉烯类、单酰胺菌素类、氨基糖甙类(例如链霉素、新霉素、庆大霉素、阿米卡星或妥布霉素)、喹诺酮类(例如环丙沙星)、大环内酯类(例如红霉素)、硝基咪唑类(例如替硝唑)、林可酰胺(例如克林霉素)、糖肽类(例如万古霉素)、多肽类(例如杆菌肽)、莫匹罗星等，
-维生素类和自由基清除剂如维生素A、B、C、D或E、过氧化氢酶、超氧化物歧化酶、还原型谷胱甘肽等，
-抗糖尿病剂如格列本脲、格列甲嗪、格列齐特、格列美脲、曲格列酮等，
-安眠药如地西泮类、哌啶酮二酮类、抗组胺药类，
-安定剂、抗抑郁剂和抗惊厥剂如地西泮类、酚噻嗪类、丁酰苯、硫苯酰胺、乙内酰脲类、巴比土酸盐类、琥珀酰亚胺类、酰胺咪嗪等，
-全身活性药如硝酸异山梨酯、单硝酸异山梨酯、阿扑吗啡和大麻素类，
-抗炎药，
-激素及其合成类似物如雄激素(例如睾酮)、抗雌激素、LHRH、醋酸亮丙瑞林、降钙素、甲状旁腺激素、生长激素、催产素、催乳素、高血糖素、促红细胞生成素、心房肽激素、促黑激素、促甲状腺激素、促性激素、后叶加压素、胰岛素等，
-潜能剂如前列地尔，
-细胞抑制剂如氮芥衍生物(例如ifosphamide)、N-亚硝脲衍生物(例如环己亚硝脲)、嘌呤和嘧啶碱基拮抗剂(例如氟尿嘧啶)、铂络合物(例如碳铂)、蒽环类抗生素(例如阿霉素)、鬼臼素(podophylline)衍生物(例如鬼臼毒素)。
尽管本发明优选的药物是那些不经常以肺气溶胶给药的，但是本发明的气溶胶溶液制剂也可以有益地用于已用于吸入组合物的化合物，例如β-拟态物如沙美特罗；优选选自氟羟泼尼松龙、环索奈德、氟替卡松和莫米松的皮质类固醇；抗胆碱能药如氧托溴铵和噻托溴铵；肥大细胞抑制剂如色甘酸、奈多罗米等。
高效云状物的产生使得能够制备含有标称剂量降低的药物的制剂，并且相对于参照组合物，临床有用的药物沉积百分比更大(FPF为递送剂量的至少30％，优选高于40％，甚至更优选高于50％)，同时限定寻靶肺的特定区域的颗粒大小。
所述药物任选可以其酯、异构体、对映异构体或旋光异构体的形式使用，在为酸或碱的情况下，本身就可以使用或者以其药用可接受的盐的形式使用。
有益地，活性成分的浓度是至少0.01％w/v，优选0.05％w/v，更优选在0.1％w/v-1.0％w/v之间，甚至更优选至少1.0％w/v。
优选在一次或两次促动中制剂适合递送治疗量的活性成分。有益地制剂适合递送至少25μg/剂，优选50-500μg/剂的治疗剂量。“治疗剂量”是指单次促动吸入器能够产生药效的活性成分的量。
本发明的制剂可以装入适合递送药用气溶胶制剂的罐中。某些药物当与经常由铝制得的标准金属容器接触贮藏时会遇到化学降解率提高。在这些情况下，这些制剂优选装入部分或全部内表面由阳极化铝、不锈钢制成或者衬有一惰性有机涂层的罐中。优选涂层的实例是环氧-苯酚树脂、全氟烷氧基链烷、全氟烷氧基链烯、全氟链烯如聚四氟乙烯、氟化-乙烯-丙烯、聚醚砜和氟化-乙烯-丙烯聚醚砜共聚物。其它合适的涂层可以是聚酰胺、聚酰亚胺、聚酰胺酰亚胺、聚苯硫醚或其组合。
为了进一步提高稳定性，使用包金箔内边并优选部分或完全翻转边的罐。
制剂通过能够递送容积在25μl-100μl之间的计量阀促动。
按照本领域技术人员的知识选择计量阀和垫圈的类型。垫圈可以包括任何适宜的弹性材料如低密度聚乙烯、EPDM、氯丁二烯和TPE。
合适的阀可从气溶胶工业公知的厂商商购获得，例如从Valois，France、Bespak plc，UK和3M，Neotechnic Ltd，UK。
鉴于药物在溶液中的化学稳定性，在一些情况下优选与制剂接触的计量阀组分的内表面涂布有惰性材料。
对本发明的气溶胶制剂而言，通常可以使用目前使用的孔径为0.20-0.50mm(尤其是0.22、0.33、0.42和0.45mm)的阀促动器。当需要大量乙醇溶解药物时，为了获得具有最佳可呼吸分数的气溶胶云状物，有益地使用配备有孔径在0.10-0.20mm之间(尤其是0.12、0.14、0.16、0.18mm)的阀促动器。
可以按照名字为申请人的欧洲专利申请号01 130521.6制备这类孔口。
在一些情况下，为了稳定溶液中的药物，必须提供具有特定表观pH的气溶胶溶液，该表观pH可以由本领域技术人员按照WO 01/894080测定。
氢氟烃推进剂优选选自HFA 134a、HFA 227及其混合物。
助溶剂可以包括一种或多种溶剂，在这种情况下其比例是有效气溶胶化的关键因素。无论如何，本领域技术人员可以根据考虑的药物的化学物理特性对所述比例进行选择。
优选的助溶剂经常是醇类例如乙醇、丙醇、丙二醇、聚乙二醇、甘油及其混合物，其总量至多30％w/w，优选至多25％w/w，更优选至多20％w/w。
在一些制剂中，另一有用的助溶剂是水。
有益地，小滴颗粒大小在约0.5μm-2.5μm之间，相应地MMAD是约1-2μm。
HFA溶液pMDIs的制备
使用手工操作卷曲和填充设备装配该pMDI罐。精确地称取所需量的药物到罐或小瓶中制备制剂。然后加入适当体积的乙醇和其它助溶剂(如果需要的话)。将阀卷曲到小瓶/罐上并将装配的该小瓶/罐超声处理约10分钟。经阀装入该HFA推进剂并将该pMDI再次超声处理10分钟。在仅含药物和推进剂的制剂的情况下，在加入推进剂之后，将该pMDI超声处理1次。计算最终组成，对活性成分以百分比w/v计，对助溶剂而言以百分比w/w计。
溶解度研究
所有溶解度研究是在配备有连续喷雾阀的涂布有塑料的玻璃pMDI小瓶中进行的。一旦制得该药物-HFA溶液，将pMDIs在冰箱中于4℃(±0.1℃)下贮藏。定期取出pMDI小瓶并借助偏振光装置肉眼评价小瓶的结晶生长。
格栅撞击研究
所有撞击研究都是用配备有50μl或100μl阀的切边阳极化铝罐中装的制剂进行的。这些研究是使用配备有USP XXII金属咽门入口的安徒生阶式撞击取样器(ACI)进行的。
该ACI以28.3±21min-1的流速操作。将该HFA溶液制剂经孔径为0.14-0.45mm的促动器倒入ACI中。通过高压液相色谱法(HPLC)测定药物在每个ACI板上的沉积。
MMAD值和相应的几何标准偏差(GSD)是由各ACI板上收集的筛下药物累计百分数(概率单位标度)相对各ACI板的上截止直径(log 10标度)的曲线计算出来的。
测定以下参数：计量剂量，它是通过安徒生设备递送的剂量与沉积在设备促动器上的活性成分残余量之和；沉积在各个ACI阶段上的活性颗粒的累积量；促动器上的量；适配器和咽门中的量(adp/咽门)；细粒剂量或可呼吸剂量(FPD)，它是沉积在阶段3到ACI的过滤器上的量并相当于颗粒大小小于4.7μm的颗粒的量；细粒分数或可呼吸分数，它是可呼吸剂量与外促动器递送的剂量之比。
本发明的制剂的实例包括：
-阿扑吗啡酯，在选自HFA 134a、HFA 227及其混合物的HFA推进剂和选自醇、多元醇及其混合物的助溶剂中。在一个特定实施方式中，制剂包括至多1％w/v阿扑吗啡二异丁酰酯、至多5％w/w乙醇、0-0.1％w/w甘油和HFA 134a，
-醋酸亮丙瑞林，在选自HFA 134a、HFA 227及其混合物的HFA推进剂和选自醇、水及其混合物的助溶剂中。在一个特定实施方式中，制剂包括至多0.26％w/v醋酸亮丙瑞林、15-30％w/w乙醇、2-5％w/w水和HFA 134a。
实施例1
阿扑吗啡二异丁酰酯的溶解度研究、其相应pMDI制剂的气溶胶递
送特性和稳定性
溶解度研究
以不同百分比的乙醇于HFA 134a或HFA 227中制备pMDI制剂来研究阿扑吗啡二异丁酰酯的溶解度。
结果显示含有至多1％w/v阿扑吗啡二异丁酰酯的制剂易溶于HFA134a或HFA 227中。
气溶胶递送特性研究
制备含有5％w/w乙醇和0.1％w/w甘油的0.5％和1％w/v(分别为250μg或500μg/50μl)阿扑吗啡二异丁酰酯HFA 134a溶液制剂。将这些罐安装孔径为0.22mm的促动器。
用每个制剂进行两个ACI沉积测定。将20喷倒入该ACI中。
按照本发明制备的阿扑吗啡二异丁酰酯制剂具有约2.0μm的MMAD，至少70-75％的细粒分数(FPF)，而颗粒大小在0.43-3.3μm范围内的活性颗粒的量为至少60％。
稳定性研究
对直立和倒置的涂布过的铝罐中于25℃下贮藏的按照实施例1制备的制剂的稳定性进行研究。
通过HPLC测定阿扑吗啡二异丁酰酯的回收率。
在6个月评价中活性成分的回收率优异并且发生的降解最小。在直立和倒置贮藏的这些罐之间的差异不明显。
实施例2
醋酸亮丙瑞林的溶解度研究、其相应pMDI制剂的气溶胶递送特性
和稳定性
溶解度研究
以不同百分比的乙醇和水于HFA 134a或HFA 227中制备pMDI制剂来研究醋酸亮丙瑞林的溶解度。
结果显示含有至多0.26％w/v醋酸亮丙瑞林的制剂易溶于乙醇、水、HFA 134a体系中。
当加入水时，醋酸亮丙瑞林在乙醇/HFA134a体系中的溶解度明显增强。
气溶胶递送特性研究
制备含有15％w/w乙醇和2％w/w水的0.04％w/v(40μg/100μl)醋酸亮丙瑞林HFA 134a溶液制剂。将这些罐安装孔径为0.14mm的促动器。
用该制剂进行两个ACI沉积测定。将10喷倒入该ACI中。
按照本发明制备的醋酸亮丙瑞林制剂具有约1.0μm的MMAD，至少72％的细粒分数(FPF)，而颗粒大小在0.43-3.3μm范围内的活性颗粒的量为至少61％。
制备另一含有0.08％w/v(80μg/100μl)醋酸亮丙瑞林、18％w/w乙醇和3％w/w水的HFA 134a溶液制剂。将这些罐安装孔径为0.14mm的促动器。
用该制剂进行两个ACI沉积测定。将10喷倒入该ACI中。
按照本发明制备的醋酸亮丙瑞林制剂具有约1.3μm的MMAD，至少59％的细粒分数(FPF)，而颗粒大小在0.43-3.3μm范围内的活性颗粒的量为至少52％。
稳定性研究
对直立和倒置的涂布过的铝罐中于25℃下贮藏的含有30％w/w乙醇和5％w/w水的亮丙瑞林100μg/50μl HFA 134a pMDIs进行稳定性研究。
通过HPLC测定醋酸亮丙瑞林含量。
在6个月的稳定性研究中观察到优异的稳定性。
Claims (16)
1、一种气溶胶药用组合物，包括在氢氟烷烃推进剂和一种或多种助溶剂的混合物中的药物溶液，其中促动吸入器递送的气溶胶液滴的颗粒大小在0.5μm-2.5μm之间，同时质量中值空气动力学直径为约1-2μm，并且其中细粒分数是至少30％。
2、如权利要求1的药剂，特征在于药物的浓度是至少0.01w/v。
3、如权利要求1-2的药剂，特征在于药物的浓度是至少0.05％w/w。
4、如权利要求1-3的药剂，其中所述推进剂包括一种或多种选自HFA 134a和HFA 227的HFAs。
5、如权利要求1-4的药剂，其中所述助溶剂是乙醇，其量最多30％w/w。
6、如权利要求1-5的药剂，其中所述助溶剂选自乙醇、低级烷基(C1-C4)醇、多元醇或聚亚烷基二醇及其组合。
7、如权利要求6的药剂，其中多元醇选自甘油和丙二醇，并且聚亚烷基二醇是聚乙二醇。
8、如权利要求1-5的药剂，其中所述助溶剂是选自聚烷氧基醇和聚氧链烷基醚和酯的(聚)烷氧基衍生物。
9、如权利要求8的药剂，其中聚烷氧基醇是Transcutol。
10、如权利要求8的药剂，其中聚氧链烷基醚和酯选自聚氧乙烯烷基醚类、聚氧乙烯山梨糖醇酐脂肪酸酯类和聚氧乙烯硬脂酸酯。
11、如权利要求1-5的药剂，其中所述助溶剂包括选自油酸乙酯、肉豆蔻酸异丙酯和棕榈酸异丙酯的脂肪酸烷基酯。
12、如权利要求1-6的药剂，其中助溶剂包括最多10％w/w水。
13、如任意前述权利要求的药剂，其中细粒分数是至少40％。
14、如任意前述权利要求的药剂，其中细粒分数是至少50％。
15、一种气溶胶吸入器，含有如权利要求1-14任意一项所述的制剂，其中阀促动器具有0.20-0.50mm的孔径。
16、一种气溶胶吸入器，含有如权利要求1-14任意一项所述的制剂，其中阀促动器具有0.10-0.20mm的孔径。
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP02004786A EP1340492A1 (en) | 2002-03-01 | 2002-03-01 | Aerosol formulations for pulmonary administration of medicaments having systemic effects |
| EP02004786.6 | 2002-03-01 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1638731A true CN1638731A (zh) | 2005-07-13 |
Family
ID=27675679
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA038049775A Pending CN1638731A (zh) | 2002-03-01 | 2003-02-26 | 用于经肺给药以产生全身效应的气溶胶制剂 |
| CNA2009100074339A Pending CN101502500A (zh) | 2002-03-01 | 2003-02-27 | 含有β2-激动剂的溶液的加压计量吸入器 |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2009100074339A Pending CN101502500A (zh) | 2002-03-01 | 2003-02-27 | 含有β2-激动剂的溶液的加压计量吸入器 |
Country Status (27)
| Country | Link |
|---|---|
| US (1) | US20050129621A1 (zh) |
| EP (2) | EP1340492A1 (zh) |
| JP (1) | JP2005519094A (zh) |
| KR (1) | KR20040091050A (zh) |
| CN (2) | CN1638731A (zh) |
| AR (2) | AR038643A1 (zh) |
| AT (1) | ATE488224T1 (zh) |
| AU (1) | AU2003215597B2 (zh) |
| BR (1) | BR0303348A (zh) |
| CA (1) | CA2477879C (zh) |
| DE (1) | DE60334973D1 (zh) |
| EA (1) | EA008571B1 (zh) |
| ES (1) | ES2358293T3 (zh) |
| GE (1) | GEP20063985B (zh) |
| HR (1) | HRP20040751A2 (zh) |
| IL (1) | IL163842A0 (zh) |
| MA (1) | MA27107A1 (zh) |
| MX (1) | MXPA04008370A (zh) |
| NO (1) | NO20034874L (zh) |
| NZ (1) | NZ535019A (zh) |
| PE (1) | PE20030949A1 (zh) |
| PL (1) | PL372261A1 (zh) |
| TN (1) | TNSN04148A1 (zh) |
| TW (1) | TW200304833A (zh) |
| UA (2) | UA81238C2 (zh) |
| WO (1) | WO2003074023A1 (zh) |
| ZA (3) | ZA200406918B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114641290A (zh) * | 2019-09-04 | 2022-06-17 | 锐能制药有限公司 | 药物组合物 |
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| US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
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| US6315985B1 (en) * | 1999-06-18 | 2001-11-13 | 3M Innovative Properties Company | C-17/21 OH 20-ketosteroid solution aerosol products with enhanced chemical stability |
| IT1317720B1 (it) * | 2000-01-07 | 2003-07-15 | Chiesi Farma Spa | Dispositivo per la somministrazione di aerosol dosati pressurizzati inpropellenti idrofluoroalcani. |
| IT1318514B1 (it) * | 2000-05-12 | 2003-08-27 | Chiesi Farma Spa | Formulazioni contenenti un farmaco glucocorticosteroide per iltrattamento di patologie broncopolmonari. |
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| HU230804B1 (hu) * | 2000-05-22 | 2018-06-28 | Chiesi Farmaceutici S.P.A | Gyógyászati célú stabil aeroszol összetétel, inhalátor az aeroszol pontos adagolásához és eljárás ennek feltöltésére |
| ATE267591T1 (de) * | 2001-07-02 | 2004-06-15 | Chiesi Farma Spa | Optimierte tobramycin-formulierung zur aerosolbildung |
| JP2005523905A (ja) * | 2002-03-01 | 2005-08-11 | キエシ・フアルマチエウテイチ・ソチエタ・ペル・アチオニ | ホルモテロール（ｆｏｒｍｏｔｅｒｏｌ）超微細調合物 |
| EP1415647A1 (en) * | 2002-10-23 | 2004-05-06 | CHIESI FARMACEUTICI S.p.A. | "Long-acting beta-2 agonists ultrafine formulations" |
| EP1452179A1 (en) * | 2003-02-27 | 2004-09-01 | CHIESI FARMACEUTICI S.p.A. | Novel medicament combination of a highly potent long-lasting beta2-agonist and a corticosteroid |
| GB0311701D0 (en) * | 2003-05-21 | 2003-06-25 | Karib Kemi Pharm Liited | Improved metered dose inhaler product |
| JP2007505831A (ja) * | 2003-09-15 | 2007-03-15 | ベクトゥラ・リミテッド | 肺吸入による、早漏を治療するための医薬品組成物 |
| EP1595531A1 (en) * | 2004-05-13 | 2005-11-16 | CHIESI FARMACEUTICI S.p.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
| IL177103A0 (en) * | 2004-02-27 | 2006-12-10 | Chiesi Farma Spa | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
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| RU2457832C2 (ru) * | 2005-09-25 | 2012-08-10 | Сипла Лимитед | Состав на основе тровентола |
| US20070243262A1 (en) * | 2005-12-21 | 2007-10-18 | Hurley Kevin P | Stable S-nitrosothiol formulations |
| DE102006017320A1 (de) * | 2006-04-11 | 2007-10-18 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Aerosolsuspensionsformulierungen mit TG 227 ea oder TG 134 a als Treibmittel |
| EP2011534A1 (en) * | 2007-07-03 | 2009-01-07 | CHIESI FARMACEUTICI S.p.A. | Metered dose inhaler actuator |
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| WO2009049159A1 (en) | 2007-10-10 | 2009-04-16 | Parion Sciences, Inc. | Delivering osmolytes by nasal cannula |
| US8555875B2 (en) * | 2008-12-23 | 2013-10-15 | Map Pharmaceuticals, Inc. | Inhalation devices and related methods for administration of sedative hypnotic compounds |
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| CA2273835A1 (en) * | 1996-12-04 | 1998-06-11 | Bioglan Ireland (R & D) Limited | Pharmaceutical compositions and devices for their administration |
| US20010031244A1 (en) * | 1997-06-13 | 2001-10-18 | Chiesi Farmaceutici S.P.A. | Pharmaceutical aerosol composition |
| GB2326334A (en) * | 1997-06-13 | 1998-12-23 | Chiesi Farma Spa | Pharmaceutical aerosol compositions |
| US6309623B1 (en) * | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
| US6284282B1 (en) * | 1998-04-29 | 2001-09-04 | Genentech, Inc. | Method of spray freeze drying proteins for pharmaceutical administration |
| IT1303788B1 (it) * | 1998-11-25 | 2001-02-23 | Chiesi Farma Spa | Formulazioni di aerosol medicinali. |
| DZ2947A1 (fr) * | 1998-11-25 | 2004-03-15 | Chiesi Farma Spa | Inhalateur à compteur de dose sous pression. |
| EP1143930B8 (en) * | 1999-09-11 | 2008-03-19 | Glaxo Group Limited | Pharmaceutical formulation of fluticasone propionate |
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| CA2402020C (en) * | 2000-03-09 | 2006-08-29 | Gw Pharma Limited | Pharmaceutical compositions |
| BR0005797A (pt) * | 2000-03-20 | 2001-10-16 | Abbott Lab | Métodos para o tratamento de disfunção sexual com apomorfina em nìveis de concentração plasmática especificados |
| IT1318514B1 (it) * | 2000-05-12 | 2003-08-27 | Chiesi Farma Spa | Formulazioni contenenti un farmaco glucocorticosteroide per iltrattamento di patologie broncopolmonari. |
| HU230804B1 (hu) * | 2000-05-22 | 2018-06-28 | Chiesi Farmaceutici S.P.A | Gyógyászati célú stabil aeroszol összetétel, inhalátor az aeroszol pontos adagolásához és eljárás ennek feltöltésére |
| JP2005523905A (ja) * | 2002-03-01 | 2005-08-11 | キエシ・フアルマチエウテイチ・ソチエタ・ペル・アチオニ | ホルモテロール（ｆｏｒｍｏｔｅｒｏｌ）超微細調合物 |
| EP1595531A1 (en) * | 2004-05-13 | 2005-11-16 | CHIESI FARMACEUTICI S.p.A. | Stable pharmaceutical solution formulations for pressurized metered dose inhalers |
-
2002
- 2002-03-01 EP EP02004786A patent/EP1340492A1/en not_active Withdrawn
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2003
- 2003-02-26 NZ NZ535019A patent/NZ535019A/en unknown
- 2003-02-26 UA UA20040806744A patent/UA81238C2/uk unknown
- 2003-02-26 DE DE60334973T patent/DE60334973D1/de not_active Expired - Lifetime
- 2003-02-26 ES ES03743339T patent/ES2358293T3/es not_active Expired - Lifetime
- 2003-02-26 KR KR10-2004-7012649A patent/KR20040091050A/ko not_active Application Discontinuation
- 2003-02-26 EA EA200401006A patent/EA008571B1/ru not_active IP Right Cessation
- 2003-02-26 AU AU2003215597A patent/AU2003215597B2/en not_active Ceased
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- 2003-02-26 EP EP03743339A patent/EP1480616B1/en not_active Expired - Lifetime
- 2003-02-26 WO PCT/EP2003/001962 patent/WO2003074023A1/en active Application Filing
- 2003-02-26 CA CA2477879A patent/CA2477879C/en not_active Expired - Fee Related
- 2003-02-26 JP JP2003572543A patent/JP2005519094A/ja active Pending
- 2003-02-26 MX MXPA04008370A patent/MXPA04008370A/es unknown
- 2003-02-26 CN CNA038049775A patent/CN1638731A/zh active Pending
- 2003-02-26 AT AT03743339T patent/ATE488224T1/de active
- 2003-02-26 GE GEAP8390A patent/GEP20063985B/en unknown
- 2003-02-26 IL IL16384203A patent/IL163842A0/xx unknown
- 2003-02-26 US US10/505,679 patent/US20050129621A1/en not_active Abandoned
- 2003-02-26 BR BR0303348-1A patent/BR0303348A/pt not_active IP Right Cessation
- 2003-02-27 TW TW092104190A patent/TW200304833A/zh unknown
- 2003-02-27 CN CNA2009100074339A patent/CN101502500A/zh active Pending
- 2003-02-27 UA UA20040806968A patent/UA80695C2/uk unknown
- 2003-02-28 AR ARP030100686A patent/AR038643A1/es unknown
- 2003-02-28 PE PE2003000200A patent/PE20030949A1/es not_active Application Discontinuation
- 2003-10-31 NO NO20034874A patent/NO20034874L/no not_active Application Discontinuation
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2004
- 2004-08-06 TN TNP2004000148A patent/TNSN04148A1/en unknown
- 2004-08-09 MA MA27816A patent/MA27107A1/fr unknown
- 2004-08-20 HR HRP20040751 patent/HRP20040751A2/hr not_active Application Discontinuation
- 2004-08-31 ZA ZA200406918A patent/ZA200406918B/xx unknown
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114641290A (zh) * | 2019-09-04 | 2022-06-17 | 锐能制药有限公司 | 药物组合物 |
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