CN1090019C - 组合物 - Google Patents

组合物 Download PDF

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CN1090019C
CN1090019C CN97123049A CN97123049A CN1090019C CN 1090019 C CN1090019 C CN 1090019C CN 97123049 A CN97123049 A CN 97123049A CN 97123049 A CN97123049 A CN 97123049A CN 1090019 C CN1090019 C CN 1090019C
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mixture
substance
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lactose
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CN1195523A (zh
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E·A·C·特罗发斯特
L·E·布里纳
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Abstract

本发明涉及一种生产细粒物质或物质混合物的稳定晶型的方法，此物质或物质混合物它在保持吸入其所需气体动力学特性的同时，可被生产、贮存和使用，该方法是a)在使用物质混合物的情况下，制备物质的均匀混合物；b)通过任何常规方法，使物质或物质混合物微粉化、直接沉淀或减小为吸入所需的颗粒大小，颗粒尺寸小于10μm；c)当各物质由步骤b)制成单独的细颗粒时，可以制成或不制成所需物质的均匀混合物；d)通过用含水的汽相以控制方式处理来调节所述物质或物质混合物；和e)干燥。

Description

组合物
本申请是申请号为94193793.3、申请日为1994年8月25日、发明名称为“调节物质的方法”的发明专利申请的分案申请。
本发明涉及一种生产细粒物质或物质混合物的方法，此物质或物质混合物在保持吸入其所需的气体动力学特性的同时，可被生产、贮存和使用，并且改善了干燥状态下的理化特性，这样便于技术操作并显著增加所述物质或其混合物的医疗价值。
现在有几种可购得的用于治疗患有哮喘或其它呼吸疾病的有效药物。已认识到，这些药物应当尽可能通过吸入途径给药。吸入药物的理想释放系统将是对使用者和环境有益的多剂量吸入剂，它给予准确剂量的具有良好气体动力学行为的颗粒的稳定制剂。
在过去几年中，事实已屡次表明选择最合适的晶型可显著影响所给化学物质的临床结果。特定剂型中固体的化学和物理稳定性可因合适晶型的物质的存在得以改善。剂型中物质的固态相转变显著改变制剂的药学特性。所给物质的固态相可影响如生物利用度和理化稳定性(具体的表面积、颗粒径等)的重要因素。固体状态的化学稳定性和吸湿性常与结晶性密切相关。
固态相变可在机械过程中(微粉化)发生。在微粉化过程中，晶体结构的破裂或活化常因形成缺陷或非晶型区而改变无序度。此类区域常常对外界影响(如湿度)敏感。需要建立可将不同形式的物质转变成单一稳定形式的条件，因而消除固体状态特性的差异和随后的不同理化特性和药学特性。
在药物工业中，细粉的增产和使用已集中在对评价其理化特性和技术操作的可靠方法的需求上。粘合粉末的混合会受到同种颗粒之间和不同种颗粒之间的颗粒之间作用力的影响。因为细粉附聚，混合物常常是不均匀的，尤其是小组分会出现倾斜的分布。一个原因可能是，附聚的小组分未完全分散在其组分颗粒中；详见Chem.Eng.(1973)，12-19。粘合粉末因此而很难以一种准确的方法混合成均匀的混合物，特别是当一种组分仅存在小部分时。
当喷雾干燥、冷冻干燥、快速溶剂聚冷或采用控制沉淀时，常会获得非晶型状态的和/或亚稳态结晶型的物质。非晶型或亚稳态结晶型的使用常因其热动力学的不稳定性而受到限制。因此，需要将非晶型或亚稳态结晶型转化为更稳定的结晶状态。对于结晶物质来说，破碎操作步骤会产生使颗粒对湿度和化学降解更敏感的颗粒的非晶型区。本发明涉及这种物理变化，或者更重要地如何能够利用它们并可通过这些固体状态现象的方式来控制。
在欧洲专利申请EP 508969中描述了使用类似于乙醇、丙酮等溶剂来重排或调节水溶性物质(非晶型的或部分非晶型的)，其中处理了单一的化合物。然而，这种方法不能用在含结晶水的某些物质中，因为有机溶剂会消除含结晶水而显著改变物质的特性。据了解，水溶性物质不能在保持细粒物质颗粒分布完整的同时用水来调节。
参考文献：Amorphous-to-Crystalline Transformation of Sucrose，Phar.Res.，7(12)，1278(1990)by J.T.Carstensen和K.Van Scoik.Effect of Surface Characteristics of TheophyllineAnhydrate Powder on Hygroscopic Stability，J.Pharm.Pharmacol.42，606(1990)by M.Otsuka等.Process for conditioning of water-soluble substances，
欧洲专利申请508969 by J.Trofast等.The molecular basis of moisture effect on the physicaland chemical stability of drugs in the solid state，Int.J.Pharm.62(1990)，87-95 by C.Ahlneck和G.Zografi.
本发明的目的是提供一种细粒物质或物质混合物，此物质或物质混合物在保持吸入其所需气体动力学特性的同时，可被生产、贮存和使用，其中以控制方法来调节该物质或混合物，这样便于技术操作并显著增加所使用物质或混合物的医疗价值。
本发明的目的是提供一种以稳定晶型获得细粒物质或物质混合物的可靠方法，此物质或物质混合物在保持吸入其所需的气体动力学特性的同时，可被生产、贮存和使用。本发明的方法包括下列步骤：
a)在使用物质混合物的情况下，制备该物质的均匀混合物；
b)通过任何常规方法，使物质或物质混合物微粉化、直接沉淀或减小为吸入所需的粒径，该粒径小于10μm；
c)当各物质由步骤b)制成单独的细颗粒时，可以制成或不制成所需物质的均匀混合物；
d)通过用含水的汽相以控制方式处理来调节所述物质或物质混合物；和
e)干燥。
通过用含水的汽相处理来进行调节步骤。所述含水的汽相是存在或不存在有任何有机溶剂蒸汽的水蒸汽相。
调节步骤在温度/相对湿度相结合的条件下进行，它抑制包括低于该方法温度的物质的玻璃化温度。玻璃化温度(Tg)是流动性非晶型材料由不流动玻璃态变为流动的橡胶态(相转变)时的温度。
通常在0到100℃的温度下进行调节，优选10到50℃。由于实际原因，调节常在室温下进行。选择调节时的相对湿度(RH)，以便产生相转变，通常在35％RH以上，优选在50％RH以上，最优选在75％RH以上。采用的时间受批量、相对湿度和包装等的显著影响，可以是几分钟到数天。
制剂可包含如，强化药理活性药物在肺中吸收的物质。所使用的强化剂可以是任何种类的化合物，其作用是强化通过排列在肺泡上的上皮细胞层并进入邻近的肺脉管系统的吸收作用。在已知具有强化吸收作用特性的物质中有表面活性剂，如脂肪酸在碱金属盐、牛磺-二氢梭链孢酸钠(Sodium tauro-dihydr of usidate)、卵磷脂、甘胆酸钠、牛磺胆酸钠、辛基吡喃葡萄糖苷等。
其它添加剂可以是载体、稀释剂、抗氧化剂、缓冲盐等，所有这些物质都可按本发明的方法来处理。
当使用吸入装置中的很小剂量时，剂量的准确性和可重现性常常是不足的。所以，高效药物可用载体来稀释，以便获得足以得到可靠且可再现剂量的粉末。此载体可以是碳水化合物如乳糖、葡萄糖、果糖、半乳糖、海藻糖、蔗糖、麦芽糖、棉子糖、maltitol、松三糖、淀粉、木糖醇、甘露糖醇、肌醇等及其水合物，优选乳糖和甘露糖醇，和氨基酸如丙氨酸及甜菜碱等。
大小在10μm以上的较粗颗粒也可采用本发明的方法来调节。
例如，本发明可用于下列药理活性物质：
福莫特罗(如富马酸盐)和沙美特罗(如xinafoate)是具有支气管痉挛缓解(bronchospasmolytic)作用的高选择性长效β2-肾上腺素能激动剂且可有效的治疗各种可逆的引起阻塞的肺遗传病(特别是哮喘病)。舒喘灵(如硫酸盐)、班布特罗(如，盐酸盐)、间羟舒喘宁(如，硫酸盐)、非诺特罗(如，氢溴酸盐)、克仑特罗(如，盐酸盐)、丙卡特罗(如，盐酸盐)、比托特罗(如，甲磺酸盐)和溴噁特罗是高选择性β2-肾上腺素能激动剂，溴化异丙托品是抗胆碱能支气管扩张药。消炎剂糖皮质激素的例子为布地奈德，(22R)-6α，9α-二氟-11β，21-二羟基-16α，17α-丙基亚甲基二氧基-4-孕烯-3，20-二酮，氟替卡松(如，丙酸酯形式)，氯地米松(如，二丙酸酯)，替泼尼旦、莫米松(momethasone)等。某些化合物可以是药用可接受的酯、盐、溶剂化物(如，水合物)或该类酯或盐的溶剂化物(若有的话)形式。
应用于本发明的优选的物质是硫酸间羟舒喘宁、硫酸舒喘灵、氢溴酸非诺特罗、溴化异丙托品、盐酸班布特罗、富马酸福莫特罗和沙莫特罗xinafoate及其溶剂化物，特别是其水合物。
应用于本发明的最优选的物质混合物是福莫特罗(如福莫特罗富马酸盐二水合物)/乳糖(一水合物)，相同的原则也可用于下述结合：如舒喘灵(如硫酸舒喘灵)/乳糖，间羟舒喘宁(如硫酸间羟舒喘宁)/乳糖，溴化异丙托品/乳糖，布地奈德/乳糖，(22R)-6α，9α-二氟-11β，21-二羟基-16α，17α-丙基亚甲基二氧基-4-孕烯-3，20-二酮/甘露醇，(22R)-6α，9α-二氟-11β，21-二羟基-16α，17α-丙基亚甲基二氧基-4-孕烯-3，20-二酮/肌醇和(22R)-6α，9α-二氟-11β，21-二羟基-16α，17α-丙基亚甲基二氧基-4-孕烯-3，20-二酮/乳糖。在调节步骤中，当一种成分不溶于水时，可使用有机溶剂作为一种化合物的调节剂并用水蒸汽作为其他化合物的调节剂。在这种情况下，调节可分两步过程来进行，其中第一步用有机溶剂来调节，然后在第二步中用水蒸汽来调节；或者反过来也是这样。
非晶型或部分非晶型的物质或物质混合物的重排或调节包括用含水的汽相以控制方式处理物质。该调节步骤是在具有控制和可调节湿度的特定环境中如在柱中用含有所需量水蒸汽的惰性气体和/或有机溶剂蒸汽来进行的。物质或物质混合物的装填影响所需时间及调节结果。块结的趋向影响颗粒的数量和大小。在使用物质混合物的情况下，在微粉化步骤之前混合物质通常是有利的，以便在使用低比例的药物与添加物时，确保混合物均匀。
在本发明中，采用同一方法调节两种或多种物质同时保持颗粒的分布是可能的，而且从技术的观点来看，这是极为有利。
物质混合物中物质间的配比在1∶1到1∶1000之间，优选在1∶1到1∶500之间，且最优选是在1∶1到1∶200之间，在这种情况下，一种物质是药理活性物质而另一种为添加剂。
在调节步骤前后，使用不同仪器如Malvern Master Sizer，Coulter Counter或显微镜测得细粒物质的粒径应是相同的。
获得的颗粒易于确定大小和分布以及从小批量到批量变化也是特别重要的，以便获得在使用吸入剂时会完全崩解为最初颗粒的附聚物。
本发明的目的是提供一种可靠的方法，它可方便地且可重现地制备单一药物或药物/添加剂结合(优选福莫特罗富马酸二水合物/乳糖)的药物制剂。
对于某些材料如福莫特罗/乳糖来说，药物和添加剂之间的Tg(玻璃化转变温度，它是流动性非晶型物质从不流动的玻璃状态变为流动的橡胶态时的温度)或水敏感性是十分不同的，可在两个连续的步骤中进行该过程，即，在一种温度/RH结合下调节一种物质，再在较高温度/RH下调节第二种物质。
混合步骤优选在微粉化步骤前进行，以便确保成分均匀，或采用I.Krycer和J.A.Hersey在Int.J.Pharm.6，119-129(1980)中报告的使用振动球磨机在一个步骤中进行。也可在微粉化后或各物质被调节后再混合物质。
在某些实例中，可使用红外光谱以便研究非晶型或部分非结晶型向稳态结晶型的转化。其它可采用的方法包括BET气体吸附、X-射线粉末衍射、等温微量热法和差示扫描量热法(DSC)。我们发现BET气体吸附和等温微量热法是区分试验化合物不同形式的最好方法。
当物质或物质混合物附聚并就此使用时，暴露在高湿度下发现的可呼吸颗粒滴为约70-80％。惊奇地发现，当附聚前调节物质或物质混合物(50％RH，福莫特罗富马酸二水合物/乳糖混合物)并暴露在高湿度下时可呼吸颗粒滴仅为约25-30％。在75％RH下进一步调节后，会产生仅5-10％的可呼吸颗粒滴。在75％RH下调节前后用Malvern仪器测量，其颗粒分布没有差别。假如用附聚产物进行调节，颗粒分布变得很糟，吸入装置中的制剂是无用的。实验过程
1.按一定比例混合药物或添加剂或其混合物。
2.微粉化混合物。
3.在温度/相对湿度结合条件下调节，该调节抑制包括低于该方法温度的物质的玻璃化温度。玻璃化温度(Tg)是流动的非晶型材料从不流动的玻璃态转变为流动的橡胶态时的温度。
4.用干燥的氮或空气干燥，或真空干燥。
实施例
通过按实验过程描述的方法进行的下列实施例来进一步说明本发明但不对本发明构成限制。测量了数批各物质或物质混合物。数据表示非调节的和含水的汽相调节的物质所释放出的热(T/g)的比较。使用Thermal Activety Monitor 2277(Thermomertrics AB，Sweden)进行该实验。
实施例1
硫酸舒喘灵(25％)/乳糖(75％)
调节时的相对湿度 (RH) 50-60％ RH
非调节物质(J/g)  5-8
调节物质(J/g)  ＜0.5
实施例2
溴化异丙托品(6％)/乳糖(94％)
调节时的相对湿度(RH)  50-60％  RH
非调节物质(J/g)  6-8
调节物质(J/g)  ＜0.5
实施例3
福莫特罗富马酸二水合物
调节时的相对湿度(RH)  75％ RH
非调节物质(J/g)  6
调节物质(J/g)  ＜0.5
实施例4
乳糖(见图1)
调节时的相对湿度(RH)  50％ RH
非调节物质(J/g)  10-14
调节物质(J/g)  ＜0.5
实施例5
松三糖
调节时的相对湿度(RH)  50％ RH
非调节物质(J/g)  12
调节物质(J/g)  ＜0.5
实施例6
福莫特罗富马酸二水合物(2％)/乳糖(98％)
调节时的相对湿度(RH) 50％ RH
非调节物质(J/g)  10-14
调节物质(J/g)  ＜0.5
重结晶期间，放出大量的热，通过检测量热信号(CalometricalSignal)，检查样品中的任何非晶型成分。图1显示调节前(I)和后(II)微粉化的乳糖。如此，在本发明调节期间，获得了完全的晶体。

Claims (1)

1.一种组合物，它含有粒度小于10μm的福莫特罗富马酸盐二水合物，其与乳糖混合并且该混合物经过如下处理：将混合物的粒度减至少于10μm，用含水的汽相处理来调节所述混合物，并且干燥，所述处理在温度/相对湿度相结合的条件下进行，它抑制包括低于该方法温度的物质的玻璃化温度。
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Families Citing this family (100)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5980949A (en) * 1994-10-03 1999-11-09 Astra Aktiebolag Formulation for inhalation
SE9700134D0 (sv) * 1997-01-20 1997-01-20 Astra Ab New formulation
US5983956A (en) 1994-10-03 1999-11-16 Astra Aktiebolag Formulation for inhalation
SE9501384D0 (sv) * 1995-04-13 1995-04-13 Astra Ab Process for the preparation of respirable particles
US6309671B1 (en) 1995-04-14 2001-10-30 Inhale Therapeutic Systems Stable glassy state powder formulations
US6258341B1 (en) 1995-04-14 2001-07-10 Inhale Therapeutic Systems, Inc. Stable glassy state powder formulations
GB9526392D0 (en) 1995-12-22 1996-02-21 Glaxo Group Ltd Medicaments
US6652837B1 (en) 1996-05-24 2003-11-25 Massachusetts Institute Of Technology Preparation of novel particles for inhalation
US5874064A (en) 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
SE9700135D0 (sv) * 1997-01-20 1997-01-20 Astra Ab New formulation
SE9700133D0 (sv) * 1997-01-20 1997-01-20 Astra Ab New formulation
NL1005514C2 (nl) * 1997-03-12 1998-09-15 Bronswerk Heat Transfer Bv Inrichting voor het uitvoeren van een fysisch en/of chemisch proces, zoals een warmtewisselaar.
ES2316681T3 (es) * 1997-03-20 2009-04-16 Schering Corporation Formas de dosificacion de aglomerados en polvo.
US6495167B2 (en) 1997-03-20 2002-12-17 Schering Corporation Preparation of powder agglomerates
US6503537B2 (en) * 1997-03-20 2003-01-07 Schering Corporation Preparation of powder agglomerates
SE9701956D0 (sv) * 1997-05-23 1997-05-23 Astra Ab New composition of matter
CA2295076A1 (en) * 1997-06-27 1999-01-07 Astra Aktiebolag New combination of antiasthma medicaments
US7052678B2 (en) 1997-09-15 2006-05-30 Massachusetts Institute Of Technology Particles for inhalation having sustained release properties
SE512663C2 (sv) * 1997-10-23 2000-04-17 Biogram Ab Inkapslingsförfarande för aktiv substans i en bionedbrytbar polymer
SE9704186D0 (sv) * 1997-11-14 1997-11-14 Astra Ab New composition of matter
FI105074B (fi) * 1997-12-31 2000-06-15 Leiras Oy Farmaseuttisen formulaation valmistusmenetelmä
US6287693B1 (en) * 1998-02-25 2001-09-11 John Claude Savoir Stable shaped particles of crystalline organic compounds
GB9806477D0 (en) 1998-03-26 1998-05-27 Glaxo Group Ltd Improved crystals
SE9802073D0 (sv) 1998-06-11 1998-06-11 Astra Ab New use
US6956021B1 (en) 1998-08-25 2005-10-18 Advanced Inhalation Research, Inc. Stable spray-dried protein formulations
DE19847969A1 (de) * 1998-10-17 2000-04-20 Boehringer Ingelheim Pharma Lagerfähig flüssige Formulierung mit Formoterol
US6235725B1 (en) 1998-10-30 2001-05-22 Baker Norton Pharmaceuticals, Inc. Methods and compositions for the prevention of tolerance to medications
SE9804001D0 (sv) 1998-11-23 1998-11-23 Astra Ab New process
SE9804000D0 (sv) * 1998-11-23 1998-11-23 Astra Ab New composition of matter
GB9826284D0 (en) * 1998-12-01 1999-01-20 Rhone Poulence Rorer Limited Process
GB9826286D0 (en) 1998-12-01 1999-01-20 Rhone Poulence Rorer Limited Process
US8722668B2 (en) * 1998-12-23 2014-05-13 Daryl W. Hochman Methods and compositions for the treatment of neuropathic pain and neuropsychiatric disorders
US6623760B1 (en) 1999-01-28 2003-09-23 Schering Corporation Method of preparing particles for agglomeration
AR022695A1 (es) * 1999-01-28 2002-09-04 Schering Corp PORTADOR SoLIDO PARTICULADO Y MÉTODO PARA PROVEER CONTROL DE LA PARTICULADA PARA LA DISTRIBUCIoN DE TAMANO DE PARTíCULAS Y DE CONTENIDO AMORFO CONVERTIBLE DURANTE SU PREPARACION
GB9902689D0 (en) * 1999-02-08 1999-03-31 Novartis Ag Organic compounds
GB9903759D0 (en) * 1999-02-18 1999-04-14 Novartis Ag Organic compounds
GB9904919D0 (en) 1999-03-03 1999-04-28 Novartis Ag Organic compounds
DE19921693A1 (de) * 1999-05-12 2000-11-16 Boehringer Ingelheim Pharma Neuartige Arzneimittelkompositionen auf der Basis von anticholinergisch wirksamen Verbindungen und ß-Mimetika
GB9919693D0 (en) * 1999-08-19 1999-10-20 Rhone Poulenc Rorer Ltd Process
US6586008B1 (en) * 1999-08-25 2003-07-01 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles during spray drying
AU763041B2 (en) * 1999-08-25 2003-07-10 Alkermes, Inc. Modulation of release from dry powder formulations
US7678364B2 (en) 1999-08-25 2010-03-16 Alkermes, Inc. Particles for inhalation having sustained release properties
US7252840B1 (en) 1999-08-25 2007-08-07 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles
US20010036481A1 (en) * 1999-08-25 2001-11-01 Advanced Inhalation Research, Inc. Modulation of release from dry powder formulations
US6749835B1 (en) 1999-08-25 2004-06-15 Advanced Inhalation Research, Inc. Formulation for spray-drying large porous particles
WO2001078735A1 (en) * 2000-04-13 2001-10-25 Innovata Biomed Limited Medicaments for treating respiratory disorders comprising formoterol and fluticasone
GB0012260D0 (en) 2000-05-19 2000-07-12 Astrazeneca Ab Novel composition
GB0012261D0 (en) * 2000-05-19 2000-07-12 Astrazeneca Ab Novel process
FI20002215A0 (fi) * 2000-10-06 2000-10-06 Orion Yhtymae Oyj Yhdistelmäpartikkelit
FI20002216A0 (fi) * 2000-10-06 2000-10-06 Orion Yhtymae Oyj Yhdistelmäpartikkelit astman hoitoon
US20020141946A1 (en) * 2000-12-29 2002-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
EP1345629A2 (en) 2000-12-29 2003-09-24 Advanced Inhalation Research, Inc. Particles for inhalation having sustained release properties
ITMI20010428A1 (it) * 2001-03-02 2002-09-02 Chemo Breath S A Composizioni ad uso inalatorio a base di formoterolo
RU2294737C2 (ru) * 2001-03-30 2007-03-10 Яготек Аг Медицинские аэрозольные составы
US6667344B2 (en) 2001-04-17 2003-12-23 Dey, L.P. Bronchodilating compositions and methods
US20030055026A1 (en) 2001-04-17 2003-03-20 Dey L.P. Formoterol/steroid bronchodilating compositions and methods of use thereof
US6482429B1 (en) * 2001-06-20 2002-11-19 Boehringer Ingelheim Pharmaceuticals, Inc. Stable powder inhalation dosage formulation
WO2003043603A1 (en) * 2001-11-20 2003-05-30 Advanced Inhalation Research, Inc. Particulate compositions for improving solubility of poorly soluble agents
ES2415654T3 (es) * 2001-11-20 2013-07-26 Civitas Therapeutics, Inc. Composiciones particuladas mejoradas para suministro pulmonar
SE523806C2 (sv) * 2002-02-26 2004-05-18 Ericsson Telefon Ab L M Förfarande och anordning för att inrikta polarisationsaxlarna hos fiberändar i två optiska polarisationsbevarande fibrer med varandra
SE0200657D0 (sv) * 2002-03-04 2002-03-04 Astrazeneca Ab Novel Formulation
DE10212264A1 (de) 2002-03-20 2003-10-02 Boehringer Ingelheim Pharma Kristallines Mikronisat, Verfahren zu dessen Herstellung und dessen Verwendung zur Herstellung eines Arzneimittels
US7309707B2 (en) 2002-03-20 2007-12-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg Crystalline micronisate, process for the manufacture thereof and use thereof for the preparation of a medicament
US7244415B2 (en) 2002-03-28 2007-07-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg HFA suspension formulations of an anhydrate
GB0208609D0 (en) * 2002-04-13 2002-05-22 Glaxo Group Ltd Compositions
AU2003246603A1 (en) * 2002-07-12 2004-02-02 Boehringer Ingelheim Pharma Gmbh And Co. Kg Process for providing a stable crystalline form of salbutamol
US20040023935A1 (en) * 2002-08-02 2004-02-05 Dey, L.P. Inhalation compositions, methods of use thereof, and process for preparation of same
US20040109826A1 (en) * 2002-12-06 2004-06-10 Dey, L.P. Stabilized albuterol compositions and method of preparation thereof
GB0312148D0 (en) 2003-05-28 2003-07-02 Aventis Pharma Ltd Stabilized pharmaceutical products
GB0315889D0 (en) * 2003-07-08 2003-08-13 Aventis Pharma Ltd Stable pharmaceutical products
TWI359675B (en) 2003-07-10 2012-03-11 Dey L P Bronchodilating β-agonist compositions
GB0316335D0 (en) * 2003-07-11 2003-08-13 Glaxo Group Ltd Pharmaceutical formulations
GB0323684D0 (en) * 2003-10-09 2003-11-12 Jagotec Ag Improvements in or relating to organic compounds
GB0323685D0 (en) * 2003-10-09 2003-11-12 Jagotec Ag Improvements in or relating to organic compounds
CA2547597A1 (en) * 2003-12-04 2005-06-16 Pfizer Products Inc. Multiparticulate compositions with improved stability
GB0409703D0 (en) * 2004-04-30 2004-06-02 Vectura Ltd Pharmaceutical compositions
DE102004048389A1 (de) 2004-10-01 2006-04-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Modifizierung von Oberflächen von Laktose als Hilfsstoff zur Verwendung für Pulverinhalativa
DE102004048390A1 (de) 2004-10-01 2006-04-06 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue Pulverinhalativa auf Basis modifizierter Laktosemischungen als Hilfsstoff
WO2007011743A2 (en) 2005-07-14 2007-01-25 Lipothera, Inc. Sustained release enhanced lipolytic formulation for regional adipose tissue treatment
US20070286814A1 (en) * 2006-06-12 2007-12-13 Medispray Laboratories Pvt. Ltd. Stable aerosol pharmaceutical formulations
DE102006030166A1 (de) * 2006-06-29 2008-01-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Tempern
GB2436412A (en) * 2006-11-27 2007-09-26 Cvon Innovations Ltd Authentication of network usage for use with message modifying apparatus
JP2012509922A (ja) * 2008-11-27 2012-04-26 ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング 新規粉末化結晶質吸入薬
US9132084B2 (en) 2009-05-27 2015-09-15 Neothetics, Inc. Methods for administration and formulations for the treatment of regional adipose tissue
US8815258B2 (en) 2009-05-29 2014-08-26 Pearl Therapeutics, Inc. Compositions, methods and systems for respiratory delivery of two or more active agents
AU2010253776B2 (en) 2009-05-29 2015-01-22 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting B2 adrenergic receptor agonists and associated methods and systems
GB0918149D0 (en) 2009-10-16 2009-12-02 Jagotec Ag Improved medicinal aerosol formulation
SG182485A1 (en) * 2010-01-15 2012-08-30 Lithera Inc Lyophilized cake formulations
US20110224229A1 (en) 2010-03-10 2011-09-15 Astrazeneca Ab Novel Crystalline Form
NO2560611T3 (zh) 2010-04-21 2018-06-02
AU2011305566A1 (en) 2010-09-22 2013-05-02 Map Pharmaceuticals, Inc. Aerosol composition for administering drugs
CN103269693A (zh) 2010-11-24 2013-08-28 利赛拉公司 选择性、亲脂性及长效型β激动剂单一治疗调配物和用于肥胖及外形凸起的美容治疗的方法
RU2013153466A (ru) 2011-06-29 2015-08-10 Астразенека Аб Кристаллическая форма производных индазолиламида для лечения опосредованных глюкокортикоидными рецепторами расстройств
WO2014144894A1 (en) * 2013-03-15 2014-09-18 Pearl Therapeutics, Inc. Methods and systems for conditioning of particulate crystalline materials
RU2015154720A (ru) 2013-05-22 2017-06-27 Перл Терапьютикс, Инк. Композиции, способы и системы для респираторной доставки трех или более активных средств
CN103773773A (zh) * 2013-11-08 2014-05-07 青岛科技大学 中华绒螯蟹双wap结构域蛋白基因及其编码蛋白的应用
MY181647A (en) 2014-09-09 2020-12-30 Vectura Ltd Formulation comprising glycopyrrolate, method and apparatus
EP3346990B1 (en) 2015-09-09 2020-03-18 Vectura Limited Jet milling method
MX2024000465A (es) 2021-07-09 2024-04-05 Astrazeneca Pharmaceuticals Lp Composiciones, metodos y sistemas para la administracion de farmacos en aerosol.
CN118414148A (zh) 2021-12-20 2024-07-30 阿斯利康(瑞典)有限公司 用于气溶胶药物递送的组合物、方法和系统

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713249A (en) * 1981-11-12 1987-12-15 Schroeder Ulf Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof
WO1991016882A1 (en) * 1990-05-08 1991-11-14 Liposome Technology, Inc. Direct spray-dried drug/lipid powder composition
EP0508969A1 (en) * 1991-04-11 1992-10-14 Astra Aktiebolag Process for conditioning of water-soluble substances

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3994974A (en) * 1972-02-05 1976-11-30 Yamanouchi Pharmaceutical Co., Ltd. α-Aminomethylbenzyl alcohol derivatives
US3987192A (en) * 1974-01-07 1976-10-19 The Upjohn Company Compositions and process of treatment
US4405598A (en) * 1976-01-30 1983-09-20 Fisons, Limited Composition for treating asthma
SE8204244L (sv) * 1982-07-09 1984-01-10 Ulf Schroder Kristalliserad kolhydratsmatris for biologiskt aktiva substanser
US4476130A (en) * 1982-09-09 1984-10-09 Riker Laboratories, Inc. 3-(1H-Tetrazol-5-yl)-4H-pyrimido[2,1-b]benzoxazol-4-one compounds exhibiting anti-allergic activity
JPH08186B2 (ja) * 1985-06-21 1996-01-10 ゲルゲリイ、ゲルハルト プロセス材料から反応生成物を製造する方法及びその装置
KR100229754B1 (ko) * 1989-11-24 1999-11-15 샬러 한스, 하우스 한스 루돌프 판크레아틴구형입자, 이의 제조방법 및 이를 함유하는 약제학적 조성물
US5376386A (en) * 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
CN111164157B (zh) * 2017-12-14 2021-09-07 Dic株式会社 着色组合物和滤色器

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4713249A (en) * 1981-11-12 1987-12-15 Schroeder Ulf Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof
WO1991016882A1 (en) * 1990-05-08 1991-11-14 Liposome Technology, Inc. Direct spray-dried drug/lipid powder composition
EP0508969A1 (en) * 1991-04-11 1992-10-14 Astra Aktiebolag Process for conditioning of water-soluble substances

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