CN104324362A - 以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法 - Google Patents
以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法 Download PDFInfo
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Abstract
本申请涉及以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法,提供了通过修饰活性试剂的结构特征从而促进同微粒的有利缔合来促进微粒吸附活性试剂的方法。
Description
与相关申请的交叉引用
本申请是申请日为2006年9月14日、题目为“以提高活性试剂对结晶微粒表面的亲和力为基础的药物配制方法”的第200680033768.2号中国发明专利申请的分案申请。
本申请基于35U.S.C.§119(e)要求于2005年9月14日提交的美国临时连续申请No.60/717,524和2006年4月14日提交的美国临时连续申请No.60/744,882的优先权,每份文献的整体内容都通过引用整体并入本文。
技术领域
本发明涉及药物配制,特别涉及方法。更特别地,公开了结晶微粒表面上活性试剂的结合或吸附。
背景技术
治疗剂的递送一直是主要的问题。口服施用由于易于施用、患者顺从和降低的成本而是最常见和优选的递送途径之一。然而,该途径的缺点包括治疗物的效能低或多变以及吸收无效。当待递送的化合物在胃肠道条件下不稳定时,这特别明显。本领域已开发了大量包覆和封装方法,但很少能够有效地解决上述问题。而且,有些治疗化合物在肠胃道条件下容易损失活性,因此为了以有效量吸收到血管中,必须以更大的剂量给药。。
已经开发了广泛的药物配制体系来解决最佳药物递送的问题,所述体系基于将药物掺入基质(其作为运载体作用)。药物配制中考虑到的因素包括以下需求:所述体系是无毒的并与待递送的药物是不反应的,制造成本低,由易于获得的成分形成,并与最终组合物和物理特性(包括稳定性和释放率)一致。而且优选地,药物输送体系由容易通过常规生理过程从人体中移除的材料制成。
微粒技术中的进展已经促进了改良的药物配方的开发。然而,尽管有这些进步,但是本领域仍然需要稳定的药物配方,其具有长期有效性并在作为药物(特别是通过肺途径)施用时具有最优的吸附。解决该缺陷的一个途径是靶向所述活性试剂结构特性/特征,这可促进其对微粒表面的吸附并降低其存留在溶液中的倾向。
发明内容
提供了用于将活性试剂结合、包覆或吸附在结晶微粒表面的方法。通常如下用活性试剂包覆微粒:修饰包含微粒和溶解的活性试剂的体系,使得与残留在溶液中相比,所述活性试剂对所述微粒表面具有更大的亲和力。本发明特别地寻求通过修饰/利用活性试剂的特征进一步促进溶液中多种条件下活性试剂与微粒表面的吸附。
因此,在本发明中提供了用于促进活性试剂与悬浮液中预先形成的结晶微粒结合的方法,所述方法包括步骤:i)修饰所述活性试剂的化学势,其中所述修饰允许所述活性试剂和微粒之间在能量上有利的相互作用而不依赖于溶剂的去除;和ii)将所述活性试剂吸附在所述微粒的表面上。
在本发明特定的实施方案中,修饰化学势包括(独立或组合地)修饰活性试剂的结构、柔性、刚性、可溶性或稳定性。修饰活性试剂的化学势包括改变溶液条件。改变溶液条件包括向溶液中添加活性试剂改性剂。
在特定的实施方案中,活性试剂改性剂选自盐、表面活性剂、离子、渗透物(osmolyte)、醇、离液剂(chaotrope)、补偿溶质(kosmotrope)、酸、碱和有机溶剂。在一个实施方案中,盐为氯化钠。
还在本发明的另一实施方案中,该方法还包括将所述活性试剂溶解在微粒悬浮液的流动相中并改变所述流动相pH的步骤。一方面,将活性试剂溶解在流动相中的步骤是指固体的溶解。另一方面,溶解活性试剂的步骤是指添加活性试剂的浓缩溶液。
在本发明的另一实施方案中,活性试剂改性剂促进了活性试剂的结构稳定性。
还在本发明的另一实施方案中,活性试剂为蛋白质、肽、多肽、小分子或核酸分子。在本发明的另一实施方案中,活性试剂选自胰岛素、脑肠肽(ghrelin)、生长激素和甲状旁腺激素(PTH)。活性试剂可包含抗体或抗体片段。在本发明的多个方面,抗体可以识别疾病相关的抗原,包括但不限于肿瘤相关抗原或传染性病原体相关抗原。
还在本发明的另一实施方案中,小分子为可离子化的分子或疏水分子,例如但不限于环孢菌素A。
在本发明的另一实施方案中,修饰活性试剂的化学势包括调节活性试剂和微粒表面之间的一种或多种在能量上有利的相互作用,例如但不限于静电相互作用、疏水作用和/或氢键相互作用。在一个实施方案中,微粒包括二酮哌嗪,例如但不限于富马酰二酮哌嗪。
还在本发明的另一实施方案中,该方法还包括去除或交换溶剂的步骤。本文使用的“溶剂”是指活性试剂和微粒“沐浴”在其中的流体介质。其不应被解释为要求所有的成分为溶液。事实上在许多情况下,其可用于表示微粒被悬浮在其中的液体介质。
在本发明的另一实施方案中,提供了用于制备药物递送组合物的过程,所述组合物包含活性试剂和结晶微粒,所述过程包括步骤:提供包含活性试剂分子的活性试剂溶液;修饰所述活性试剂的化学势;提供微粒悬浮液或粉末;和将所述活性试剂溶液与所述微粒悬浮液或粉末组合。所述粉末可以例如被过滤,但不经干燥。
在本发明的另一实施方案中,修饰活性试剂化学势的过程允许活性试剂和微粒之间的相互作用。在一个实施方案中,修饰活性试剂的化学势包括向溶液中添加活性试剂改性剂。这类活性试剂改性剂可选自盐、表面活性剂、离子、渗透物、醇、离液剂、补偿溶质、酸、碱和有机溶剂。还在另一实施方案中,所述活性试剂改性剂降低所述活性试剂分子的溶解度,促进所述活性试剂和微粒(如二酮哌嗪颗粒)之间的缔合,和/或促进所述活性试剂分子的结构稳定性。
附图说明
以下的图表来自本说明书的部分并被包括以进一步阐述本文公开的实施例的某些方面。参考一个或多个这些图表,结合本文存在的具体实施方案的详细描述,本发明能够被更好地理解。
图1A-1C描述了根据本发明的教导离液剂和补偿溶质对富马酰二酮哌嗪(FDKP)微粒上活性试剂负载曲线的效应,该效应是pH和100mM离液剂/补偿溶质的函数。图1A描述了存在离液剂和补偿溶质时、pH 3.0-5.0下0.75mg/mL胰岛素在5mg/mL FDKP微粒上的负载。图1B描述了存在离液剂和补偿溶质时、pH 2.0-4.0下0.25mg/mL高血糖素样肽1(GLP-1)在5mg/mL FDKP微粒上的负载。图1C描述了存在强离液剂(NaSCN和NaClO4)时、pH 4.0-5.0下0.25mg/mL甲状旁腺激素(PTH)在5mg/mLFDKP微粒上的负载。
图2A-2C描述了根据本发明的教导描述了渗透物对FDKP微粒上活性试剂负载曲线的效应,该效应是pH和渗透物(100mM)的函数。图2A描述了pH 3.0-5.0下存在渗透物时,5mg/mL FDKP微粒上0.75mg/mL的胰岛素负载。图2B描述了pH 2.0-4.0之间存在渗透物时5mg/mL FDKP微粒上0.25mg/mL GLP-1的负载。图2C描述了pH 4.0-5.0下存在强渗透物时5mg/mL FDKP上0.10mg/mL脑肠肽肽的负载。
图3A-3D描述了根据本发明的教导醇对FDKP微粒上活性试剂负载曲线的效应,该效应是pH和醇的函数。图3A描述了pH 2.0-4.0之间存在5%、10%、15%和20%v/v的六氟异丙醇(HFIP)时5mg/mL FDKP微粒上0.10mg/mL脑肠肽的负载。图3B描述了pH 2.0-4.0之间存在5%、10%、15%和20%v/v的三氟乙醇(TFE)时5mg/mL FDKP微粒上0.10mg/mL脑肠肽的负载。图3C和3D描述了pH 2.0-5.0下分别存在HFIP和TFE时,5mg/mL FDKP微粒上0.25mg/mL GLP-1的负载。
图4A-4D描述了根据本发明的教导盐对FDKP微粒上活性试剂负载曲线的效应,该效应是pH和NaCl浓度的函数。图4A描述了pH 2.0-5.0下存在0-500mM NaCl时5mg/mL FDKP微粒上0.75mg/mL胰岛素的负载。图4B描述了pH 2.0-5.0下存在0-500mM NaCl时5mg/mL FDKP微粒上0.25mg/mL GLP-1的负载。图4C描述了pH 2.0-5.0下存在0-1000mMNaCl时5mg/mL FDKP微粒上0.25mg/mL PTH肽的负载。图4D描述了多种盐浓度(20℃)下PTH的二级结构分析。pH 5.8下4.3mg/mL PTH的远UV CD阐明了当NaCl浓度上升时,肽的二级结构采取了更加螺旋的构象。
图5A-5B描述了根据本发明的教导,微粒上疏水分子的吸附。图5A描述了有提高的抗溶剂(水)浓度(60%、80%和90%)时,环孢菌素A对FDKP微粒的结合。图5B描述了存在90%的抗溶剂时,在不同的环孢菌素A/FDKP微粒质量比下对环孢菌素A所达到的理论最大负载百分比。
图6描述了根据本发明的教导,在90%的抗溶剂下使用多种环孢菌素A/FDKP微粒质量比时,在大鼠中单一静脉注射(IV)和肺吹入(IS)的药物代谢动力学。
发明详述
本文描述了用于稳定与结晶微粒组合的药物活性试剂的方法。得到的组合物提供了包覆在结晶微粒表面上的稳定活性试剂。
要被包覆或吸附在结晶微粒上的物质在本文中是指活性试剂。活性试剂种类的例子包括具有治疗、预防和/或诊断用途的药物组合物、合成的化合物和有机大分子。
通常,大部分活性试剂可以被包覆或吸附在结晶微粒的表面,包括但不限于有机大分子、核酸、合成的有机化合物、多肽、肽、蛋白质、多糖和其他糖,和脂质。肽、蛋白质和多肽均为通过肽键连接的氨基酸链。肽通常被认为少于30个氨基酸残基,但是可以包含更多。蛋白质是能够含有多于30个氨基酸残基的多聚体。在本领域和本文使用术语“多肽”可以表示肽、蛋白质或任意长度的含有多个肽键的任何其他氨基酸链,尽管通常含有至少10个氨基酸。包覆配方中使用的活性试剂可以属于大量生物活性类别,例如血管活性物质、神经活性试剂、激素、抗凝血剂、免疫调节剂、细胞毒素剂、抗生素、抗病毒剂、抗原和抗体。
可用于本发明中的活性试剂的例子(以非限制的方式)包括:生长激素、抗体及其片段、炔、环孢菌素(例如环孢菌素A)、PPACK(D-苯丙氨酰基-L-脯氨酰-L-精氨酸氯甲基酮)、CMFDA(5-氯甲基荧光素二乙酸酯)、得克萨斯红(Texas Red)、clopiogrel、粒细胞巨噬细胞集落刺激因子(GM-CSF)、高血糖素样肽1(GLP-1)、脑肠肽、甲状旁腺素(PTH)、胰岛素和胰岛素类似物(例如速效胰岛素制剂(aspart insulin)和胰岛素)和抗体及其片段,包括但不限于:人源化的或嵌合的抗体;F(ab),F(ab)2或单链抗体(单独的或与其他多肽融合);针对癌症抗原的治疗或诊断的单克隆抗体、细胞因子、传染剂、炎症介体、激素和细胞表面抗原。针对肿瘤抗原的抗体的非限制性例子包括抗SSX-241-49(滑膜肉瘤,X断裂点2)、抗-NY-ESO-1(食管肿瘤相关抗原)、抗-PRAME(黑色素瘤优先表达的抗原)、抗PSMA(前列腺特异膜抗原)、抗-Melan-A(黑色素瘤肿瘤相关抗原)、抗酪氨酸酶(黑色素瘤相关抗原)和抗-MOPC-21(骨髓瘤浆细胞蛋白质)。
微粒
基本上,术语“微粒”是指具有约0.5-1000μm直径的颗粒,不考虑精确的外部或内部结构。在微粒的广泛范畴内,“微球”是指具有均匀球形性状的微粒。本文使用结晶微粒是指下述微粒,所述微粒具有晶体的内部结构但不必须具有晶体的外部结构,并且在空间点阵中具有规则的原子排列。可离子化的晶体表面是指下述结晶微粒,其具有携带电荷的额外能力。在一些实施方案中,微粒可以是单个规则性状的晶体。在多种优选的实施方案中,微粒性状不规则、是多孔的、具有溶解的活性试剂可接近的内部表面,或包含有任意组合的多种晶体。这类特征会一般地增加表面区域,从而增加负载能力。这类特征也可有助于有利的气动力学(aerodynamic)特征,如果活性试剂要通过干粉(其包含微粒)吸入来递送的话,这是重要的。
优选地,组成结晶微粒的化学物质与要递送的活性试剂是可逆反应的、无毒的以及不被啮齿类和人代谢的。尽管有前述内容,但是一些水平的毒性是可以忍受的,取决于例如要被处理的病症的严重性或患者暴露于物质的量。类似地,不要求该物质是完全代谢惰性的。另外,在用活性试剂包覆或结合的过程中,优选的微粒的晶体结构不被显著破坏。结晶微粒的组成决定了何种类型的化学相互作用可以被操作,以驱动活性试剂到微粒表面的吸附。
大量物质可用于形成结晶微粒。这样的微粒具有表面,所述表面的性质能够如与本申请同日提交的未决的美国专利申请No._/_(代理人档案号No.51300-00025)和美国临时申请No.60/717,524(2005年9月14日)中所述在包覆过程中被操作,每个参考文件通过引用整体并入本文。可形成结晶微粒的代表性材料包括,但不限于:芳香族氨基酸或在给定pH范围中具有有限溶解度的化合物,例如二酮哌嗪和吗啉硫酸盐。
本发明中考虑的微粒的一个特别的例子为二酮哌嗪(DKP)微粒。如本文所讨论的,使用DKP微粒以便吸收活性试剂。美国专利No.5,352,461和5,503,852(每个参考文献通过引用整体并入本文)描述了一种药物递送体系,该体系基于由在低pH下稳定并在血或小肠的pH下溶解的二酮哌嗪衍生物形成二酮哌嗪(DKP)微粒为基础,所述衍生物例如3,6-二[N-富马酰-N-(正-丁基)氨基]-2,5-二酮哌嗪(也称作富马酰二酮哌嗪或FDKP;也称作(E)-3,6-二[4-(N-羧基-2-丙烯基)酰胺基丁基]-2,5-二酮哌嗪)。以二酮哌嗪结构元件或其取代衍生物之一为基础的体系(包括但不限于吗啉二酮和二氧六环二酮)形成具有预期的尺寸分布和pH范围以及良好的有效负载耐性(payload tolerance)的微粒。用取代基的适当操作能够产生大范围的稳定的、可再现的特性。这些专利公开了存在活性试剂时沉淀DKP以形成包含所述活性试剂的微粒。合成、制备和使用二酮哌嗪和二酮哌嗪微粒的其他细节公开于美国专利6,071,497;6,331,318;6,428,771和美国专利申请公开No.20060040953和No.20060041133中,每个参考文献通过引用整体并入本文。包含二酮哌嗪颗粒的组合物公开于美国专利No.6,991,779和美国专利申请公开No.20040038865;每个参考文献通过引用整体并入本文。
本发明关注的其他二酮哌嗪包括3,6-二(4-氨基丁基)-2,5-二酮哌嗪;3,6-二(琥珀酰-4-氨基丁基)-2,5-二酮哌嗪(琥珀酰二酮哌嗪或SDKP);3,6-二(马来酰-4-氨基丁基)-2,5-二酮哌嗪;3,6-二(柠康酰-4-氨基丁基)-2-5-二酮哌嗪;3,6-二(戊二酰-4-氨基丁基)-2,5-二酮哌嗪;3,6-二(丙二酰-4-氨基丁基)-2,5-二酮哌嗪;3,6-二(乙二酰-4-氨基丁基)-2,5-二酮哌嗪及来自它们的衍生物。二酮哌嗪盐也可用于本发明中并可包括例如可药用盐,如Na、K、Li、Mg、Ca、铵盐或单、双或三烷基铵盐(如衍生自三乙胺、氨基丁烷、二乙醇胺、三乙醇胺或吡啶等等)。所述盐可以是单、双或混合的盐。对二酮哌嗪而言也考虑更高级别的盐,其中R基团含有多于一个酸基团。在本发明的其他方面,试剂的碱性形式可以与二酮哌嗪混合以在药物和二酮哌嗪之间形成盐键,从而所述药物成为二酮哌嗪的反阳离子。用于药物递送的DKP盐在美国专利申请公开No.20060040953中更详细地公开,其通过引用整体并入本文。
美国专利No.6,444,226和No.6,652,885(每个参考文献通过引用整体并入本文)描述了在水性悬浮液(活性试剂溶液被加入所述悬浮液中)中制备并提供DKP微粒,然后是冻干悬浮液以得到具有活性试剂包衣的微粒的关键步骤。这种配制方法是基于通过冷冻干燥来去除液体介质从而在微粒上包覆活性试剂。(还可参阅美国专利No.6,440,463,其通过引用整体并入本文)。与现有技术中的教导相反,本发明提供了去除溶剂前调节活性试剂与微粒结合的手段。因此,通过批量物理方法(例如过滤或沉降)或蒸发方法(例如冻干法或喷雾干燥)去除液体介质可得到相当的负载。
促进活性试剂的吸附
将活性试剂吸附在结晶微粒的表面可涉及在多种溶液条件下改变溶液或流体悬浮液中活性试剂的特征,从而促进到微粒表面的吸附并减少溶液中残余的活性试剂的量。可以使用改性剂对活性试剂进行改变或修饰,所述改性剂例如,但不限于离液剂和补偿溶质、盐、有机物(例如但不限于醇)、渗透物和表面活性剂。这些改性剂可以作用于活性试剂以改变其化学势,从而改变其结构、柔性、刚性或稳定性,而不在化学上改变试剂本身。术语“化学势”是普通技术人员所公知的。在本发明的实施方案中,“化学势”是指驱动化学反应(例如活性试剂和溶剂之间的相互作用,或活性试剂吸附在微粒上)必需的自由能。本文使用术语“在能量上有利的”是指活性试剂在微粒上的已吸附状态的自由能水平相对于未包覆的微粒或未结合的活性试剂和/或不溶形式(包括聚集或沉淀)的活性试剂的自由能水平较低。本文使用术语“结构”是指活性试剂分子的二级结构,并包括活性试剂分子(例如蛋白质)的α螺旋结构、β片层或随机螺旋(无序的)。另外,术语结构也可包括分子的三级或四级结构,但不仅限于此,并也可表示分子的自缔合、聚集、多聚化、二聚化等等。本文使用术语“稳定性”是指存在改性剂时活性试剂结构的稳定或去稳定。
另外,改变溶液或流体悬浮液中活性试剂的特征很可能影响由活性试剂和/或微粒的疏水特性、氢键特性和静电特性引起的相互作用。
疏水相互作用是水性溶液中非极性基团由于它们在水中的不溶性引起的彼此间的缔合。疏水相互作用可以影响大量分子过程,包括但不限于(单个分子、两个或三个分子的复合物,或更大的集合的)结构稳定和动力学,并对蛋白质-蛋白质和蛋白质-配体结合过程有重大贡献。这些相互作用也已知在蛋白质折叠的早期事件中起到重要作用,并涉及复合物装配和自我装配现象(例如膜的形成)。
氢键相互作用是分子之间特别强的偶极-偶极力;极性键(例如H-F、H-O或H-N)中的氢原子可以受到附近电负性分子或离子的吸引力,所述电负性分子或离子具有未成对电子(通常是另一个分子上的F、O或N原子)。氢键是造成水的独特特征的原因,并在生物分子的组构中非常重要,特别是在影响蛋白质和DNA的结构时非常重要。
静电相互作用是相反电荷之间的吸引或相同电荷之间的排斥,其随着电荷彼此更加接近而变得更强。静电相互作用构成了理解离子溶液中带电体之间相互作用的关键成分。例如,分散于溶剂中的胶粒的稳定性可以通过考虑排斥的静电相互作用和吸引的范德华相互作用之间的竞争来解释。当考虑颗粒之间的相互作用和粘附时,静电相互作用也是重要的。
盐
在本发明的一些实施方案中,使用盐(例如但不限于氯化钠)改变活性试剂的特征。活性试剂(例如PTH和GLP-1)在存在盐时发生显著的结构变化。如实施例5(图4D)所示,盐的存在通过促进肽构象的更加螺旋来提高PTH的二级结构。盐也被发现影响GLP-1的结构,如2006年4月14日提交并通过引用整体并入本文的美国临时专利申请No.60/744,882中所公开。另外,盐和其他离子化合物能够通过与带电残基特异结合来稳定或去稳定蛋白质和肽,特别是当溶液pH和蛋白质或肽的pI之间的差异变大时(Antosiewiez J,et al.,J.MoI.Biol.238:415-436,1994)。
离液剂
本领域公知,离液剂是与水显示弱相互作用并从而将分子(例如蛋白质或肽)去稳定的离子。这些化合物破坏水的氢键网络并降低其表面张力,从而促进蛋白质和肽更多的结构自由和变性。离液剂的例子包括,但不限于NaSCN、(CH3)3N-HCl、Na2NO3和NaClO4和氯化铯(CsCl)。
另一方面,补偿溶质(kosmotrope)或感胶离子(lyotrope)是与水显示强相互作用的离子,通常稳定大分子如蛋白质和肽。该稳定效应通过提高水分子的有序和提高其表面张力引起。补偿溶质的例子包括,但不限于柠檬酸钠(Na Citrate)和硫酸钠(Na2SO4)。
醇
本发明中使用的另一类活性试剂改性剂为醇。醇能够破坏蛋白质和肽的天然结构,也能够在大分子中稳定和诱导α-螺旋构象,最值得注意的是在未结构化的蛋白质和多肽中。这类醇可包括,但不限于甲醇(MeOH)、乙醇(EtOH)、三氟乙醇(TFE)和六氟异丙醇(HFIP)。其中,TFE和HFIP分别是用于在肽和蛋白质中诱导螺旋转换的最有效的醇之一(Hirota et al.,Protein Sci.,6:416-421;1997,通过引用将其涉及肽和蛋白质中螺旋转换的所有内容并入本文)。这些醇可以通过它们破坏溶剂氢键特征的能力影响蛋白质和肽的结构(参阅Eggers and Valentine,Protein Sci.,10:250-261;2001,通过引用将其含有的涉及醇对蛋白质结构效应的所有内容并入本文)。
渗透物
影响活性试剂对微粒亲和力的另一类改性剂为渗透物。本领域技术人员公知,渗透物是由大部分生物细胞在高胁迫处境(例如极端温度波动、高盐环境等)中产生以稳定其大分子的小化合物。它们不直接与大分子反应,而是通过改变细胞环境中溶剂的特征来起作用,从而它们的存在间接地影响蛋白质的稳定性。这些化合物包括多种多元醇、糖、多糖、有机溶剂和多种氨基酸及其衍生物。尽管渗透物的机制尚未阐明,但是据推测,这些化合物很可能通过提高变性状态相对于天然状态的化学势,从而提高天然的和变性的总体之间(正的)吉布斯能差异(ΔG)来起作用(Arakawaand Timasheff,Biochemistry 29:1914-1923;1990)。
本发明所关注的渗透物以非限制性的方式包括己烯二醇(Hex-Gly)、海藻糖、甘氨酸、聚乙二醇(PEG)、三甲胺N-氧化物(TMAO)、甘露醇和脯氨酸。
方法概述
在本发明的方法中,至少三种成分在液体介质中组合:至少一种活性试剂、(预先形成的)微粒,和至少一种如上所述的活性试剂改性剂。该体系的成分可以以任何顺序组合。在一些实施方案中,改性剂和活性试剂在混合物与微粒悬浮液组合之前彼此组合。在其他实施方案中,试剂和微粒首先组合,然后添加改性剂。在一些实施方案中,提供活性试剂或改性剂并与其他成分组合为溶液。在其他实施方案中,任何成分可以以固体形式提供或溶解于(或在微粒的情况下悬浮于)含另一成分的液体介质中。其他的变化会是本领域技术人员显而易见的。
微粒在与体系的其他成分组合之前形成,其本身作为悬浮液存在。但是微粒悬浮在其中的液体介质有时在本文中被称作溶剂。本方法中使用的液体介质通常是水性的。然而在一些情况下,液体介质可以包含多于一种有机化合物,例如将醇而不是水用作改性剂。
将所有成分聚集在体系中后,活性试剂将吸附在微粒表面上。在本发明递进优选的实施方案中,体系中至少50%、60%、70%、80%、90%、95%或几乎所有的活性试剂被吸附至微粒上,至多100%。在本发明的一些实施方案中,微粒上可接近的表面区域应足够使得所有被吸附的活性试剂与微粒表面直接接触,即所述包覆是单层的。然而,应当理解可存在额外的相互作用。在一些情况下,例如活性试剂的自缔合也可以是在能量上有利的,从而多层活性试剂包覆所述颗粒。不要求这些层中任一是完整的或包覆的厚度是均一的。两种形式的自缔合可以被识别:多聚化和聚集。多聚化由特异的分子间相互作用和固定的化学计量表征。聚集通过非特异的分子间相互作用和不确定的化学计量表征。应当理解多聚的活性试剂可以在多聚状态下被吸附,或解聚为单体或较低等级的多聚体并在该状态下被吸附至表面。在任一情况下,聚集可调节活性试剂在微粒上成层。
经负载的微粒组成了药物递送组合物,其可以以多种形式使用。颗粒可以用作粉末,固体剂型如片剂或含在胶囊中,或悬浮于液体载剂中。通常这会需要交换和/或去除其中发生负载的液体介质。这可通过多种手段之任一完成,包括物理方法(例如但不限于沉降或过滤)和蒸发方法(例如但不限于冻干或喷雾干燥)。这些技术为本领域技术人员已知。在本发明的一个实施方案中,通过喷雾干燥去除溶剂。喷雾干燥二酮哌嗪微粒的方法公开于例如2006年2月22日提交的美国临时专利申请号No.60/776,605中,其通过引用将涉及喷雾干燥二酮哌嗪微粒的所有内容并入本文。
如果负载不是基本完全的,则使用物理溶剂去除法的本发明实施方案会典型地丢失未吸附的活性试剂,但是例如可以用于确保包覆不会发展到单层之外。相反,使用蒸发干燥用于溶剂去除的实施方案在一些情况下能够将额外的活性试剂沉积在颗粒上从而避免其丢失,但是所涉及的吸附相互作用与在该方法较早步骤中结合的分子所建立的可能有所差异。在其他实施方案中,通过蒸发进行的溶剂去除不导致显著的活性试剂进一步沉积,包括几乎所有活性试剂已被吸附在颗粒上的情况。
实施例
包括以下的实施例以阐述本发明优选的实施方案。本领域技术人员应当明白,下文实施例中公开的技术代表了本发明人发现在本发明的实践中作用良好的技术,因此可以被认为构成了用于其实践的优选模型。尽管讨论可集中在特定的机制上,但是应当理解一些改性剂可对所述试剂具有多重效应,或事实上对所述颗粒表面也有多重作用,每种作用可有助于促进颗粒对试剂的吸附。然而,在本公开的启发下,本领域技术人员应当理解可以在公开的具体实施方案中进行许多修改并仍然获得相似或类似的结果,而不偏离本发明的精神和范围。
实施例1
实验操作:活性试剂/FDKP微粒吸附研究
活性试剂胰岛素、PTH、脑肠肽和GLP-1购自American Peptide(Sunnyvale,CA)或AnaSpec(San Jose,CA)或内部制作(MannKindCorporation,Valencia,CA)。分析处于多种pH下和20℃下(除非另有说明)的水性样品。样品通常为新鲜制备的,并在添加FDKP微粒之前与特定添加剂(例如盐、pH缓冲液等,如果有的话)混合。
活性试剂与悬浮液中二酮哌嗪(DKP)颗粒的缔合通过进行吸附研究来评估。吸附研究中研究的参数探测了静电相互作用、氢键、水结构、蛋白质柔性和特异的盐配对相互作用对活性试剂/富马酰二酮哌嗪(FDKP)微粒相互作用的影响。另外,测试了若干常见的蛋白质稳定剂对活性试剂与FDKP微粒表面吸附的干扰。
研究了促进活性试剂在预先形成的FDKP颗粒表面上吸附的多种条件。将15mg/mL FDKP微粒悬浮液与3X pH缓冲液和3X的添加剂或赋形剂溶液组合。最终的溶液含有5mg/mL的FDKP微粒浓度和0.25mg/mL(5%w/w)的GLP-1浓度,或0.25mg/mL(5%w/w)的PTH浓度,或0.75mg/mL(15%w/w)的胰岛素浓度或0.10mg/mL(2%w/w)的脑肠肽浓度。从悬浮液中滤除上清液中未缔合的活性试剂。带有已缔合的活性试剂的FDKP颗粒溶解(重溶)于100mM碳酸氢铵中并过滤以分离出任何聚集的活性试剂分子。通过HPLC定量上清液和重溶的级分中的活性试剂量。进行一组实验,其中使用的条件包括添加剂(如盐、渗透物、离液剂和补偿溶质和醇)的使用。这些研究的结果描述于下文。
实施例2
离液剂和补偿溶质对FDKP颗粒上活性试剂吸附的效应
研究影响水和蛋白质结构的离子种类(离液剂和补偿溶质)以调查活性试剂通过疏水机制(低pH下)在FDKP微粒表面上的吸附。在5mg/mL微粒和0.25mg/mL(5%w/w)的GLP-1浓度,或0.25mg/mL(5%w/w)的PTH浓度,或0.75mg/mL(15%w/w)的胰岛素浓度下进行活性试剂在FDKP颗粒上的负载。样品中离液剂或补偿溶质的浓度被保持恒定在100mM,pH从2.0到5.0变化。离液剂或补偿溶质选自以下:NaSCN、CsCl、Na2SO4、(CH3)3N-HCl、Na2NO3、柠檬酸钠、和NaClO4。对照实验没有添加离液剂或补偿溶质。
图1A-1C描述了存在多种离液剂或补偿溶质时,胰岛素、GLP-1和PTH分别在FDKP微粒表面上的负载曲线,所述负载曲线是pH的函数。在低pH(3.0)下与对照相比,所有被分析的离液剂和补偿溶质促进了胰岛素对微粒表面的亲和力并显示了显著的负载。在pH 4下,未观察到该效应(图1A)。在更高的pH(5.0)下,离液剂和补偿溶质通过沉淀胰岛素蛋白质干扰胰岛素对微粒表面的吸附(与对照相比)。因此,这些试剂在低pH下促进胰岛素对FDKP颗粒的结合,但是在更高的pH条件下很少具有效应或甚至具有有害效应。
存在离液剂和补偿溶质时,在pH2.0-4.0下GLP-1显示对FDKP微粒的提高的亲和力,pH更低时效应更大(图1B)。相似的观察结果公开于美国临时申请No.60/744,882中。其中注意到存在NaSCN、NaClO4、Na2SO4、NaNO3和柠檬酸钠时在重溶的不含微粒的对照样品中检测到约0.02-0.04mg/mL的GLP-1肽(其对应于0.004到0.008的质量比),表明小部分的GLP-1沉淀,而不是吸附在颗粒上。
存在强离液剂NaSCN和NaClO4时,PTH对FDKP微粒表面的亲和力在pH 4.0到约4.5时(图1C)。
该数据支持离液剂和补偿溶质在促进活性试剂对FDKP微粒表面吸附中起重要作用,在低pH时最为显著。因为这些改性剂在低pH(此时微粒表面离子性较弱)具有更大的效应,所以很可能吸附由疏水机制引起。在更高pH观察到的吸附减少可由颗粒表面带更多电荷与离液剂和补偿溶质对提高活性试剂疏水性的效应相结合而引起。另外,由于离子种类的关系,这些改性剂可与活性试剂竞争结合微粒,或破坏活性试剂与微粒之间的静电相互作用。最后也注意到德拜(Debye)屏蔽可有助于降低对带更多电荷的表面的吸附。
实施例3
渗透物对活性试剂与FDKP颗粒的吸附的效应
为了评估活性试剂稳定性对吸附的重要性,通过HPLC分析检查渗透物对活性试剂与FDKP颗粒结合的效应。图2A-2C显示存在常见稳定剂(渗透物)时胰岛素(图2A)、GLP-1(图2B)和脑肠肽(图2C)在FDKP颗粒上的负载曲线,其为pH的函数。活性试剂在FDKP微粒上的负载在5mg/mL微粒和0.75mg/mL(15%w/w)胰岛素浓度,或0.25mg/mL(5%w/w)的GLP-1浓度或0.10mg/mL(2%w/w)的脑肠肽浓度下进行。样品中渗透物(稳定剂)的浓度保持恒定在100mM,pH从约2.0变化到约5.0。渗透物选自己烯二醇(Hex-Gly)、海藻糖、甘氨酸、PEG、TMAO、甘露醇和脯氨酸;对照实验没有渗透物。
在研究的活性试剂中,在存在渗透物(PEG、甘氨酸、海藻糖、甘露醇和Hex-Gly)时和在3.0到5.0的pH范围内胰岛素显示显著提高的对FDKP颗粒表面的亲和力(图2A)。在研究的渗透物中,PEG和脯氨酸在从2.0到4.0的pH范围内提高GLP-1在FDKP颗粒表面上的吸附亲和力。在低pH(2.0)下,渗透物TMAO在将GLP-1结合至FDKP微粒表面上较之PEG或脯氨酸更为有效,但是在pH 3.0及以上时轻度有害(图2B)。然而,在约4.0到5.0的pH范围内,存在100mM甘露醇、PEG、甘氨酸、Hex-Gly和海藻糖时,与对照相比脑肠肽显示了对微粒表面更大的亲和力(图2C)。
这些负载曲线提示了渗透物能够增强活性试剂对FDKP微粒表面的吸附。很可能该效应由改性剂稳定活性试剂的能力引起,所述能力使得吸附更加在能量上有利。
实施例4
醇对活性试剂对FDKP颗粒的亲和力的效应
在评估改性剂对活性试剂的效应(其允许通过疏水机制吸附至微粒表面)时,检测醇的效应。已知能通过提高氢键强度在未结构化的肽和蛋白质中诱导螺旋构象的醇被评价,以确定螺旋构象在活性试剂与FDKP颗粒表面吸附中所起的作用。分析了如GLP-1和脑肠肽的活性试剂。活性试剂在FDKP颗粒上的负载在5mg/mL的微粒和0.25mg/mL(5%w/w)的GLP-1浓度或0.10mg/mL(2%w/w)的脑肠肽浓度下进行。每种醇的效应在2.0到5.0的pH范围内观察。使用的醇为三氟乙醇(TFE)和六氟异丙醇(HFIP)。每种醇在多种浓度(其包括5%、10%、15%或20%v/v)下评价。
图3A-3D显示了对于每种醇和每种活性试剂而言活性试剂在FDKP微粒上的负载曲线,其为pH的函数。在pH 2.0-4.0下,存在所有测试浓度(5%、10%、15%和20%,通过脑肠肽对FDKP颗粒的质量比所确定)的HFIP和TFE时,脑肠肽显示大大提高的对微粒表面的亲和力(图3A-3B)。
在pH 2.0-5.0下,存在所示浓度(5%和10%)的HFIP和TFE时,GLP-1显示对微粒表面提高的亲和力(图3C-3D)。TFE的效应较不显著,并且在测试的较低pH下是有害的。注意到在pH 4.0下存在10%HFIP和TFE时,重溶的不含颗粒的对照样品中检测到了大量的GLP-1肽(0.13-0.19mg/mL,其对应于0.026到0.038的质量比),表明一些GLP-1已经沉淀。然而,在较低的pH(2.0-3.0)下,存在10%HFIP或TFE时,重溶的不含微粒的对照中GLP-1肽的数量显著减少。在pH 3.0下,检测到0到0.02mg/mL(其对应于0到0.004的质量比)的GLP-1肽,而在pH2.0下的对照样品未检测到GLP-1。图3C-D中的质量比反映了吸附的和沉淀的活性试剂,尽管当pH朝3.0降低时沉淀是越来越次要的成分。
数据指出醇能够促进活性试剂在FDKP微粒表面上的吸附。吸附的该提高很可能是由存在醇时活性试剂和微粒表面增强的疏水相互作用引起的。
实施例5
盐对活性试剂与FDKP颗粒吸附的效应
为了进一步研究结合的疏水机制,通过HPLC分析观察盐对活性试剂与FDKP微粒吸附的效应。
在存在0、25、50、100、250和500mM NaCl时,在5mg/mL微粒和0.75mg/mL(15%w/w)的胰岛素浓度,或0.25mg/mL(5%w/w)的GLP-1浓度,或0.25mg/mL(5%w/w)的PTH浓度下进行活性试剂在FDKP颗粒上的负载(图4A-4C)。也在1000mM NaCl下评估PTH在FDKP上的负载。评估了重溶的不含微粒的对照样品中检测的活性试剂量,其为pH和NaCl浓度的函数。用20mM磷酸钾/20mM醋酸钾混合物控制pH。
如图4A中所观察到的,在从约2.5到约3.5的pH下,胰岛素在FDKP颗粒上提高的结合(吸附)在100-500mM的高盐浓度下是明显的。在从约4.0到约5.0的pH下,对于检测的所有盐浓度而言,观察到胰岛素对FDKP颗粒吸附的降低。
在从约2.0到约3.5的pH下,在检测的所有盐浓度下GLP-1对FDKP的增强的结合(吸附)都是明显的(图4B)。在pH 4.0及以上,也注意到了结合的降低。
使用PTH作为活性试剂的类似研究显示了在从约2.0到约3.5的pH下,在250到1000mM的高盐浓度下,PTH对FDKP颗粒的增强的结合(图4C)。在从约3.5到约5.0的pH下,存在盐时PTH对微粒的结合减少。
在低pH下(此时吸附不是有利的),添加盐能够修饰活性试剂的化学势,从而提高其对微粒表面的亲和力。这类结合的增强很可能由疏水机制引起。另外,数据表明pH提高时,吸附随着盐浓度的提高而降低。当微粒表面随着提高的pH而带有更多电荷时,假设的疏水机制可以被预期在促进活性试剂吸附上不太有效。该减少也可以由盐竞争微粒表面上的结合位点而引起。注意到德拜屏蔽也有助于所观察到的减少的吸附。
数据还显示了盐能够改变活性试剂的结构。例如,PTH的圆二色性测量显示当盐浓度上升时,肽的二级结构采取了更为螺旋的构象(图4D)。这提示了PTH结构的改变可促进其在低pH下与微粒表面的结合。
在水性溶液中,盐的存在也显示将染料得克萨斯红分配在微粒的表面上。
实施例6
环孢菌素A对FDKP颗粒吸附的效应
使用环孢菌素A作为活性试剂,体外和体内研究了对小疏水分子在FDKP颗粒上吸附的效应。通过改变活性试剂的溶解度促进吸附。
研究了一种亲脂的环状多肽——环孢菌素A,以显示疏水分子如何被加工以吸附在微粒上。另外,环孢菌素A的尺寸(1202.61MW)被用于证明微粒对较小化合物的负载能力。
为了完成负载,使用溶剂/抗溶剂方法。该方法的基本原则在于将化合物溶解在溶剂(甲醇)中,然后使用抗溶剂(水)将化合物赶出溶剂并处在微粒的表面上。利用该溶剂/抗溶剂途径,将环孢菌素A成功地负载在了微粒的表面上。
在测定溶解度模式的预实验中,环孢菌素A在甲醇中溶解为10mg/mL,并通过HPLC分析具有多种浓度的抗溶剂(10-90%H2O,增量10%)时其在1mg/mL的溶解度。将环孢菌素A峰面积与只含有甲醇的样品比较,以确定沉淀的损失百分比。观察到在低于60%的H2O中溶解度被大量保持。在70%的H2O中,明显的大部分试剂不溶,在80-90%的H2O中,保持了少于5%的溶解度。
为了评估颗粒负载,将FDKP微粒悬浮于环孢菌素A的甲醇溶液中。然后以分步的方式添加水至60%、80%和90%的终浓度。沉淀一半样品,将另一半冻干。然后重溶每半份样品,使得最终百分比为20%FDKP微粒/环孢菌素A,20%的0.5M碳酸氢铵(AmBicarb)和60%的甲醇(溶解微粒和环孢菌素A二者所必需的浓度)。通过HPLC分析每份的环孢菌素A含量,并进行比较来确定已被颗粒吸附的比例。结果在图5A中显示。在60%H2O中,观察到约20%的环孢菌素A与颗粒结合。在80%和90%的H2O中,负载分别为约90%和95%,表明环孢菌素A与FDKP微粒的强结合。
在90%的抗溶剂水平下,通过改变环孢菌素A的输入(从而假设所有的环孢菌素被吸附时,回收的固体的最终含量将是从2%到20%)来分析微粒对环孢菌素A的负载能力。观察到当输入量沿着该范围提高时,与微粒结合的可获得的环孢菌素A的百分比从输入量的50%的提高到输入量的90%(图5B)。应当注意,考虑到在90%的H2O中环孢菌素A的溶解度为0.05mg/mL,这些结果表明实质上所有可溶的环孢菌素A都被吸附在颗粒上而不是沉淀出来。
实施例7
环孢菌素A/DKP颗粒的肺吹入
为了检查环孢菌素A/FDKP微粒的药物代谢动力学,在通过肺吹入或静脉注射被施用了多种环孢菌素A/FDKP微粒配方的雌性Sprague Dawley大鼠中评价环孢菌素A的血浆浓度。使用在90%抗溶剂中配制的环孢菌素A/FDKP微粒和如上文实施例中所述的0.05、0.10或0.20的理论最大质量比进行这些研究。它们被称作5%、10%和20%负载。
单剂2.5mg的环孢菌素A/FDKP微粒通过肺吸入或静脉注射被递送给八组大鼠。在每组给药的给药前(时间0)和给药后5、20、40、60、240、480分钟和24小时采取血样。在每个时间点,将来自侧尾静脉(lateral tail vein)的约100μL全血收集在冷冻管中,倒置并存于冰上。在4000rpm将血样离心,将约40μL血浆移液入96孔板中,将其储存在-80℃直到分析。
如图6所示,通过肺吸入施用2.5mg FDKP微粒/环孢菌素A在给药后24小时引起雌性Sprague Dawley大鼠中最大的血清环孢菌素水平。在该时间点,10%的负载达到了32.4ng/mL的Cmax。通过静脉注射施用了0.1mL的2.5mg of FDKP微粒/环孢菌素A的动物直到给药后24小时都显示最小水平的环孢菌素。观察到对静脉注射和肺吸入组而言,FDKP微粒水平均在给药后20分钟出现峰值并在4小时中回归基线水平。
总之,数据显示环孢菌素A/FDKP微粒的生物可利用度。应注意到240分钟处的单峰是异常的。对处理的所有动物而言,通过肉眼和显微镜观察确定的病理学均是正常的。
除非另有说明,用于说明书和权利要求书中的表达成分数量、如分子量的性质、反应条件的所有数字等应理解为在所有情况下由术语“约”修饰。因此,除非指出反例,以下说明书和附加的权利要求书中公开的数量参数是近似值,其可根据本发明想要获得的所需性质而变化。至少,并不企图限制将等同原则应用于权利要求书的范围,每个数量参数至少应按照经报导的有效数字的位数并通过应用常规约数技术解释。不反对公开本发明广大范围的数量范围和参数为约数,而特定实施例中公开的数量值则是尽可能精确地报导的。然而,任何数量值固有地包含误差,这是从它们各自检测测量中发现的标准差必然地产生的。
除非在本文另有说明或同上下文明显抵触,描述本发明的上下文中(特别是在所附的权利要求书上下文中)未明确提及数量的名词(用″a″,″an"修饰的)和使用的术语“该”、“所述”("the")和类似的指代被解释为包括单数和复数。对本文数值范围的叙述仅意图用作为引用落入该范围的每个单独的值的速记方法(shorthand method)。除非本文另有说明,每个单独的值都被并入说明书,就像其被单独地并入本文一样。除非在本文另有说明或与上下文明显抵触,本文所述的所有方法可以以任何合适的顺序进行。本文所提供的任何和所有实例或举例文字(例如“例如”)的使用仅意欲用来更好地阐述本发明,而非对本发明所要求保护的范围设定限制。说明书中没有提及的文字应被解释为指代实施本发明必需的任何不要求保护的元素。
权利要求书中术语“或”的使用用于表示“和/或”,除非明确地指出仅表示备选方案或备选方案是排他性唯一的,尽管本公开支持表示仅为备选和“和/或”的定义。
本文公开的备选元素或实施方案的分组不应解释为限制。各组成员可被单独提到或要求保护,或与本文发现的组的其它成员或其它元素任意组合。应当理解,由于便利和/或专利的原因,一组的一个或多个成员可以被包括进一组中或从该组删除。当任何这类包括或删除发生时,本申请文件被认为含有经改写的组,以满足对附加的权利要求书中所用的所有马库什组的书面描述。
本文描述了根据本发明的某些实施方案,包括本发明的发明人已知的实现本发明的最佳模式。当然,本领域常规技术人员阅读上述描述后会明白这些实施方案的变更。本发明人预期熟练的技术人员能适当地采用这类变更,且本发明者意欲使得本发明以与本文特定描述不同的方式应用。因此,至少可适用的法律允许,本发明包括附加的权利要求书中所述的主体内容的所有修饰和等价物。另外,除非本文另有说明或与上下文明显抵触,在其所有可能变化中,上述元件的任何组合由本发明所包括。
另外,在本申请文件中,引用了大量专利和印刷出版物作为参考文献。上述各参考文献和印刷出版物通过引用其整体并入本文。
另外,应理解本文公开的本发明的实施方案仅用于阐述本发明的原则。其它可使用的修饰也在本发明的范围内。因此,通过示例而非限制的方式,可根据本文的教导利用本发明的备选形式。因此,本发明并非被限制为如精确地所示和所述的。
Claims (32)
1.促进活性试剂与悬浮液中预先形成的结晶微粒结合的方法,其包括步骤:
i)修饰所述活性试剂的化学势,其中所述修饰允许所述活性试剂和微粒之间在能量上有利的相互作用而不依赖于溶剂的去除;和
ii)将所述活性试剂吸附在所述微粒的表面上。
2.如权利要求1所述的方法,其中所述化学势的修饰包括修饰所述活性试剂的结构、柔性、刚性、可溶性或稳定性。
3.如权利要求2所述的方法,其中修饰所述活性试剂的所述化学势包括改变溶液条件。
4.如权利要求3所述的方法,其中改变溶液条件包括向溶液中添加活性试剂改性剂。
5.如权利要求4所述的方法,其中所述活性试剂改性剂选自盐、表面活性剂、离子、渗透物、醇、离液剂、补偿溶质、酸、碱和有机溶剂。
6.如权利要求5所述的方法,其中所述盐为氯化钠。
7.如权利要求1所述的方法,其还包括将所述活性试剂溶解在微粒悬浮液的流动相中并改变所述流动相pH的步骤。
8.如权利要求7所述的方法,其中在添加活性试剂之前改变所述pH。
9.如权利要求7所述的方法,其中在添加活性试剂之后改变所述pH。
10.如权利要求5所述的方法,其中所述活性试剂改性剂促进所述活性试剂的结构稳定性或药物效应动力学。
11.如权利要求1所述的方法,其中所述活性试剂为蛋白质、肽、多肽、小分子或核酸分子。
12.如权利要求11所述的方法,其中所述活性试剂选自胰岛素、脑肠肽、生长激素和甲状旁腺激素(PTH)。
13.如权利要求11所述的方法,其中所述活性试剂包含抗体或抗体片段。
14.如权利要求11所述的方法,其中所述小分子为疏水分子。
15.如权利要求14所述的方法,其中所述小分子为环孢菌素A。
16.如权利要求11所述的方法,其中所述小分子为可电离的分子。
17.如权利要求2所述的方法,其中修饰所述活性试剂的化学势包括调节与所述微粒表面的一种或多种在能量上有利的相互作用。
18.如权利要求17所述的方法,其中所述活性试剂和微粒之间的所述一种或多种在能量上有利的相互作用包括静电作用。
19.如权利要求17所述的方法,其中所述活性试剂和微粒之间的所述一种或多种在能量上有利的相互作用包括疏水作用。
20.如权利要求17所述的方法,其中所述活性试剂和微粒之间的所述一种或多种在能量上有利的相互作用包括氢键相互作用。
21.如权利要求1中所述的方法,其中所述微粒包含二酮哌嗪。
22.如权利要求21中所述的方法,其中所述二酮哌嗪为富马酰二酮哌嗪。
23.如权利要求1中所述的方法,其还包括去除所述溶剂的步骤。
24.用于制备药物递送组合物的过程,所述组合物包含活性试剂和结晶微粒,所述过程包括步骤:
提供包含活性试剂分子的活性试剂溶液;
修饰所述活性试剂的化学势;
提供微粒悬浮液或粉末;和
将所述活性试剂溶液与所述微粒悬浮液或粉末组合。
25.如权利要求24所述的过程,其中修饰所述活性试剂的化学势允许所述活性试剂和所述微粒之间相互作用。
26.如权利要求24所述的过程,其中修饰所述活性试剂的化学势包括向所述溶液中添加活性试剂改性剂。
27.如权利要求26所述的过程,其中所述活性试剂改性剂选自盐、表面活性剂、离子、渗透物、醇、离液剂、补偿溶质、酸、碱和有机溶剂。
28.如权利要求27所述的过程,其中所述活性试剂改性剂降低所述活性试剂分子的溶解度。
29.如权利要求27所述的过程,其中所述活性试剂改性剂促进所述活性试剂和微粒之间的缔合。
30.如权利要求27所述的过程,其中所述活性试剂改性剂促进所述活性试剂分子的结构稳定性。
31.如权利要求24所述的过程,其中所述微粒包含二酮哌嗪。
32.如权利要求31所述的过程,其中所述二酮哌嗪为富马酰二酮哌嗪。
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Families Citing this family (70)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
AU779986B2 (en) | 1999-06-29 | 2005-02-24 | Mannkind Corporation | Purification and stabilization of peptide and protein pharmaceutical agents |
ES2300568T3 (es) | 2002-03-20 | 2008-06-16 | Mannkind Corporation | Aparato de inhalacion. |
US20080260838A1 (en) * | 2003-08-01 | 2008-10-23 | Mannkind Corporation | Glucagon-like peptide 1 (glp-1) pharmaceutical formulations |
US9078866B2 (en) | 2003-08-01 | 2015-07-14 | Mannkind Corporation | Method for treating hyperglycemia with GLP-1 |
US8921311B2 (en) | 2003-08-01 | 2014-12-30 | Mannkind Corporation | Method for treating hyperglycemia |
MX2007001903A (es) | 2004-08-20 | 2007-08-02 | Mannkind Corp | Catalisis de sintesis de dicetopiperazina. |
KR101306384B1 (ko) | 2004-08-23 | 2013-09-09 | 맨카인드 코포레이션 | 약물 전달용 디케토피페라진염, 디케토모르포린염 또는디케토디옥산염 |
JP5465878B2 (ja) | 2005-09-14 | 2014-04-09 | マンカインド コーポレイション | 活性薬剤に対する結晶性微粒子表面の親和性を増大させることに基づく薬物処方の方法 |
CN104383546B (zh) | 2006-02-22 | 2021-03-02 | 曼金德公司 | 用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法 |
MX2008013216A (es) * | 2006-04-14 | 2008-10-27 | Mannkind Corp | Formulaciones farmaceuticas de peptido-1 tipo glucagon (glp-1). |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
AU2008316636B2 (en) * | 2007-10-24 | 2014-02-06 | Mannkind Corporation | Delivery of active agents |
MX2010004510A (es) * | 2007-10-24 | 2010-07-02 | Mannkind Corp | Metodo para prevenir los efectos nocivos de peptido 1 tipo glucagon (glp-1). |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
CN104689432B (zh) | 2008-06-13 | 2018-07-06 | 曼金德公司 | 干粉吸入器和用于药物输送的系统 |
JP5479465B2 (ja) | 2008-06-20 | 2014-04-23 | マンカインド コーポレイション | 吸入努力をリアルタイムにプロファイルする対話式機器および方法 |
RU2508093C2 (ru) * | 2008-07-01 | 2014-02-27 | Нитто Денко Корпорейшн | Фармацевтическая композиция, содержащая микрочастицы с поверхностным покрытием |
TWI494123B (zh) * | 2008-08-11 | 2015-08-01 | Mannkind Corp | 超快起作用胰島素之用途 |
JP6087504B2 (ja) | 2008-11-07 | 2017-03-01 | マサチューセッツ インスティテュート オブ テクノロジー | アミノアルコールリピドイドおよびその使用 |
US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
CA2748490C (en) | 2008-12-29 | 2016-10-04 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
PL2405963T3 (pl) | 2009-03-11 | 2014-04-30 | Mannkind Corp | Urządzenie, układ i sposób pomiaru oporu inhalatora |
EP2440184B1 (en) * | 2009-06-12 | 2023-04-05 | MannKind Corporation | Diketopiperazine microparticles with defined specific surface areas |
MY172858A (en) | 2009-06-12 | 2019-12-12 | Mannkind Corp | Diketopiperazine microparticles with defined isomer contents |
WO2011017554A2 (en) | 2009-08-07 | 2011-02-10 | Mannkind Corporation | Val (8) glp-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome |
CN102596238B (zh) | 2009-11-02 | 2014-06-18 | 曼康公司 | 用于对药物组合物进行低温造粒的装置和方法 |
WO2011053963A1 (en) | 2009-11-02 | 2011-05-05 | Mannkind Corporation | Reactor for producing pharmaceutical particles in a precipitation process |
WO2011056889A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
EP2567219B1 (en) | 2010-05-07 | 2019-09-18 | MannKind Corporation | Method and apparatus for determining weight percent of microparticles of diketopiperazine in suspension using raman spectroscopy |
RU2571331C1 (ru) * | 2010-06-21 | 2015-12-20 | Маннкайнд Корпорейшн | Системы и способы доставки сухих порошковых лекарств |
US10140619B2 (en) * | 2010-06-22 | 2018-11-27 | Sizmek Technologies, Inc. | Dynamic creative creation and delivery |
EP2637657B1 (en) | 2010-11-09 | 2019-05-22 | MannKind Corporation | Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines |
DK2694402T3 (en) | 2011-04-01 | 2017-07-03 | Mannkind Corp | BLISTER PACKAGE FOR PHARMACEUTICAL CYLINDER AMPULS |
US9890200B2 (en) | 2011-04-12 | 2018-02-13 | Moerae Matrix, Inc. | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
MX359516B (es) | 2011-04-12 | 2018-10-01 | Moerae Matrix Inc | Composiciones y metodos para prevenir o tratar enfermedades, afecciones, o procesos caracterizados por la proliferacion abrellante de fibro blasto y deposicion de matriz extracelular. |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
AU2012328885B2 (en) | 2011-10-24 | 2017-08-31 | Mannkind Corporation | Methods and compositions for treating pain |
AU2012328570B2 (en) | 2011-10-27 | 2017-08-31 | Massachusetts Institute Of Technology | Amino acid derivatives functionalized on the n-terminus capable of forming drug encapsulating microspheres and uses thereof |
US20130261372A1 (en) * | 2012-03-30 | 2013-10-03 | Elwha LLC, a limited liability company of the State of Delaware | Device, System, and Method for Delivery of Sugar Glass Stabilized Compositions |
AU2013289957B2 (en) | 2012-07-12 | 2017-02-23 | Mannkind Corporation | Dry powder drug delivery systems and methods |
US20150231067A1 (en) * | 2012-08-29 | 2015-08-20 | Mannkind Corporation | Method and composition for treating hyperglycemia |
US9795689B2 (en) * | 2012-09-11 | 2017-10-24 | University Of Massachusetts | Crosslinked polymer nano-assemblies and uses thereof |
UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
WO2014066856A1 (en) | 2012-10-26 | 2014-05-01 | Mannkind Corporation | Inhalable influenza vaccine compositions and methods |
WO2014096150A1 (en) | 2012-12-21 | 2014-06-26 | Sanofi | Dual glp1/gip or trigonal glp1/gip/glucagon agonists |
EP3587404B1 (en) * | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
BR112016000937A8 (pt) | 2013-07-18 | 2021-06-22 | Mannkind Corp | formulações farmacêuticas de pó seco, método para a fabricação de uma formulação de pó seco e uso de uma formulação farmacêutica de pó seco |
JP2016530930A (ja) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | 通気装置及び方法 |
TW201609795A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 作為雙重glp-1/gip受體促效劑的艾塞那肽-4(exendin-4)胜肽類似物 |
WO2015086733A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Dual glp-1/glucagon receptor agonists |
EP3080154B1 (en) | 2013-12-13 | 2018-02-07 | Sanofi | Dual glp-1/gip receptor agonists |
WO2015086730A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽-4(Exendin-4)之肽類雙重GLP-1/升糖素受體促效劑 |
TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重glp-1/昇糖素受體激動劑之艾塞那肽-4衍生物 |
TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自exendin-4之雙重glp-1/升糖素受體促效劑 |
US10336788B2 (en) | 2014-04-17 | 2019-07-02 | Moerae Matrix, Inc. | Inhibition of cardiac fibrosis in myocardial infarction |
MA48050A (fr) | 2014-05-30 | 2020-02-12 | Translate Bio Inc | Lipides biodégradables pour l'administration d'acides nucléiques |
US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
WO2015200465A1 (en) | 2014-06-24 | 2015-12-30 | Shire Human Genetic Therapies, Inc. | Stereochemically enriched compositions for delivery of nucleic acids |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
SG11201703939XA (en) | 2014-11-17 | 2017-06-29 | Moerae Matrix Inc | Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition |
MX2017011633A (es) | 2015-03-12 | 2017-11-02 | Moerae Matrix Inc | Uso de composiciones que contienen peptido inhibidor de mk2 para tratar cancer de pulmon de celulas no pequeñas con las mismas. |
AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
US10201618B2 (en) | 2015-06-19 | 2019-02-12 | Massachusetts Institute Of Technology | Alkenyl substituted 2,5-piperazinediones, compositions, and uses thereof |
TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重glp-1/升糖素受體促效劑之新毒蜥外泌肽(exendin-4)衍生物 |
SG11201806304PA (en) * | 2016-01-29 | 2018-08-30 | Mannkind Corp | Dry powder inhaler |
EP3801552A4 (en) * | 2018-06-07 | 2022-02-23 | MannKind Corporation | COMPOSITION AND METHOD OF INHALATION |
CN114471750A (zh) * | 2020-10-23 | 2022-05-13 | 南京工业大学 | 一种通过诱导液-液相分离可靠地合成纳米/亚微米液滴的方法及其应用 |
Family Cites Families (1114)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB475440A (en) | 1935-09-23 | 1937-11-19 | Mine Safety Appliances Co | Improvements in or relating to apparatus for determining the flow resistance of breathing apparatus elements |
US2549303A (en) | 1949-04-20 | 1951-04-17 | Bristol Lab Inc | Inhaler for crystalline pencilllin or the like |
BE509861A (zh) | 1952-03-13 | |||
US2754276A (en) | 1953-02-12 | 1956-07-10 | Du Pont | Cellular compositions utilizing dinitrosopentamethylene-tetramine as the blowing agent |
US3337740A (en) | 1962-02-13 | 1967-08-22 | Deering Milliken Res Corp | Process for separating acrylic acid from impurities |
US4187129A (en) | 1962-05-14 | 1980-02-05 | Aerojet-General Corporation | Gelled mechanically stable high energy fuel composition containing metal platelets |
FR1451293A (fr) | 1964-05-18 | 1966-01-07 | Entoleter | Matière composite et son procédé de préparation |
US3407203A (en) | 1965-03-22 | 1968-10-22 | Union Carbide Corp | Novel process for the preparation of diketopiperazines |
US3669113A (en) | 1966-03-07 | 1972-06-13 | Fisons Ltd | Inhalation device |
US3518340A (en) | 1968-04-15 | 1970-06-30 | Dow Corning | Method of forming silicone rubber drug carriers |
US3622053A (en) | 1969-12-10 | 1971-11-23 | Schering Corp | Aerosol inhaler with flip-up nozzle |
US3673698A (en) | 1970-11-25 | 1972-07-04 | Albert S Guerard | Process for freeze drying with carbon dioxide |
BE794951A (fr) | 1972-02-03 | 1973-05-29 | Parke Davis & Co | Conditionnement soluble dans l'eau |
US3873651A (en) | 1972-05-12 | 1975-03-25 | Atomic Energy Commission | Freeze drying method for preparing radiation source material |
US3823843A (en) | 1972-10-26 | 1974-07-16 | Lilly Co Eli | Locking capsule |
US3856142A (en) | 1973-01-24 | 1974-12-24 | Mine Safety Appliances Co | Inhalant package |
FR2224175B1 (zh) | 1973-04-04 | 1978-04-14 | Isf Spa | |
US3980074A (en) | 1973-07-18 | 1976-09-14 | Beecham Group Limited | Device for the administration of powders |
GB1479283A (en) | 1973-07-23 | 1977-07-13 | Bespak Industries Ltd | Inhaler for powdered medicament |
GB1459488A (en) | 1974-03-19 | 1976-12-22 | Wyeth John & Brother Ltd | Piperazinedione derivatives |
IT1017153B (it) | 1974-07-15 | 1977-07-20 | Isf Spa | Apparecchio per inalazioni |
US4018619A (en) | 1974-09-23 | 1977-04-19 | Iu Technology Corporation | Highly activated mixtures for constructing load bearing surfaces and method of making the same |
US4005711A (en) | 1975-01-13 | 1977-02-01 | Syntex Puerto Rico, Inc. | Inhalation device |
DE2502251A1 (de) | 1975-01-17 | 1976-07-22 | Schering Ag | Vorrichtung zur inhalation pulverfoermiger feststoffe |
US4040536A (en) | 1975-05-05 | 1977-08-09 | R. P. Scherer Corporation | Locking hard gelatin capsule |
JPS528096A (en) | 1975-06-09 | 1977-01-21 | Nat Distillers Chem Corp | Method for resisting agglomeration of ethyleneevinyl acetate copolymers |
US4153689A (en) | 1975-06-13 | 1979-05-08 | Takeda Chemical Industries, Ltd. | Stable insulin preparation for nasal administration |
US3998226A (en) | 1975-09-22 | 1976-12-21 | Edward G. Gomez | Inhalation device for encapsulated concentrates |
GB1509979A (en) | 1975-11-28 | 1978-05-10 | Fisons Ltd | Pharmaceutical compositions containing aspirin or indomethacin |
US4102953A (en) | 1976-05-25 | 1978-07-25 | The United States Of America As Represented By The Secretary Of The Navy | Method for making extruded, solventless, composite-modified double base propellant |
USD252707S (en) | 1977-01-03 | 1979-08-21 | Joel Besnard | Inhaler |
GB1598081A (en) | 1977-02-10 | 1981-09-16 | Allen & Hanburys Ltd | Inhaler device for dispensing medicaments |
US4171000A (en) | 1977-03-23 | 1979-10-16 | Uhle Klaus P | Smoking device |
IE46865B1 (en) | 1977-04-29 | 1983-10-19 | Allen & Hanburys Ltd | Device for dispensing medicaments |
US4148308A (en) | 1977-05-31 | 1979-04-10 | Sayer William J | Mouthpiece with a tongue retractor |
US4110240A (en) | 1977-07-29 | 1978-08-29 | Wyrough And Loser, Inc. | Coprecipitation process |
US4091077A (en) | 1977-08-12 | 1978-05-23 | The United States Of America As Represented By The United States Department Of Energy | Process for recovering filler from polymer |
US4211769A (en) | 1977-08-24 | 1980-07-08 | Takeda Chemical Industries, Ltd. | Preparations for vaginal administration |
US4268460A (en) | 1977-12-12 | 1981-05-19 | Warner-Lambert Company | Nebulizer |
CA1113044A (en) | 1977-12-16 | 1981-11-24 | J. Paul Leblond | Personal repellant device |
US4356167A (en) | 1978-01-27 | 1982-10-26 | Sandoz, Inc. | Liposome drug delivery systems |
US4175556A (en) | 1978-04-07 | 1979-11-27 | Freezer Winthrop J | Inhaler with flow-through cap |
US4196196A (en) | 1978-06-19 | 1980-04-01 | Tiholiz Ivan C | Divalen/monovalent bipolar cation therapy for enhancement of tissue perfusion and reperfusion in disease states |
US4168002A (en) | 1978-08-03 | 1979-09-18 | Crosby Leslie O | Multiple-seed package card |
US4272398A (en) | 1978-08-17 | 1981-06-09 | The United States Of America As Represented By The Secretary Of Agriculture | Microencapsulation process |
DE2840442C2 (de) | 1978-09-16 | 1982-02-11 | C.H. Boehringer Sohn, 6507 Ingelheim | Verwendung des Diketopiperazins L-Leu-L-Trp als Geschmacksstoff für Getränke mit bitterer Geschmacksrichtung |
DE2849493C2 (de) | 1978-11-15 | 1982-01-14 | Carl Heyer Gmbh, Inhalationstechnik, 5427 Bad Ems | In der Hand zu haltender Aerosolspender |
USD269463S (en) | 1978-12-08 | 1983-06-21 | Fisons Limited | Container for a medicinal inhaler |
JPS5837833Y2 (ja) | 1979-04-27 | 1983-08-26 | 凸版印刷株式会社 | アンプル収納容器 |
JPS6034925B2 (ja) | 1979-07-31 | 1985-08-12 | 帝人株式会社 | 持続性鼻腔用製剤およびその製造法 |
US4407525A (en) | 1979-10-04 | 1983-10-04 | Gao Gesellschaft Fur Automation Und Organisation Mbh | Identification card with hallmark for authentication by incident and transmitted light |
GB2072536B (en) | 1980-03-25 | 1983-12-07 | Malem H | Nebuliser |
US4289759A (en) | 1980-06-23 | 1981-09-15 | Ortho Pharmaceutical Corporation | Immunoregulatory diketopiperazine compounds |
DE3167658D1 (en) | 1980-12-12 | 1985-01-17 | Combi Co | Inhaler |
US4900730A (en) | 1981-01-14 | 1990-02-13 | Toyo Jozo Co., Ltd. | Preparation which promotes the absorption of peptides |
GB2092136B (en) | 1981-01-17 | 1985-06-05 | Mitsui Toatsu Chemicals | Production of n-substituted amide compounds |
JPS58140026A (ja) | 1982-01-14 | 1983-08-19 | Toyo Jozo Co Ltd | 吸収性良好な製剤 |
IT1220979B (it) | 1981-06-04 | 1990-06-21 | Lofarma Farma Lab | Capsule contenenti un allergene e procedimento per la loro preparazione |
CY1492A (en) | 1981-07-08 | 1990-02-16 | Draco Ab | Powder inhalator |
SE438261B (sv) | 1981-07-08 | 1985-04-15 | Draco Ab | Anvendning i dosinhalator av ett perforerat membran |
US5260306A (en) | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
USD276654S (en) | 1981-09-15 | 1984-12-04 | Aktiebolaget Draco | Medical aerosol inhalation device |
KR890000664B1 (ko) | 1981-10-19 | 1989-03-22 | 바리 안소니 뉴우샘 | 미분된 베클로메타손 디프로피오네이트 일수화물의 제조방법 |
US4659696A (en) | 1982-04-30 | 1987-04-21 | Takeda Chemical Industries, Ltd. | Pharmaceutical composition and its nasal or vaginal use |
US4483922A (en) | 1982-05-14 | 1984-11-20 | Amf Inc. | Inactivation of enzymes |
US4526804A (en) | 1982-08-30 | 1985-07-02 | Ball Corporation | Method for providing sheet metal stock with finely divided powder |
US4487327A (en) | 1982-12-21 | 1984-12-11 | Grayson Robert E | Locking capsule |
JPS59163313A (ja) | 1983-03-09 | 1984-09-14 | Teijin Ltd | 経鼻投与用ペプチドホルモン類組成物 |
US4481139A (en) | 1983-04-13 | 1984-11-06 | Board Of Regents, The University Of Texas System | Peptide antagonists of substance P |
AU90762S (en) | 1983-06-29 | 1985-08-15 | Glaxo Group Ltd | Inhaler |
US4581020A (en) | 1983-07-18 | 1986-04-08 | Trimedyne, Inc. | Medication delivery device and system for percutaneous administration of medication |
GB8325529D0 (en) | 1983-09-23 | 1983-10-26 | Lilly Industries Ltd | Medicinal forms |
CH661878A5 (de) | 1983-11-04 | 1987-08-31 | Warner Lambert Co | Kapsel-dosierungsformen. |
US4671954A (en) | 1983-12-13 | 1987-06-09 | University Of Florida | Microspheres for incorporation of therapeutic substances and methods of preparation thereof |
USD295321S (en) | 1984-03-13 | 1988-04-19 | Glaxo Group Limited | Inhaler container for a medical aerosol |
JPS60248618A (ja) | 1984-05-24 | 1985-12-09 | Nippon Zoki Pharmaceut Co Ltd | ジペプチドを含有する潰瘍治療剤 |
US4927555A (en) | 1984-08-13 | 1990-05-22 | Colgate-Palmolive Company | Process for making thixotropic detergent compositions |
USD288852S (en) | 1984-08-29 | 1987-03-17 | Aruman Co., Ltd. | Disposable inhaler |
US4757066A (en) | 1984-10-15 | 1988-07-12 | Sankyo Company Limited | Composition containing a penem or carbapenem antibiotic and the use of the same |
IE58468B1 (en) | 1984-10-25 | 1993-09-22 | Warner Lambert Co | Method for sealing capsules and capsule |
US4592348A (en) | 1984-12-17 | 1986-06-03 | Waters Iv William C | Aerosol inhaler |
US4946828A (en) | 1985-03-12 | 1990-08-07 | Novo Nordisk A/S | Novel insulin peptides |
SE448277B (sv) | 1985-04-12 | 1987-02-09 | Draco Ab | Indikeringsanordning vid en doseringsanordning for lekemedel |
JPS6320301Y2 (zh) | 1985-04-18 | 1988-06-06 | ||
US5785989A (en) | 1985-05-01 | 1998-07-28 | University Utah Research Foundation | Compositions and methods of manufacturing of oral dissolvable medicaments |
US4615817A (en) | 1985-05-17 | 1986-10-07 | Mccoy Frederic C | Additives containing polytetrafluoroethylene for making stable lubricants |
CA1318730C (en) | 1985-05-30 | 1993-06-01 | C. Edward Capes | Method of separating carbonaceous components from particulate coal containing inorganic solids and apparatus therefor |
US5098590A (en) | 1988-02-04 | 1992-03-24 | Colgate Palmolive Co. | Thixotropic aqueous automatic dishwasher detergent compositions with improved stability |
US4811731A (en) | 1985-07-30 | 1989-03-14 | Glaxo Group Limited | Devices for administering medicaments to patients |
AT384552B (de) | 1985-08-01 | 1987-12-10 | Hurka Wilhelm | Inhalationsgeraet zur dosierung und verteilung von festkoerpern in die atemluft |
US4624861A (en) | 1985-09-05 | 1986-11-25 | Gte Products Corporation | Rare earth oxysulfide phosphors and processes for creating same |
US4742156A (en) | 1985-09-30 | 1988-05-03 | Mcneilab, Inc. | Peptide antagonists of neurokinin B and opthalmic solutions containing them |
PT83613B (en) | 1985-10-28 | 1988-11-21 | Lilly Co Eli | Process for the selective chemical removal of a protein amino-terminal residue |
WO1987003197A1 (en) | 1985-11-29 | 1987-06-04 | Fisons Plc | Pharmaceutical composition including sodium cromoglycate |
LU86258A1 (fr) | 1986-01-21 | 1987-09-03 | Rech Dermatologiques C I R D S | Composes benzamido aromatique,leur procede de preparation et leur utilisation en medecine humaine ou veterinaire et en cosmetique |
SE453566B (sv) | 1986-03-07 | 1988-02-15 | Draco Ab | Anordning vid pulverinhalatorer |
US4849227A (en) * | 1986-03-21 | 1989-07-18 | Eurasiam Laboratories, Inc. | Pharmaceutical compositions |
US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
US6849708B1 (en) | 1986-05-05 | 2005-02-01 | The General Hospital Corporation | Insulinotropic hormone and uses thereof |
US4926852B1 (en) | 1986-06-23 | 1995-05-23 | Univ Johns Hopkins | Medication delivery system phase one |
USD301273S (en) | 1986-07-10 | 1989-05-23 | Leonard G Darin | Hand held fly suction device |
JPS6320301A (ja) | 1986-07-11 | 1988-01-28 | Dainichi Color & Chem Mfg Co Ltd | キトサン微小粒体 |
US5042975A (en) | 1986-07-25 | 1991-08-27 | Rutgers, The State University Of New Jersey | Iontotherapeutic device and process and iontotherapeutic unit dose |
ES2053549T3 (es) | 1986-08-11 | 1994-08-01 | Innovata Biomed Ltd | Un proceso para la preparacion de una formulacion farmaceutica apropiada para inhalacion. |
USRE35862E (en) | 1986-08-18 | 1998-07-28 | Emisphere Technologies, Inc. | Delivery systems for pharmacological agents encapsulated with proteinoids |
CH671155A5 (zh) | 1986-08-18 | 1989-08-15 | Clinical Technologies Ass | |
ATE76311T1 (de) | 1986-08-19 | 1992-06-15 | Genentech Inc | Einrichtung und dispersion zum intrapulmonalen eingeben von polypeptidwuchsstoffen und zytokinen. |
DE3639836A1 (de) | 1986-11-21 | 1988-06-01 | Sigrid Bechter | Mundstueck fuer ein inhalationsgeraet |
KR890003520Y1 (ko) | 1986-12-20 | 1989-05-27 | 주식회사 서흥캅셀 | 의약용 캅셀 |
US4861627A (en) | 1987-05-01 | 1989-08-29 | Massachusetts Institute Of Technology | Preparation of multiwall polymeric microcapsules |
US4981295A (en) | 1987-05-11 | 1991-01-01 | City Of Hope | Respiratory training using feedback |
US6645504B1 (en) | 1987-06-24 | 2003-11-11 | Autoimmune Inc. | Bystander suppression of type I diabetes by oral administration of glucagon |
US4913173A (en) | 1987-06-25 | 1990-04-03 | International Beauty Distributors, Inc. | High efficiency wrap package, and process, for nails |
DE3727894A1 (de) | 1987-08-21 | 1989-03-02 | Stephan Dieter | Kapsel fuer pharmazeutisch wirksame inhaltsstoffe einer droge |
GB8723846D0 (en) | 1987-10-10 | 1987-11-11 | Danbiosyst Ltd | Bioadhesive microsphere drug delivery system |
US4887722A (en) | 1987-12-11 | 1989-12-19 | Greenward Sr Edward H | Method for beneficiating by carbonaceous refuse |
DE3801326A1 (de) | 1988-01-19 | 1989-07-27 | Asea Brown Boveri | Verfahren zur herstellung einer keramiksuspension |
US4981625A (en) | 1988-03-14 | 1991-01-01 | California Institute Of Technology | Monodisperse, polymeric microspheres produced by irradiation of slowly thawing frozen drops |
CH675267A5 (zh) | 1988-03-16 | 1990-09-14 | Geberit Ag | |
GB8813338D0 (en) | 1988-06-06 | 1988-07-13 | Osprey Metals Ltd | Powder production |
USD316902S (en) | 1988-09-02 | 1991-05-14 | Hoelfing H Curt | Meter hose inhaler reservoir |
GB8821287D0 (en) | 1988-09-12 | 1988-10-12 | Ici Plc | Device |
EP0360340A1 (en) | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
USD321570S (en) | 1988-09-30 | 1991-11-12 | Blasdell Richard J | Inhaler |
EP0363060B1 (en) | 1988-10-04 | 1994-04-27 | The Johns Hopkins University | Aerosol inhaler |
JPH02104531A (ja) | 1988-10-14 | 1990-04-17 | Toyo Jozo Co Ltd | 経鼻投与用生理活性ペプチド組成物 |
US4984158A (en) | 1988-10-14 | 1991-01-08 | Hillsman Dean | Metered dose inhaler biofeedback training and evaluation system |
JPH02115154A (ja) | 1988-10-25 | 1990-04-27 | Kao Corp | イミド化合物及びその用途 |
USD326517S (en) | 1988-10-27 | 1992-05-26 | Glaxo Group Limited | Inhalator |
JP2692742B2 (ja) | 1988-11-30 | 1997-12-17 | 株式会社ツムラ | 新規なリグナン類 |
US5006343A (en) | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
US5075027A (en) | 1989-02-06 | 1991-12-24 | Colgate Palmolive Co. | Thixotropic aqueous scented automatic dishwasher detergent compositions |
US5514646A (en) | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
IT1228459B (it) | 1989-02-23 | 1991-06-19 | Phidea S R L | Inalatore con svuotamento regolare e completo della capsula. |
IT1228460B (it) | 1989-02-23 | 1991-06-19 | Phidea S R L | Inalatore monouso con capsula pre-forata |
US4983402A (en) | 1989-02-24 | 1991-01-08 | Clinical Technologies Associates, Inc. | Orally administerable ANF |
SE466684B (sv) | 1989-03-07 | 1992-03-23 | Draco Ab | Anordning vid en inhalator samt foerfarande foer att med anordningen registrera medicinering med inhalator |
US5358734A (en) | 1989-03-30 | 1994-10-25 | Gte Products Corporation | Process for producing a blue emitting lamp phosphor |
US5215739A (en) | 1989-04-05 | 1993-06-01 | Toko Yakuhin Kogyo Kabushiki Kaisha | Spray gel base and spray gel preparation using thereof |
US5067500A (en) | 1989-04-24 | 1991-11-26 | Philip Morris Incorporated | Container for additive materials for smoking articles |
US4991605A (en) | 1989-04-24 | 1991-02-12 | Philip Morris Incorporated | Container for additive materials for smoking articles |
GB8909891D0 (en) | 1989-04-28 | 1989-06-14 | Riker Laboratories Inc | Device |
ES2087911T3 (es) | 1989-04-28 | 1996-08-01 | Riker Laboratories Inc | Dispositivo de inhalacion de polvo seco. |
DK0432232T3 (da) | 1989-05-01 | 1994-01-31 | Alkermes Inc | Fremgangsmåde til fremstilling af små partikler af biologisk aktive molekyler |
US5019400A (en) | 1989-05-01 | 1991-05-28 | Enzytech, Inc. | Very low temperature casting of controlled release microspheres |
US5017383A (en) | 1989-08-22 | 1991-05-21 | Taisho Pharmaceutical Co., Ltd. | Method of producing fine coated pharmaceutical preparation |
GB8919131D0 (en) | 1989-08-23 | 1989-10-04 | Riker Laboratories Inc | Inhaler |
US5270305A (en) | 1989-09-08 | 1993-12-14 | Glaxo Group Limited | Medicaments |
GB8921222D0 (en) | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
DK544589D0 (da) | 1989-11-01 | 1989-11-01 | Novo Nordisk As | Manuel betjent apparat til dispensering af en forudbestemt maengde af et pulverformet stof |
JPH0741428Y2 (ja) | 1989-11-04 | 1995-09-27 | アップリカ葛西株式会社 | ベビーバス |
JP2571874B2 (ja) | 1989-11-06 | 1997-01-16 | アルカーメス コントロールド セラピューティクス,インコーポレイテッド | タンパク質マイクロスフェア組成物 |
US5188837A (en) | 1989-11-13 | 1993-02-23 | Nova Pharmaceutical Corporation | Lipsopheres for controlled delivery of substances |
US5105291A (en) * | 1989-11-20 | 1992-04-14 | Ricoh Company, Ltd. | Liquid crystal display cell with electrodes of substantially amorphous metal oxide having low resistivity |
US5131539A (en) | 1989-12-06 | 1992-07-21 | Canon Kabushiki Kaisha | Package for ink jet cartridge |
USD331106S (en) | 1989-12-30 | 1992-11-17 | Ing. Erich Pfeiffer Gmbh & Co. Kg | Single use inhaler |
US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
GB9001635D0 (en) | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
US5201308A (en) | 1990-02-14 | 1993-04-13 | Newhouse Michael T | Powder inhaler |
SK280967B6 (sk) | 1990-03-02 | 2000-10-09 | Glaxo Group Limited | Inhalačný prístroj |
US6536427B2 (en) | 1990-03-02 | 2003-03-25 | Glaxo Group Limited | Inhalation device |
UA26230A (uk) | 1990-03-02 | 1999-07-19 | Глексо Груп Лімітед | Іhгалятор для спільhого використаhhя з лікувальhим блоком і лікувальhий блок |
US5615670A (en) | 1990-03-07 | 1997-04-01 | Fisons Plc | Powder inhaler with centrifugal force used to meter powder |
IT1240750B (it) | 1990-04-12 | 1993-12-17 | Chiesi Farma Spa | Dispositivo per la somministrazione di sostanze medicamentose in polvere |
JPH05963A (ja) | 1990-04-13 | 1993-01-08 | Toray Ind Inc | ポリペプチド類組成物 |
US5328464A (en) | 1990-04-24 | 1994-07-12 | Science Incorporated | Closed drug delivery system |
USD338268S (en) | 1990-05-04 | 1993-08-10 | Omron Corporation | Heating inhaler |
JPH05507090A (ja) | 1990-05-08 | 1993-10-14 | リポサーム テクノロジー インコーポレイテッド | 直接噴霧乾燥された薬剤/脂質粉末組成物 |
NZ238489A (en) | 1990-06-14 | 1995-09-26 | Rhone Poulenc Rorer Ltd | Inhaler with capsule in swirling chamber: capsule pierced in chamber |
DE4021263C2 (de) | 1990-07-04 | 1996-04-11 | Pfeiffer Erich Gmbh & Co Kg | Austragvorrichtung für Medien |
GB9015522D0 (en) | 1990-07-13 | 1990-08-29 | Braithwaite Philip W | Inhaler |
US6331318B1 (en) * | 1994-09-30 | 2001-12-18 | Emisphere Technologies Inc. | Carbon-substituted diketopiperazine delivery systems |
US5443841A (en) | 1992-06-15 | 1995-08-22 | Emisphere Technologies, Inc. | Proteinoid microspheres and methods for preparation and use thereof |
US5541155A (en) | 1994-04-22 | 1996-07-30 | Emisphere Technologies, Inc. | Acids and acid salts and their use in delivery systems |
US5629020A (en) | 1994-04-22 | 1997-05-13 | Emisphere Technologies, Inc. | Modified amino acids for drug delivery |
US5451410A (en) | 1993-04-22 | 1995-09-19 | Emisphere Technologies, Inc. | Modified amino acids for encapsulating active agents |
US5714167A (en) | 1992-06-15 | 1998-02-03 | Emisphere Technologies, Inc. | Active agent transport systems |
US5447728A (en) | 1992-06-15 | 1995-09-05 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
US5578323A (en) | 1992-06-15 | 1996-11-26 | Emisphere Technologies, Inc. | Proteinoid carriers and methods for preparation and use thereof |
US5693338A (en) * | 1994-09-29 | 1997-12-02 | Emisphere Technologies, Inc. | Diketopiperazine-based delivery systems |
JPH04103585A (ja) | 1990-08-24 | 1992-04-06 | Nisshin Flour Milling Co Ltd | ピロリジン環を有する化合物 |
SE9002895D0 (sv) | 1990-09-12 | 1990-09-12 | Astra Ab | Inhalation devices for dispensing powders i |
US5074418A (en) | 1990-09-12 | 1991-12-24 | Pitney Bowes Inc. | Ink replenishing system transport and storage container |
DE69132850T2 (de) | 1990-09-26 | 2002-05-29 | Pharmachemie Bv | Wirbelkammer-Pulverinhalator |
US5170801A (en) | 1990-10-02 | 1992-12-15 | Glaxo Inc. | Medical capsule device actuated by radio-frequency (rf) signal |
FR2667509B1 (fr) | 1990-10-04 | 1995-08-25 | Valois | Inhalateur a poudre, dispositif de conditionnement de microdoses de poudre sous forme de bandes adaptees a etre utilisees dans un inhalateur a poudre, et procede de fabrication de ces bandes. |
IL99699A (en) | 1990-10-10 | 2002-04-21 | Autoimmune Inc | Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes |
GB9024760D0 (en) | 1990-11-14 | 1991-01-02 | Riker Laboratories Inc | Inhalation device and medicament carrier |
US5124291A (en) | 1990-11-15 | 1992-06-23 | The Standard Oil Company | Method for deagglomerating and re-exposing catalyst in a fluid bed reactor |
GB9026191D0 (en) | 1990-12-01 | 1991-01-16 | Harris Pharma Ltd | Breath actuated dispensing device |
GB9027234D0 (en) | 1990-12-15 | 1991-02-06 | Harris Pharma Ltd | An inhalation device |
DE69127826T2 (de) | 1990-12-17 | 1998-04-09 | Minnesota Mining & Mfg | Inhalationsgerät |
US5145684A (en) | 1991-01-25 | 1992-09-08 | Sterling Drug Inc. | Surface modified drug nanoparticles |
GB2253200A (en) | 1991-02-01 | 1992-09-02 | Harris Pharma Ltd | Inhalation apparatus and fracturable capsule for use therewith |
WO1992014449A1 (en) | 1991-02-20 | 1992-09-03 | Nova Pharmaceutical Corporation | Controlled release microparticulate delivery system for proteins |
US5208998A (en) | 1991-02-25 | 1993-05-11 | Oyler Jr James R | Liquid substances freeze-drying systems and methods |
AU6130694A (en) | 1991-03-05 | 1994-08-15 | Miris Medical Corporation | An automatic aerosol medication delivery system and methods |
US5469750A (en) | 1991-03-05 | 1995-11-28 | Aradigm Corporation | Method and apparatus for sensing flow in two directions and automatic calibration thereof |
US5404871A (en) | 1991-03-05 | 1995-04-11 | Aradigm | Delivery of aerosol medications for inspiration |
USD338062S (en) | 1991-03-06 | 1993-08-03 | Innovata Biomed Limited | Inhaler |
USD347057S (en) | 1991-03-14 | 1994-05-17 | Technosystem Limited | Inhaler |
JPH05273772A (ja) | 1991-03-28 | 1993-10-22 | Mita Ind Co Ltd | ヒドラゾン系化合物およびそれを用いた感光体 |
US5797391A (en) | 1991-03-28 | 1998-08-25 | Rhone-Poulenc Rorer Limited | Inhaler |
US5413804A (en) | 1991-04-23 | 1995-05-09 | Cacique, Inc. | Process for making whey-derived fat substitute product and products thereof |
US5244653A (en) | 1991-05-01 | 1993-09-14 | Isp Chemicals Inc. | Glycine anhydride dimethylol as a biocide and preservative |
US5492112A (en) | 1991-05-20 | 1996-02-20 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US6060069A (en) | 1991-05-20 | 2000-05-09 | Dura Pharmaceuticals, Inc. | Pulmonary delivery of pharmaceuticals |
US5327883A (en) | 1991-05-20 | 1994-07-12 | Dura Pharmaceuticals, Inc. | Apparatus for aerosolizing powdered medicine and process and using |
US6055980A (en) | 1991-05-20 | 2000-05-02 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
FR2676929B1 (fr) | 1991-05-30 | 1994-02-11 | Aerosols Bouchage Ste Fse | Inhalateur de poudres. |
AU653026B2 (en) | 1991-06-07 | 1994-09-15 | Teikoku Seiyaku Kabushiki Kaisha | Physiologically active polypeptide-containing pharmaceutical composition |
IT1248059B (it) | 1991-06-14 | 1995-01-05 | Miat Spa | Insufflatore multidose per farmaci in polvere |
US6681767B1 (en) | 1991-07-02 | 2004-01-27 | Nektar Therapeutics | Method and device for delivering aerosolized medicaments |
ATE359842T1 (de) | 1991-07-02 | 2007-05-15 | Nektar Therapeutics | Abgabevorrichtung für nebelförmige medikamente |
US5203768A (en) | 1991-07-24 | 1993-04-20 | Alza Corporation | Transdermal delivery device |
US5337740A (en) | 1991-08-01 | 1994-08-16 | New England Pharmaceuticals, Inc. | Inhalation devices |
GB9116610D0 (en) | 1991-08-01 | 1991-09-18 | Danbiosyst Uk | Preparation of microparticles |
US5139878A (en) | 1991-08-12 | 1992-08-18 | Allied-Signal Inc. | Multilayer film constructions |
EP0528764B1 (en) | 1991-08-16 | 1996-06-12 | Sandoz Ltd. | Inhaler for administration of powdery substances |
US5287850A (en) | 1991-08-20 | 1994-02-22 | Habley Medical Technology Corporation | Timing and velocity controlled powered pharmaceutical inhaler |
US6119688A (en) | 1991-08-26 | 2000-09-19 | 3M Innovative Properties Company | Powder dispenser |
USD337636S (en) | 1991-09-12 | 1993-07-20 | Devilbiss Health Care, Inc. | Ultrasonic medicament nebulizer |
US5167506A (en) | 1991-10-24 | 1992-12-01 | Minnesota Mining And Manufacturing Company | Inhalation device training system |
USD348100S (en) | 1991-10-29 | 1994-06-21 | Fisons Plc | Medicament inhaler |
JPH0828037B2 (ja) | 1991-10-31 | 1996-03-21 | 富士通株式会社 | スピンドルシンク制御方式 |
USD350602S (en) | 1991-11-01 | 1994-09-13 | Rhone-Poulenc Rorer Limited | Combined dry powder inhaler and cap |
US6063910A (en) | 1991-11-14 | 2000-05-16 | The Trustees Of Princeton University | Preparation of protein microparticles by supercritical fluid precipitation |
USD350821S (en) | 1991-11-18 | 1994-09-20 | Smithkline Beecham P.L.C. | Oral inhaler |
SE9103572D0 (sv) | 1991-11-29 | 1991-11-29 | Astra Ab | Organic salts of n,n'-diacetyl cystine |
USD340975S (en) | 1991-12-02 | 1993-11-02 | Thayer Medical Corporation | Combined expansion chamber metered dose inhaler dispenser and adaptor |
US5338837A (en) | 1991-12-13 | 1994-08-16 | The Trustees Of Princeton University | Glycosylated steroid derivatives for transport across biological membranes and process for making same |
DE4211475A1 (de) | 1991-12-14 | 1993-06-17 | Asta Medica Ag | Pulverinhalator |
GB2262452B (en) | 1991-12-19 | 1995-12-20 | Minnesota Mining & Mfg | Inhalation device |
JP3121080B2 (ja) | 1991-12-19 | 2000-12-25 | アール・ピー・シーラー コーポレイション | カプセル封入用溶液 |
US5363842A (en) | 1991-12-20 | 1994-11-15 | Circadian, Inc. | Intelligent inhaler providing feedback to both patient and medical professional |
US5525519A (en) | 1992-01-07 | 1996-06-11 | Middlesex Sciences, Inc. | Method for isolating biomolecules from a biological sample with linear polymers |
US5320094A (en) | 1992-01-10 | 1994-06-14 | The Johns Hopkins University | Method of administering insulin |
ATE146359T1 (de) | 1992-01-21 | 1997-01-15 | Stanford Res Inst Int | Verbessertes verfahren zur herstellung von mikronisierter polypeptidarzneimitteln |
DE9209050U1 (zh) | 1992-02-13 | 1992-10-01 | Schrader, Barthold Von, 2400 Travemuende, De | |
US5476093A (en) | 1992-02-14 | 1995-12-19 | Huhtamaki Oy | Device for more effective pulverization of a powdered inhalation medicament |
US5469971A (en) | 1992-02-26 | 1995-11-28 | Estee Lauder Inc. | Method and apparatus for deagglomerating powder |
EP0558879B1 (en) | 1992-03-04 | 1997-05-14 | Astra Aktiebolag | Disposable inhaler |
US5639441A (en) | 1992-03-06 | 1997-06-17 | Board Of Regents Of University Of Colorado | Methods for fine particle formation |
US5352461A (en) | 1992-03-11 | 1994-10-04 | Pharmaceutical Discovery Corporation | Self assembling diketopiperazine drug delivery system |
DK36392D0 (da) | 1992-03-19 | 1992-03-19 | Novo Nordisk As | Anvendelse af kemisk forbindelse |
USD348929S (en) | 1992-04-03 | 1994-07-19 | Norton Healthcare Limited | Medicament inhaler |
CA2096302A1 (en) | 1992-05-15 | 1993-11-16 | David Kilis | Air flow controller and recording system |
USD350193S (en) | 1992-06-11 | 1994-08-30 | Schering Corporation | Combined inhaler and cover |
USD345013S (en) | 1992-06-11 | 1994-03-08 | Schering Corporation | Combined inhaler and cover |
USD344796S (en) | 1992-06-11 | 1994-03-01 | Schering Corporation | Combined inhaler and cover |
USD344797S (en) | 1992-06-11 | 1994-03-01 | Schering Corporation | Combined inhaler and cover |
AU660824B2 (en) | 1992-06-12 | 1995-07-06 | Teijin Limited | Pharmaceutical preparation for intra-airway administration |
US5792451A (en) | 1994-03-02 | 1998-08-11 | Emisphere Technologies, Inc. | Oral drug delivery compositions and methods |
US5811127A (en) | 1992-06-15 | 1998-09-22 | Emisphere Technologies, Inc. | Desferrioxamine oral delivery system |
US5394868A (en) | 1992-06-25 | 1995-03-07 | Schering Corporation | Inhalation device for powdered medicaments |
GB9213874D0 (en) | 1992-06-30 | 1992-08-12 | Fisons Plc | Process to novel medicament form |
US6582728B1 (en) | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
US5785049A (en) | 1994-09-21 | 1998-07-28 | Inhale Therapeutic Systems | Method and apparatus for dispersion of dry powder medicaments |
US6509006B1 (en) * | 1992-07-08 | 2003-01-21 | Inhale Therapeutic Systems, Inc. | Devices compositions and methods for the pulmonary delivery of aerosolized medicaments |
GB9214819D0 (en) | 1992-07-13 | 1992-08-26 | Minnesota Mining & Mfg | Valve assemblies |
GB9216038D0 (en) | 1992-07-28 | 1992-09-09 | Bespak Plc | Dispensing apparatus for powdered medicaments |
GB2269992A (en) | 1992-08-14 | 1994-03-02 | Rh Ne Poulenc Rorer Limited | Powder inhalation formulations |
US5239993A (en) | 1992-08-26 | 1993-08-31 | Glaxo Inc. | Dosage inhalator providing optimized compound inhalation trajectory |
GB2270293A (en) | 1992-09-05 | 1994-03-09 | Medix Ltd | Drug dispensing system |
USD348928S (en) | 1992-09-21 | 1994-07-19 | Schering Corporation | Inhaler |
US5333106A (en) | 1992-10-09 | 1994-07-26 | Circadian, Inc. | Apparatus and visual display method for training in the power use of aerosol pharmaceutical inhalers |
WO1994008599A1 (en) | 1992-10-14 | 1994-04-28 | The Regents Of The University Of Colorado | Ion-pairing of drugs for improved efficacy and delivery |
EP0665759B1 (en) | 1992-10-19 | 1998-12-23 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
AU121578S (en) | 1992-10-22 | 1994-09-20 | Fisons Plc | An inhalation device |
USD359555S (en) | 1992-11-18 | 1995-06-20 | Nippon Glaxo Limited | Nasal medicine inhaler |
USD349572S (en) | 1992-12-10 | 1994-08-09 | Schering Corporation | Aerosol inhaler |
USD352107S (en) | 1992-12-10 | 1994-11-01 | Ciba-Geigy Corporation | Inhaler |
SE9203743D0 (sv) | 1992-12-11 | 1992-12-11 | Astra Ab | Efficient use |
US6250300B1 (en) | 1992-12-11 | 2001-06-26 | Ab Astra | System for dispensing pharmaceutically active compounds |
CZ287848B6 (en) | 1992-12-18 | 2001-02-14 | Schering Corp | Inhalator of powder substances |
US5401516A (en) | 1992-12-21 | 1995-03-28 | Emisphere Technologies, Inc. | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof |
US6105571A (en) | 1992-12-22 | 2000-08-22 | Electrosols, Ltd. | Dispensing device |
US6880554B1 (en) | 1992-12-22 | 2005-04-19 | Battelle Memorial Institute | Dispensing device |
US5896855A (en) | 1992-12-24 | 1999-04-27 | Rhone-Poulenc Rorer Limited | Multi dose inhaler apparatus |
FR2700279B1 (fr) | 1993-01-14 | 1995-03-17 | Valois | Dispositif portatif pour projeter des doses d'une substance fluide à l'aide d'un flux d'air comprimé. |
AU119600S (en) | 1993-01-21 | 1994-03-07 | Boehringer Ingelheim Kg | Inhaler device |
US5672581A (en) | 1993-01-29 | 1997-09-30 | Aradigm Corporation | Method of administration of insulin |
US5364838A (en) | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
US5888477A (en) | 1993-01-29 | 1999-03-30 | Aradigm Corporation | Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin |
US6131567A (en) | 1993-01-29 | 2000-10-17 | Aradigm Corporation | Method of use of monomeric insulin as a means for improving the reproducibility of inhaled insulin |
US7448375B2 (en) | 1993-01-29 | 2008-11-11 | Aradigm Corporation | Method of treating diabetes mellitus in a patient |
US6024090A (en) | 1993-01-29 | 2000-02-15 | Aradigm Corporation | Method of treating a diabetic patient by aerosolized administration of insulin lispro |
US5441060A (en) | 1993-02-08 | 1995-08-15 | Duke University | Dry powder delivery system |
IL108780A (en) | 1993-02-27 | 1999-06-20 | Fisons Plc | inhaler |
AU6360394A (en) * | 1993-03-03 | 1994-09-26 | Mayo Foundation For Medical Education And Research | Vasonatrin peptide and analogs thereof |
US5437271A (en) | 1993-04-06 | 1995-08-01 | Minnesota Mining And Manufacturing Company | Deagglomerators for dry powder inhalers |
US5372128A (en) | 1993-04-14 | 1994-12-13 | Habley Medical Technology Corporation | Fluidizing powder inhaler |
ZA939608B (en) | 1993-04-22 | 1994-08-24 | Emisphere Tech Inc | Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof. |
EP1025840B1 (en) | 1993-04-22 | 2005-06-29 | Emisphere Technologies, Inc. | Oral drug compositions |
US5643957A (en) | 1993-04-22 | 1997-07-01 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
US5360614A (en) | 1993-04-26 | 1994-11-01 | The Estee Corporation | Method of controlling the release of carbohydrates by encapsulation and composition therefor |
CA2150251C (en) | 1993-04-28 | 2005-02-22 | Arnold Titus Philip Skrabanja | Lyospheres comprising gonadotropin |
DE69416245T2 (de) | 1993-05-12 | 1999-07-08 | Teijin Ltd | Vorrichtung und verfahren zur dosierten abgabe von pulverförmigen arzneistoffen |
US5424286A (en) | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
US5533502A (en) | 1993-05-28 | 1996-07-09 | Vortran Medical Technology, Inc. | Powder inhaler with aerosolization occurring within each individual powder receptacle |
USD365876S (en) | 1993-06-16 | 1996-01-02 | Chawla Brindra P S | Medicament inhaler |
IS1796B (is) | 1993-06-24 | 2001-12-31 | Ab Astra | Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband |
TW402506B (en) | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
US6632456B1 (en) | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
US5506203C1 (en) * | 1993-06-24 | 2001-02-06 | Astra Ab | Systemic administration of a therapeutic preparation |
US5747445A (en) | 1993-06-24 | 1998-05-05 | Astra Aktiebolag | Therapeutic preparation for inhalation |
US6794357B1 (en) | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
US5562909A (en) | 1993-07-12 | 1996-10-08 | Massachusetts Institute Of Technology | Phosphazene polyelectrolytes as immunoadjuvants |
GB9314614D0 (en) | 1993-07-14 | 1993-08-25 | Minnesota Mining & Mfg | Dry powder inhalers |
US5371046A (en) | 1993-07-22 | 1994-12-06 | Taiwan Semiconductor Manufacturing Company | Method to solve sog non-uniformity in the VLSI process |
JPH0741428A (ja) | 1993-07-30 | 1995-02-10 | Teijin Ltd | ペプチド、蛋白質性薬物経鼻・経肺製剤 |
US5306453A (en) | 1993-08-18 | 1994-04-26 | Edward Shulman | Apparatus and method of making a non-woven fabric |
JP3545764B2 (ja) | 1993-08-18 | 2004-07-21 | フアイソンズ・ピーエルシー | 吸息率制御器を備えた吸入装置 |
US5524613A (en) | 1993-08-25 | 1996-06-11 | Habley Medical Technology Corporation | Controlled multi-pharmaceutical inhaler |
BE1007551A3 (nl) | 1993-09-24 | 1995-08-01 | Philips Electronics Nv | Werkwijze voor het in een rekenmachine automatisch herstellen van consistentie in een hierarchische objektstruktuur na een interaktie door een gebruiker en rekenmachine voorzien van zo een systeem voor automatische consistentieherstelling. |
US5477285A (en) | 1993-10-06 | 1995-12-19 | Thomson Consumer Electronics, Inc. | CRT developing apparatus |
GB9322014D0 (en) | 1993-10-26 | 1993-12-15 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
US5726156A (en) | 1995-03-06 | 1998-03-10 | Trega Biosciences, Inc. | Cytokine regulatory agents and methods of use in pathologies and conditions associated with altered cytokine levels |
CA2176712C (en) | 1993-11-16 | 2000-05-23 | Mantripragada Sankaram | Synthetic membrane vesicles with controlled release of encapsulated biologically active substances |
EP0655237A1 (de) | 1993-11-27 | 1995-05-31 | Hoechst Aktiengesellschaft | Medizinische Aerosolformulierung |
USD358880S (en) | 1993-12-02 | 1995-05-30 | Tenax Corporation | Dry powder inhalator |
US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
DE4422710C1 (de) | 1994-06-29 | 1995-09-14 | Boehringer Ingelheim Kg | Inhalationsgerät mit einem Elektronikmodul zur Funktionsüberwachung |
DK0732952T3 (da) | 1993-12-18 | 2000-09-25 | Merck Patent Gmbh | Pulverinhalator |
USD357603S (en) | 1993-12-20 | 1995-04-25 | Wolff Stephen H | Base for displaying or holding items |
US5415162A (en) | 1994-01-18 | 1995-05-16 | Glaxo Inc. | Multi-dose dry powder inhalation device |
US5484606A (en) | 1994-01-24 | 1996-01-16 | The Procter & Gamble Company | Process for reducing the precipitation of difficulty soluble pharmaceutical actives |
PT101450B (pt) | 1994-02-02 | 1999-11-30 | Hovione Produtos Farmaceuticos | Novo dispositivo para inalacao |
AU680727B2 (en) | 1994-02-09 | 1997-08-07 | Kinerton Limited | Process for drying a material from solution |
SE9400462D0 (sv) | 1994-02-11 | 1994-02-11 | Astra Ab | Filling device |
MX9603936A (es) | 1994-03-07 | 1997-05-31 | Inhale Therapeutic Syst | Metodos y composiciones para el suministro pulmonar de insulina. |
US6051256A (en) * | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
US5505194A (en) | 1994-03-23 | 1996-04-09 | Abbott Laboratories | Aerosol inhalation device having slideably and rotatably connected elliptical cylinder portions |
AU124387S (en) | 1994-03-25 | 1995-08-11 | Astra Ab | Training device for an inhaler |
US5839429A (en) | 1994-03-25 | 1998-11-24 | Astra Aktiebolag | Method and apparatus in connection with an inhaler |
DE59500494D1 (de) * | 1994-04-15 | 1997-09-18 | Fissler Gmbh | Gar- und/oder Kochgerät, welches für eine bodenseitige Zuführung von Wärmeenergie durch Wärmeleitung oder durch elektromagnetische Induktion eingerichtet ist |
US6395744B1 (en) | 1994-04-22 | 2002-05-28 | Queen's University At Kingston | Method and compositions for the treatment or amelioration of female sexual dysfunction |
FI942196A (fi) | 1994-05-11 | 1995-11-12 | Orion Yhtymae Oy | Jauheinhalaattori |
AU696387B2 (en) * | 1994-05-18 | 1998-09-10 | Inhale Therapeutic Systems, Inc. | Methods and compositions for the dry powder formulation of interferons |
WO1995031979A1 (en) | 1994-05-19 | 1995-11-30 | R.P. Scherer International Corporation | Solutions of aryl or heteroaryl substituted alkanoic acids in lipophilic solvents and soft gelatin capsules containing such solutions |
JP3372105B2 (ja) | 1994-05-26 | 2003-01-27 | 株式会社日立ユニシアオートモティブ | 吸入式投薬器 |
FR2720943B1 (fr) * | 1994-06-09 | 1996-08-23 | Applic Transferts Technolo | Emulsions inverses stables à forte concentration en composé(s) fluoré(s) et leur utilisation pour l'administration pulmonaire de médicaments et pour la fabrication d'émulsions multiples. |
US5483954A (en) | 1994-06-10 | 1996-01-16 | Mecikalski; Mark B. | Inhaler and medicated package |
IL110024A (en) | 1994-06-15 | 1998-04-05 | Yissum Res Dev Co | Controlled release oral drug delivery system containing hydrogel- forming polymer |
USD363775S (en) | 1994-06-21 | 1995-10-31 | Rhone-Poulenc Rorer Limited | Multidose dry powder inhaler |
USD362500S (en) | 1994-06-28 | 1995-09-19 | Thayer Medical Corporation | Medication inhaler spacer |
US5641510A (en) | 1994-07-01 | 1997-06-24 | Genentech, Inc. | Method for treating capsules used for drug storage |
US6039208A (en) | 1994-07-29 | 2000-03-21 | Ortho Pharmaceutical Corporation | Variable day start tablet dispenser |
US5562231A (en) | 1994-07-29 | 1996-10-08 | Ortho Pharmaceutical Corporation | Variable day start tablet dispenser |
US5623724A (en) | 1994-08-09 | 1997-04-22 | Northrop Grumman Corporation | High power capacitor |
GB9416884D0 (en) | 1994-08-20 | 1994-10-12 | Danbiosyst Uk | Drug delivery compositions |
USD359153S (en) | 1994-08-25 | 1995-06-13 | Viggiano Bernard J | Muffin top |
US5574008A (en) | 1994-08-30 | 1996-11-12 | Eli Lilly And Company | Biologically active fragments of glucagon-like insulinotropic peptide |
US5547929A (en) * | 1994-09-12 | 1996-08-20 | Eli Lilly And Company | Insulin analog formulations |
WO1996009085A1 (en) | 1994-09-21 | 1996-03-28 | Inhale Therapeutic Systems | Apparatus and methods for dispersing dry powder medicaments |
FR2725626A1 (fr) | 1994-10-18 | 1996-04-19 | Sofab | Dispositif pour l'inhalation de produits en poudre |
WO1996013250A1 (en) * | 1994-10-27 | 1996-05-09 | Amgem Inc. | Compositions for increased bioavailability of orally delivered therapeutic agents |
SE9404140D0 (sv) | 1994-11-29 | 1994-11-29 | Astra Ab | Dose indicating device |
WO1996016947A1 (fr) * | 1994-12-01 | 1996-06-06 | Toyama Chemical Co., Ltd. | Nouveau derive de 2,3-dicetopiperazine ou sel de celui-ci |
SE9404439D0 (sv) | 1994-12-21 | 1994-12-21 | Astra Ab | Inhalation device |
AR002009A1 (es) | 1994-12-22 | 1998-01-07 | Astra Ab | Composicion farmaceutica, procedimiento para la manufactura de un polvo de proliposoma como el utilizado en dicha composicion, procedimiento para lamanufactura de dicha composicion, uso de dicha composicion farmaceutica en la manufactura de un medicamento y dispositivo inhalador de polvo seco. |
US6485726B1 (en) | 1995-01-17 | 2002-11-26 | The Brigham And Women's Hospital, Inc. | Receptor specific transepithelial transport of therapeutics |
NZ298384A (en) | 1995-01-23 | 1998-07-28 | Direct Haler As | Inhaler - single dose of particulate substance arranged in air flow passage |
USD368364S (en) | 1995-02-02 | 1996-04-02 | Reitano Joseph R | Inhaler case |
US5901703A (en) | 1995-02-06 | 1999-05-11 | Unisia Jecs Corporation | Medicine administering device for nasal cavities |
US5660835A (en) | 1995-02-24 | 1997-08-26 | East Carolina University | Method of treating adenosine depletion |
WO1996028367A2 (en) | 1995-03-10 | 1996-09-19 | Minnesota Mining And Manufacturing Company | Aerosol valves |
US5653961A (en) | 1995-03-31 | 1997-08-05 | Minnesota Mining And Manufacturing Company | Butixocort aerosol formulations in hydrofluorocarbon propellant |
US5542539A (en) | 1995-04-04 | 1996-08-06 | Ethicon Endo-Surgery, Inc. | Container for quick release packages for surgical instruments |
USD377215S (en) | 1995-04-13 | 1997-01-07 | Glaxo Group Limited | Inhaler |
US5990077A (en) | 1995-04-14 | 1999-11-23 | 1149336 Ontario Inc. | Glucagon-like peptide-2 and its therapeutic use |
US6309671B1 (en) | 1995-04-14 | 2001-10-30 | Inhale Therapeutic Systems | Stable glassy state powder formulations |
US5645051A (en) | 1995-04-21 | 1997-07-08 | Dura Pharmaceuticals, Inc. | Unit dose dry powder inhaler |
US5921237A (en) | 1995-04-24 | 1999-07-13 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US5622166A (en) | 1995-04-24 | 1997-04-22 | Dura Pharmaceuticals, Inc. | Dry powder inhaler delivery system |
US6428771B1 (en) | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
US5922253A (en) | 1995-05-18 | 1999-07-13 | Alkermes Controlled Therapeutics, Inc. | Production scale method of forming microparticles |
US5809997A (en) | 1995-05-18 | 1998-09-22 | Medtrac Technologies, Inc. | Electronic medication chronolog device |
US5924419A (en) | 1995-05-22 | 1999-07-20 | Kotliar; Igor K. | Apparatus for passive hypoxic training and therapy |
DE19519840A1 (de) | 1995-05-31 | 1996-12-05 | Kaewert Klaus | Gelantinekapsel |
US5714007A (en) | 1995-06-06 | 1998-02-03 | David Sarnoff Research Center, Inc. | Apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate |
AU128811S (en) | 1995-06-06 | 1996-12-03 | Orion Yhtymae Oy | A protective cover for example a moisture protective cover for a powder inhaler |
US5824345A (en) | 1995-06-07 | 1998-10-20 | Emisphere Technologies, Inc. | Fragrances and flavorants |
US5919897A (en) | 1995-06-07 | 1999-07-06 | Torrey Pines Institute For Molecular Studies | MU opioid receptor ligands: agonists and antagonists |
US5610271A (en) | 1995-06-07 | 1997-03-11 | Torrey Pines Institute For Molecular Studies | Kappa receptor selective opioid peptides |
US6193844B1 (en) | 1995-06-07 | 2001-02-27 | Mclaughlin John R. | Method for making paper using microparticles |
US5641861A (en) | 1995-06-07 | 1997-06-24 | Torrey Pines Institute For Molecular Studies | μopioid receptor ligands: agonists and antagonists |
US6672304B1 (en) | 1995-06-08 | 2004-01-06 | Innovative Devices, Llc | Inhalation actuated device for use with metered dose inhalers (MDIs) |
US6357442B1 (en) | 1995-06-08 | 2002-03-19 | Innovative Devices, Llc | Inhalation actuated device for use with metered dose inhalers (MDIS) |
ATE209518T1 (de) | 1995-06-21 | 2001-12-15 | Asta Medica Ag | Arzneipulverkartusche mit integrierter dosiereinrichtung, sowie pulverinhalator |
GB9513218D0 (en) | 1995-06-29 | 1995-09-06 | Fisons Plc | Inhalation device and method |
DE19523516C1 (de) | 1995-06-30 | 1996-10-31 | Asta Medica Ag | Inhalator zum Verabreichen von Medikamenten aus Blisterpackungen |
AU131838S (en) | 1995-07-01 | 1997-10-21 | Glaxo Group Ltd | Inhalation device |
JP3098401B2 (ja) | 1995-07-12 | 2000-10-16 | 株式会社エルティーティー研究所 | 経鼻投与用製剤 |
US5758638A (en) | 1995-07-24 | 1998-06-02 | Kreamer; Jeffry W. | Indicator for a medicament inhaler |
US5642727A (en) | 1995-07-25 | 1997-07-01 | David Sarnoff Research Center, Inc. | Inhaler apparatus using a tribo-electric charging technique |
WO1997004747A1 (en) | 1995-07-27 | 1997-02-13 | Dunn James M | Drug delivery systems for macromolecular drugs |
US6209538B1 (en) | 1995-08-02 | 2001-04-03 | Robert A. Casper | Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament |
SE9502800D0 (sv) | 1995-08-10 | 1995-08-10 | Astra Ab | Disposable inhaler |
SE9502799D0 (sv) | 1995-08-10 | 1995-08-10 | Astra Ab | Device in inhalers |
JP3317823B2 (ja) | 1995-08-11 | 2002-08-26 | 株式会社ユニシアジェックス | 投薬器 |
US5690910A (en) | 1995-08-18 | 1997-11-25 | Baker Norton Pharmaceuticals, Inc. | Method for treating asthma |
US5980865A (en) | 1995-08-18 | 1999-11-09 | Baker Norton Pharmaceuticals, Inc. | Method for treating late phase allergic reactions and inflammatory diseases |
US5746197A (en) | 1995-08-18 | 1998-05-05 | Williams; Jeffery W. | Extension for metered dose inhaler |
US6852690B1 (en) | 1995-08-22 | 2005-02-08 | Amylin Pharmaceuticals, Inc. | Method and composition for enhanced parenteral nutrition |
FR2738153B1 (fr) | 1995-09-04 | 1998-01-02 | Valois | Appareil d'inhalation destine a distribuer des doses precises et reproductibles de produit pulverulent |
US5617844A (en) | 1995-09-21 | 1997-04-08 | King; Russell W. | Aerosol medication delivery system |
KR0124764Y1 (ko) | 1995-09-23 | 1998-09-15 | 양주환 | 의약 및 식품용 하드 공 캅셀 |
SE9503344D0 (sv) | 1995-09-27 | 1995-09-27 | Astra Ab | Inhalation device |
US5849322A (en) | 1995-10-23 | 1998-12-15 | Theratech, Inc. | Compositions and methods for buccal delivery of pharmaceutical agents |
US5766620A (en) | 1995-10-23 | 1998-06-16 | Theratech, Inc. | Buccal delivery of glucagon-like insulinotropic peptides |
CA2236579C (en) | 1995-11-13 | 2009-06-30 | Minimed, Inc. | Methods and compositions for the delivery of monomeric proteins |
DE19545257A1 (de) | 1995-11-24 | 1997-06-19 | Schering Ag | Verfahren zur Herstellung von morphologisch einheitlichen Mikrokapseln sowie nach diesem Verfahren hergestellte Mikrokapseln |
US7131441B1 (en) | 1995-12-07 | 2006-11-07 | Skyepharma Ag | Inhaler for multiple dosed administration of a pharmacological dry powder |
DK0865302T3 (da) | 1995-12-07 | 2000-10-02 | Jago Pharma Ag | Inhalator til gentagen dosisvis afgivelse af farmakologisk tørpulver |
CZ212598A3 (cs) | 1996-01-03 | 1998-11-11 | Glaxo Group Limited | Inhalační zařízení |
US6026809A (en) | 1996-01-25 | 2000-02-22 | Microdose Technologies, Inc. | Inhalation device |
US6470884B2 (en) | 1996-01-29 | 2002-10-29 | Aventis Pharma Limited | Capsule opening arrangement for use in a powder inhaler |
JPH09208485A (ja) | 1996-01-31 | 1997-08-12 | Teijin Ltd | ペプチド・蛋白質性薬物の水難溶性組成物 |
EP0880562B1 (en) | 1996-02-06 | 2000-12-06 | E.I. Du Pont De Nemours And Company | Treatment of deagglomerated particles with plasma-activated species |
USD381416S (en) | 1996-02-08 | 1997-07-22 | Astra Aktiebolag | Unit dose inhaler |
USD377861S (en) | 1996-02-21 | 1997-02-11 | Medport, Inc. | Inhaler carrying case |
JP3830972B2 (ja) | 1996-02-21 | 2006-10-11 | シェーリング コーポレイション | 粉体薬剤吸入器 |
DK0943326T4 (da) | 1996-02-27 | 2007-01-22 | Teijin Ltd | Pulveragtigt præparat til nasal administration |
US6509313B1 (en) | 1996-02-28 | 2003-01-21 | Cornell Research Foundation, Inc. | Stimulation of immune response with low doses of cytokines |
US5699789A (en) | 1996-03-11 | 1997-12-23 | Hendricks; Mark R. | Dry powder inhaler |
JP3328132B2 (ja) | 1996-03-21 | 2002-09-24 | 株式会社ユニシアジェックス | 吸入式投薬器 |
GB9606188D0 (en) | 1996-03-23 | 1996-05-29 | Danbiosyst Uk | Pollysaccharide microspheres for the pulmonary delivery of drugs |
USD395499S (en) | 1996-04-08 | 1998-06-23 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US5858099A (en) | 1996-04-09 | 1999-01-12 | Sarnoff Corporation | Electrostatic chucks and a particle deposition apparatus therefor |
US5875776A (en) | 1996-04-09 | 1999-03-02 | Vivorx Pharmaceuticals, Inc. | Dry powder inhaler |
AU724503B2 (en) | 1996-04-29 | 2000-09-21 | Dura Pharmaceuticals, Inc. | Methods of dry powder inhalation |
US5817343A (en) | 1996-05-14 | 1998-10-06 | Alkermes, Inc. | Method for fabricating polymer-based controlled-release devices |
AU132977S (en) | 1996-05-17 | 1998-02-17 | Astrazeneca Ab | Container for inhaling apparatus |
USRE37053E1 (en) | 1996-05-24 | 2001-02-13 | Massachusetts Institute Of Technology | Particles incorporating surfactants for pulmonary drug delivery |
US6503480B1 (en) | 1997-05-23 | 2003-01-07 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
US5985309A (en) | 1996-05-24 | 1999-11-16 | Massachusetts Institute Of Technology | Preparation of particles for inhalation |
US6254854B1 (en) | 1996-05-24 | 2001-07-03 | The Penn Research Foundation | Porous particles for deep lung delivery |
US5874064A (en) | 1996-05-24 | 1999-02-23 | Massachusetts Institute Of Technology | Aerodynamically light particles for pulmonary drug delivery |
JPH1053765A (ja) | 1996-06-04 | 1998-02-24 | Denso Corp | スメクチック液晶組成物及び液晶セル |
JP2000512280A (ja) | 1996-06-05 | 2000-09-19 | ラポポート,バジル | ヒト甲状腺刺激ホルモンレセプター組成物およびその使用 |
US5871010A (en) | 1996-06-10 | 1999-02-16 | Sarnoff Corporation | Inhaler apparatus with modified surfaces for enhanced release of dry powders |
AUPO066096A0 (en) | 1996-06-26 | 1996-07-18 | Peptide Delivery Systems Pty Ltd | Oral delivery of peptides |
US5769276A (en) | 1996-07-10 | 1998-06-23 | Terronics Development Corporation | Powder atomizer |
US5783556A (en) | 1996-08-13 | 1998-07-21 | Genentech, Inc. | Formulated insulin-containing composition |
AU133903S (en) | 1996-08-19 | 1998-05-29 | Orion Yhtymae Oy | Inhaler device |
US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
JP3890099B2 (ja) | 1996-09-30 | 2007-03-07 | キヤノン株式会社 | パターン認識装置及びその方法、及びそのプログラムを記憶した記憶媒体 |
JP3020141B2 (ja) | 1996-10-07 | 2000-03-15 | 株式会社富士薬品 | 経鼻投与用製剤 |
US6532437B1 (en) | 1996-10-23 | 2003-03-11 | Cornell Research Foundation, Inc. | Crystalline frap complex |
UA65549C2 (uk) | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
US6441172B1 (en) | 1996-11-07 | 2002-08-27 | Torrey Pines Institute For Molecular Studies | Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof |
DE69732572T2 (de) | 1996-11-12 | 2005-12-29 | Novo Nordisk A/S | Verwendung von glp-1 peptiden |
DE19647947A1 (de) | 1996-11-20 | 1998-05-28 | Pfeiffer Erich Gmbh & Co Kg | Austragvorrichtung für Medien |
US5868774A (en) | 1996-11-21 | 1999-02-09 | Reil; Vladimir | Unique cartridge and earring stud gun system |
US6159360A (en) | 1996-11-22 | 2000-12-12 | Heinkel Industriezentrifugen Gmbh & Co. | Invertible filter centrifuge including a solids drier |
PT948410E (pt) | 1996-12-11 | 2002-09-30 | Earth Sciences Ltd | Metodos e aparelhos para a tilizacao no tratamento de cinzas |
USD390651S (en) | 1996-12-12 | 1998-02-10 | Inhale Therapeutics Systems | Medicament inhaler housing |
GB9626233D0 (en) | 1996-12-18 | 1997-02-05 | Chawla Brinda P S | Medicament packaging and deliveery device |
GB9626263D0 (en) | 1996-12-18 | 1997-02-05 | Innovata Biomed Ltd | Powder inhaler |
GB2320489A (en) | 1996-12-20 | 1998-06-24 | Norton Healthcare Ltd | Inhaler dose counter |
JP2001507702A (ja) * | 1996-12-31 | 2001-06-12 | インヘイル・セラピューティックス・システムズ・インコーポレテッド | 親水性賦形剤を有する疎水性薬剤の水性懸濁液を噴霧乾燥させる方法およびその方法によって作製された組成物 |
USD397435S (en) | 1997-01-03 | 1998-08-25 | GGU Gesellschaft fuer Gesundheits-und Umweltforschung mbH | Combined inhaler and cover |
US5794613A (en) | 1997-01-09 | 1998-08-18 | Sepracor, Inc. | Multiple-dose dispenser for dry powder inhalers |
USD389238S (en) | 1997-01-24 | 1998-01-13 | Healthscan Products, Inc. | Inhaler mask |
EP0898978B1 (en) | 1997-01-30 | 2005-03-02 | Unisia Jecs Corporation | Suction type medicator |
US6884435B1 (en) * | 1997-01-30 | 2005-04-26 | Chiron Corporation | Microparticles with adsorbent surfaces, methods of making same, and uses thereof |
SE9700422D0 (sv) | 1997-02-07 | 1997-02-07 | Astra Ab | Single dose inhaler II |
SE9700423D0 (sv) | 1997-02-07 | 1997-02-07 | Astra Ab | Disposable inhaler |
SE9700424D0 (sv) | 1997-02-07 | 1997-02-07 | Astra Ab | Powder inhaler |
SE9700421D0 (sv) | 1997-02-07 | 1997-02-07 | Astra Ab | Single dose inhaler I |
JP3011898B2 (ja) | 1997-02-20 | 2000-02-21 | フォルテ グロウ メディカル株式会社 | 吸引器 |
DE19708406A1 (de) | 1997-03-03 | 1998-09-10 | Alfred Von Schuckmann | Gerät zur dosierten Ausgabe von Substanzen |
USD390653S (en) | 1997-03-04 | 1998-02-10 | Blasdell Richard J | Inhaler |
SE9700940D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhaler IV |
SE9700937D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhaler I |
SE9700935D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Inhalation device |
SE9700948D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhaler X |
SE9700936D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Inhalation device |
TW469832U (en) | 1997-03-14 | 2001-12-21 | Astra Ab | Inhalation device |
SE9700938D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhaler II and a method of construction thereof |
SE9700943D0 (sv) | 1997-03-14 | 1997-03-14 | Astra Ab | Powder inhaler V |
US6043214A (en) * | 1997-03-20 | 2000-03-28 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
US6006747A (en) | 1997-03-20 | 1999-12-28 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
US8391104B2 (en) | 1997-03-28 | 2013-03-05 | Carlos De La Huerga | Interactive medication container labeling |
US5904139A (en) | 1997-03-28 | 1999-05-18 | Hauser; Stephen G. | Breath coordinated inhaler |
US5981488A (en) | 1997-03-31 | 1999-11-09 | Eli Lillly And Company | Glucagon-like peptide-1 analogs |
PT1015352E (pt) | 1997-04-01 | 2007-09-24 | Cima Labs Inc | ''embalagem alveolar e comprimidos embalados'' |
EP0975328A1 (en) | 1997-04-02 | 2000-02-02 | Purdue Research Foundation | Method for oral delivery of proteins |
PT101988B (pt) | 1997-04-04 | 2004-02-27 | Hovione Farmaciencia Sa | Sistema de orientacao e posicionamento de um objecto |
USD410541S (en) | 1997-06-30 | 1999-06-01 | Novartis Ag | Inhaler |
SE9702796D0 (sv) | 1997-07-25 | 1997-07-25 | Pharmacia & Upjohn Ab | A device at a pharmaceutical container or inhaler |
CA2212430A1 (en) | 1997-08-07 | 1999-02-07 | George Volgyesi | Inhalation device |
GB2327895B (en) | 1997-08-08 | 2001-08-08 | Electrosols Ltd | A dispensing device |
US5855564A (en) | 1997-08-20 | 1999-01-05 | Aradigm Corporation | Aerosol extrusion mechanism |
US5846447A (en) | 1997-08-26 | 1998-12-08 | E. I. Du Pont De Nemours And Company | Process for forming a dispersion of polytetrafluoroethylene |
USD416085S (en) | 1997-09-05 | 1999-11-02 | Pharmacia & Upjohn | Inhaler |
USD417271S (en) | 1997-09-10 | 1999-11-30 | Medic-Aid Limited | Drug delivery device |
EP1012188B1 (de) | 1997-09-12 | 2004-08-18 | Pharis Biotec GmbH | Zusammensetzung zur therapie von diabetes mellitus und fettsucht |
US5848589A (en) | 1997-09-18 | 1998-12-15 | Welnetz; Robert J. | Altitude mask simulator |
AU135340S (en) | 1997-09-24 | 1998-10-12 | Innovata Biomed Ltd | An inhaler |
US6073629A (en) | 1997-09-25 | 2000-06-13 | Norton Healthcare Ltd. | Inhaler spacer |
US6394085B1 (en) | 1997-09-25 | 2002-05-28 | Norton Healthcare Ltd. | Inhaler spacer |
USD463544S1 (en) | 1997-09-26 | 2002-09-24 | 1263152 Ontario Inc. | Aerosol medication delivery inhaler |
US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
EP1029536B1 (en) | 1997-10-01 | 2007-11-28 | Novadel Pharma Inc. | Buccal non-polar spray |
US6228394B1 (en) | 1997-10-14 | 2001-05-08 | Boehringer Ingelheim Pharmaceuticals, Inc. | Supercritical fluid extraction of mould lubricant from hard shell capsules |
US5954047A (en) | 1997-10-17 | 1999-09-21 | Systemic Pulmonary Development, Ltd. | Methods and apparatus for delivering aerosolized medication |
USD398992S (en) | 1997-10-21 | 1998-09-29 | Schering-Plough Healthcare Products, Inc. | Nasal inhaler |
ZA989744B (en) | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
IN188720B (zh) | 1997-11-06 | 2002-11-02 | Panacea Biotec Ltd | |
AU135120S (en) | 1997-11-14 | 1998-09-21 | Astrazeneca Ab | Inhaler |
SE9704184D0 (sv) | 1997-11-14 | 1997-11-14 | Astra Ab | Inhalation device |
USD412978S (en) | 1997-12-02 | 1999-08-17 | Dura Pharmaceuticals, Inc. | Inhaler |
US6116238A (en) | 1997-12-02 | 2000-09-12 | Dura Pharmaceuticals, Inc. | Dry powder inhaler |
USD418600S (en) | 1997-12-04 | 2000-01-04 | Charmaine Haerle | Inhaler clip |
EP1049486A4 (en) | 1997-12-05 | 2006-01-04 | Lilly Co Eli | GLP-1 FORMULATIONS |
US6192876B1 (en) | 1997-12-12 | 2001-02-27 | Astra Aktiebolag | Inhalation apparatus and method |
US6380357B2 (en) | 1997-12-16 | 2002-04-30 | Eli Lilly And Company | Glucagon-like peptide-1 crystals |
US5965701A (en) | 1997-12-23 | 1999-10-12 | Ferring Bv | Kappa receptor opioid peptides |
US6077940A (en) | 1997-12-24 | 2000-06-20 | Genentech, Inc. | Free solution ligand interaction molecular separation method |
US6358058B1 (en) | 1998-01-30 | 2002-03-19 | 1263152 Ontario Inc. | Aerosol dispensing inhaler training device |
JP3530004B2 (ja) | 1998-02-06 | 2004-05-24 | 株式会社日立ユニシアオートモティブ | 吸入式投薬器 |
US6158431A (en) | 1998-02-13 | 2000-12-12 | Tsi Incorporated | Portable systems and methods for delivery of therapeutic material to the pulmonary system |
USD421800S (en) | 1998-02-19 | 2000-03-21 | Pierre Fabre Medicament | Powder and compressed-air inhaler |
USD412979S (en) | 1998-02-27 | 1999-08-17 | Diemolding Corporation | Metered dose inhaler spacer |
US7143764B1 (en) | 1998-03-13 | 2006-12-05 | Astrazeneca Ab | Inhalation device |
AP1342A (en) | 1998-03-16 | 2004-12-15 | Nektar Therapeutics | Aerosolized active agent delivery. |
US6998387B1 (en) | 1998-03-19 | 2006-02-14 | Amylin Pharmaceuticals, Inc. | Human appetite control by glucagon-like peptide receptor binding compounds |
SE9801078D0 (sv) | 1998-03-27 | 1998-03-27 | Shl Medical Ab | Inhalator |
AU138849S (en) | 1998-03-30 | 1999-11-22 | Astra Ab | Inhaler with cap |
AU138848S (en) | 1998-03-30 | 1999-11-22 | Astra Ab | Inhaler with cap |
AU138847S (en) | 1998-03-30 | 1999-11-22 | Astra Ab | Inhaler with cap |
CN1304290A (zh) | 1998-04-08 | 2001-07-18 | 伊莱利利公司 | 雷洛昔芬的肺和鼻传递给药 |
HUP0101912A2 (hu) | 1998-04-09 | 2001-10-28 | Axiva Gmbh | Különleges hatóanyag-hordozó tüdőben való alkalmazáshoz |
FR2777283B1 (fr) | 1998-04-10 | 2000-11-24 | Adir | Nouveaux composes peptidiques analogues du glucagon-peptide- 1 (7-37), leur procede de preparation et les compositions pharmaceutiques qui les contiennent |
US6578571B1 (en) | 1998-04-20 | 2003-06-17 | Infamed Ltd. | Drug delivery device and methods therefor |
GB9810126D0 (zh) | 1998-05-13 | 1998-07-08 | Glaxo Group Ltd | |
US6257233B1 (en) | 1998-06-04 | 2001-07-10 | Inhale Therapeutic Systems | Dry powder dispersing apparatus and methods for their use |
SE9802080D0 (sv) | 1998-06-11 | 1998-06-11 | Hellstroem | Pharmaceutical composition for the treatment of functional dyspepsia and/or irritable bowel syndrome and new use of substances therein |
AU758825B2 (en) | 1998-06-12 | 2003-04-03 | Amylin Pharmaceuticals, Inc. | Glucagon-like peptide-1 improves beta-cell response to glucose in subjects with impaired glucose tolerance |
US6152130A (en) | 1998-06-12 | 2000-11-28 | Microdose Technologies, Inc. | Inhalation device with acoustic control |
USD412572S (en) | 1998-06-19 | 1999-08-03 | Gray Gene W | Nasal inhaler adaptor for left and right nostril |
JP4225692B2 (ja) | 1998-06-22 | 2009-02-18 | アストラゼネカ・アクチエボラーグ | 粉末含有キャビティを吸入により空にするための装置 |
WO2000001351A1 (en) * | 1998-07-07 | 2000-01-13 | Transdermal Technologies, Inc. | Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof |
DE19831525A1 (de) | 1998-07-14 | 2000-01-20 | Pfeiffer Erich Gmbh & Co Kg | Spender für Medien |
US6703381B1 (en) | 1998-08-14 | 2004-03-09 | Nobex Corporation | Methods for delivery therapeutic compounds across the blood-brain barrier |
US6087334A (en) | 1998-08-21 | 2000-07-11 | Amylin Pharmaceuticals, Inc. | Anti-diabetic peptides |
ES2263282T3 (es) | 1998-08-26 | 2006-12-01 | Teijin Limited | Composiciones en polvo para administracion nasal. |
US6720407B1 (en) | 1998-08-28 | 2004-04-13 | Eli Lilly And Company | Method for administering insulinotropic peptides |
HUP0103369A3 (en) | 1998-08-28 | 2002-03-28 | Lilly Co Eli | Use of insulinotropic peptides |
KR20010075308A (ko) | 1998-09-24 | 2001-08-09 | 추후제출 | 흡입기 |
US20020088458A1 (en) | 1998-09-24 | 2002-07-11 | Astrazeneca Ab | Inhaler |
GB9820937D0 (en) | 1998-09-26 | 1998-11-18 | Glaxo Group Ltd | Inhalation device |
GB9820886D0 (en) | 1998-09-26 | 1998-11-18 | Glaxo Group Ltd | Inhalation device |
US6187291B1 (en) | 1998-09-28 | 2001-02-13 | Robert Weinstein | Method and device for facilitating combined aerosol and oral treatments for diabetes mellitus |
USD411005S (en) | 1998-09-29 | 1999-06-15 | Pharmadesign Inc. | Arthritic aid for metered dose inhaler |
UA73924C2 (en) | 1998-10-09 | 2005-10-17 | Nektar Therapeutics | Device for delivering active agent formulation to lungs of human patient |
US6279511B1 (en) | 1998-10-23 | 2001-08-28 | Instech Laboratories, Inc. | Powered multichannel infusion and monitoring system |
US6263871B1 (en) | 1998-10-29 | 2001-07-24 | Richard I. Brown | Mouthpiece with coupler |
US6235725B1 (en) | 1998-10-30 | 2001-05-22 | Baker Norton Pharmaceuticals, Inc. | Methods and compositions for the prevention of tolerance to medications |
JP3747134B2 (ja) | 1998-11-04 | 2006-02-22 | キヤノン株式会社 | インクジェット記録ヘッドカートリッジの保管容器 |
US6261594B1 (en) | 1998-11-25 | 2001-07-17 | The University Of Akron | Chitosan-based nitric oxide donor compositions |
US6540672B1 (en) | 1998-12-09 | 2003-04-01 | Novo Nordisk A/S | Medical system and a method of controlling the system for use by a patient for medical self treatment |
GB9827145D0 (en) | 1998-12-09 | 1999-02-03 | Co Ordinated Drug Dev | Improvements in or relating to powders |
US6375975B1 (en) | 1998-12-21 | 2002-04-23 | Generex Pharmaceuticals Incorporated | Pharmaceutical compositions for buccal and pulmonary application |
US6552024B1 (en) | 1999-01-21 | 2003-04-22 | Lavipharm Laboratories Inc. | Compositions and methods for mucosal delivery |
SE9900215D0 (sv) | 1999-01-26 | 1999-01-26 | Pharmacia & Upjohn Ab | New use |
JP2000217917A (ja) | 1999-01-27 | 2000-08-08 | Unisia Jecs Corp | 吸入式投薬器 |
US6248363B1 (en) | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
SK286981B6 (sk) | 1999-03-05 | 2009-08-06 | Chiesi Farmaceutici S.P.A. | Prášok na použitie v inhalátore na suché prášky, nosič na tento prášok a spôsob výroby prášku |
IT1309592B1 (it) | 1999-03-05 | 2002-01-24 | Chiesi Farma Spa | Particelle veicolo modificate da utilizzarsi nella preparazione diformulazioni farmaceutiche sotto forma di polimeri per inalazione e |
US6632258B1 (en) | 1999-03-16 | 2003-10-14 | The United States Of America As Represented By The United States Department Of Energy | Coal beneficiation by gas agglomeration |
US6803044B1 (en) | 1999-03-24 | 2004-10-12 | Zengen, Inc. | Antimicrobial and anti-inflammatory peptides for use in human immunodeficiency virus |
US6630169B1 (en) | 1999-03-31 | 2003-10-07 | Nektar Therapeutics | Particulate delivery systems and methods of use |
US6440463B1 (en) | 1999-04-05 | 2002-08-27 | Pharmaceutical Discovery Corporation | Methods for fine powder formation |
USD441859S1 (en) | 1999-04-06 | 2001-05-08 | Istituto Biochimico Pavese Pharma S.P.A. | Disposable dry-powder inhaler |
WO2000068160A1 (en) | 1999-05-07 | 2000-11-16 | Imerys Pigments, Inc. | A method of treating an aqueous suspension of kaolin |
US6417920B1 (en) | 1999-05-11 | 2002-07-09 | Shimadzu Corporation | Particle size analyzer based on laser diffraction method |
US6514500B1 (en) | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
GB9911388D0 (en) | 1999-05-18 | 1999-07-14 | Glaxo Group Ltd | Dispenser |
CA2373239A1 (en) | 1999-05-20 | 2000-11-30 | Pharmasol Gmbh | Stability, biocompatibility optimized adjuvant (sba) for enhancing humoral and cellular immune response |
DE19924277A1 (de) | 1999-05-27 | 2000-11-30 | Beiersdorf Ag | Zubereitungen von Emulsionstyp W/O mit erhöhtem Wassergehalt mit einem Gehalt an mittelpolaren Lipiden und Siliconemulgatoren und gegebenenfalls kationischen Polymeren |
US7919119B2 (en) * | 1999-05-27 | 2011-04-05 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
US6395300B1 (en) * | 1999-05-27 | 2002-05-28 | Acusphere, Inc. | Porous drug matrices and methods of manufacture thereof |
DE69910987T2 (de) * | 1999-06-14 | 2004-05-19 | Baxter International Inc., Deerfield | Mikrosphären mit verzögerter Wirkstoffabgabe |
US6644315B2 (en) | 1999-06-18 | 2003-11-11 | Saeed Ziaee | Nasal mask |
SE516826C2 (sv) | 1999-06-18 | 2002-03-05 | Shl Medical Ab | Anordning i en inhalator med organ för aktivering och avaktivering av en kanister som svar på ett luftflöde |
US7169889B1 (en) | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
WO2000078333A2 (en) | 1999-06-21 | 2000-12-28 | Eli Lilly And Company | Synergetic use of thiazolidinediones with glucagon-like peptide-1 and agonists thereof to treat non-insulin dependant diabetes |
US6858199B1 (en) | 2000-06-09 | 2005-02-22 | Advanced Inhalation Research, Inc. | High efficient delivery of a large therapeutic mass aerosol |
GB2353222B (en) | 1999-06-23 | 2001-09-19 | Cambridge Consultants | Inhalers |
USD444226S1 (en) | 1999-06-24 | 2001-06-26 | Novo Nordisk A/S | Inhaler |
AU779986B2 (en) | 1999-06-29 | 2005-02-24 | Mannkind Corporation | Purification and stabilization of peptide and protein pharmaceutical agents |
US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
US6606992B1 (en) | 1999-06-30 | 2003-08-19 | Nektar Therapeutics | Systems and methods for aerosolizing pharmaceutical formulations |
ITMI991582A1 (it) | 1999-07-16 | 2001-01-16 | Chiesi Farma Spa | Polveri costituite da particelle aventi la superficie perfettamente levigata da utilizzare come veicoli per la preparazione di miscele inala |
JP2003520777A (ja) | 1999-07-22 | 2003-07-08 | アベンティス・ファーマスーティカルズ・インコーポレイテツド | 防腐医薬製剤 |
US7305986B1 (en) | 1999-07-23 | 2007-12-11 | Mannkind Corporation | Unit dose capsules for use in a dry powder inhaler |
WO2001007107A2 (en) | 1999-07-23 | 2001-02-01 | Pharmaceutical Discovery Corporation | Unit dose capsules and dry powder inhaler |
US7464706B2 (en) | 1999-07-23 | 2008-12-16 | Mannkind Corporation | Unit dose cartridge and dry powder inhaler |
US20010036481A1 (en) | 1999-08-25 | 2001-11-01 | Advanced Inhalation Research, Inc. | Modulation of release from dry powder formulations |
CN1175961C (zh) | 1999-09-17 | 2004-11-17 | 株式会社新王磁材 | 稀土合金的切割方法和切割装置 |
USD438612S1 (en) | 1999-09-27 | 2001-03-06 | G-Intek Co., Ltd. | Snivel inhaler |
EP1220700B1 (de) | 1999-10-06 | 2003-04-09 | Eckardt, Angela | Atemzugskontrolliertes Inhalationsgerät für Trockenpulver |
ATE313318T1 (de) | 1999-10-29 | 2006-01-15 | Nektar Therapeutics | Trockenpulverzusammensetzungen mit verbesserter dispersität |
SE9903990D0 (sv) | 1999-11-02 | 1999-11-02 | Shl Medical Ab | Inhalator with aerosolizing unit |
GB9928311D0 (en) | 1999-11-30 | 2000-01-26 | Novartis Ag | Organic compounds |
IT1308581B1 (it) | 1999-12-03 | 2002-01-08 | Medel Italiana Srl | Apparato per nebulizzare un liquido, in particolare per uso medico. |
SE9904706D0 (sv) | 1999-12-21 | 1999-12-21 | Astra Ab | An inhalation device |
AR026914A1 (es) | 1999-12-11 | 2003-03-05 | Glaxo Group Ltd | Distribuidor de medicamento |
US7022674B2 (en) | 1999-12-16 | 2006-04-04 | Eli Lilly And Company | Polypeptide compositions with improved stability |
US7204250B1 (en) | 1999-12-16 | 2007-04-17 | Compumedics Limited | Bio-mask |
DE19961300A1 (de) | 1999-12-18 | 2001-06-21 | Asta Medica Ag | Vorratssystem für Arzneimittel in Pulverform und damit ausgestatteter Inhalator |
WO2001045731A1 (en) | 1999-12-21 | 2001-06-28 | Rxkinetix, Inc. | Particulate drug-containing products and method of manufacture |
US7080642B2 (en) | 1999-12-22 | 2006-07-25 | 3M Innovative Properties Company | Refillable device with counting means |
CN100333790C (zh) * | 1999-12-30 | 2007-08-29 | 希龙公司 | 含白细胞介素-2的药物组合物在制药中的应用 |
AU2353701A (en) | 2000-01-11 | 2001-07-24 | Novo Nordisk A/S | Transepithelial delivery of glp-1 derivatives |
US6894026B1 (en) | 2000-01-11 | 2005-05-17 | Atossa Healthcare, Inc. | Long-acting oxytocin analogues for the treatment and prevention of breast cancer and psychiatric disorders |
ES2258072T3 (es) | 2000-01-19 | 2006-08-16 | Mannkind Corporation | Preparacion de liberacion en varias etapas para la administracion de medicamentos. |
AU2001231000A1 (en) | 2000-01-19 | 2001-07-31 | Pharmaceutical Discovery Corporation | Dry powder formulations of antihistamine for nasal administration |
US6443307B1 (en) | 2000-01-25 | 2002-09-03 | Michael D. Burridge | Medication dispenser with an internal ejector |
US6540982B1 (en) | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
US6540983B1 (en) | 2000-01-25 | 2003-04-01 | Aeropharm Technology Incorporated | Medical aerosol formulation |
US7598222B2 (en) | 2000-01-27 | 2009-10-06 | Eli Lilly And Company | Process for solubilizing glucagon-like peptide 1 compounds |
US7171965B2 (en) | 2000-02-01 | 2007-02-06 | Valois S.A.S. | Breath actuated dry powder inhaler and tape dose strip |
US6427688B1 (en) | 2000-02-01 | 2002-08-06 | Dura Pharmaceuticals, Icn. | Dry powder inhaler |
USD439325S1 (en) | 2000-02-08 | 2001-03-20 | Baker Norton Pharmaceuticals, Inc. | Cover for a nasal inhaler |
EP1129705A1 (en) | 2000-02-17 | 2001-09-05 | Rijksuniversiteit te Groningen | Powder formulation for inhalation |
GB0004456D0 (en) | 2000-02-26 | 2000-04-19 | Glaxo Group Ltd | Medicament dispenser |
AU2001234005B2 (en) | 2000-02-28 | 2006-01-19 | Pharmakodex Limited | Improvements in or relating to the delivery of oral drugs |
USD439656S1 (en) | 2000-03-06 | 2001-03-27 | Astrazeneca Uk Limited | Inhaler |
US6443151B1 (en) | 2000-03-08 | 2002-09-03 | Aradigm Corporation | Fluid velocity-sensitive trigger mechanism |
AU3110201A (en) | 2000-03-10 | 2001-09-24 | Univ North Carolina | Dry powder inhaler devices, multi-dose dry powder drug packages, control systems, and associated methods |
US6608038B2 (en) | 2000-03-15 | 2003-08-19 | Novartis Ag | Methods and compositions for treatment of diabetes and related conditions via gene therapy |
US6823863B2 (en) | 2000-03-18 | 2004-11-30 | Astrazeneca Ab | Inhaler |
GB2360216A (en) | 2000-03-18 | 2001-09-19 | Astrazeneca Uk Ltd | Inhaler |
GB0006525D0 (en) | 2000-03-18 | 2000-05-10 | Astrazeneca Uk Ltd | Inhaler |
GB2360218A (en) | 2000-03-18 | 2001-09-19 | Astrazeneca Uk Ltd | Inhaler |
SE0000935D0 (sv) | 2000-03-21 | 2000-03-21 | Astrazeneca Ab | An inhalation device |
AU145610S (en) | 2000-03-24 | 2001-10-18 | Astrazeneca U K Ltd | Inhaler |
US6432383B1 (en) | 2000-03-30 | 2002-08-13 | Generex Pharmaceuticals Incorporated | Method for administering insulin |
EP1267718A2 (en) | 2000-04-03 | 2003-01-02 | IEP Pharmaceutical Devices, Inc. | Method for measuring changes in the airways of humans and other mammals |
US6998137B2 (en) | 2000-04-07 | 2006-02-14 | Macromed, Inc. | Proteins deposited onto sparingly soluble biocompatible particles for controlled protein release into a biological environment from a polymer matrix |
CA2733850C (en) | 2000-04-11 | 2013-10-22 | Trudell Medical International | Aerosol delivery apparatus with positive expiratory pressure capacity |
DE10019879A1 (de) | 2000-04-20 | 2001-10-25 | Degussa | Verfahren zur Herstellung von 2,5-Diketopiperazinen, neue 2,5-Diketopiperazine und deren Verwendung |
MY136453A (en) | 2000-04-27 | 2008-10-31 | Philip Morris Usa Inc | "improved method and apparatus for generating an aerosol" |
US6468507B1 (en) | 2000-05-01 | 2002-10-22 | Aeropharm Technology, Inc. | Non-aqueous aerosol formulation comprising rosiglitazone maleate, a non-aqueous carrier, and an amino acid stabilizer |
US6447750B1 (en) | 2000-05-01 | 2002-09-10 | Aeropharm Technology Incorporated | Medicinal aerosol formulation |
USD442685S1 (en) | 2000-05-02 | 2001-05-22 | Salter Labs | Medication inhaler spacer |
US20010039442A1 (en) | 2000-05-06 | 2001-11-08 | Sal Gorge | Headache relief device |
US6948494B1 (en) | 2000-05-10 | 2005-09-27 | Innovative Devices, Llc. | Medicament container with same side airflow inlet and outlet and method of use |
US20020000225A1 (en) | 2000-06-02 | 2002-01-03 | Carlos Schuler | Lockout mechanism for aerosol drug delivery devices |
CN1141974C (zh) | 2000-06-07 | 2004-03-17 | 张昊 | 结肠定位释放的口服生物制剂 |
DE60124710T2 (de) | 2000-06-16 | 2007-09-13 | Eli Lilly And Co., Indianapolis | Analoge des glucagon ähnlichen peptid-1 |
RU2181297C2 (ru) | 2000-06-20 | 2002-04-20 | Эпштейн Олег Ильич | Способ лечения патологического синдрома и лекарственное средство |
GB0015043D0 (en) | 2000-06-21 | 2000-08-09 | Glaxo Group Ltd | Medicament dispenser |
GB0015034D0 (en) | 2000-06-21 | 2000-08-09 | Glaxo Group Ltd | Inhalation device |
TWI224511B (en) | 2000-06-23 | 2004-12-01 | Norton Healthcare Ltd | De-agglomerator for breath-actuated dry powder inhaler |
US6562807B2 (en) | 2000-06-23 | 2003-05-13 | Novo Nordisk A/S | Glucagon antagonists/inverse agonists |
TWI224513B (en) | 2000-06-23 | 2004-12-01 | Norton Healthcare Ltd | Dose counter for medicament inhaler |
PE20020066A1 (es) | 2000-06-23 | 2002-02-23 | Norton Healthcare Ltd | Deposito de dosis medidas previamente para inhalador de polvo seco accionado por la respiracion |
USD450117S1 (en) | 2000-06-29 | 2001-11-06 | Innovata Biomed Limited | Inhaler |
USD452910S1 (en) | 2000-06-29 | 2002-01-08 | Innovata Biomend Limited | Inhaler |
MXPA02012272A (es) | 2000-07-04 | 2003-04-25 | Novo Nordisk As | Compuestos heterociclicos que son inhibidores de la enzima dipeptidilpeptidasa-iv. |
US6363932B1 (en) | 2000-07-06 | 2002-04-02 | Clinical Technologies, Inc. | Aerosol enhancement device |
US6951215B1 (en) | 2000-07-14 | 2005-10-04 | Tufts University | Drug delivery device for animals |
US6360929B1 (en) | 2000-07-17 | 2002-03-26 | Mccarthy Madeleine | Medicinal atomizing inhaler pouch/retainer |
GB2364919A (en) | 2000-07-21 | 2002-02-13 | Cambridge Consultants | Inhalers |
US6967202B2 (en) | 2000-08-04 | 2005-11-22 | Dmi Biosciences, Inc. | Method of synthesizing diketopiperazines |
CA2774959C (en) * | 2000-08-04 | 2016-05-31 | Dmi Biosciences, Inc. | Method of using diketopiperazines and composition containing them |
SE0002822L (sv) | 2000-08-04 | 2002-01-29 | Microdrug Ag | Elektropulver |
AR032361A1 (es) | 2000-08-05 | 2003-11-05 | Glaxo Group Ltd | Derivados de androstano y sales y solvatos de los mismos, su uso para la fabricacion de medicamentos, composiciones farmaceuticas que comprenden tales compuestos, proceso para la preparacion de dichos compuestos, e intermediarios utiles en la preparacion de tales compuestos |
CA2418960A1 (en) * | 2000-08-07 | 2002-02-14 | Inhale Therapeutic Systems, Inc. | Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation |
AU2001283546A1 (en) | 2000-08-14 | 2002-02-25 | Advanced Inhalation Research, Inc. | Inhalation device and method |
US6704255B2 (en) * | 2000-08-22 | 2004-03-09 | Ricoh Company, Ltd. | Lens actuator |
US6613308B2 (en) | 2000-09-19 | 2003-09-02 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
US6514482B1 (en) | 2000-09-19 | 2003-02-04 | Advanced Inhalation Research, Inc. | Pulmonary delivery in treating disorders of the central nervous system |
AU2001279544A1 (en) | 2000-09-20 | 2002-04-02 | Franco Del Bon | Inhalator and pertaining atomizer |
USD460173S1 (en) | 2000-09-20 | 2002-07-09 | P.A. Knowledge Limited | Inhaler device |
SE517225C2 (sv) | 2000-09-21 | 2002-05-14 | Microdrug Ag | Optimering av en elektrostatiskt doserad inhalator för torrt pulver |
SE517228C2 (sv) | 2000-09-25 | 2002-05-14 | Microdrug Ag | Inhalator för torrt pulver med andningsaktivering |
SE517226C2 (sv) | 2000-09-25 | 2002-05-14 | Microdrug Ag | Inhalator med luftbroms för torrt pulver |
GB0023653D0 (en) | 2000-09-27 | 2000-11-08 | Cambridge Consultants | Device for dispensing particulate material |
AU2001290087A1 (en) | 2000-09-29 | 2002-04-08 | Pa Knowledge Limited | Dosing device |
US6756062B2 (en) | 2000-11-03 | 2004-06-29 | Board Of Regents University Of Texas System | Preparation of drug particles using evaporation precipitation into aqueous solutions |
CN100400031C (zh) | 2000-11-29 | 2008-07-09 | 伊藤火腿株式会社 | 粉末制剂及其制备方法 |
GB0029562D0 (en) | 2000-12-04 | 2001-01-17 | Novartis Ag | Organic compounds |
USD455208S1 (en) | 2000-12-05 | 2002-04-02 | Clinical Designs Limited | Inhaler |
MXPA03005135A (es) * | 2000-12-13 | 2003-12-04 | Lilly Co Eli | Regimen de tratamiento cronico usando peptidos insulinotropicos similares al glucagon. |
ATE355849T1 (de) * | 2000-12-21 | 2007-03-15 | Nektar Therapeutics | Lagerstabile pulverzusammensetzungen mit interleukin-4 rezeptor |
US7077130B2 (en) | 2000-12-22 | 2006-07-18 | Chrysalis Technologies Incorporated | Disposable inhaler system |
US6799572B2 (en) | 2000-12-22 | 2004-10-05 | Chrysalis Technologies Incorporated | Disposable aerosol generator system and methods for administering the aerosol |
EP1345629A2 (en) * | 2000-12-29 | 2003-09-24 | Advanced Inhalation Research, Inc. | Particles for inhalation having sustained release properties |
US20020141946A1 (en) | 2000-12-29 | 2002-10-03 | Advanced Inhalation Research, Inc. | Particles for inhalation having rapid release properties |
US6626173B2 (en) | 2001-01-08 | 2003-09-30 | Iep Pharmaceutical Devices Inc. | Dry powder inhaler |
US6644309B2 (en) | 2001-01-12 | 2003-11-11 | Becton, Dickinson And Company | Medicament respiratory delivery device and method |
FI20010144A0 (fi) | 2001-01-24 | 2001-01-24 | Valtion Teknillinen | Menetelmä ja laite aerosolilähteiden tutkimiseksi |
AUPR272901A0 (en) * | 2001-01-25 | 2001-02-22 | Gainful Plan Limited | Method of preparing biological materials and preparations produced using same |
US20040022861A1 (en) | 2001-01-30 | 2004-02-05 | Williams Robert O. | Process for production of nanoparticles and microparticles by spray freezing into liquid |
WO2002067995A1 (en) * | 2001-02-26 | 2002-09-06 | Council Of Scientific And Industrial Research | Carrier systems comprising vitamin b12 - biodegradable micro particulate conju gates for peroral delivery of drugs, peptides/proteins and vaccines |
EP1238680B1 (en) | 2001-03-05 | 2003-12-10 | Ivo Pera | Inhaling device for dispersing powdered medicaments contained in a capsule through the respiratory tract |
US6698422B2 (en) | 2001-03-12 | 2004-03-02 | Birdsong Medical Devices, Inc. | Canister inhaler having a spacer and easy to operate lever mechanism and a flexible, elastic mouthpiece |
US6523536B2 (en) | 2001-03-12 | 2003-02-25 | Birdsong Medical Devices, Inc. | Dual-canister inhaler having a spacer and easy to operate lever mechanism |
USD453264S1 (en) | 2001-03-30 | 2002-02-05 | Benjamin Acevedo, Jr. | Pouch for medical inhaler |
GB0108213D0 (en) | 2001-04-02 | 2001-05-23 | Glaxo Group Ltd | Medicament dispenser |
SE0101233L (sv) | 2001-04-05 | 2002-10-01 | Microdrug Ag | Förfarande och anordning för frigörande av pulver och inhalatoranordning för administrering av medicinskt pulver |
US6652838B2 (en) | 2001-04-05 | 2003-11-25 | Robert E. Weinstein | Method for treating diabetes mellitus |
CA2444481A1 (en) | 2001-04-11 | 2002-10-24 | Bristol-Myers Squibb Company | Amino acid complexes of c-aryl glucosides for treatment of diabetes and method |
US6766799B2 (en) | 2001-04-16 | 2004-07-27 | Advanced Inhalation Research, Inc. | Inhalation device |
US6447751B1 (en) | 2001-04-18 | 2002-09-10 | Robert E. Weinstein | Method and device for facilitating combined aerosol and oral treatments for diabetes mellitus |
ATE452617T1 (de) | 2001-04-19 | 2010-01-15 | Technology Innovation Ltd | Arzneimittelbehälter |
US7232897B2 (en) | 2001-04-24 | 2007-06-19 | Harvard University, President And Fellows Of Harvard College | Compositions and methods for modulating NH2-terminal Jun Kinase activity |
USD451597S1 (en) | 2001-04-24 | 2001-12-04 | G-Intek Co.,Ltd | Snivel inhaler |
JP4663906B2 (ja) | 2001-04-26 | 2011-04-06 | 富士フイルム株式会社 | セルロースアシレートフイルム |
EP1392382B1 (en) | 2001-05-10 | 2008-08-06 | Vectura Delivery Devices Limited | Inhaler |
CN1314445C (zh) | 2001-05-21 | 2007-05-09 | 耐科塔医药公司 | 化学修饰胰岛素的肺部给药 |
SE0101825D0 (sv) | 2001-05-22 | 2001-05-22 | Astrazeneca Ab | An Inhalation device |
JP2005506956A (ja) | 2001-06-01 | 2005-03-10 | イーライ・リリー・アンド・カンパニー | 長時間作用性glp−1製剤 |
US7035294B2 (en) | 2001-06-04 | 2006-04-25 | Calix Networks, Inc. | Backplane bus |
EG24184A (en) | 2001-06-15 | 2008-10-08 | Otsuka Pharma Co Ltd | Dry powder inhalation system for transpulmonary |
FI20011317A0 (fi) | 2001-06-20 | 2001-06-20 | Orion Corp | Jauheinhalaattori |
EP1399374B1 (en) | 2001-06-22 | 2005-08-10 | 3M Innovative Properties Company | Method of improving flow of aerosol formulation in a metering valve for a metered dose inhaler |
US6681768B2 (en) | 2001-06-22 | 2004-01-27 | Sofotec Gmbh & Co. Kg | Powder formulation disintegrating system and method for dry powder inhalers |
US6614197B2 (en) | 2001-06-30 | 2003-09-02 | Motorola, Inc. | Odd harmonics reduction of phase angle controlled loads |
US7414720B2 (en) | 2001-07-27 | 2008-08-19 | Herbert Wachtel | Measuring particle size distribution in pharmaceutical aerosols |
DE10136555A1 (de) | 2001-07-27 | 2003-02-13 | Boehringer Ingelheim Int | Optimierte Verfahren zur Bestimmung der Aerosol-Partikelgrößenverteilung und Vorrichtung zur Durchführung derartiger Verfahren |
GB0120018D0 (en) | 2001-08-16 | 2001-10-10 | Meridica Ltd | Pack containing medicament and dispensing device |
BR0211995A (pt) | 2001-08-22 | 2004-09-28 | Aventis Pharma Deustschland Gm | Preparados de combinação de derivados de propanolamina substituìdos por arila com outras substâncias ativas e sua aplicação |
BR0212080A (pt) | 2001-08-23 | 2006-04-04 | Lilly Co Eli | composto de glp-1, método de estimulação de receptor de glp-1 em um indivìduo necessitando de tal estimulação, e, uso de um composto de glp-1 |
WO2003020201A2 (en) | 2001-08-28 | 2003-03-13 | Eli Lilly And Company | Pre-mixes of glp-1 and basal insulin |
GB0121709D0 (en) | 2001-09-07 | 2001-10-31 | Imp College Innovations Ltd | Food inhibition agent |
AU2002333644A1 (en) | 2001-09-17 | 2003-04-01 | Glaxo Group Limited | Dry powder medicament formulations |
CA2460904C (en) | 2001-09-19 | 2011-03-22 | Advent Pharmaceuticals Pty Ltd | An inhaler for delivering metered doses of powdered medicament |
US6640050B2 (en) | 2001-09-21 | 2003-10-28 | Chrysalis Technologies Incorporated | Fluid vaporizing device having controlled temperature profile heater/capillary tube |
US6568390B2 (en) | 2001-09-21 | 2003-05-27 | Chrysalis Technologies Incorporated | Dual capillary fluid vaporizing device |
JP4795637B2 (ja) | 2001-09-28 | 2011-10-19 | カーブ テクノロジー,インコーポレイティド | 鼻ネブライザー |
US7093595B2 (en) | 2001-10-08 | 2006-08-22 | Eli Lilly And Company | Portable medication inhalation kit |
CA2462976A1 (en) | 2001-10-16 | 2003-04-24 | International Non-Toxic Composites Corporation | High density non-toxic composites comprising tungsten, another metal and polymer powder |
USD461239S1 (en) | 2001-10-18 | 2002-08-06 | Anna L. Cassidy | Inhaler sleeve with spring clip |
US7179788B2 (en) | 2001-10-19 | 2007-02-20 | Eli Lilly And Company | Biphasic mixtures of GLP-1 and insulin |
EP1438019A1 (en) | 2001-10-24 | 2004-07-21 | PARI GmbH Spezialisten für effektive Inhalation | Kit for the preparation of a pharmaceutical composition |
USD473298S1 (en) | 2001-11-01 | 2003-04-15 | Astrazeneca Ab | Inhaler refill |
EP2314712B1 (en) | 2001-11-07 | 2014-01-08 | Mannkind Corporation | Expression vectors encoding epitopes of antigens and methods for their design |
JP2005514393A (ja) | 2001-12-19 | 2005-05-19 | ネクター セラピューティクス | アミノグリコシドの肺への供給 |
US6994083B2 (en) | 2001-12-21 | 2006-02-07 | Trudell Medical International | Nebulizer apparatus and method |
GB0130857D0 (en) | 2001-12-22 | 2002-02-06 | Glaxo Group Ltd | Medicament dispenser |
USD474536S1 (en) | 2002-01-07 | 2003-05-13 | Aerogen, Inc. | Inhaler for dispensing medications |
US20030198666A1 (en) | 2002-01-07 | 2003-10-23 | Richat Abbas | Oral insulin therapy |
USD471273S1 (en) | 2002-01-07 | 2003-03-04 | Aerogen, Inc. | Inhaler for dispensing medication |
USD479745S1 (en) | 2002-01-07 | 2003-09-16 | Aerogen, Inc. | Inhaler for dispensing medications |
USD469866S1 (en) | 2002-01-07 | 2003-02-04 | Aerogen, Inc. | Inhaler for dispensing medication |
ITMI20020078A1 (it) | 2002-01-16 | 2003-07-16 | Fabrizio Niccolai | Dispositivo utilizzabile nel tratamento di affezzioni delle vie respiratorie |
US6991779B2 (en) | 2002-01-18 | 2006-01-31 | Mannkind Corporation | Compositions for treatment or prevention of bioterrorism |
US7105489B2 (en) | 2002-01-22 | 2006-09-12 | Amylin Pharmaceuticals, Inc. | Methods and compositions for treating polycystic ovary syndrome |
US7258118B2 (en) | 2002-01-24 | 2007-08-21 | Sofotec Gmbh & Co, Kg | Pharmaceutical powder cartridge, and inhaler equipped with same |
ES2614603T3 (es) | 2002-02-20 | 2017-06-01 | Emisphere Technologies, Inc. | Procedimiento de administración de moléculas GLP-1 |
US6591832B1 (en) | 2002-02-21 | 2003-07-15 | Saint-Gobain Calmar Inc. | Dry powder dispenser |
US6830149B2 (en) | 2002-03-08 | 2004-12-14 | Musculoskeletal Transplant Foundation | Package with insert for holding allograft implant to preclude lipid transfer |
US7008644B2 (en) | 2002-03-20 | 2006-03-07 | Advanced Inhalation Research, Inc. | Method and apparatus for producing dry particles |
ES2300568T3 (es) | 2002-03-20 | 2008-06-16 | Mannkind Corporation | Aparato de inhalacion. |
UA80123C2 (en) | 2002-04-09 | 2007-08-27 | Boehringer Ingelheim Pharma | Inhalation kit comprising inhalable powder of tiotropium |
US20030235538A1 (en) | 2002-04-09 | 2003-12-25 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Method for the administration of an anticholinergic by inhalation |
US20030194420A1 (en) | 2002-04-11 | 2003-10-16 | Richard Holl | Process for loading a drug delivery device |
USD475133S1 (en) | 2002-04-18 | 2003-05-27 | Mcluckie Lynne E. | Luminescent-colored inhaler |
US7316748B2 (en) | 2002-04-24 | 2008-01-08 | Wisconsin Alumni Research Foundation | Apparatus and method of dispensing small-scale powders |
US6830046B2 (en) | 2002-04-29 | 2004-12-14 | Hewlett-Packard Development Company, L.P. | Metered dose inhaler |
USD478983S1 (en) | 2002-05-01 | 2003-08-26 | Chrysalis Technologies Incorporated | Inhaler |
US20040151059A1 (en) | 2002-05-01 | 2004-08-05 | Roberts Ii William Leroy | Deagglomerator apparatus and method |
WO2004039830A2 (en) * | 2002-05-07 | 2004-05-13 | Regents Of The University Of California | Bioactivation of particles |
AU2003218635A1 (en) | 2002-05-07 | 2003-11-11 | Novo Nordisk A/S | Soluble formulations comprising insulin aspart and insulin detemir |
US6889690B2 (en) | 2002-05-10 | 2005-05-10 | Oriel Therapeutics, Inc. | Dry powder inhalers, related blister devices, and associated methods of dispensing dry powder substances and fabricating blister packages |
USD473640S1 (en) | 2002-05-13 | 2003-04-22 | Iep Pharmaceutical Devices Inc. | Breath actuated inhaler |
USD492769S1 (en) | 2002-05-24 | 2004-07-06 | Glaxosmithkline K.K. | Lens for an inhaler |
USD477665S1 (en) | 2002-06-12 | 2003-07-22 | Microdrug Ag | Inhaler |
AU154760S (en) | 2002-06-20 | 2004-03-02 | Astrazeneca Ab | Inhaler |
US8003179B2 (en) | 2002-06-20 | 2011-08-23 | Alcan Packaging Flexible France | Films having a desiccant material incorporated therein and methods of use and manufacture |
SI1531794T1 (sl) | 2002-06-28 | 2017-12-29 | Civitas Therapeteutics, Inc. | Epinefrin za vdihavanje |
US20060003316A1 (en) | 2002-07-15 | 2006-01-05 | John Simard | Immunogenic compositions derived from poxviruses and methods of using same |
GB0217198D0 (en) | 2002-07-25 | 2002-09-04 | Glaxo Group Ltd | Medicament dispenser |
GB0217382D0 (en) | 2002-07-26 | 2002-09-04 | Pfizer Ltd | Process for making orally consumable dosage forms |
ATE503517T2 (de) | 2002-07-31 | 2011-04-15 | Chiesi Farma Spa | Pulverinhalator |
USD489448S1 (en) | 2002-07-31 | 2004-05-04 | Advanced Inhalations Revolutions, Inc. | Vaporization apparatus |
DE10235168A1 (de) | 2002-08-01 | 2004-02-12 | Aventis Pharma Deutschland Gmbh | Verfahren zur Reinigung von Preproinsulin |
US20080260838A1 (en) | 2003-08-01 | 2008-10-23 | Mannkind Corporation | Glucagon-like peptide 1 (glp-1) pharmaceutical formulations |
CA2493478C (en) * | 2002-08-01 | 2014-11-18 | Mannkind Corporation | Cell transport compositions and uses thereof |
US20040038865A1 (en) | 2002-08-01 | 2004-02-26 | Mannkind Corporation | Cell transport compositions and uses thereof |
US20150283213A1 (en) | 2002-08-01 | 2015-10-08 | Mannkind Corporation | Method for treating hyperglycemia with glp-1 |
GB0315791D0 (en) | 2003-07-07 | 2003-08-13 | 3M Innovative Properties Co | Two component molded valve stems |
US20040121964A1 (en) | 2002-09-19 | 2004-06-24 | Madar David J. | Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV) |
USD509296S1 (en) | 2002-09-21 | 2005-09-06 | Aventis Pharma Limited | Inhaler |
US7322352B2 (en) | 2002-09-21 | 2008-01-29 | Aventis Pharma Limited | Inhaler |
JP2004121061A (ja) * | 2002-10-01 | 2004-04-22 | Sanei Gen Ffi Inc | 粉末組成物の製造方法 |
CA2694183C (en) | 2002-10-11 | 2013-06-25 | Otsuka Techno Corporation | Powder inhalator |
ITMO20020297A1 (it) | 2002-10-16 | 2004-04-17 | Roberto Oliva | Inalatore per preparati monodose in capsule. |
CN1176649C (zh) | 2002-10-16 | 2004-11-24 | 上海医药工业研究院 | 舒马普坦干粉吸入剂及其制备方法 |
NZ540318A (en) | 2002-10-31 | 2007-09-28 | Umd Inc | Therapeutic compositions for drug delivery to and through covering epithelia |
GB0225621D0 (en) | 2002-11-02 | 2002-12-11 | Glaxo Group Ltd | Medicament carrier |
AU2003276447A1 (en) | 2002-11-04 | 2004-06-07 | Cambridge Consultants Limited | Inhalers |
USD493220S1 (en) | 2002-11-06 | 2004-07-20 | Merck Patent Gmbh | Inhaler |
US20080015457A1 (en) | 2002-11-07 | 2008-01-17 | Silva Carlos D | Device for Monitoring Respiratory Movements |
USD483860S1 (en) | 2002-11-12 | 2003-12-16 | Pari Gmbh Spezialisten Fur Effektive Inhalation | Electronic inhaler and control unit |
US6904907B2 (en) | 2002-11-19 | 2005-06-14 | Honeywell International Inc. | Indirect flow measurement through a breath-operated inhaler |
GB0227128D0 (en) | 2002-11-20 | 2002-12-24 | Glaxo Group Ltd | A capsule |
US7913688B2 (en) | 2002-11-27 | 2011-03-29 | Alexza Pharmaceuticals, Inc. | Inhalation device for producing a drug aerosol |
US20040138099A1 (en) | 2002-11-29 | 2004-07-15 | Draeger Eberhard Kurt | Insulin administration regimens for the treatment of subjects with diabetes |
WO2004050152A1 (en) | 2002-12-02 | 2004-06-17 | The Governors Of The University Of Alberta | Device and method for deagglomeration of powder for inhalation |
US7284553B2 (en) | 2002-12-12 | 2007-10-23 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Powder inhaler comprising a chamber for a capsule for taking up a non-returnable capsule being filled with an active ingredient |
TWI313181B (en) | 2002-12-13 | 2009-08-11 | Otsuka Pharma Co Ltd | Inhalation device for transpulmonary administration |
US20060057106A1 (en) | 2002-12-13 | 2006-03-16 | Chikamasa Yamashita | Freeze-dried interferon-y composition for transpulmonary administration and inhalation system therefor |
EA008829B1 (ru) | 2002-12-17 | 2007-08-31 | Нэстек Фармасьютикал Кампани Инк. | Композиции и способы для усовершенствованной доставки пептидов, связывающихся с y-рецепторами, которую осуществляют через слизистые оболочки, и способы лечения и предотвращения ожирения |
US6941947B2 (en) | 2002-12-18 | 2005-09-13 | Quadrant Technologies Limited | Unit dose dry powder inhaler |
US7185650B2 (en) | 2002-12-19 | 2007-03-06 | Arie Huber | Systems and methods for determining a minimum effective dose of an inhaled drug for an individual patient at a given time |
US6962006B2 (en) | 2002-12-19 | 2005-11-08 | Acusphere, Inc. | Methods and apparatus for making particles using spray dryer and in-line jet mill |
KR20050086948A (ko) | 2002-12-27 | 2005-08-30 | 디오벡스, 인코포레이티드 | 인슐린으로 인한 저혈당증을 예방하고 조절하기 위한조성물 및 방법 |
DE10300032B3 (de) | 2003-01-03 | 2004-05-27 | E. Braun Gmbh | Pulverinhalator |
GB0309154D0 (en) | 2003-01-14 | 2003-05-28 | Aventis Pharma Inc | Use of insulin glargine to reduce or prevent cardiovascular events in patients being treated for dysglycemia |
US20040187869A1 (en) | 2003-01-17 | 2004-09-30 | Schering Corporation | Training device for medicament inhalers |
DE50303808D1 (de) * | 2003-01-29 | 2006-07-27 | I & T Innovation Tech Entw | Abisolieren von Flachleitern |
JP2006514119A (ja) | 2003-02-12 | 2006-04-27 | アール アンド ピー コリア カンパニー リミテッド | 溶解率が向上した難溶性薬剤の溶媒系 |
GB0303870D0 (en) | 2003-02-20 | 2003-03-26 | Norton Healthcare Ltd | Pre-metered dose magazine for breath-actuated dry powder inhaler |
US20040171518A1 (en) | 2003-02-27 | 2004-09-02 | Medtronic Minimed, Inc. | Compounds for protein stabilization and methods for their use |
WO2004078197A1 (en) * | 2003-03-04 | 2004-09-16 | The Technology Development Company Ltd. | Delivery system for drug and cell therapy |
US7331340B2 (en) | 2003-03-04 | 2008-02-19 | Ivax Corporation | Medicament dispensing device with a display indicative of the state of an internal medicament reservoir |
EP1605895A4 (en) | 2003-03-06 | 2011-08-24 | Emisphere Tech Inc | ORAL INSULIN THERAPY AND PROTOCOL |
WO2004080482A2 (en) | 2003-03-11 | 2004-09-23 | Institut De Cardiologie De Montréal / | Use of angiotensin converting enzyme (ace) inhibitors to prevent diabetes in a subject with chronic heart failure |
USD499802S1 (en) | 2003-04-01 | 2004-12-14 | Chiesi Farmaceutici S.P.A. | Powder inhaler |
CA2520265C (en) | 2003-04-09 | 2015-02-17 | Nektar Therapeutics | Aerosolization apparatus with capsule puncture alignment guide |
US20040204439A1 (en) | 2003-04-14 | 2004-10-14 | Staniforth John Nicholas | Composition, device, and method for treating sexual dysfunction via inhalation |
EP1468935A1 (de) | 2003-04-16 | 2004-10-20 | Alcan Technology & Management Ltd. | Blisterverpackung |
AU155845S (en) | 2003-05-15 | 2004-07-13 | Glaxo Group Ltd | A dispensing device for example an inhaler device |
PT2537524T (pt) | 2003-05-15 | 2016-09-05 | Ampio Pharmaceuticals Inc | Tratamento de doenças mediadas pela célula t |
AU155632S (en) | 2003-05-16 | 2004-06-01 | Henkel Kgaa | Blister pack |
WO2004101040A1 (en) | 2003-05-16 | 2004-11-25 | University Of Alberta | Add-on spacer design concept for dry-powder inhalers |
GB0312007D0 (en) | 2003-05-24 | 2003-07-02 | Innovata Biomed Ltd | Container |
ES2596553T3 (es) | 2003-06-02 | 2017-01-10 | Glaxosmithkline Biologicals Sa | Composiciones inmunogénicas a base de micropartículas que comprenden toxoide adsorbido y un antígeno que contiene un polisacárido |
ES2872350T3 (es) | 2003-06-13 | 2021-11-02 | Civitas Therapeutics Inc | Polvos farmacéuticos de dosis baja para inhalación |
EP1641671B1 (en) | 2003-06-27 | 2015-06-24 | Portaclave LLP | Portable fuel cartridge for fuel cells |
US7001622B1 (en) | 2003-06-30 | 2006-02-21 | Robert Berndt | Composition and method for treatment and prevention of pruritis |
GB0315509D0 (en) | 2003-07-02 | 2003-08-06 | Meridica Ltd | Dispensing device |
AU158576S (en) | 2003-07-05 | 2006-08-22 | Clinical Designs Ltd | Inhaler |
US7462367B2 (en) | 2003-07-11 | 2008-12-09 | Boehringer Ingelheim International Gmbh | Anticholinergic powder formulations for inhalation |
US9078866B2 (en) | 2003-08-01 | 2015-07-14 | Mannkind Corporation | Method for treating hyperglycemia with GLP-1 |
US8921311B2 (en) | 2003-08-01 | 2014-12-30 | Mannkind Corporation | Method for treating hyperglycemia |
USD569967S1 (en) | 2003-08-06 | 2008-05-27 | Meridica Limited | Inhaler |
US20050043247A1 (en) * | 2003-08-18 | 2005-02-24 | Boehringer Ingelheim International Gmbh | Spray-dried amorphous BIBN 4096, process for preparing and the use thereof as inhalative |
DE10338402A1 (de) | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Sprühgetrocknetes, amorphes BIBN 4096, Verfahren zu dessen Herstellung sowie dessen Verwendung als Inhalativum |
US20050056535A1 (en) | 2003-09-15 | 2005-03-17 | Makoto Nagashima | Apparatus for low temperature semiconductor fabrication |
DE10343668A1 (de) | 2003-09-18 | 2005-04-14 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Arzneimittelblister |
EP1675822A2 (en) | 2003-10-16 | 2006-07-05 | Cara Therapeutics, Inc. | Amide or thioamide derivatives and their use in the treatment of pain |
GB2398065A (en) | 2003-10-16 | 2004-08-11 | Bespak Plc | Dispensing apparatus |
WO2005041022A1 (en) | 2003-10-24 | 2005-05-06 | Judy Singley | Method, system, and computer program for performing carbohydrate/insulin calculation based upon food weight |
USD511208S1 (en) | 2003-10-24 | 2005-11-01 | Valois Sas | Metered dose inhaler |
US7377277B2 (en) | 2003-10-27 | 2008-05-27 | Oriel Therapeutics, Inc. | Blister packages with frames and associated methods of fabricating dry powder drug containment systems |
WO2005041848A2 (en) | 2003-10-27 | 2005-05-12 | Oriel Therapeutics, Inc. | Dry powder drug containment system packages with tabs, inhalers and associated methods |
US7451761B2 (en) | 2003-10-27 | 2008-11-18 | Oriel Therapeutics, Inc. | Dry powder inhalers, related blister package indexing and opening mechanisms, and associated methods of dispensing dry powder substances |
US20050147581A1 (en) * | 2003-11-19 | 2005-07-07 | The Board Of Trustees Of The University Of Illinois | Macromolecular drug complexes having improved stability and therapeutic use of the same |
SE0303269L (sv) | 2003-12-03 | 2005-06-04 | Microdrug Ag | Medicinsk produkt |
GB0329884D0 (en) | 2003-12-23 | 2004-01-28 | Glaxo Group Ltd | Method |
EP1701714A2 (en) | 2004-01-07 | 2006-09-20 | Nektar Therapeutics | Improved sustained release compositions for pulmonary administration of insulin |
JP2007517892A (ja) * | 2004-01-12 | 2007-07-05 | マンカインド コーポレイション | 2型糖尿病における血清プロインスリンレベルを低下させる方法 |
US20070027063A1 (en) | 2004-01-12 | 2007-02-01 | Mannkind Corporation | Method of preserving the function of insulin-producing cells |
EP1711220A1 (en) | 2004-01-16 | 2006-10-18 | Biodel, Inc. | Sublingual drug delivery device |
DE102004006450B4 (de) | 2004-02-05 | 2012-09-27 | Ing. Erich Pfeiffer Gmbh | Dosiervorrichtung |
DE102004008141A1 (de) | 2004-02-19 | 2005-09-01 | Abbott Gmbh & Co. Kg | Guanidinverbindungen und ihre Verwendung als Bindungspartner für 5-HT5-Rezeptoren |
USD512777S1 (en) | 2004-02-19 | 2005-12-13 | Chrysalis Technologies Incorporated | Inhaler |
EP1718354B1 (en) | 2004-02-24 | 2020-04-29 | MicroDose Therapeutx, Inc. | Inhaler with a directional flow sensor |
CA2554136C (en) | 2004-02-24 | 2013-05-28 | Microdose Technologies, Inc. | Synthetic jet based medicament delivery method and apparatus |
US7279457B2 (en) | 2004-03-12 | 2007-10-09 | Biodel, Inc. | Rapid acting drug delivery compositions |
ITMO20040060A1 (it) | 2004-03-18 | 2004-06-18 | Roberto Oliva | Inalatore per preparati in polvere |
USD515696S1 (en) | 2004-03-19 | 2006-02-21 | Innovata Biomed Limited | Inhaler |
WO2005092301A1 (en) * | 2004-03-26 | 2005-10-06 | Universita' Degli Studi Di Parma | Insulin highly respirable microparticles |
AU2005229779A1 (en) | 2004-04-05 | 2005-10-20 | Universite Bordeaux 2 | Peptides and peptidomimetics binding to CD23 |
USD533268S1 (en) | 2004-04-18 | 2006-12-05 | Bahram Olfati | Inhaler |
WO2005102429A1 (en) | 2004-04-21 | 2005-11-03 | Innovata Biomed Limited | Inhaler |
HUE026152T2 (en) | 2004-04-23 | 2016-05-30 | Philip Morris Products Sa | Aerosol Generator and Method for Aerosol Production |
WO2005102428A1 (en) | 2004-04-23 | 2005-11-03 | The Governors Of The University Of Alberta | Enhanced drug delivery for inhaled aerosols |
GB0410712D0 (en) | 2004-05-13 | 2004-06-16 | Novartis Ag | Organic compounds |
USD527817S1 (en) | 2004-05-13 | 2006-09-05 | Novartis Ag | Inhaler |
US20050265927A1 (en) | 2004-05-17 | 2005-12-01 | Yale University | Intranasal delivery of nucleic acid molecules |
AR052759A1 (es) | 2004-05-19 | 2007-04-04 | Cipla Ltd | Dispositivo inhalador de medicamentos |
USD548833S1 (en) | 2004-05-28 | 2007-08-14 | Quadrant Technologies Limited | Dry powder inhaler |
USD529604S1 (en) | 2004-05-28 | 2006-10-03 | Quadrant Technologies Limited | Dry powder inhaler |
RU2006145654A (ru) | 2004-06-07 | 2008-07-20 | Медерио Аг (Ch) | Защита дозированного лекарства, предназначенного для ингаляции |
SE528190C2 (sv) | 2004-06-07 | 2006-09-19 | Mederio Ag | Inhalator |
RU2006145886A (ru) | 2004-06-25 | 2008-06-27 | Такеда Фармасьютикал Компани Лимитед (Jp) | Производные метастина и их применение |
US20060000469A1 (en) | 2004-07-02 | 2006-01-05 | Tseng Daniel C | Nebulizing apparatus for medical use with improved nozzle positioning structure |
CA2574642A1 (en) | 2004-07-23 | 2006-01-26 | Intercure Ltd. | Apparatus and method for breathing pattern determination using a non-contact microphone |
AU2005266789B2 (en) | 2004-07-26 | 2010-11-25 | 1355540 Ontario Inc. | Powder inhaler featuring reduced compaction inhaler |
CA2575756A1 (en) | 2004-08-03 | 2006-02-16 | Biorexis Technology, Inc. | Combination therapy using transferrin fusion proteins comprising glp-1 |
MX2007001903A (es) | 2004-08-20 | 2007-08-02 | Mannkind Corp | Catalisis de sintesis de dicetopiperazina. |
EP1781254A2 (en) * | 2004-08-23 | 2007-05-09 | Mannkind Corporation | Pulmonary delivery of inhibitors of phosphodiesterase type 5 |
KR101306384B1 (ko) | 2004-08-23 | 2013-09-09 | 맨카인드 코포레이션 | 약물 전달용 디케토피페라진염, 디케토모르포린염 또는디케토디옥산염 |
GB0419849D0 (en) | 2004-09-07 | 2004-10-13 | Pfizer Ltd | Pharmaceutical combination |
US8210171B2 (en) | 2004-09-13 | 2012-07-03 | Oriel Therapeutics, Inc. | Tubular dry powder drug containment systems, associated inhalers and methods |
US8365725B2 (en) | 2004-09-13 | 2013-02-05 | Oriel Therapeutics, Inc. | Dry powder inhalers that inhibit agglomeration, related devices and methods |
USD537936S1 (en) | 2004-09-15 | 2007-03-06 | Glaxo Group Limited | Cap with an extension, particularly for a dust cap of a metered dose inhaler |
USD537522S1 (en) | 2004-09-15 | 2007-02-27 | Glaxo Group Limited | Telescopic strap, particularly for a dust cap of a metered dose inhaler |
USD518170S1 (en) | 2004-09-28 | 2006-03-28 | Vectura, Ltd. | Inhaler |
WO2006037636A2 (en) | 2004-10-06 | 2006-04-13 | Boehringer Ingelheim International Gmbh | Dispensing device, storage device and method for dispensing powder |
US7469696B2 (en) | 2004-10-13 | 2008-12-30 | Hewlett-Packard Development Company, L.P. | Thermal drop generator |
USD515924S1 (en) | 2004-11-01 | 2006-02-28 | Warner-Lambert Company Llc | Blister card |
DE102005033398A1 (de) | 2004-11-10 | 2006-05-11 | Alfred Von Schuckmann | Inhalier-Gerät |
SE0402976L (sv) | 2004-12-03 | 2006-06-04 | Mederio Ag | Medicinsk produkt |
EP1827381A1 (en) | 2004-12-03 | 2007-09-05 | Mederio AG | A medical product comprising a glucagon-like peptide medicament intended for pulmonary inhalation |
GB0427028D0 (en) | 2004-12-09 | 2005-01-12 | Cambridge Consultants | Dry powder inhalers |
US20060130838A1 (en) | 2004-12-20 | 2006-06-22 | Lee Yong Y | Data logger for monitoring asthmatic conditions |
AU2005337493A1 (en) | 2004-12-22 | 2007-04-26 | Centocor, Inc. | GLP-1 agonists, compositions, methods and uses |
JP2008526893A (ja) | 2005-01-10 | 2008-07-24 | マンカインド コーポレイション | 肺における吸入可能なインスリンの自然増加を最少化するための方法及び組成物 |
US20060165756A1 (en) | 2005-01-27 | 2006-07-27 | Catani Steven J | Method for weight management |
USD538423S1 (en) | 2005-02-04 | 2007-03-13 | Berube-White | Panda bear inhaler |
GB0503738D0 (en) | 2005-02-23 | 2005-03-30 | Optinose As | Powder delivery devices |
US20060219242A1 (en) | 2005-03-30 | 2006-10-05 | Boehringer Ingelheim International | Method for the Administration of an Anticholinergic by Inhalation |
JP4656397B2 (ja) | 2005-03-31 | 2011-03-23 | 株式会社吉野工業所 | 粉体用容器 |
CN100431634C (zh) | 2005-04-04 | 2008-11-12 | 陈庆堂 | 干粉气溶胶化吸入器 |
US7762953B2 (en) | 2005-04-20 | 2010-07-27 | Adidas Ag | Systems and methods for non-invasive physiological monitoring of non-human animals |
US7694676B2 (en) | 2005-04-22 | 2010-04-13 | Boehringer Ingelheim Gmbh | Dry powder inhaler |
EP1885335A1 (en) * | 2005-04-27 | 2008-02-13 | BAXTER INTERNATIONAL INC. (a Delaware corporation) | Surface-modified microparticles and methods of forming and using the same |
US7219664B2 (en) | 2005-04-28 | 2007-05-22 | Kos Life Sciences, Inc. | Breath actuated inhaler |
JP2008540264A (ja) | 2005-05-02 | 2008-11-20 | アストラゼネカ・アクチエボラーグ | キャビティを開口するための構成と方法、薬剤パッケージ及び配布デバイス |
USD544093S1 (en) | 2005-06-02 | 2007-06-05 | Bang & Olufsen A/S | Inhaler |
CN103948927B (zh) | 2005-06-17 | 2017-11-07 | 威斯康星校友研究基金会 | 在癌症化疗和放疗时保护细胞的局部血管收缩剂制品和方法 |
US20080251072A1 (en) | 2005-07-13 | 2008-10-16 | Amar Lulla | Inhaler Device |
US8763605B2 (en) | 2005-07-20 | 2014-07-01 | Manta Devices, Llc | Inhalation device |
USD550835S1 (en) | 2005-07-22 | 2007-09-11 | Omron Healthcare Co., Ltd. | Atomizer for inhaler |
JP2009503093A (ja) | 2005-08-01 | 2009-01-29 | マンカインド コーポレイション | インスリン産生細胞の機能を保持する方法 |
JP5694643B2 (ja) | 2005-08-05 | 2015-04-01 | スリーエム イノベイティブ プロパティズ カンパニー | 改善された流動性を示す組成物 |
EP1934805A4 (en) | 2005-08-25 | 2017-01-11 | Oriel Therapeutics, Inc. | Drug containment systems with sticks, related kits, dry powder inhalers and methods |
US7900625B2 (en) | 2005-08-26 | 2011-03-08 | North Carolina State University | Inhaler system for targeted maximum drug-aerosol delivery |
JP2009506069A (ja) | 2005-08-26 | 2009-02-12 | ブレインセルス,インコーポレイティド | ムスカリン性受容体調節による神経発生 |
JP2007061281A (ja) | 2005-08-30 | 2007-03-15 | Hitachi Ltd | 吸入量測定システム |
US20100041612A1 (en) | 2005-09-08 | 2010-02-18 | Martin Beinborn | Fragments of the Glucagon-Like Peptide-1 and Uses Thereof |
JP5465878B2 (ja) | 2005-09-14 | 2014-04-09 | マンカインド コーポレイション | 活性薬剤に対する結晶性微粒子表面の親和性を増大させることに基づく薬物処方の方法 |
USD540671S1 (en) | 2005-09-21 | 2007-04-17 | The Procter & Gamble Company | Cap for product dispenser |
US20070086952A1 (en) | 2005-09-29 | 2007-04-19 | Biodel, Inc. | Rapid Acting and Prolonged Acting Inhalable Insulin Preparations |
US20070074989A1 (en) | 2005-09-30 | 2007-04-05 | Musculoskeletal Transplant Foundation | Container for lyophilization and storage of tissue |
GB0520794D0 (en) | 2005-10-12 | 2005-11-23 | Innovata Biomed Ltd | Inhaler |
ITMI20051999A1 (it) | 2005-10-21 | 2007-04-22 | Eratech S R L | Formulazioni inalatorie di farmaci in fora di polvere secca per somministrazione come tale o con nebulizzatore e dotate di elevata erogabilita' respirabilita' e stabilita' |
USD566549S1 (en) | 2005-10-26 | 2008-04-15 | Reckitt Benckiser (Uk) Limited | Cap |
US8039432B2 (en) | 2005-11-09 | 2011-10-18 | Conjuchem, Llc | Method of treatment of diabetes and/or obesity with reduced nausea side effect |
AR058289A1 (es) | 2005-12-12 | 2008-01-30 | Glaxo Group Ltd | Colector para ser usado en dispensador de medicamento |
AR058290A1 (es) | 2005-12-12 | 2008-01-30 | Glaxo Group Ltd | Dispensador de medicamento |
US8293869B2 (en) | 2005-12-16 | 2012-10-23 | Nektar Therapeutics | Polymer conjugates of GLP-1 |
CN101404980A (zh) | 2006-01-24 | 2009-04-08 | 耐百生物制药有限公司 | 大分子微球的制备技术 |
USD557798S1 (en) | 2006-01-25 | 2007-12-18 | Valois S.A.S. | Inhaler |
US7390949B2 (en) | 2006-02-01 | 2008-06-24 | Wanne, Inc. | Saxophone and clarinet mouthpiece cap |
GB0602897D0 (en) | 2006-02-13 | 2006-03-22 | Jagotec Ag | Improvements In Or Relating To Dry Powder Inhaler Devices |
EP1991840A1 (en) | 2006-02-14 | 2008-11-19 | Battelle Memorial Institute | Accurate metering system |
CN104383546B (zh) * | 2006-02-22 | 2021-03-02 | 曼金德公司 | 用于改善包含二酮哌嗪和活性剂的微粒的药物性质的方法 |
US7928058B2 (en) | 2006-02-22 | 2011-04-19 | Merck Sharp & Dohme Corp. | Pharmaceutical composition comprising oxyntomodulin derivatives and a method for reducing body weight using the composition |
DE102006010089A1 (de) | 2006-02-24 | 2007-10-18 | Aha-Kunststofftechnik Gmbh | Trockenpulver-Inhalator |
USD541151S1 (en) | 2006-03-20 | 2007-04-24 | The Procter & Gamble Company | Cap for product dispenser |
US8037880B2 (en) | 2006-04-07 | 2011-10-18 | The University Of Western Ontario | Dry powder inhaler |
WO2007121256A2 (en) | 2006-04-12 | 2007-10-25 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
EP1844806A1 (de) | 2006-04-13 | 2007-10-17 | Boehringer Ingelheim Pharma GmbH | Medikamenten-Ausgabevorrichtung, Medikamentenmagazin dafür, und Verfahren zur Entnahme eines Medikaments aus einer Medikamentenkammer |
EP1844809A1 (de) | 2006-04-13 | 2007-10-17 | Boehringer Ingelheim Pharma GmbH & Co. KG | Medikamentenmagazin für einen Inhalator, sowie Mehrdosispulverinhalator |
MX2008013216A (es) | 2006-04-14 | 2008-10-27 | Mannkind Corp | Formulaciones farmaceuticas de peptido-1 tipo glucagon (glp-1). |
US20070243216A1 (en) | 2006-04-14 | 2007-10-18 | Stanley Kepka | Stable solutions of prostaglandin and uses of same |
GR1005620B (el) | 2006-05-09 | 2007-09-03 | Βελτιωση συσκευης εισπνοων ξηρης σκονης | |
DE102006021978A1 (de) | 2006-05-10 | 2007-11-15 | Robert Bosch Gmbh | Vorrichtung und Verfahen zum Verstärken eines Blisters |
EP2022445A1 (en) | 2006-05-10 | 2009-02-11 | S.K.I.Net Inc. | Anesthetic system for small animal |
PT103481B (pt) | 2006-05-16 | 2008-08-01 | Hovione Farmaciencia S A | Inalador de uso simples e método de inalação |
GB0611659D0 (en) | 2006-06-13 | 2006-07-19 | Cambridge Consultants | Dry powder inhalers |
GB0611656D0 (en) | 2006-06-13 | 2006-07-19 | Cambridge Consultants | Dry powder inhalers |
MX2008016153A (es) | 2006-06-16 | 2009-01-20 | Cipla Ltd | Inhalador mejorado de polvo seco. |
CN101484201B (zh) | 2006-06-27 | 2011-06-15 | 大冢制药株式会社 | 粉末吸入器 |
US8201555B2 (en) | 2006-06-27 | 2012-06-19 | Brintech International Limited | Inhaler |
GB0613161D0 (en) | 2006-06-30 | 2006-08-09 | Novartis Ag | Organic Compounds |
CN2917673Y (zh) | 2006-07-06 | 2007-07-04 | 兴安药业有限公司 | 一种胶囊型干粉吸入器 |
CN101489613A (zh) | 2006-07-14 | 2009-07-22 | 阿斯利康(瑞典)有限公司 | 用于对干粉状药物进行给药的吸入系统和递送装置 |
US8900555B2 (en) | 2006-07-27 | 2014-12-02 | Nektar Therapeutics | Insulin derivative formulations for pulmonary delivery |
WO2008014613A1 (en) | 2006-08-04 | 2008-02-07 | Manus Pharmaceuticals (Canada) Ltd. | Multifunctional bioactive compounds |
GB0616299D0 (en) | 2006-08-16 | 2006-09-27 | Cambridge Consultants | Drug Capsules for dry power inhalers |
US20080066739A1 (en) | 2006-09-20 | 2008-03-20 | Lemahieu Edward | Methods and systems of delivering medication via inhalation |
WO2008039863A2 (en) | 2006-09-27 | 2008-04-03 | Braincells, Inc. | Composition comprising a melanocortin receptor (mcr) modulating agent alone or in combination with a second neurogenic agent for treating nervous system disorders |
US8236766B2 (en) | 2006-11-10 | 2012-08-07 | Cara Therapeutics, Inc. | Uses of synthetic peptide amides |
EP2064228B1 (en) | 2006-11-10 | 2012-08-29 | Cara Therapeutics, Inc. | Synthetic peptide amides |
US7842662B2 (en) | 2006-11-10 | 2010-11-30 | Cara Therapeutics, Inc. | Synthetic peptide amide dimers |
EP2086691A2 (en) | 2006-11-10 | 2009-08-12 | Proveris Scientific Corporation | Automated nasal spray pump testing |
US7713937B2 (en) | 2006-11-10 | 2010-05-11 | Cara Therapeutics, Inc. | Synthetic peptide amides and dimeric forms thereof |
US7824014B2 (en) | 2006-12-05 | 2010-11-02 | Canon Kabushiki Kaisha | Head substrate, printhead, head cartridge, and printing apparatus |
USD548618S1 (en) | 2006-12-06 | 2007-08-14 | Eveready Battery Company, Inc. | Zinc-air hearing aid battery package |
USD549111S1 (en) | 2006-12-06 | 2007-08-21 | Eveready Battery Company, Inc. | Zinc-air hearing aid battery package |
USD548619S1 (en) | 2006-12-06 | 2007-08-14 | Eveready Battery Company, Inc. | Zinc-air hearing aid battery package |
BRPI0720846A2 (pt) | 2006-12-22 | 2014-03-04 | Almirall Lab | Dispositivo de inalação para fármacos na forma de pó |
WO2008092864A1 (en) | 2007-01-29 | 2008-08-07 | Novo Nordisk A/S | Method and devices for aerosolizing a drug formulation |
US8172817B2 (en) | 2007-01-31 | 2012-05-08 | Allegiance Corporation | Liquid collection system and related methods |
KR20090119876A (ko) | 2007-02-15 | 2009-11-20 | 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 | 글루카곤/glp-1 수용체 공동-항진물질 |
US8196576B2 (en) | 2007-02-28 | 2012-06-12 | Microdose Therapeutx, Inc. | Inhaler |
WO2009005546A1 (en) | 2007-03-05 | 2009-01-08 | Board of Governors for Higher Education, State of Rhode Island and the Providence Plantations | High efficiency mouthpiece/adaptor for inhalers |
JP2008212436A (ja) | 2007-03-06 | 2008-09-18 | Canon Inc | 吸入装置 |
US8146745B2 (en) | 2007-03-09 | 2012-04-03 | Cardpak, Inc. | Environmentally separable packaging device with attaching base |
GB0704928D0 (en) | 2007-03-14 | 2007-04-25 | Cambridge Consultants | Dry powder inhalers |
WO2009076325A2 (en) | 2007-04-11 | 2009-06-18 | Starr Life Sciences Corp. | Noninvasive photoplethysmographic sensor platform for mobile animals |
JP4417400B2 (ja) | 2007-04-16 | 2010-02-17 | アンリツ株式会社 | はんだ検査ライン集中管理システム、及びそれに用いられる管理装置 |
AU2008244523B2 (en) | 2007-04-23 | 2012-02-16 | Intarcia Therapeutics, Inc. | Suspension formulations of insulinotropic peptides and uses thereof |
JP2010527914A (ja) | 2007-04-26 | 2010-08-19 | クォーク ファーマシューティカルズ インコーポレーティッド | 呼吸器系への抑制性核酸分子の治療的送達 |
USD583463S1 (en) | 2007-04-30 | 2008-12-23 | Sun Pharma Advanced Research Company Limited | Inhaler |
WO2009008001A2 (en) | 2007-04-30 | 2009-01-15 | Sun Pharma Advanced Research Company Limited | Inhalation device |
USD577815S1 (en) | 2007-04-30 | 2008-09-30 | Sun Pharma Advanced Research Company Limited | Inhaler |
EP1992378A1 (en) | 2007-05-16 | 2008-11-19 | Boehringer Ingelheim Pharma GmbH & Co. KG | Dispensing device |
CA2688689C (en) | 2007-05-16 | 2015-06-30 | Mystic Pharmaceuticals, Inc. | Combination unit dose dispensing containers |
USD579547S1 (en) | 2007-06-07 | 2008-10-28 | Novartis Ag | Inhaler |
BRPI0812768A2 (pt) | 2007-06-08 | 2014-12-02 | Massachusetts Inst Technology | Igf para o tratamento de síndrome de rett e transtornos sinápticos. |
JP5485148B2 (ja) | 2007-06-21 | 2014-05-07 | カラ セラピューティクス インコーポレイテッド | 置換イミダゾ複素環 |
CN101795723B (zh) | 2007-07-06 | 2013-06-19 | 蒙塔设备有限公司 | 用于存储和输送药物的吸入装置 |
WO2009046072A1 (en) | 2007-10-02 | 2009-04-09 | Baxter International Inc | Dry powder inhaler |
EP2048112A1 (en) | 2007-10-09 | 2009-04-15 | Kemira Kemi AB | Use of a nozzle for manufacturing sodium percarbonate |
MX2010004510A (es) | 2007-10-24 | 2010-07-02 | Mannkind Corp | Metodo para prevenir los efectos nocivos de peptido 1 tipo glucagon (glp-1). |
US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
AU2008316636B2 (en) | 2007-10-24 | 2014-02-06 | Mannkind Corporation | Delivery of active agents |
JP5350388B2 (ja) | 2007-10-25 | 2013-11-27 | ノバルティス アーゲー | 単位用量薬物パッケージの粉体調整 |
GB0721394D0 (en) | 2007-10-31 | 2007-12-12 | Vectura Group Plc | Compositions for trating parkinson's disease |
BRPI0817384A2 (pt) | 2007-11-06 | 2015-03-31 | 3M Innovative Properties Co | "método para a fabricação de um dispositivo, dispositivo para inalação e dispositivo ou componente" |
CN101317821B (zh) | 2007-11-15 | 2012-01-04 | 陈晓东 | 适用于肺部给药的超细干粉颗粒及其制备方法 |
EP2060268A1 (en) | 2007-11-15 | 2009-05-20 | Novo Nordisk A/S | Pharmaceutical compositions for pulmonary or nasal delivery of peptides |
EP2230934B8 (en) | 2007-12-14 | 2012-10-24 | AeroDesigns, Inc | Delivering aerosolizable food products |
USD594753S1 (en) | 2007-12-14 | 2009-06-23 | The Procter & Gamble Company | Blister card |
WO2009082343A1 (en) | 2007-12-20 | 2009-07-02 | Astrazeneca Ab | Dispenser and method for entraining powder in an airflow 537 |
US7584846B2 (en) | 2007-12-21 | 2009-09-08 | S.C. Johnson & Son, Inc. | Shaped packaging for a refill |
CA2728808A1 (en) | 2008-02-01 | 2009-08-06 | Vectura Limited | Pulmonary formulations of triptans |
GB0802028D0 (en) | 2008-02-05 | 2008-03-12 | Dunne Stephen T | Powder inhaler flow regulator |
USD614045S1 (en) | 2008-02-22 | 2010-04-20 | Ima Safe S.R.L. | Blister packaging |
CA2719205C (en) | 2008-03-27 | 2017-04-25 | Mannkind Corporation | A dry powder inhalation system |
CA2720864C (en) | 2008-04-07 | 2017-07-04 | National Institute Of Immunology | Compositions useful for the treatment of diabetes and other chronic disorder |
DE102008023376A1 (de) | 2008-05-13 | 2009-11-19 | Alfred Von Schuckmann | Spender für in einer gesonderten Verpackung enthaltenen, pulverförmigen Massen |
US8834930B2 (en) | 2008-05-15 | 2014-09-16 | Novartis Ag | Pulmonary delivery of a fluoroquinolone |
USD597418S1 (en) | 2008-05-22 | 2009-08-04 | Wm. Wrigley Jr. Company | Blister card |
USD598785S1 (en) | 2008-05-22 | 2009-08-25 | Wm. Wrigley Jr. Company | Blister card |
USD614760S1 (en) | 2008-06-13 | 2010-04-27 | Mannkind Corporation | Dry powder inhaler |
USD605752S1 (en) | 2008-06-13 | 2009-12-08 | Mannkind Corporation | Dry powder inhaler |
USD613849S1 (en) | 2008-06-13 | 2010-04-13 | Mannkind Corporation | Cartridge for a dry powder inhaler |
USD605753S1 (en) | 2008-06-13 | 2009-12-08 | Mannkind Corporation | Cartridge for a dry powder inhaler |
USD604832S1 (en) | 2008-06-13 | 2009-11-24 | Mannkind Corporation | Cartridge for a dry powder inhaler |
CN104689432B (zh) | 2008-06-13 | 2018-07-06 | 曼金德公司 | 干粉吸入器和用于药物输送的系统 |
USD597657S1 (en) | 2008-06-13 | 2009-08-04 | Mannkind Corporation | Dry powder inhaler |
USD604833S1 (en) | 2008-06-13 | 2009-11-24 | Mannkind Corporation | Dry powder inhaler |
USD635241S1 (en) | 2008-06-13 | 2011-03-29 | Mannkind Corporation | Dry powder inhaler |
US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
JP5479465B2 (ja) | 2008-06-20 | 2014-04-23 | マンカインド コーポレイション | 吸入努力をリアルタイムにプロファイルする対話式機器および方法 |
TWI494123B (zh) | 2008-08-11 | 2015-08-01 | Mannkind Corp | 超快起作用胰島素之用途 |
USD635242S1 (en) | 2008-12-01 | 2011-03-29 | Mannkind Corporation | Dry powder inhaler |
USD629887S1 (en) | 2008-12-01 | 2010-12-28 | Mannkind Corporation | Dry powder inhaler |
USD629888S1 (en) | 2008-12-01 | 2010-12-28 | Mannkind Corporation | Dry powder inhaler |
USD629505S1 (en) | 2008-12-01 | 2010-12-21 | Mannkind Corporation | Dry powder inhaler |
USD629886S1 (en) | 2008-12-01 | 2010-12-28 | Mannkind Corporation | Dry powder inhaler |
USD635243S1 (en) | 2008-12-01 | 2011-03-29 | Mannkind Corporation | Dry powder inhaler |
USD629506S1 (en) | 2008-12-01 | 2010-12-21 | Mannkind Corporation | Dry powder inhaler |
CA2748490C (en) | 2008-12-29 | 2016-10-04 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
US8314106B2 (en) * | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
US8550074B2 (en) | 2009-01-15 | 2013-10-08 | Manta Devices, Llc | Delivery device and related methods |
CA2791847C (en) | 2009-03-04 | 2017-05-02 | Mannkind Corporation | An improved dry powder drug delivery system |
PL2405963T3 (pl) | 2009-03-11 | 2014-04-30 | Mannkind Corp | Urządzenie, układ i sposób pomiaru oporu inhalatora |
CA2992927A1 (en) | 2009-03-18 | 2010-09-23 | Mannkind Corporation | Inhaler adaptor for a laser diffraction apparatus and method for measuring particle size distribution |
GB0907425D0 (en) | 2009-04-29 | 2009-06-10 | Glaxo Group Ltd | Compounds |
USD626836S1 (en) | 2009-04-30 | 2010-11-09 | Bryce Lien | Bottle cap |
USD628090S1 (en) | 2009-05-07 | 2010-11-30 | Mccormick & Company, Incorporated | Seasoning package |
USD620375S1 (en) | 2009-05-11 | 2010-07-27 | Mcneil-Ppc, Inc. | Blister |
MY159925A (en) | 2009-05-21 | 2017-02-15 | Microdose Therapeutx Inc | Rotary cassette system for dry powder inhaler |
CN107412212B (zh) | 2009-05-29 | 2021-01-22 | 珍珠治疗公司 | 经肺递送长效毒蕈碱拮抗剂及长效β2肾上腺素能受体激动剂的组合物及相关方法与系统 |
EP2440184B1 (en) | 2009-06-12 | 2023-04-05 | MannKind Corporation | Diketopiperazine microparticles with defined specific surface areas |
MY172858A (en) | 2009-06-12 | 2019-12-12 | Mannkind Corp | Diketopiperazine microparticles with defined isomer contents |
US9180263B2 (en) | 2009-07-01 | 2015-11-10 | Microdose Therapeutx, Inc. | Laboratory animal pulmonary dosing device |
WO2011017554A2 (en) | 2009-08-07 | 2011-02-10 | Mannkind Corporation | Val (8) glp-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome |
WO2011031564A2 (en) * | 2009-08-27 | 2011-03-17 | Stc.Unm | Methods and systems for dosing and coating inhalation powders onto carrier particles |
IT1395945B1 (it) | 2009-09-30 | 2012-11-02 | Oliva | Inalatore perfezionato per preparati in polvere |
USD647195S1 (en) | 2009-10-09 | 2011-10-18 | Vectura Delivery Devices Limited | Inhaler having cover |
USD647196S1 (en) | 2009-10-09 | 2011-10-18 | Vectura Delivery Devices Limited | Inhaler having cover |
WO2011056889A1 (en) | 2009-11-03 | 2011-05-12 | Mannkind Corporation | An apparatus and method for simulating inhalation efforts |
USD650295S1 (en) | 2009-11-13 | 2011-12-13 | Avidiamed Gmbh | Blister pack for pharmaceuticals |
CN102686261B (zh) | 2009-12-23 | 2014-09-10 | Map药物公司 | 增强型的喷射器设计 |
CN102111798A (zh) | 2009-12-29 | 2011-06-29 | 中兴通讯股份有限公司 | 一种td-scdma模拟测试信号的生成方法和装置 |
US20130190244A1 (en) | 2009-12-31 | 2013-07-25 | Stealth Peptides International, Inc. | Methods for performing a coronary artery bypass graft procedure |
AU332056S (en) | 2010-01-08 | 2010-08-04 | Teva Pharma Ireland | Inhaler |
USD641076S1 (en) | 2010-03-26 | 2011-07-05 | Oriel Therapeutics, Inc. | Dry powder inhaler |
PT105065B (pt) | 2010-04-26 | 2012-07-31 | Hovione Farmaciencia S A | Um inalador simples de cápsulas |
GB201006901D0 (en) | 2010-04-26 | 2010-06-09 | Sagentia Ltd | Device for monitoring status and use of an inhalation or nasal drug delivery device |
USD645954S1 (en) | 2010-05-21 | 2011-09-27 | Consort Medical Plc | Mechanical dosage counter apparatus |
USD636867S1 (en) | 2010-06-14 | 2011-04-26 | Mannkind Corporation | Dry powder inhaler |
USD636868S1 (en) | 2010-06-14 | 2011-04-26 | Mannkind Corporation | Dry powder inhaler |
USD636869S1 (en) | 2010-06-14 | 2011-04-26 | Mannkind Corporation | Dry powder inhaler |
RU2571331C1 (ru) | 2010-06-21 | 2015-12-20 | Маннкайнд Корпорейшн | Системы и способы доставки сухих порошковых лекарств |
CN101851213A (zh) | 2010-06-21 | 2010-10-06 | 于清 | 3,6-双(4-双反丁烯二酰基氨丁基)-2,5-二酮哌嗪及其盐取代物的合成方法 |
CA2808469A1 (en) | 2010-08-19 | 2012-02-23 | Sanofi-Aventis Deutschland Gmbh | Method and system for determining information related to a drug reservoir using an electronic sensor |
USD643308S1 (en) | 2010-09-28 | 2011-08-16 | Mannkind Corporation | Blister packaging |
DK3470057T3 (da) | 2010-09-29 | 2021-11-22 | Pulmatrix Operating Co Inc | Kationiske tørpulvere omfattende magnesiumsalt |
EP2637657B1 (en) | 2010-11-09 | 2019-05-22 | MannKind Corporation | Composition comprising a serotonin receptor agonist and a diketopiperazine for treating migraines |
CA140810S (en) | 2010-12-01 | 2012-05-23 | Teva Pharma | Inhaler cap |
USD642483S1 (en) | 2010-12-03 | 2011-08-02 | Mccormick & Company, Incorporated | Seasoning package |
MX346331B (es) | 2011-02-10 | 2017-03-15 | Mannkind Corp | Formación de bis-3, 6-(4-aminoalquil) - 2, 5-dicetopiperazina con n protegido. |
DK2694402T3 (en) | 2011-04-01 | 2017-07-03 | Mannkind Corp | BLISTER PACKAGE FOR PHARMACEUTICAL CYLINDER AMPULS |
WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
TR201900670T4 (tr) | 2011-08-01 | 2019-02-21 | Univ Monash | İnhalasyon için yöntem ve formülasyon. |
USD674893S1 (en) | 2011-10-20 | 2013-01-22 | Mannkind Corporation | Inhaler device |
AU2012328885B2 (en) | 2011-10-24 | 2017-08-31 | Mannkind Corporation | Methods and compositions for treating pain |
CN102436238B (zh) | 2011-11-03 | 2014-04-16 | 广东轻工职业技术学院 | 基于生产线数据采集及信息管理系统的数据采集方法 |
RU2014143116A (ru) | 2012-04-27 | 2016-06-20 | Маннкайнд Корп | Способы синтеза этилфумаратов и их применение в качестве промежуточных соединений |
AU2013289957B2 (en) | 2012-07-12 | 2017-02-23 | Mannkind Corporation | Dry powder drug delivery systems and methods |
US20150231067A1 (en) | 2012-08-29 | 2015-08-20 | Mannkind Corporation | Method and composition for treating hyperglycemia |
WO2014066856A1 (en) | 2012-10-26 | 2014-05-01 | Mannkind Corporation | Inhalable influenza vaccine compositions and methods |
CN103110611A (zh) | 2012-12-11 | 2013-05-22 | 苏州惠仁生物科技有限公司 | 吸入剂及其制备方法与普鲁兰糖作为吸入剂载体的应用 |
USD711740S1 (en) | 2013-01-22 | 2014-08-26 | H204K9, Inc. | Bottle cap |
EP3587404B1 (en) | 2013-03-15 | 2022-07-13 | MannKind Corporation | Microcrystalline diketopiperazine compositions, methods for preparation and use thereof |
BR112016000937A8 (pt) | 2013-07-18 | 2021-06-22 | Mannkind Corp | formulações farmacêuticas de pó seco, método para a fabricação de uma formulação de pó seco e uso de uma formulação farmacêutica de pó seco |
JP2016530930A (ja) | 2013-08-05 | 2016-10-06 | マンカインド コーポレイション | 通気装置及び方法 |
GB201319265D0 (en) | 2013-10-31 | 2013-12-18 | Norton Waterford Ltd | Medicament inhaler |
WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
USD771237S1 (en) | 2014-10-02 | 2016-11-08 | Mannkind Corporation | Mouthpiece cover |
US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
SG11201806304PA (en) | 2016-01-29 | 2018-08-30 | Mannkind Corp | Dry powder inhaler |
CA3225148A1 (en) | 2016-05-19 | 2017-11-23 | Mannkind Corporation | Apparatus, system and method for detecting and monitoring inhalations |
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