CN1116030C - 吸入性组合物 - Google Patents
吸入性组合物 Download PDFInfo
- Publication number
- CN1116030C CN1116030C CN94192867A CN94192867A CN1116030C CN 1116030 C CN1116030 C CN 1116030C CN 94192867 A CN94192867 A CN 94192867A CN 94192867 A CN94192867 A CN 94192867A CN 1116030 C CN1116030 C CN 1116030C
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- polypeptide
- composition
- enhancer
- reinforcing agent
- surfactant
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Abstract
药物组合物，含有药效活性多肽和促进多肽在患者肺中吸收的增强剂的混合物，该混合物为干粉剂型，其中粒径等于或小于10微米(μm)的主要颗粒至少占多肽和增强剂总量的50%；其主要颗粒可任选形成凝聚物；以及该药物组合物的吸入给药方法。
Description
本发明涉及药用肽和蛋白质的给药方法及其组合物。
本发明背景
虽然DNA重组技术的出现使肽基药物名单迅速扩大，但是肽基药物的治疗有一个较大缺点，严重地妨碍了在本领域的充分利用。一般肽基药物的口服疗法不能达到有效的剂量，因为它在进入血流之前，已被胃肠道中的酶迅速降解。除非能够改变这种多肽，使之较好地耐受这些酶，唯一的实用给药方法可能是非肠道途径，例如静脉注射、肌肉注射或皮下注射。其它非肠道途径(如经鼻、口腔或直肠粘膜或者经肺吸收)给药的成功率较低。
本发明概要
已发现，当肽或蛋白质(以后统称多肽)与一种合适的吸收增强剂合用并以粒度合适的粉剂送入肺内时，它会从下呼吸道的上皮细胞层吸收而易于进入肺循环。用一个吸入装置吸入这种粉剂方便易行，该吸入装置可将多肽粉剂/增强剂度配成正确的剂量(当对着口腔和咽喉吸入时)使其最大地沉着在下呼吸道。(方便起见，多肽和增强剂以后一起称作“活性化合物”)。为实现这一送入肺内的方式，活性化合物的粒径应尽可能约小于10μm(即0.01-10μm，最好为1-6μm)。在优选实施方案中，吸入装置中＜10μm颗粒的活性化合物至少占总量的50％(优选至少占60％，更优选至少占70％，很好的至少达80％，最好的至少占90％)使从吸入装置送出的活性化合物粒度达到所需的范围。
本发明包括一种药用组合物，其中含有活性化合物(A)药效活性多肽及(B)能促进多肽在患者下呼吸道(最好在肺部)全身性吸收的增强剂的混合物，该混合物为一种适于吸入的干粉剂，其中：直径小于或等于10微米的主要颗粒至少占活性化合物(A)和(B)的50％。这些主要颗粒可以包裹起来，或者可以任选地形成凝聚物，然后在进入患者呼吸道前进行解聚。该组合物当然可以含有其它需要的成分，包括其它药效活性成分、其它增强剂以及药用赋形剂如稀释剂或载体。因此，本发明的治疗制剂可以只含有上述活性化合物或者含有其它物质，例如药用载体。这种载体大部分由粒径约小于10微米的颗粒组成，这样，任选凝聚的粒径约小于10微米的主要颗粒在整个所得粉末中至少占50％；载体也可含有许多较大的颗粒(“粗粒”)；这样，在活性化合物和所述载体之间形成一种“给定混合物”。在给定混合物中(也可认为是一种相互作用或粘附的混合物)，细小药物颗粒(本发明中的活性化合物))是十分均匀地分布在粗赋形剂颗粒上(本发明中的药用载体)。优选活性化合物在做成给定混合物前最好不是凝聚物。粗粒的直径可以大于20微米，例如大于60微米。超过这些低限时，粗粒的直径并不十分重要，因此可以根据特定制剂的实际需要而使用各种粗粒。给定混合物中粗粒不必具有相同的粒度，但是在给定混合物中具有相同粒度的粗粒更为有利。粗粒的直径最好为60至800微米。
需用于全身性给药的多肽是药用或诊断用的中小大小的肽或蛋白质，即分子量至多为约40千道尔顿。虽然，改进吸收的程度随多肽分子量和理化性质和所用特定的增强剂而异，但是按照本发明改进多肽吸收的机制是普遍适用的，并且可用于所有这样的多肽。分子量至多约为30千道尔顿的多肽很适用于本发明，例如分子至多为25千道尔顿或至多20千道尔顿，特别是至多15千道尔顿或至多10千道尔顿的多肽。利用本文所述的体内或体外试验易于检测本发明中所要求的任何多肽与所用的具体增强剂。
用于本发明组合物的增强剂可以是任一种能促进多肽在下呼吸道上皮吸收而进入体循环的化合物。“促进吸收”意指在使用增强剂的情况下吸收后进入体循环的多肽量高于不用增强剂时。在使用增强剂时所吸收的多肽量显著增高(p＜0.05)。利用本文所述的体内或体外试验便于评价本发明中任何可能有效的增强剂的适用性。
按照本发明的方法所吸收的多肽量至少达到不使用增强剂时的150％。在优选的实施方案中，存在增强剂时多肽的吸收量至少比不用增强剂时增加1倍，较好的增加2倍，很好的增加3倍。
可选用的增强剂是一种表面活性剂，如脂肪酸盐、胆汁酸盐、胆汁酸盐的衍生物、烷基糖苷、环糊精或磷脂。例如，增强剂可以用脂肪酸的钠盐、钾盐或有机胺盐，并且脂肪酸可选用癸酸或10-14个碳原子的脂肪酸。优选的增强剂是癸酸钠。多肽与增强剂可选用比优选为约9∶1至1∶1。尽管增强剂的比例大于1∶1时其吸收程度可能与比例小的一样或者更大，但是所用增强剂的量被认为是不应大于产生所需增强作用的必需量，因为过量的增强剂可引发不良副作用，如局部刺激。
本发明还包括全身性施用药效活性多肽的方法，该方法是使患者吸入本发明的混合药物，其中进入呼吸道的粒径小于或等于10微米的药粒至少占活性化合物总量的50％。这种方法优选通过使用吸入装置让患者吸入这种药粉而得以实现。当粉状组合物的主要颗粒为凝聚物时，该吸入装置优选设计成在患者从其中吸入药粉时可使凝聚物大量解聚，这样，在药粉进入患者呼吸系统之前，大部分凝聚物破裂成直径约小于或等于10微米的药粒。这一解聚作用发生在该装置内部，并由吸入的力量使装置中产生的气流诱发解聚。凝聚物一般不会在给定混合物中形成。在给定混合物中，活性化合物应在吸入时从大部分颗粒中释出，或者通过机械方法在吸入装置中或仅仅通过吸入而释出，或者通过其它方式释出，然后活性化合物沉着在下呼吸道，载体颗粒落在口腔内。
吸入装置最好只是一次剂量的干粉吸入器，但也可以是多次剂量的干粉吸入器。
本发明也包括生产适于吸入给药的药用组合物的方法。一种方法是，首先提供一种溶液，其中溶有(a)药效活性的多肽和(b)可促进多肽在患者下呼吸道系统吸收的增强化合物。然后将溶剂从溶液中除去而得到一种含有多肽和增强剂的干燥固体，再将干燥固体粉碎而得药粉。第二种方法包括干法混合(a)药效活性的多肽和(b)增强剂化合物，并且微粉粉碎所得的混合物。第三种适当的方法包括首先得到含有多肽的微粉化制剂，其次得到含有增强剂化合物的微粉化制剂，然后将两种微粉化制剂混合均匀，除了所需的给定混合物外，在含有载体时，可加入溶液中或在微粉化粉碎前加入药效活性多肽进行干燥混合，或者将微粉化的载体与其它微粉化的成分进行干燥混合。在生产给定混合物时，将微粉化的多肽和增强剂与适当的载体混合。
附图的简要说明
图1示明不同浓度的癸酸钠增强剂对单层培养的上皮细胞转运标记物(甘露醇)的影响。
图2示明不同浓度的癸酸钠增强剂在多肽存在下(癸酸钠与多肽的重量比为1∶3)对单层培养的上皮细胞转运标记物(甘露醇)的影响。
图3显示单独吸入多肽、吸入比例为90∶10的多肽和癸酸钠、吸入比例为75∶25多肽和癸酸钠后的血浆多肽浓度对时间的函数。
详细说明
本发明的一些优选的实施方案在下文中作一般描述。多肽
除胰岛素外多肽优选肽类激素，如加压素、加压素类似物、去氨加压素、胰高血糖素、促肾上腺皮质激素(ACTH)、促性腺激素(促黄体生成素或促黄体激素释放因子LHRH)、降钙素、胰岛素的C-肽、甲状旁腺激素(PTH)、人生长激素(hGH)、生长激素(HG)、生长激素释放激素(GHRH)、催产素、促皮质素释放激素(CRH)、生长激素释放抑制因子类似物、促性腺激素激动剂类似物(GnRHa)、前房促尿钠排泄肽(hANP)、促甲状腺激素释放激素(TRHrh)、促卵泡生成激素(FSH)及催乳激素。
其它可能的多肽包括生长因子、白细胞介素、多肽疫苗、酶、内啡肽、糖蛋白、脂蛋白及参与凝血链的多肽类，这些药物可呈现全身性药理作用。可以预料，这些分子量个到中等，有较大水溶性和等电点在pH3至pH8之间的多肽，如果不是全部，那么大部分也均可使用本发明的方法进行有效的给药。增强剂
促进吸收的增强剂的使用特别关键，因为单独的多肽很难通过肺吸收。所用的增强剂可以是促进下呼吸道上皮细胞层吸收并进入相邻肺血管的任何一种化合物。增强剂可以通过以下任何一种可能的机制达到上述要求：
(1)通过改变上皮细胞间的严密连接结构而促进细胞间对多肽的通透性。
(2)通过与膜蛋白质或脂组分相互作用或消除这些组分从而失去膜的完整性而增强细胞对多肽的通透性。
(3)增强剂与多肽间的相互作用，这种作用增加多肽的水溶性。可用阻止形成胰岛素聚集体(二聚体、三聚体、六聚体)的方法或通过在增强剂胶团中增溶多肽分子而实现。
(4)降低肺泡和肺通道粘液屏障的粘稠度或溶解肺泡和肺通道粘液屏障，从而使上皮表面外露，以致直接吸收多肽。
增强剂可以通过上述单一机制或更多机制，发挥其作用。应用多种机制作用的增强剂比只用一种或两种机制的增强剂更可能有效地促进吸收多肽。
例如，表面活性剂被认为是通过上述所有四种机制起作用的一类增强剂。表面活性剂是同时具有亲脂性和亲水性部分的两性分子，而这两种性质间不保持平衡。如果是非常亲脂的分子，则其水中的低溶解度将会限制其使用。如果亲水性部分显著占优势，那么分子的表面活性特性将变得最小。为使其有效，表面活性剂必须在足够的溶解度和足够的表面活性之间达到适当的平衡。
表面活性剂的另一个重要的性质是在肺内pH值(约7.4)时维持表面活性剂的净电荷。pH为7.4时，一些多肽带有净负电荷。这将导致分子间的静电排斥，由此防止了聚集作用，因而增加了溶解度。如果表面活性剂也带负电，那么由于疏水性相互作用它便能与多肽产生相互作用，并且在多肽分子间发生一种排斥现象。在这种情况下，阴离子表面活性剂具有另一个优点(与那些生理性pH时为中性或净正电荷的表面活性剂相比)，它使多肽处于单(分子物)体状态而促进其吸收。
本发明方法中可能用作增强剂的各种化合物可用大鼠进行测试，如下面实施例2所述。其它已知具有促进吸收作用的物质或具有本发明方法中能用作候选增强剂的物理性质的物质均可以用一种普通的整体动物试验进行检测，或用实施例1中所述体外试验进行检测。
两种或多种增强剂合用也可能得到令人满意的结果。在本发明的方法中合用增强剂被认为是本发明的范围。
用于本发明的增强剂应能有效地促进多肽的吸收，同时还应具有(1)所用的浓度无毒及(2)良好的粉质，即不呈粘性或蜡样稠度的固体。所用物质的毒性可通过标准方法检测，例如MTT检测法(如在Int.J.Pharm.，65(1990)，249-259所述)。所用物质的粉质可通过该物质已公布的数据确定，或者凭经验确定。
一类很有前景的增强剂是脂肪酸盐。已发现碳链长度为10(即癸酸钠)、12(月桂酸钠)及14(肉豆蔻酸钠)个碳的饱和脂肪酸钠盐在本发明的方法中使用具有良好性能。癸酸的钾盐和赖氨酸盐也发现在本发明的方法中有效。如果碳链的长度小于10个碳，表面活性剂的表面活性就太低；如果碳链长度大于14个碳，脂肪酸在水中的溶解度就会降低，而限制了它的应用。
本发明促进下呼吸道吸收多肽的优选物质为癸酸钠。
各种抗衡离子可以改变饱和脂肪酸盐在水中的溶解度，以致证实碳链长度不是10-14个碳的增强剂会优于上文中特别提到的增强剂。不饱和脂肪酸盐也可用于本发明，因为它比饱和脂肪酸盐更易溶于水，因而它的碳链可比后者更长而同时仍能保持有效促进多肽吸收所需的溶解度。
所有测试的胆汁盐和胆汁盐衍生物(乌索脱氧胆酸、牛磺胆酸、甘胆酸及牛磺二氢褐霉酸(taurodihydrofusidate)的钠盐)可有效地促进多肽在肺中的吸收。
磷脂已被测试作为增强剂。发现单链磷脂(溶血卵磷脂)是一个有效的增强剂，而两个双链的磷脂(二辛酰磷脂酰胆碱和二癸酰磷脂酰胆碱)则否。这可以通过双链磷脂比其单链对应物在水中更不易溶解的事实进行解释，但是，期望短双链磷脂的水溶性优于长双链磷脂，短双链磷脂用作本发明的增强剂是合理的，这样单链和双链磷脂都可用作增强剂。
检测用作本发明增强剂的一种葡萄糖苷，即辛基吡喃葡糖苷，发现它具有一些增强吸收的性质。其它烷基糖苷，例如硫代吡喃葡糖苷和吡喃麦芽糖苷也预计在本发明方法中呈现促进吸收的性质。
环糊精及其衍生物可有效地增强鼻吸收，在肺中也有相似的作用。二甲基-β-环糊精经测试后，发现具有增强吸收的作用。
其它可能有用的表面活性剂为水杨酸钠、5-甲氧水杨酸钠和天然存在的表面活性剂，如甘草酸盐、皂角苷及酰基肉碱。
离子型增强剂(例如上述阴离子表面活性剂)的抗衡离子的性质是很重要的。所选的特殊抗衡离子可影响增强剂或含有增强剂的任一制剂的粉质的溶解度、稳定性、吸湿性及局部或全身性毒性。其也可影响与之合用的多肽的稳定性和/或溶解度。一般预计一价金属阳离子如钠、钾、锂、铷和铯可用作阴离子增强剂的抗衡离子。氨和有机胺形成另一类阳离子，预计它们适用于带有羧酸部分的阴离子增强剂。这些有机胺的实例包括乙醇胺、二乙醇胺、三乙醇胺、2-氨基-2-甲基乙胺、甜菜碱、1，2-乙二胺、N，N-二苄基亚乙基四胺、精氨酸、六亚甲基四胺、组氨酸、N-甲基哌啶、赖氨酸、哌嗪、亚精胺、精胺及三(羟甲基)氨基甲烷。
由于观察到许多所测试的增强剂可以有效地促进多肽在肺中吸收，预计还可发现许多有类似功能的增强剂。微球淀粉粒状可有效地提高经鼻粘膜方式给药的多肽的生物利用度，并且经测试可用作本发明方法的增强剂。尽管在所用本动物模型中发现经肺途径给药几乎没有效用，但是这主要是由于技术的障碍，如果克服后，可能会成功地经肺途径给药。
络合物被认为是一类结合钙离子而发挥作用的增强剂。因为钙离子有助于维持细胞间隙的宽度并且也可降低多肽的溶解度，所以这些离子结合理论上既可增加多肽的溶解度，又能增加多肽对副细胞(paracellular)的渗透性。虽然测试了一种乙二胺四乙酸(EDTA)钠盐的络合物，但是经大鼠模型测试中发现不增加胰岛素的吸收，而其它与钙离子结合的络合剂可能会更有用。多肽与增强剂的比例
多肽和增强剂的相对比例可根据需要而不同。应有足量的增强剂以使吸入的多肽有效地吸收，但是，增强剂的含量尽可能地少以此降低增强剂所引起的不良作用。尽管每种特定多肽与增强剂的混合物必须测试以确定其最佳比例，但是要获得多肽的适宜的吸收量，多肽与增强剂的混合物中增强剂必须多于10％；对于大多数增强剂而言，增强剂的比例应大于15％或大于20％，优选在25％与50％之间。每种多肽和增强剂(或多肽、增强剂和稀释剂)的混合物的优选比例可以通过一种普通药理学技术的标准方法并采用如下指标，如吸收效果、恒定的最佳吸入剂量、最小的副作用及适宜的吸收速率，加以测定。
制剂中不再需要其它的成分，但是，如果需要也可添加，例如，可用药用稀释剂稀释粉末的办法来增加由给定多肽/表面活性剂混合物的单一剂量中的药粉量(如用于所设计的吸入装置要求每个剂量有很大的药粉体积时)。可含有其它添加剂以便于加工或改善药粉的性质或制剂的稳定性。加入调味剂时一部分药粉会不可避免地沉着于口腔和咽喉而为患者提供正反馈，即这是从吸入装置送药时产生的。任何这样的添加剂应具有如下性质：(a)稳定且不对多肽和增强剂的稳定性不产生不良影响；(b)不消极地干扰多肽的吸收；(c)具有良好的粉剂性质在药学领域中理解该术语；(d)不吸湿；及(e)所用的浓度对气道无不良影响。有用的添加剂的类型有单糖、二糖及多糖，糖醇及其它多元醇：例如乳糖、葡萄糖、棉子糖、松三糖、乳糖醇、麦芽糖醇、海藻糖、蔗糖、甘露醇和淀粉。还原糖如乳糖和葡萄糖趋于与蛋白质形成复合物，非还原糖例如棉子糖、松三糖、乳糖醇、麦芽糖醇、海藻糖、蔗糖、甘露醇和淀粉是优选用于本发明的添加剂。这些添加剂的组成在任何时候可占总制剂的0％(即没有添加剂)至将近100％。
在一个优选的实施方案中，本发明提供了一种药效活性的多肽及促进下呼吸道吸收上述多肽的治疗制剂，该制剂可做成适于吸入的干粉制剂，其中(a)直径小于10微米的颗粒或(b)所述颗粒的凝聚物约占重量比的50％；在另一个优选的实施方案中，本发明提供了一种含有药效活性的多肽、可促进多肽在下呼吸道吸收的物质以及药用载体的治疗剂，该制剂为适于吸入的干粉剂型，其中(a)直径小于10微米颗粒或(b)所述颗粒的凝聚物至少占重量比的50％；另外一个优选的实施方案中，本发明提供了一种含有活性化合物(A)药效活性多肽和(B)促进所述多肽在下呼吸道吸收的物质和药用载体的治疗制剂，其中活性化合物(A)和(B)的直径小于10微米的颗粒至少占重量比的50％，该制剂为适于吸入的干粉剂型，其中给定的混合物在活性化合物及药用载体间形成。
所述粉剂可以用若干种常规技术方法进行生产。许多情况下，纯化的多肽可由市售获得。另外，可从天然资源中用标准生化技术纯化多肽，或者通过表达原核或真核细胞(包括为制备所需多肽或蛋白质(例如在乳中)而经遗传工程技术处理的转基因动物)而获得所述多肽，所述原核或真核细胞是经过遗传工程技术处理过的，其中含有编码所述多肽的核苷酸序列，并且该核苷酸序列上连有合适的表达控制序列。这些方法是本领域的标准方法(例如，见Sambrook et al.，Molecular Cloning：A laboratory Manual；Cold SpringHarbor Laboratory Press，Cold Spring Harbor，NY，1989)。肽类(即，具有30个或更少些氨基酸残基的多肽)也可用已知的化学方法合成。
上述吸收增强剂一般也可从市售得到，或者用公开的方法生产。对离子型增强剂而言，与增强剂相关的抗衡离子可以用其它离子替换，如果需要，可用标准的离子交换技术处理。
生产所述粉剂时，在某个生产过程中，为了获得粒度范围适于在下呼吸道产生最大沉着的主要颗粒(即，＜10微米)，一般需要在合适的粉碎机(如射流粉碎机)中将药粉粉碎。例如，可以将多肽与增强剂粉进行干燥混合，然后将其粉碎；另一方法，可以将物质分别粉碎，然后混合。当需混合的化合物具有不同的物理性质(如硬度和脆性)而对粉碎的耐力不同时，需要用不同的压力才能粉碎成合适的粒度。因此，在一起粉碎时，所获得的某种成分的粒度会不令人满意。在这种情况下，最好是将不同的组分分别进行粉碎，然后混合。
也可以先将各组分溶于适当的溶剂(如水)中以获得在分子水平的混合。这一方法也可以将pH值调到所需的水平，例如改善多肽的吸收。必须考虑吸入产品的药用pH限制值为pH3.0至8.5，因为超过这一限值范围的产品会引起气道的刺激及收缩。为了得到这种粉剂，必须通过一种保留多肽生物活性的方法除去溶剂。适当的干燥方法包括真空浓缩、敞口干燥、喷雾干燥及冷冻干燥。一般应避免数分钟超过温度40℃，因为某些多肽会发生一些降解。干燥后，固态物，如果需要，可以磨碎而获得粗粉，然后，如果需要，进行粉碎。
如有必要，在装入预定的吸入装置前，可以加工粉碎好的药粉以改善其流动性质，例如通过干燥成粒使之具有良好输送性能的球形凝聚物。在这种情况下，该装置构形应做成确保凝聚物在排出装置前彻底解聚，这样进入患者呼吸道的粉粒大部分在所要求的粒度范围内。当需要给定混合物时，可以将活性化合物加工(例如，进行粉碎)，如有必要，以获得特定粒度范围内的颗粒。载体也可加工，例如为获得所需的粒度及理想的表面性状(如特殊的表面积与重量比，或者一定的坚固性)时，并在给定混合物中最佳的粘合力。给定混合物的这种物理性质与获得符合这些要求的给定混合物的各种方法一样是熟知的，并且技术人员可在特定的情况下容易进行测定。
优选的吸入装置具有下列设计性质：药粉要防潮并无偶尔增大剂量的危险；此外，尽可能地具有下列性质：药粉要避光；在大部分流速段中可吸入的药粉量和肺沉着量要多；剂量误差和可吸入的药量差异要小；面罩内药粉滞留量要小，这一点对多次剂量给药的吸入装置成为重要，因为滞留在面罩的多肽降解后可随下一次剂量一起被吸入；吸入装置表面的吸附量低，剂量的波动及吸入阻力要低。优选用单剂量吸入装置，尽管也可使用多剂量吸入装置，例如可多次剂量、有呼吸调节、用于多次使用的干粉吸入装置。最好选用单一剂量、有呼吸调节、一次使用的干粉吸入装置。
已配制了并且体内试验测试了许多含有多肽和各种增强剂的干粉制剂，并描述如下。同时在下文中描述了用于检测多肽/增强剂混合物的体外试验方法。
实施例1：测定本发明中具体多肽用途的体外试验方法
使用上皮细胞即CaCo-2(通过American Type CultureCollection(ATCC)，Rockville，MD，USA获得)的标准体外试验已发展成为评价不同增强剂化合物促进标记物通过单层上皮细胞转运的能力，这种试验作为隔离肺泡与肺血供应在肺中作用的上皮细胞层的模型。
在这种测定中，将增强剂和多肽或其它标记物按不同的比例和/或不同浓度溶于水中，滴于单层细胞的顶端。在37℃及95％的相对湿度(RH)下孵育60分钟后，测定底边外侧细胞的标记物含量，例如使用放射性同位素标记的标记物。
在测定增强剂-癸酸钠时，在底边外侧的标记物(甘露糖醇，分子量360)含量取决于所用增强剂的浓度，癸酸钠至少约为16mM(图1)。甚至当将多肽胰岛素加入增强剂/甘露糖醇混合物中(癸酸钠与胰岛素重量比为1∶3)也是如此(图2)。发现这一癸酸钠的浓度(16mM)可促进两种低分子量多肽-胰岛素(分子量5734)和加压素(分子量1208)经单层细胞的吸收。当有16mM癸酸钠时，进入单层细胞的胰岛素量为无任何增强剂时的2倍；单层细胞吸收的加压素数量为无任何增强剂时的10-15倍。
相反，在测试16mM癸酸钠时，未观察到大蛋白质，例如细胞色素C(分子量12300)、碳酸酐酶(分子量30000)及白蛋白(分子量69000)转运速率的增加。预计较高浓度的癸酸钠可进一步增加细胞的通透性，从而使较大分子量的多肽转运；但是，癸酸钠的潜在细胞毒性会妨碍使用太高浓度的这种特定增强剂。
其它增强剂可促进转运较大的多肽；这些增强剂也可用这种离体上皮细胞模型检测其通透性。这种模型能用作快速检测本发明方法中所需任何多肽/增强剂混合物用途的筛检工具。
实施例2：对本发明中所用增强剂的选择方法
表1中所列每个化合物已在大鼠模型上对促进多肽(胰岛素)的吸收能力作了测试。胰岛素的测试结果被用来作为增强剂促进其它多肽类吸收能力的指示。
在不同的试验中使用了不同的胰岛素剂型：重组的八胰岛素、半合成的人或牛胰岛素。按上述方法制备了各种制剂，干燥并加工胰岛素/增强剂或胰岛素/增强剂/乳糖溶液而得到可吸入的药粉。将药粉给大鼠吸入法用药，连续监测大鼠血糖水平以测定胰岛素的吸收程度。将这些血糖水平与吸入不含增强剂的胰岛素制剂的大鼠所得相应值进行比较。
也可用相同的动物模型体系来测定任何用于本发明方法的某种多肽或蛋白质，即将所需多肽或蛋白质与增强剂合用的制剂，采用相同的吸入给药法，并测定动物体循环中这种多肽或蛋白质的浓度(例如，采用适于测定这种多肽或蛋白质的标准免疫测定法或生化测定法)。
表1
+ 表示有效，即增强剂使血糖含量有显著性下降。- 无效或效果很小(+) 有一定效果，但不如标记“+”的效果水平。
| 化合物名称 | 增强剂∶胰岛素∶乳糖 | 效果 |
| 辛基葡萄糖苷 | 4∶4∶92 | (+) |
| 乌索脱氧胆酸钠 | 4∶4∶92 | + |
| 牛磺胆酸钠 | 4∶4∶92 | + |
| 甘胆酸钠 | 4∶4∶92 | + |
| 溶血磷脂酰胆碱 | 4∶4∶92 | + |
| 二辛酰磷脂酰胆碱 | 2∶4∶94 | (+) |
| 二癸酰磷脂酰胆碱 | 4∶4∶94 | - |
| 牛磺二氢褐霉酸钠 | 2∶4∶94 | + |
| 辛酸钠 | 25∶75∶0 | - |
| 癸酸钠 | 10∶90∶0 | (+) |
| 癸酸钠 | 17.5∶82.5∶0 | (+) |
| 癸酸钠 | 25∶75∶0 | + |
| 癸酸钠 | 4∶4∶92 | + |
| 月桂酸钠 | 25∶75∶0 | (+) |
| 油酸钾 | 4∶4∶92 | + |
| 癸酸钾 | 27∶73∶0 | + |
| 癸酸赖氨酸 | 35∶65∶0 | + |
| 肉豆蔻酸钠 | 30∶70∶0 | + |
| 二甲基-β-环糊精 | 75∶25∶0 | + |
实施例3：根据本发明的治疗用制剂
将人生长激素(hGH，分子量22kD，source Humatrope fromLilly，3份)与癸酸钠(1份)混合。混合物在Retsch射流粉碎机中粉碎至颗粒的质量平均直径(MMD)为6.7μm。
将所得药粉给大鼠气管内给药，并将hGH的吸收量与含有相同比例hGH及甘露糖醇并如上述方法制备的药粉(MMD9.6μm)相比较。
结果表明，含有癸酸钠的制剂中hGH的吸收量比没有增强剂的制剂的吸收量有所增加。
实施例4：含有多肽胰岛素的制剂
将胰岛素用作本发明其它多肽的指示物。
将生物合成的人胰岛素(53克)于压缩氮气下(进料压7bar，室内压5bar)在Airfilco射流粉碎机(商标，Airfilco ProcessPlant Limited)中粉碎，直至质量平均粒径(MMD)为2.4微米。
将癸酸钠(170克)用压缩氮气(进料压5bar，室内压3bar)的Airfilco射流粉碎机(商标)中粉碎，直至MMD为1.6微米。
粉碎的生物合成人胰岛素(45克)及癸酸钠(14.26克)按照下列步骤进行干式混合：将一半胰岛素加入4.4升混合量筒的混合装置中，该量筒用宽为1毫米的细筛分成两部分，每部分带有一个金属环，以便混合及搅拌。将混合量筒封闭，旋转180度，并置于一个电动摇动装置上。开动发动机，连续振摇约2分钟，直到所有的胰岛素和癸酸钠都通过了细筛。关掉发动机，将混合量筒旋转180度，再置于振摇装置上，然后再振摇至所有的药粉都通过了细筛。将这一步骤重复八次，使得总混合时间约为20分钟。
将由此获得的制剂以1U./kg的剂量给5只狗吸入给药，给药后测定不同时间点的血浆胰岛素浓度。
将所得的结果与上法粉碎至MMD2.4微米的合成胰岛素，并以相同剂量和方法，给5条狗后的血浆胰岛素量相比较，而且也与用胰岛素和癸酸钠的比例为90∶10的治疗制剂以相同的剂量和方法给5条狗所得血浆胰岛素水平作比较。在这种情况下，治疗制剂如下制备：将半合成人胰岛素进行凝胶过滤以使与胰岛素有关的锌含量，由0.52％降至0.01％。将胰岛素(4.5克)和癸酸钠(0.5克)溶于水中(232毫升)。搅拌溶液直至澄清，调节pH值至7.0。溶液置温度37℃下约蒸发两天，至浓缩。将所得固体饼研碎并过0.5毫米的细筛子，然后用射流粉碎机将所得的药粉粉碎至MMD为3.1微米的颗粒。
这些比较的结果如图3所示(按75∶25和100∶0比例配制的药剂的差异，p＝0.0147)。结果表明，与只含胰岛素的制剂相比，90∶10制剂中胰岛素的生物利用度有所改善，含有癸酸钠的75∶25制剂中的胰岛素生物利用度大大提高。
Claims (28)
1.一种药物组合物，其特征在于它包括活性化合物(A)除胰岛素之外的药物活性的多肽和(B)可促进所述多肽在患者下呼吸道全身性吸收的作为增强剂的表面活性剂化合物；所述表面活性剂是胆汁盐，胆汁盐衍生物，烷基糖苷，环糊精或其衍生物，单链磷脂，或脂肪酸盐；所述组合物为适于从干粉吸入器吸入到下呼吸道的干粉形式，其中，直径小于或等于约10微米的主要颗粒至少占活性化合物总量的50％，所述主要颗粒可任选形成凝聚物。
2.如权利要求1所述的药物组合物，尚含有药用载体，其组成如下：
(a)直径小于约10微米的颗粒，以使所得药粉中可任选凝聚的直径小于10微米的主要颗粒至少占50％。
(b)粗颗粒，以使给定的混合物在活性化合物和所述载体间形成。
3.如权利要求1或2所述的组合物，其中所述多肽是多肽激素。
4.如权利要求3所述的组合物，其中所述激素是加压素、加压素类似物、去氨加压素、胰高血糖素、促肾上腺皮质激素、促性腺激素、降钙素、胰岛素的C-肽、甲状旁腺激素、人生长激素、生长激素、生长激素释放激素、催产素、促皮质素释放激素、生长激素释放抑制因子类似物、促性腺激素激动剂类似物、前房促尿钠排泄肽、促甲状腺激素释放激素、促卵泡生成激素或催乳激素。
5.如权利要求1或2所述的组合物，其中所述的多肽是生长因子、白细胞介素、多肽疫苗、酶、内啡肽、糖蛋白、脂蛋白或参与凝血链过程的多肽，它在全身发挥药理作用。
6.如权利要求1所述的组合物，其中所述的多肽分子量应小于30kD。
7.如权利要求1所述的组合物，其中所述的多肽分子量应小于25kD。
8.如权利要求1所述的组合物，其中所述的多肽分子量应小于20kD。
9.如权利要求1所述的组合物，其中所述的多肽分子量应小于15kD。
10.如权利要求1所述的组合物，其中所述的多肽分子量应小于10kD。
11.如权利要求1的组合物，其中所述的表面活性剂是脂肪酸盐。
12.如权利要求1所述的组合物，其中所述的表面活性剂是胆汁盐。
13.如权利要求12所述的组合物，其中所述的胆汁盐是乌索脱氧胆酸、牛磺胆酸、甘胆酸及牛磺二氢褐霉酸的钠盐。
14.如权利要求13所述的组合物，其中所述的胆汁盐是牛磺胆酸钠。
15.如权利要求2所述的组合物，其中的药用载体选自单糖、二糖和多糖，糖醇及其它多元醇。
16.如权利要求15所述的组合物，其中的载体是非还原糖。
17.如权利要求15的组合物，其中的载体是棉子糖、松三糖、乳糖醇、麦芽糖醇、海藻糖、蔗糖、甘露醇和淀粉。
18.如前述任意一项权利要求所述的组合物，其中增强剂的含量占多肽和增强剂总量的10％以上。
19.如权利要求18所述的组合物，其中的增强剂含量占多肽和增强剂总量的15％以上。
20.如权利要求19所述的组合物，其中的增强剂含量占多肽和增强剂总量的20％以上。
21.如权利要求19所述的组合物，其中的增强剂含量占多肽和增强剂总量的25～50％。
22.一种含有权利要求1-21中任一权项所述的组合物的吸入装置。
23.权利要求22的吸入装置，其中所述的组合物是一种所述凝聚物的形式，所述装置设计成在从所述装置吸入所述凝聚物时可使大部分所述凝聚物破碎为直径小于或等于10微米的颗粒。
24.权利要求22的吸入装置，其中吸入装置是用于一次使用的单剂量、有呼吸调节的干粉吸入器。
25.权利要求22的吸入装置，其中吸入装置是用于多次使用的多剂量、有呼吸调节的干粉吸入器。
26.一种如权利要求1所述的适用于吸入给药的药用组合物的生产方法，包括
i.提供一种溶液，其中溶有(a)除胰岛素之外的药效活性的多肽和(b)促进多肽在患者下呼吸道全身性吸收的作为增强剂的表面活性剂化合物；所述表面活性剂是胆汁盐，胆汁盐衍生物，烷基糖苷，环糊精或其衍生物，或单链磷脂；
ii.从所述溶液中除去溶剂从而得到含有所述多肽和所述增强剂表面活性剂化合物的干燥固体；然后
iii.将所述干燥固体粉碎成药粉。
27.一种如权利要求1所述的适用于吸入给药的药用组合物的配制方法，包括
i.将(a)除胰岛素之外的药效活性的多肽和(b)促进多肽在患者下呼吸道全身性吸收的作为增强剂的表面活性剂化合物进行干燥混合；所述表面活性剂是胆汁盐，胆汁盐衍生物，烷基糖苷，环糊精或其衍生物，或单链磷脂；然后
ii.粉碎所得的混合物。
28.一种如权利要求1所述的适用于吸入给药的药用组合物的生产方法，包括
i.提供第一种含有除胰岛素之外药效活性多肽的粉剂，和第二种含有促进多肽在患者下呼吸道全身性吸收的作为增强剂的表面活性剂化合物的粉剂；所述表面活性剂是胆汁盐，胆汁盐衍生物，烷基糖苷，环糊精或其衍生物，或单链磷脂；
ii.将所述的第一种和第二种粉剂混合。
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9302198A SE9302198D0 (sv) | 1993-06-24 | 1993-06-24 | Powder preparation for inhalation |
| SE93021988 | 1993-06-24 | ||
| SE9302198-8 | 1993-06-24 | ||
| SE94003712 | 1994-02-04 | ||
| SE9400371A SE9400371L (sv) | 1994-02-04 | 1994-02-04 | Kompositioner för inhalation |
| SE9400371-2 | 1994-02-04 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1127471A CN1127471A (zh) | 1996-07-24 |
| CN1116030C true CN1116030C (zh) | 2003-07-30 |
Family
ID=26661779
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN94192867A Expired - Fee Related CN1116030C (zh) | 1993-06-24 | 1994-06-23 | 吸入性组合物 |
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| US (1) | US5952008A (zh) |
| EP (1) | EP0706383B1 (zh) |
| JP (2) | JPH09500621A (zh) |
| KR (1) | KR100372674B1 (zh) |
| CN (1) | CN1116030C (zh) |
| AT (1) | ATE206046T1 (zh) |
| AU (1) | AU692781B2 (zh) |
| BR (1) | BR9406908A (zh) |
| CA (1) | CA2166109C (zh) |
| CZ (1) | CZ287656B6 (zh) |
| DE (1) | DE69428442T2 (zh) |
| DK (1) | DK0706383T3 (zh) |
| EE (1) | EE03222B1 (zh) |
| EG (1) | EG21484A (zh) |
| ES (1) | ES2162865T3 (zh) |
| FI (1) | FI111909B (zh) |
| HK (1) | HK1009587A1 (zh) |
| HU (1) | HU226474B1 (zh) |
| IL (1) | IL110085A (zh) |
| IS (1) | IS1796B (zh) |
| MX (1) | MX9404762A (zh) |
| MY (1) | MY114125A (zh) |
| NO (1) | NO313080B1 (zh) |
| NZ (1) | NZ268138A (zh) |
| PL (1) | PL178261B1 (zh) |
| PT (1) | PT706383E (zh) |
| SA (1) | SA94150060B1 (zh) |
| SK (1) | SK283253B6 (zh) |
| UA (1) | UA48111C2 (zh) |
| WO (1) | WO1995000128A1 (zh) |
Families Citing this family (165)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6743777B1 (en) * | 1992-03-19 | 2004-06-01 | Eli Lilly And Company | Cyclic peptide antifungal agents and process for preparation thereof |
| US6582728B1 (en) * | 1992-07-08 | 2003-06-24 | Inhale Therapeutic Systems, Inc. | Spray drying of macromolecules to produce inhaleable dry powders |
| US6632456B1 (en) * | 1993-06-24 | 2003-10-14 | Astrazeneca Ab | Compositions for inhalation |
| US6794357B1 (en) * | 1993-06-24 | 2004-09-21 | Astrazeneca Ab | Compositions for inhalation |
| US5830853A (en) | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| 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 |
| CZ295827B6 (cs) | 1994-03-07 | 2005-11-16 | Nektar Therapeutics | Způsob aerosolizace dávky inzulinu, inzulinový přípravek a jeho použití |
| US6051256A (en) | 1994-03-07 | 2000-04-18 | Inhale Therapeutic Systems | Dispersible macromolecule compositions and methods for their preparation and use |
| US6290991B1 (en) | 1994-12-02 | 2001-09-18 | Quandrant Holdings Cambridge Limited | Solid dose delivery vehicle and methods of making same |
| US6524557B1 (en) * | 1994-12-22 | 2003-02-25 | Astrazeneca Ab | Aerosol formulations of peptides and proteins |
| CA2206657C (en) * | 1994-12-22 | 2009-05-19 | Astra Aktiebolag | Therapeutic preparation for inhalation containing parathyroid hormone, pth |
| EE9700138A (et) | 1994-12-22 | 1997-12-15 | Astra Aktiebolag | Aerosoolravimvormid |
| SE9404468D0 (sv) * | 1994-12-22 | 1994-12-22 | Astra Ab | Powder formulations |
| GB9501841D0 (en) | 1995-01-31 | 1995-03-22 | Co Ordinated Drug Dev | Improvements in and relating to carrier particles for use in dry powder inhalers |
| KR19980703876A (ko) * | 1995-04-14 | 1998-12-05 | 스티븐 엘. 허스트 | 분산성이 개선된 분말화된 약학적 조성물 |
| US6428771B1 (en) * | 1995-05-15 | 2002-08-06 | Pharmaceutical Discovery Corporation | Method for drug delivery to the pulmonary system |
| US5654007A (en) * | 1995-06-07 | 1997-08-05 | Inhale Therapeutic Systems | Methods and system for processing dispersible fine powders |
| GB9515182D0 (en) | 1995-07-24 | 1995-09-20 | Co Ordinated Drug Dev | Improvements in and relating to powders for use in dry powder inhalers |
| US6022737A (en) * | 1995-11-02 | 2000-02-08 | Amgen Inc. | Formulations for non-viral in vivo transfection in the lungs |
| US20020052310A1 (en) | 1997-09-15 | 2002-05-02 | Massachusetts Institute Of Technology The Penn State Research Foundation | Particles for inhalation having sustained release properties |
| US20030203036A1 (en) | 2000-03-17 | 2003-10-30 | Gordon Marc S. | Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients |
| GB9703673D0 (en) * | 1997-02-21 | 1997-04-09 | Bradford Particle Design Ltd | Method and apparatus for the formation of particles |
| JP2001518916A (ja) * | 1997-03-20 | 2001-10-16 | ノボ ノルディスク アクティーゼルスカブ | 結晶インスリンを含有する肺投与のための治療用粉末調合物 |
| US6310038B1 (en) | 1997-03-20 | 2001-10-30 | Novo Nordisk A/S | Pulmonary insulin crystals |
| US5898028A (en) * | 1997-03-20 | 1999-04-27 | Novo Nordisk A/S | Method for producing powder formulation comprising an insulin |
| US6433040B1 (en) | 1997-09-29 | 2002-08-13 | Inhale Therapeutic Systems, Inc. | Stabilized bioactive preparations and methods of use |
| US6565885B1 (en) | 1997-09-29 | 2003-05-20 | Inhale Therapeutic Systems, Inc. | Methods of spray drying pharmaceutical compositions |
| US6309623B1 (en) | 1997-09-29 | 2001-10-30 | Inhale Therapeutic Systems, Inc. | Stabilized preparations for use in metered dose inhalers |
| US6946117B1 (en) | 1997-09-29 | 2005-09-20 | Nektar Therapeutics | Stabilized preparations for use in nebulizers |
| US20060165606A1 (en) | 1997-09-29 | 2006-07-27 | Nektar Therapeutics | Pulmonary delivery particles comprising water insoluble or crystalline active agents |
| US6221378B1 (en) | 1998-02-10 | 2001-04-24 | Generex Pharmaceuticals Incorporated | Mixed micellar delivery system and method of preparation |
| US7070799B1 (en) * | 1998-02-10 | 2006-07-04 | Generex Pharmaceuticals, Inc. | Method for administering insulin to the buccal region |
| JPH11246439A (ja) * | 1998-03-02 | 1999-09-14 | Hisamitsu Pharmaceut Co Inc | 経粘膜用吸収促進剤 |
| US6284282B1 (en) * | 1998-04-29 | 2001-09-04 | Genentech, Inc. | Method of spray freeze drying proteins for pharmaceutical administration |
| TW570805B (en) * | 1998-09-01 | 2004-01-11 | Hoffmann La Roche | Water-soluble pharmaceutical composition in an ionic complex |
| GB9820746D0 (en) * | 1998-09-23 | 1998-11-18 | Pharmax Limited | Micronised pharmaceutical compositions |
| US6294153B1 (en) | 1998-12-21 | 2001-09-25 | Generex Pharmaceuticals, Inc. | Aerosol pharmaceutical formulation for pulmonary and nasal delivery |
| AU2879100A (en) * | 1999-02-12 | 2000-08-29 | Miles A. Libbey Iii | Formulation and system for intra-oral delivery of pharmaceutical agents |
| CA2362481C (en) * | 1999-03-03 | 2008-11-04 | Eli Lilly And Company | Echinocandin pharmaceutical formulations containing micelle-forming surfactants |
| ES2204548T3 (es) * | 1999-03-03 | 2004-05-01 | Eli Lilly And Company | Complejos de equinocandina/carbohidrato. |
| US6350432B1 (en) | 1999-03-19 | 2002-02-26 | Generex Pharmaceuticals Incorporated | Pressurized container having an aerosolized pharmaceutical composition |
| WO2000061178A1 (en) * | 1999-04-13 | 2000-10-19 | Inhale Therapeutics Systems, Inc. | Pulmonary administration of dry powder formulations for treating infertility |
| AU779869B2 (en) * | 1999-04-13 | 2005-02-17 | Nektar Therapeutics | Pulmonary administration of dry powder formulations for treating infertility |
| US6485706B1 (en) | 1999-06-04 | 2002-11-26 | Delrx Pharmaceutical Corp. | Formulations comprising dehydrated particles of pharma-ceutical agents and process for preparing the same |
| WO2000074754A2 (en) | 1999-06-05 | 2000-12-14 | Innovata Biomed Limited | Delivery system |
| US7169889B1 (en) * | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
| DK1808438T3 (da) * | 1999-06-29 | 2014-10-27 | Mannkind Corp | Rensning og stabilisering af peptid og proteiner i lægemidler |
| US9006175B2 (en) | 1999-06-29 | 2015-04-14 | Mannkind Corporation | Potentiation of glucose elimination |
| EP1064934A1 (en) | 1999-06-30 | 2001-01-03 | Applied Research Systems ARS Holding N.V. | GRF-containing lyophilized pharmaceutical composition |
| GB9916316D0 (en) * | 1999-07-12 | 1999-09-15 | Quadrant Holdings Cambridge | Dry powder compositions |
| GB9920839D0 (en) | 1999-09-04 | 1999-11-10 | Innovata Biomed Ltd | Inhaler |
| JP4691298B2 (ja) * | 1999-10-12 | 2011-06-01 | 科研製薬株式会社 | 粉末吸入用製剤及びその製造方法 |
| US6156294A (en) | 1999-11-28 | 2000-12-05 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
| US6676930B2 (en) | 1999-11-28 | 2004-01-13 | Scientific Development And Research, Inc. | Composition and method for treatment of otitis media |
| US7029700B2 (en) * | 2000-01-14 | 2006-04-18 | Brown University Research Foundation | Micronized freeze-dried particles |
| US6651655B1 (en) | 2000-01-18 | 2003-11-25 | Quadrant Technologies Limited | Inhaled vaccines |
| US7833549B2 (en) * | 2000-01-19 | 2010-11-16 | Mannkind Corporation | Dry powder formulations of antihistamine for nasal administration |
| US20100303769A1 (en) * | 2000-04-06 | 2010-12-02 | Franco Wayne P | Combination growth factor therapy and cell therapy for treatment of acute and chronic heart disease |
| US7166280B2 (en) | 2000-04-06 | 2007-01-23 | Franco Wayne P | Combination growth factor therapy and cell therapy for treatment of acute and chronic heart disease |
| US7871598B1 (en) | 2000-05-10 | 2011-01-18 | Novartis Ag | Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use |
| TWI290473B (en) | 2000-05-10 | 2007-12-01 | Alliance Pharma | Phospholipid-based powders for drug delivery |
| GB0011807D0 (en) * | 2000-05-16 | 2000-07-05 | Quadrant Holdings Cambridge | Formulation for inhalation |
| IL153705A0 (en) | 2000-06-27 | 2003-07-06 | Vectura Ltd | Method of making particles for use in a pharmaceutical composition |
| WO2002009669A2 (en) * | 2000-08-01 | 2002-02-07 | Inhale Therapeutic Systems, Inc. | Apparatus and process to produce particles having a narrow size distribution and particles made thereby |
| SE516555C2 (sv) * | 2000-08-04 | 2002-01-29 | Microdrug Ag | Elektropulver |
| AU2001281113B2 (en) * | 2000-08-07 | 2006-07-20 | Nektar Therapeutics | Inhaleable spray dried 4-helix bundle protein powders having minimized aggregation |
| UA75375C2 (en) * | 2000-10-12 | 2006-04-17 | Boehringer Ingelheim Pharma | Method for producing powdery preparations for inhaling |
| GB0027357D0 (en) * | 2000-11-09 | 2000-12-27 | Bradford Particle Design Plc | Particle formation methods and their products |
| CN1406131A (zh) * | 2000-12-25 | 2003-03-26 | 株式会社资生堂 | 活化交感神经的香料组合物 |
| ES2291452T3 (es) * | 2001-02-06 | 2008-03-01 | Innovata Biomed Limited | Formulacion bimodal de polvo seco para inhalacion. |
| US6867183B2 (en) | 2001-02-15 | 2005-03-15 | Nobex Corporation | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US7060675B2 (en) | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
| US20030072717A1 (en) | 2001-02-23 | 2003-04-17 | Vapotronics, Inc. | Inhalation device having an optimized air flow path |
| US6858580B2 (en) | 2001-06-04 | 2005-02-22 | Nobex Corporation | Mixtures of drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6828305B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of growth hormone drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US7713932B2 (en) | 2001-06-04 | 2010-05-11 | Biocon Limited | Calcitonin drug-oligomer conjugates, and uses thereof |
| US6828297B2 (en) | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6713452B2 (en) | 2001-06-04 | 2004-03-30 | Nobex Corporation | Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| US6913903B2 (en) | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US6770625B2 (en) | 2001-09-07 | 2004-08-03 | Nobex Corporation | Pharmaceutical compositions of calcitonin drug-oligomer conjugates and methods of treating diseases therewith |
| US7166571B2 (en) * | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7312192B2 (en) * | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7030082B2 (en) * | 2001-09-07 | 2006-04-18 | Nobex Corporation | Pharmaceutical compositions of drug-oligomer conjugates and methods of treating disease therewith |
| US7196059B2 (en) | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| US20050123509A1 (en) * | 2001-10-19 | 2005-06-09 | Lehrman S. R. | Modulating charge density to produce improvements in the characteristics of spray-dried proteins |
| KR20050044523A (ko) * | 2001-11-19 | 2005-05-12 | 벡톤 디킨슨 앤드 컴퍼니 | 입자 형태의 약제학적 조성물 |
| GB0128148D0 (en) | 2001-11-23 | 2002-01-16 | Innovata Biomed Ltd | Assembly |
| ES2364636T3 (es) | 2001-12-19 | 2011-09-08 | Novartis Ag | Administración pulmonar de aminoglucósidos. |
| AU2003220125B2 (en) | 2002-03-20 | 2006-06-15 | Mannkind Corporation | Inhalation apparatus |
| SE525027C2 (sv) * | 2002-04-12 | 2004-11-16 | Microdrug Ag | Anordning utgörande en pulverlufthyvel |
| GB0216562D0 (en) | 2002-04-25 | 2002-08-28 | Bradford Particle Design Ltd | Particulate materials |
| US20040087543A1 (en) * | 2002-04-25 | 2004-05-06 | Zachary Shriver | Methods and products for mucosal delivery |
| US9339459B2 (en) | 2003-04-24 | 2016-05-17 | Nektar Therapeutics | Particulate materials |
| US6991800B2 (en) * | 2002-06-13 | 2006-01-31 | Vicuron Pharmaceuticals Inc. | Antifungal parenteral products |
| US7601688B2 (en) | 2002-06-13 | 2009-10-13 | Biocon Limited | Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus |
| DE10234165B4 (de) * | 2002-07-26 | 2008-01-03 | Advanced Micro Devices, Inc., Sunnyvale | Verfahren zum Füllen eines Grabens, der in einem Substrat gebildet ist, mit einem isolierenden Material |
| CN1694689A (zh) * | 2002-09-30 | 2005-11-09 | 阿库斯菲尔公司 | 供吸入的缓释多孔微粒 |
| US6962006B2 (en) * | 2002-12-19 | 2005-11-08 | Acusphere, Inc. | Methods and apparatus for making particles using spray dryer and in-line jet mill |
| US20040121003A1 (en) * | 2002-12-19 | 2004-06-24 | Acusphere, Inc. | Methods for making pharmaceutical formulations comprising deagglomerated microparticles |
| EP1651248B1 (en) * | 2003-07-11 | 2009-09-09 | Novartis AG | Orally dosed pharmaceutical compositions comprising a delivery agent in micronized form |
| KR101137785B1 (ko) | 2003-07-18 | 2012-04-25 | 백스터 인터내셔널 인코포레이티드 | 제어된 상 분리에 의해 제조된 작은 구형 입자의 제조방법, 이용 방법 및 조성물 |
| ES2362038T3 (es) | 2003-09-02 | 2011-06-27 | Norton Healthcare Limited | Procedimiento para preparar un medicamento. |
| JP2007507527A (ja) * | 2003-09-30 | 2007-03-29 | スフェリックス， インコーポレイテッド | 生物学的に活性なナノ粒子治療用因子 |
| AU2004278013B2 (en) * | 2003-10-01 | 2009-01-15 | Momenta Pharmaceuticals, Inc. | Polysaccharides for pulmonary delivery of active agents |
| US7338171B2 (en) * | 2003-10-27 | 2008-03-04 | Jen-Chuen Hsieh | Method and apparatus for visual drive control |
| CA2552707C (en) * | 2004-01-12 | 2018-03-27 | Mannkind Corporation | A method of reducing serum proinsulin levels in type 2 diabetics |
| US20080248999A1 (en) * | 2007-04-04 | 2008-10-09 | Biodel Inc. | Amylin formulations |
| US20080090753A1 (en) * | 2004-03-12 | 2008-04-17 | Biodel, Inc. | Rapid Acting Injectable Insulin Compositions |
| JO3102B1 (ar) | 2004-03-17 | 2017-09-20 | Chiesi Framaceutici S P A | صيغ صيدلانية لوسائل استنشاق بها مسحوق جاف تشتمل على مكون فعال بقوة منخفضة الجرعة |
| EP1744800B1 (en) | 2004-04-21 | 2016-06-22 | Innovata Biomed Limited | Inhaler |
| DK3520779T3 (da) | 2004-04-23 | 2022-03-21 | Cydex Pharmaceuticals Inc | DPI formulering indeholdende sulfoalkylethercyclodextrin |
| US7244709B2 (en) * | 2004-05-10 | 2007-07-17 | Nastech Pharamecutical Company Inc. | Compositions and methods for enhanced mucosal delivery of parathyroid hormone |
| US20060052305A1 (en) * | 2004-05-10 | 2006-03-09 | Nastech Pharmaceutical Company Inc. | Method of treating osteoporosis using intranasal parathyroid hormone |
| US20060127320A1 (en) * | 2004-05-10 | 2006-06-15 | Nastech Pharmaceutical Company Inc. | Method of delivering parathyroid hormone to a human |
| KR101309770B1 (ko) | 2004-07-19 | 2013-09-30 | 바이오콘 리미티드 | 인슐린―올리고머 접합체，제형 및 이들의 용도 |
| DE602005024413D1 (de) | 2004-08-20 | 2010-12-09 | Mannkind Corp | Katalyse der diketopiperazinsynthese |
| EP2322180B1 (en) | 2004-08-23 | 2015-05-27 | MannKind Corporation | Diketopiperazine salts for drug delivery |
| CA2585859C (en) | 2004-10-29 | 2012-03-06 | President And Fellows Of Harvard College | Particles for treatment of pulmonary infection |
| WO2006091722A2 (en) * | 2005-02-23 | 2006-08-31 | Uab Research Foundation | Alkyl-glycoside enhanced vaccination |
| WO2007019554A2 (en) * | 2005-08-08 | 2007-02-15 | Momenta Pharmaceuticals, Inc. | Polysaccharides for delivery of active agents |
| CN102614131A (zh) | 2005-09-14 | 2012-08-01 | 曼金德公司 | 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 |
| US7713929B2 (en) | 2006-04-12 | 2010-05-11 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
| US20070086952A1 (en) * | 2005-09-29 | 2007-04-19 | Biodel, Inc. | Rapid Acting and Prolonged Acting Inhalable Insulin Preparations |
| US8084420B2 (en) * | 2005-09-29 | 2011-12-27 | Biodel Inc. | Rapid acting and long acting insulin combination formulations |
| US20070173447A1 (en) * | 2005-10-25 | 2007-07-26 | Nastech Pharmaceutical Company Inc. | Method for treating osteoporosis by intranasal delivery of teriparatide with an anti-resorptive agent |
| US7629331B2 (en) | 2005-10-26 | 2009-12-08 | Cydex Pharmaceuticals, Inc. | Sulfoalkyl ether cyclodextrin compositions and methods of preparation thereof |
| US20080051332A1 (en) * | 2005-11-18 | 2008-02-28 | Nastech Pharmaceutical Company Inc. | Method of modulating hematopoietic stem cells and treating hematologic diseases using intranasal parathyroid hormone |
| US20070178166A1 (en) * | 2005-12-15 | 2007-08-02 | Acusphere, Inc. | Processes for making particle-based pharmaceutical formulations for pulmonary or nasal administration |
| US20070148211A1 (en) * | 2005-12-15 | 2007-06-28 | Acusphere, Inc. | Processes for making particle-based pharmaceutical formulations for oral administration |
| BRPI0707991B8 (pt) | 2006-02-22 | 2021-05-25 | Mannkind Corp | métodos de preparação de um medicamento em pó seco com uma propriedade farmacêutica melhorada, dito pó seco e uso de uma quantidade efetiva do pó seco |
| AU2007238114B2 (en) * | 2006-04-12 | 2010-10-14 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
| US20090054333A1 (en) * | 2006-10-17 | 2009-02-26 | Antonio Giordano | Peptide inhibitors of cyclin-dependent kinase activity and uses thereof |
| JP4830951B2 (ja) * | 2007-04-05 | 2011-12-07 | 株式会社日立製作所 | Ｉｃチップ搬送装置、及び、ｉｃチップ製造方法 |
| KR101234540B1 (ko) | 2007-10-16 | 2013-02-19 | 바이오콘 리미티드 | 경구 투여가능한 고형 약제학적 조성물 및 그 제조방법 |
| US8785396B2 (en) | 2007-10-24 | 2014-07-22 | Mannkind Corporation | Method and composition for treating migraines |
| CA3123813A1 (en) | 2007-12-04 | 2009-06-11 | Biogen Chesapeake Llc | Improved glibenclamide formulations and methods for lyophilization thereof and lyophilates provided thereby |
| CN101951957A (zh) * | 2008-01-04 | 2011-01-19 | 百达尔公司 | 胰岛素释放作为组织的葡萄糖水平的函数的胰岛素制剂 |
| US8485180B2 (en) | 2008-06-13 | 2013-07-16 | Mannkind Corporation | Dry powder drug delivery system |
| IL313823A (en) | 2008-06-13 | 2024-08-01 | Mannkind Corp | A dry powder inhaler and system for drug delivery |
| AU2009259883B2 (en) | 2008-06-20 | 2015-02-05 | Mannkind Corporation | An interactive apparatus and method for real-time profiling of inhalation efforts |
| TWI494123B (zh) | 2008-08-11 | 2015-08-01 | Mannkind Corp | 超快起作用胰島素之用途 |
| EP2168573A1 (en) * | 2008-09-30 | 2010-03-31 | LEK Pharmaceuticals D.D. | Formulations comprising ezetimibe |
| CN102202682B (zh) * | 2008-11-04 | 2015-08-19 | Aska制药株式会社 | 含促卵泡激素的水性组合物 |
| US8314106B2 (en) | 2008-12-29 | 2012-11-20 | Mannkind Corporation | Substituted diketopiperazine analogs for use as drug delivery agents |
| ES2994042T3 (en) | 2009-02-26 | 2025-01-16 | Glaxo Group Ltd | Pharmaceutical formulations comprising 4-{(1 r)-2-[(6-{2-[(2,6-dichlorobenzyl)oxy]ethoxy}hexyl)amino]-1-hydroxyethyl}-2-(hydroxymethyl)phenol |
| US9060927B2 (en) * | 2009-03-03 | 2015-06-23 | Biodel Inc. | Insulin formulations for rapid uptake |
| CA2754595C (en) | 2009-03-11 | 2017-06-27 | Mannkind Corporation | Apparatus, system and method for measuring resistance of an inhaler |
| KR20190090092A (ko) | 2009-06-12 | 2019-07-31 | 맨카인드 코포레이션 | 한정된 비표면적을 갖는 디케토피페라진 마이크로입자 |
| EP2496295A1 (en) | 2009-11-03 | 2012-09-12 | MannKind Corporation | An apparatus and method for simulating inhalation efforts |
| GB0921075D0 (en) | 2009-12-01 | 2010-01-13 | Glaxo Group Ltd | Novel combination of the therapeutic agents |
| KR20130117755A (ko) | 2010-06-21 | 2013-10-28 | 맨카인드 코포레이션 | 건조 분말 약물 운반 시스템 및 방법 |
| MX350838B (es) | 2011-02-11 | 2017-09-18 | Grain Proc Corporation * | Composicion de sal. |
| MX353285B (es) | 2011-04-01 | 2018-01-05 | Mannkind Corp | Paquete de blister para cartuchos farmaceuticos. |
| WO2012174472A1 (en) | 2011-06-17 | 2012-12-20 | Mannkind Corporation | High capacity diketopiperazine microparticles |
| BR112014009686A2 (pt) | 2011-10-24 | 2018-08-07 | Mannkind Corp | composição analgésica inalável, pó seco e método para tratar dor |
| EP4088736A1 (en) | 2011-10-25 | 2022-11-16 | Prothena Biosciences Limited | Humanized anti-amyloid antibody formulations and methods |
| BR112015000529B1 (pt) | 2012-07-12 | 2022-01-11 | Mannkind Corporation | Inalador de pó seco |
| US10159644B2 (en) | 2012-10-26 | 2018-12-25 | Mannkind Corporation | Inhalable vaccine compositions and methods |
| KR102391750B1 (ko) | 2013-03-15 | 2022-04-28 | 맨카인드 코포레이션 | 미세결정성 디케토피페라진 조성물 및 방법 |
| 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 |
| CA2920488C (en) | 2013-08-05 | 2022-04-26 | Mannkind Corporation | Insufflation apparatus and methods |
| WO2015148905A1 (en) | 2014-03-28 | 2015-10-01 | Mannkind Corporation | Use of ultrarapid acting insulin |
| US10561806B2 (en) | 2014-10-02 | 2020-02-18 | Mannkind Corporation | Mouthpiece cover for an inhaler |
| US10806770B2 (en) | 2014-10-31 | 2020-10-20 | Monash University | Powder formulation |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990004962A1 (en) * | 1988-10-31 | 1990-05-17 | Kabivitrum Ab | A pharmaceutical composition for rapid release of the active component comprising an orderred mixture and a surfactant |
| WO1991016038A1 (en) * | 1990-04-13 | 1991-10-31 | Toray Industries, Inc. | Pharmaceutical aerosol formulation of solid polypeptide microparticles and method for the preparation thereof |
| WO1994007514A1 (en) * | 1992-09-29 | 1994-04-14 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
Family Cites Families (61)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| BE556587A (zh) * | 1957-01-31 | 1957-04-11 | ||
| GB1527605A (en) * | 1975-08-20 | 1978-10-04 | Takeda Chemical Industries Ltd | Insulin preparation for intranasal administration |
| 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 |
| JPS5795920A (en) * | 1980-12-04 | 1982-06-15 | Teijin Ltd | Remedy for respiratory disease |
| US4900730A (en) * | 1981-01-14 | 1990-02-13 | Toyo Jozo Co., Ltd. | Preparation which promotes the absorption of peptides |
| SE438261B (sv) * | 1981-07-08 | 1985-04-15 | Draco Ab | Anvendning i dosinhalator av ett perforerat membran |
| ATE23272T1 (de) * | 1981-07-08 | 1986-11-15 | Draco Ab | Pulverinhalator. |
| US5260306A (en) * | 1981-07-24 | 1993-11-09 | Fisons Plc | Inhalation pharmaceuticals |
| 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 |
| US4959358A (en) * | 1983-06-06 | 1990-09-25 | Beth Israel Hospital Assn. | Drug administration |
| US4746508A (en) * | 1983-06-06 | 1988-05-24 | Beth Israel Hospital Assn. | Drug administration |
| US4548922A (en) * | 1983-06-06 | 1985-10-22 | Beth Israel Hospital | Drug administration |
| US4963367A (en) * | 1984-04-27 | 1990-10-16 | Medaphore, Inc. | Drug delivery compositions and methods |
| US5288498A (en) * | 1985-05-01 | 1994-02-22 | University Of Utah Research Foundation | Compositions of oral nondissolvable matrixes for transmucosal administration of medicaments |
| JPS61267528A (ja) * | 1984-11-26 | 1986-11-27 | Yamanouchi Pharmaceut Co Ltd | 吸収促進剤を含有するカルシトニン経鼻剤 |
| SE448277B (sv) * | 1985-04-12 | 1987-02-09 | Draco Ab | Indikeringsanordning vid en doseringsanordning for lekemedel |
| IL78425A (en) * | 1985-04-15 | 1991-05-12 | Lilly Co Eli | Intranasal formulation containing insulin |
| US5122127A (en) * | 1985-05-01 | 1992-06-16 | University Of Utah | Apparatus and methods for use in administering medicaments by direct medicament contact to mucosal tissues |
| WO1986006959A1 (en) * | 1985-05-22 | 1986-12-04 | Liposome Technology, Inc. | Liposome inhalation method and system |
| US4847298A (en) * | 1985-08-16 | 1989-07-11 | Merck & Co., Inc. | Acylcarnitines as absorption-enhancing agents for drug delivery through mucous membranes of the nasal, buccal, sublingual and vaginal compartments |
| IL77186A0 (en) * | 1985-11-29 | 1986-04-29 | Touitou Elka | Pharmaceutical insulin composition |
| SE453566B (sv) * | 1986-03-07 | 1988-02-15 | Draco Ab | Anordning vid pulverinhalatorer |
| EP0257915B1 (en) * | 1986-08-11 | 1993-03-10 | Innovata Biomed Limited | Pharmaceutical formulations comprising microcapsules |
| US5179079A (en) * | 1986-12-16 | 1993-01-12 | Novo Nordisk A/S | Nasal formulation and intranasal administration therewith |
| NZ222907A (en) * | 1986-12-16 | 1990-08-28 | Novo Industri As | Preparation for intranasal administration containing a phospholipid absorption enhancing system |
| GB8712176D0 (en) * | 1987-05-22 | 1987-06-24 | Cosmas Damian Ltd | Drug delivery system |
| EP0360340A1 (en) * | 1988-09-19 | 1990-03-28 | Akzo N.V. | Composition for nasal administration containing a peptide |
| US5006343A (en) * | 1988-12-29 | 1991-04-09 | Benson Bradley J | Pulmonary administration of pharmaceutically active substances |
| GB8900267D0 (en) * | 1989-01-06 | 1989-03-08 | Riker Laboratories Inc | Narcotic analgesic formulations and apparatus containing same |
| US4994439A (en) * | 1989-01-19 | 1991-02-19 | California Biotechnology Inc. | Transmembrane formulations for drug administration |
| US5011678A (en) * | 1989-02-01 | 1991-04-30 | California Biotechnology Inc. | Composition and method for administration of pharmaceutically active substances |
| AU639228B2 (en) * | 1989-02-17 | 1993-07-22 | Transave, Inc. | Lipid excipient for nasal delivery and topical application |
| IT8920486A0 (it) * | 1989-05-12 | 1989-05-12 | Isf Spa | Composizioni farmaceutiche. |
| US5176132A (en) * | 1989-05-31 | 1993-01-05 | Fisons Plc | Medicament inhalation device and formulation |
| JP2642486B2 (ja) * | 1989-08-04 | 1997-08-20 | 田辺製薬株式会社 | 難溶性薬物の超微粒子化法 |
| GB8921222D0 (en) * | 1989-09-20 | 1989-11-08 | Riker Laboratories Inc | Medicinal aerosol formulations |
| US5707644A (en) * | 1989-11-04 | 1998-01-13 | Danbiosyst Uk Limited | Small particle compositions for intranasal drug delivery |
| GB9001635D0 (en) * | 1990-01-24 | 1990-03-21 | Ganderton David | Aerosol carriers |
| US5376386A (en) * | 1990-01-24 | 1994-12-27 | British Technology Group Limited | Aerosol carriers |
| US5118494A (en) * | 1990-03-23 | 1992-06-02 | Minnesota Mining And Manufacturing Company | Use of soluble fluorosurfactants for the preparation of metered-dose aerosol formulations |
| US5192548A (en) * | 1990-04-30 | 1993-03-09 | Riker Laboratoires, Inc. | Device |
| AU7908791A (en) * | 1990-05-08 | 1991-11-27 | Liposome Technology, Inc. | Direct spray-dried drug/lipid powder composition |
| ES2117642T3 (es) * | 1990-05-10 | 1998-08-16 | Bechgaard Int Res | Preparado farmaceutico que contiene n-glicofuroles y n-etilen glicoles. |
| 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 |
| US5086775A (en) * | 1990-11-02 | 1992-02-11 | University Of Rochester | Method and apparatus for using Doppler modulation parameters for estimation of vibration amplitude |
| GB9024365D0 (en) * | 1990-11-09 | 1991-01-02 | Glaxo Group Ltd | Medicaments |
| JP3507486B2 (ja) * | 1991-03-15 | 2004-03-15 | アムジエン・インコーポレーテツド | 顆粒球コロニー刺激因子の肺内投与 |
| CA2127877A1 (en) * | 1992-01-21 | 1993-07-22 | Robert M. Platz | Improved process for preparing micronized polypeptide drugs |
| EP0566135A1 (en) * | 1992-04-17 | 1993-10-20 | Takeda Chemical Industries, Ltd. | Transmucosal composition comprising a peptide and a cytidine derivative |
| DE69332240T2 (de) * | 1992-06-12 | 2003-04-10 | Teijin Ltd., Osaka | Ultrafeines pulver zur inhalation und dessen herstellung |
| ES2154673T3 (es) * | 1993-01-29 | 2001-04-16 | Aradigm Corp | Suministro intrapulmonar de hormonas. |
| US5364838A (en) * | 1993-01-29 | 1994-11-15 | Miris Medical Corporation | Method of administration of insulin |
| BE1006873A6 (nl) * | 1993-03-26 | 1995-01-10 | Merkus Franciscus W H M | Toedieningsformulering voor nasale insuline toediening. |
| DE69413528T2 (de) * | 1993-04-06 | 1999-05-06 | Minnesota Mining And Mfg. Co., Saint Paul, Minn. | Vorrichtung zum deagglomerieren für trockenpulverinhalatoren |
| US5661130A (en) * | 1993-06-24 | 1997-08-26 | The Uab Research Foundation | Absorption enhancers for drug administration |
| US5830853A (en) * | 1994-06-23 | 1998-11-03 | Astra Aktiebolag | Systemic administration of a therapeutic preparation |
| 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 |
| TW402506B (en) * | 1993-06-24 | 2000-08-21 | Astra Ab | Therapeutic preparation for inhalation |
| GB9314614D0 (en) * | 1993-07-14 | 1993-08-25 | Minnesota Mining & Mfg | Dry powder inhalers |
| US5514670A (en) * | 1993-08-13 | 1996-05-07 | Pharmos Corporation | Submicron emulsions for delivery of peptides |
-
1994
- 1994-06-21 IS IS4179A patent/IS1796B/is unknown
- 1994-06-22 EG EG36794A patent/EG21484A/xx active
- 1994-06-22 MY MYPI94001613A patent/MY114125A/en unknown
- 1994-06-22 IL IL11008594A patent/IL110085A/en not_active IP Right Cessation
- 1994-06-23 PL PL94312210A patent/PL178261B1/pl not_active IP Right Cessation
- 1994-06-23 ES ES94919961T patent/ES2162865T3/es not_active Expired - Lifetime
- 1994-06-23 NZ NZ268138A patent/NZ268138A/en not_active IP Right Cessation
- 1994-06-23 CZ CZ19953393A patent/CZ287656B6/cs not_active IP Right Cessation
- 1994-06-23 AU AU70902/94A patent/AU692781B2/en not_active Ceased
- 1994-06-23 UA UA95125418A patent/UA48111C2/uk unknown
- 1994-06-23 MX MX9404762A patent/MX9404762A/es not_active IP Right Cessation
- 1994-06-23 JP JP7502737A patent/JPH09500621A/ja not_active Withdrawn
- 1994-06-23 SK SK1602-95A patent/SK283253B6/sk not_active IP Right Cessation
- 1994-06-23 EP EP94919961A patent/EP0706383B1/en not_active Expired - Lifetime
- 1994-06-23 CN CN94192867A patent/CN1116030C/zh not_active Expired - Fee Related
- 1994-06-23 WO PCT/SE1994/000634 patent/WO1995000128A1/en active IP Right Grant
- 1994-06-23 KR KR1019950705905A patent/KR100372674B1/ko not_active Expired - Fee Related
- 1994-06-23 PT PT94919961T patent/PT706383E/pt unknown
- 1994-06-23 CA CA002166109A patent/CA2166109C/en not_active Expired - Fee Related
- 1994-06-23 BR BR9406908A patent/BR9406908A/pt not_active Application Discontinuation
- 1994-06-23 DE DE69428442T patent/DE69428442T2/de not_active Expired - Lifetime
- 1994-06-23 HU HU9503660A patent/HU226474B1/hu not_active IP Right Cessation
- 1994-06-23 AT AT94919961T patent/ATE206046T1/de active
- 1994-06-23 DK DK94919961T patent/DK0706383T3/da active
- 1994-07-05 SA SA94150060A patent/SA94150060B1/ar unknown
- 1994-11-23 EE EE9400457A patent/EE03222B1/xx not_active IP Right Cessation
-
1995
- 1995-12-21 NO NO19955227A patent/NO313080B1/no not_active IP Right Cessation
- 1995-12-22 FI FI956228A patent/FI111909B/fi not_active IP Right Cessation
-
1997
- 1997-05-19 US US08/858,122 patent/US5952008A/en not_active Expired - Lifetime
-
1998
- 1998-09-01 HK HK98110333A patent/HK1009587A1/xx not_active IP Right Cessation
-
2005
- 2005-11-09 JP JP2005325089A patent/JP2006089497A/ja active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1990004962A1 (en) * | 1988-10-31 | 1990-05-17 | Kabivitrum Ab | A pharmaceutical composition for rapid release of the active component comprising an orderred mixture and a surfactant |
| WO1991016038A1 (en) * | 1990-04-13 | 1991-10-31 | Toray Industries, Inc. | Pharmaceutical aerosol formulation of solid polypeptide microparticles and method for the preparation thereof |
| WO1994007514A1 (en) * | 1992-09-29 | 1994-04-14 | Inhale Therapeutic Systems | Pulmonary delivery of active fragments of parathyroid hormone |
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