CN1098679C - 用于胰岛素肺部给药的方法和组合物 - Google Patents

用于胰岛素肺部给药的方法和组合物 Download PDF

Info

Publication number
CN1098679C
CN1098679C CN95191910A CN95191910A CN1098679C CN 1098679 C CN1098679 C CN 1098679C CN 95191910 A CN95191910 A CN 95191910A CN 95191910 A CN95191910 A CN 95191910A CN 1098679 C CN1098679 C CN 1098679C
Authority
CN
China
Prior art keywords
insulin
dry powder
aerosol
powder
carrier
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Fee Related
Application number
CN95191910A
Other languages
English (en)
Other versions
CN1152867A (zh
Inventor
约翰·S·帕顿
琳达·C·福斯特
罗伯特·M·普莱兹
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Novartis AG
Nova Pharmaceutical Corp
Original Assignee
Inhale Therapeutics Systems Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26902263&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=CN1098679(C) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Inhale Therapeutics Systems Inc filed Critical Inhale Therapeutics Systems Inc
Publication of CN1152867A publication Critical patent/CN1152867A/zh
Application granted granted Critical
Publication of CN1098679C publication Critical patent/CN1098679C/zh
Anticipated expiration legal-status Critical
Expired - Fee Related legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats

Abstract

通过胰岛素的干粉烟雾剂的吸入进行哺乳动物宿主的胰岛素系统释放。发现胰岛素干粉能够经肺的肺泡区域快速吸收。

Description

用于胰岛素肺部给药的方法和组合物
本申请是1994年3月7日申请的申请序号08/207,472的部分续申请，全部公开在此作为参考。
本发明涉及用于糖尿病人的胰岛素呼吸(道)释放的方法和组合物。更具体的说，本发明涉及通过肺进行迅速机体吸收的干粉胰岛素的肺部释放。
胰岛素是一个50个氨基酸的多肽激素，分子量大约为6000，在正常个体(非糖尿病的)胰岛的β-细胞内生成。胰岛素是调节糖代谢，降低血糖水平所必需，系统性缺乏将导致糖尿病。糖尿病人的存活依赖于长期频繁地施用胰岛素来维持可接受的血糖水平。
胰岛素最常用的给药方法是皮下注射，一般注入腹部或大腿上部。为了维持可接受的血糖水平，通常需要每天注射胰岛素至少一次或者两次，并在必要时补充注射速效胰岛素。当糖尿病人使用家用诊断器密切监测血糖水平时，将需要更为频繁的注射来进行治疗。具体的讲，本发明是关于迅速起效胰岛素的施用方法，该方法可使血清胰岛素在一小时之内达峰，葡萄糖在90分钟内达到谷底。
通过注射施用胰岛素在许多方面不理想。首先，许多病人发现，为满足维持正常血糖水平的需要而频繁地给自己注射既困难又麻烦。这种不情愿可能会导致不遵医嘱，这在一些非常严重的病例中会危及生命。此外，皮下注射胰岛素的机体吸收也相对缓慢，即使使用速效胰岛素的制剂时，也经常需要45至90分钟。因此，提供可以避免自我注射同时胰岛素又可被机体迅速利用的其它胰岛素制剂和给药途径，长期以来一直是人们的一个目标。
现已提出了许多这种替代性的胰岛素给药途径，包括鼻内、直肠内以及阴道内的给药方法。
当这些技术避免了皮下注射的不适以及不协调的同时，它们也都遭受了自身的限制。直肠内及阴道内给药不方便，不舒适，而且后者也不能用于所有的糖尿病人。鼻内释放将方便一些，可能也比注射更容易接受，但由于鼻粘膜有一层厚的阻止大分子通过的上皮层，需要使用有潜在毒性的“增透剂”来影响胰岛素透过鼻粘膜。本发明的特殊兴趣在于肺部胰岛素给药，在此，病人吸入一种胰岛素制剂并通过肺泡区的薄的上皮细胞层进行机体吸收。看起来这种肺部胰岛素给药的机体吸收比皮下注射更为迅速，同时还避免了用针。但是，肺部胰岛素给药仍需得到广泛的接受。以前，肺部给药经常是通过液体胰岛素制剂的喷雾法来完成，这需要使用笨重的液体喷雾器。此外，由这种喷雾器形成的气雾剂只有非常低的胰岛素浓度，需要吸入相当多的次数来达到足够的剂量。胰岛素浓度的受限归因于胰岛素在合适的水溶液中的溶解度不好。在一些情况下，需要80次或以上的呼吸来达到足够的剂量，致使一次用药的时间为10至20分钟，甚至更长。
提供用于胰岛素肺部给药的改良的方法和组合物是诱人的。如果这种方法和组合物足够方便，能够允许甚至在户外时也可以自我给药，并且可以通过相对较少的呼吸次数(最好少于10次)传送需要的总剂量这将格外诱人。这种方法和组合物还应提供机体对胰岛素的迅速吸收，最好能在45分钟或更少的时间内达到血清峰值，并在1小时或更少的时间内达到血糖谷值。这种迅速起效的制剂将较好地适用于攻击性治疗记录，从而减少或消除速效或长效胰岛素的注射。本发明的组合物还应该是稳定的，最好由浓缩的干粉制剂组成。
许多文献中都描述了雾化的胰岛水溶液的呼吸给药，首先是Gansslen(1925)，Klin.Wochenschr.4：71，还有Laube等(1993)，JAMA 269：2106-21-9；Elliott(1987)，Aust.Paediatr.J.23：293-293；Wigley等(1971)，Diabetes 20：552-556Corthorpe等(1992)，Pharm Res.9：764-768；Govinda(1959)，Indian J.Physiol.Pharmacol.3：161-167；Hastings等(1992)，J Appl.Physiol.73：1310-1316；Liu等(1993)，JAMA 269：2106-2109；Nagano等(1985)，Jikeikai Med.J.32：503-506；Sakr(1992)Int.J.Phar.86：1-7；和Yoshida等(1987)，Clin.Res.35：160-166。美国专利5,254,330描述了在大颗粒载体赋形剂上的干粉药物如胰岛素的肺部给药。Lee和Sciara(1976)在J.Pharm.Sci.65：567-572中描述了用于传送悬浮于抛射剂上的结晶胰岛素的计量剂量吸入器(MDI)。美国专利5230094描述了一个将胰岛素传送到一个空隙中来调节吸气流速的MDI。重组胰岛素的支气管给药由Schluter等(摘要，1984年，Diabettes 33：75A)和Kohler等(1987年，Atemw.Lungenkrkh13：230-232)作了简要描述。美国专利5011678和Nagai当(1984)J.Contr.Rel.1：15-22)描述了在增强剂的存在下，包括胰岛素在内的多种多肽的鼻内及呼吸给药。美国专利5204108；4294829；和4153689；PCT申请WO93/02712，WO91/02545，WO90/09780和WO88/04556；英国专利1527605；Ryden和Edman(1992)Int.J.Pharm.83：1-10；以及Bjork和Edman(1988，Int.J.Pharm.47：233-238)描述了含有增强剂并且/或者包含于控释制剂中的胰岛素的鼻内给药，无定形胰岛素的制备和稳定性由Rigsbee和Pikal(American Association of Pharmaceutical Sciences(AAPS)，1993年12月14-18日，Lake Buena Vista，佛罗里达)作了描述。在载体上喷雾干燥多肽、多核苷酸以及其他不稳定药物以形成无定形结构来稳定药物的方法在欧洲专利申请520748中作了描述。
根据本发明，对一个哺乳动物，具体的讲是一个患有糖尿病的病人，胰岛素的烟雾化以及机体给药的方法和组合物在避免了皮下注射的同时，还可以迅速吸收进入血液循环。具体的讲，本发明的方法基于以干粉的形式进行胰岛素的肺部给药。令人惊奇的是，已经发现吸入的干胰岛素粉末沉积于肺泡区，并被肺泡的上皮细胞迅速吸收进入血液循环。因此，胰岛素粉末的肺部给药可以成为皮下注射给药的一个有效的替代方法。
本发明的第一个方面，所用的胰岛素是干的粉末，通常但并不必须是一个大体无定形状态，将其分散于空气或其它生理上可接受的气流中以形成烟雾剂。将该烟雾俘获于一个有喷嘴的容器中，病人可以通过喷嘴吸入烟雾。随需要，干粉胰岛素可与药物上可接受的干粉载体组合，这在下面有更详细的描述。胰岛素的干粉优选地由直径低于10μm颗粒组成，更为优选的低于7.5μm，最为优选的低于5μm，通常在0.1μm至5μm的范围之内。令人惊奇的是，本发明的干粉胰岛素组合物在肺内吸收时，无需使用象那些通过鼻粘膜及上呼吸道进行吸收时所需的增透剂。
第二个方面，本发明提供的胰岛素组合物，主要由平颗粒尺寸低于10μm的干粉胰岛素组成，其中可能组合有干粉药物载体。胰岛素组合物中最好不含增透剂并且所包含的颗粒直径优选低于10μm，更为优选低于7.5μm，最为优选低于5μm，通常在0.1至5μm范围之间。通常，在干粉胰岛素中含有重量比为5％至99％的胰岛素，较好为10％至99％的胰岛素，更为常用的是从15％至80％附着在一个合适的载体上，通常是糖、有机盐、氨基酸、多肽或蛋白质，此后会有更详细的描述。
本发明的第三个方面，胰岛素干粉的制备是通过将胰岛素溶于一个缓冲水溶液中，然后将该溶液喷雾干燥制得颗粒尺寸低于10μm至5μm之间大体无定形颗粒，随需要，将药物载体也溶于缓冲液中形成一个均相溶液，在将此溶液喷雾干燥时制得包含有胰岛素、载体、缓冲剂以及溶液中存在的所有其它成份的独立颗粒。优选载体是糖，有机盐，氨基酸，多肽或蛋白质，这些载体在喷雾干燥中可以制得大体无定形的结构。无定形载体既可以是玻璃状的，也可以是橡胶状的，可以增加胰岛素在贮存过程中的稳定性。在利的是，这种稳定了的制剂还可以在吸入到肺泡区后有效地将胰岛素释放进入血液。
通过参阅剩余部分的详细说明及插图，对于本发明的性质及优点的深入了解将变得明显。
图1是一个根据本发明的方法雾化胰岛素制剂的系统的图解说明。
图2是病人从图1的系统中吸入雾化的胰岛素的图解说明。
图3A和3B是用曲线来说明在雾化三种不同的干粉制剂后，大鼠对重组人胰岛的吸收以及引起的血糖反应。每一个点代表三只不同大鼠的平均值。在时间零点开启干粉烟雾发生器。对87％胰岛素/柠檬酸盐，20％胰岛素-甘露糖醇/柠檬酸盐，20％胰岛素-棉子糖/柠檬酸盐粉末的烟雾化作用分别在5分钟，14分钟和20分钟时完成。动物禁食过夜。
4A和4B是用曲线说明平均血清胰岛素和葡萄糖的时间-浓度曲线，对Cynomolgus猴的烟雾剂及皮下给药分别进行了比较。烟雾剂组中报道的是三只猴子平均值，皮下组中报道的是四只猴子的平均值。
图5A是用曲线说明人皮下注射(○)和吸入三次喷射(●)的平均胰岛素浓度随时间的变化。
图5B显示与5A中胰岛素浓度相对应的平均葡萄糖浓度。
图6A是人皮下注射(○)和吸入三次喷雾给药(●)所引起的血渍胰岛素浓度对时间变化的曲线说明。
图6B是对应于6A中的胰岛素水平的血清葡葡糖水平的曲线说明。
图7B和7A给出了皮下给药(○)和喷雾给药(●)的血清胰岛素(7A)和葡萄糖水平(7B)的个体间差异比较。
图8A，8B和8C显示了人胰岛素的反相HPLC(rpHPLC)。图8A足一个胰岛素标准品的色谱分析，在25℃下溶于10mMHCl中，显示人胰岛素在23.87分钟洗脱，脱氨基胰岛素在30.41分钟洗脱。图8B显示一个相似的人胰鸟素标准品的色谱图。图8C显示根据本发明制备本发明制备的喷雾干燥的重组胰岛素制剂的相似的色谱图。
图9显示了一个胰岛素制剂在喷雾干燥前后的紫外光谱。在可见光谱内没有观察到光的散射，表明胰岛素在喷雾干燥过程中没有发生聚集。
根据本发明，胰岛素是做为干粉出现。“干粉”意味着粉末中的水分含量低于重量比的大约10％，通常低于重量比的大约5％，优选低于重量比的大约3％。“粉末”意味着胰岛素包含具有选择尺寸的自由流动的颗粒，以允许穿透到肺泡中，优选直径小于10μm，更为优选低于7.5μm，最优选的低于5μm，通常是直径在0.1μm到5μm之间。
本发明至少是部分地基于干粉胰岛素可通过宿主的肺方便迅速地吸收这一意外的观察结果。很奇怪干粉胰岛素能够到达肺泡区，因为已经知道诸如胰岛颗粒等水溶性药都是吸湿的。参见Byron等编辑，Respiratory Drug Delivery，CRC Press，Baca Raton，(1990)，150页。因此，曾经预测，为颗粒经过肺的导气管时(其中37℃时的相对温度超过99％)，各颗粒将有吸水并长大形成一个有效颗粒大小超过本发明中10μm的上限的趋向。如果一个胰岛素颗粒的实在部分大于目标中的尺寸范围，预期这些颗粒将会沉积在肺的中央导气管内而不是肺泡区，从而限制了(药物)的释放及随后的机体吸收。此外，肺上皮细胞上的流动层非常薄，通常只有给药胰岛素粉末直经的几分之一。因此，在本发明之前很难预料于的胰岛素颗粒在沉积于肺泡区时是否会溶解。另人惊奇的是，干的胰岛素粉末显然既可以进入肺泡区内又可以在其沉积于肺泡区后立刻溶解。溶解了的胰岛素就可以透过上皮细胞进入循环。
现在确信，胰岛素的有效吸收是由于它在肺泡的超薄(＜0.1μm)流动层中的迅速溶解。本发明中颗粒的平均尺寸比肺流动层大10到50倍，而颗粒的溶解及机体对胰岛素的吸收却非常迅速，使人很感意外。的确，正如在此后的实验部分中所显示的，本发明的干胰岛素制剂可以提供比目前最常用的皮下注射给药方法更为迅速的血清胰岛素峰值以及葡萄糖下降。然而，实施在此描述的本发明无需对于精确机制的了解。
根据本发明，优选的组合物中将基本不含增透剂。“增透剂”是表面活性化合物，它可以促进胰岛素(或其它药物)穿透粘膜，建议在鼻内、直肠内、阴道内给药的制剂中使用。增透剂的范例包括：胆汁盐，如牛磺胆酸盐、甘胆酸盐和脱氧胆酸盐；褐霉酸，如牛磺脱氢褐霉素以及生物可容性洗涤剂，如吐温，Laureth-9以及类似物质。然而，在用于肺部的制剂中使用增透剂通常是不合适的，因为这些表面活性化合物会对肺内的上皮血液屏障产生不利影响。令人惊奇的是，已经发现本发明的干粉胰岛素组合物无需使用增透剂在肺内也很容易吸收。
适于本发明使用的胰岛素干粉包括无定形胰岛素、结晶胰岛素以及无定形和结晶胰岛素二者的混合物。干粉胰岛素优选通过一定条件下的喷雾干燥来制备，生成大体无定形粉末，颗粒的尺寸在上述范围之内。除此之外，无定形胰岛素的制备可以通过将合适的胰岛素溶液在一定条件下冷冻干燥、真空干燥、蒸发干燥来形成无定形结构。这样制得的无定形胰岛素然后可以经过研磨或碾碎制得在适宜尺寸范围之内的颗粒。结晶干粉胰岛素可以通过研磨或喷射碾碎大块的结晶胰岛素形成。形成含有颗粒在适宜尺寸范围之内的胰岛素粉末的优选方法是喷雾干燥，首先将纯净的大块胰岛素(通常是结晶的形式)溶于生量上可接受的缓冲水溶液，一般来说是PH值在2到9范围之间的柠檬酸盐缓冲液。溶解的胰岛素浓度从重量的0.01％到重量1％，通常中从0.1％到0.2％。该溶液然后可以用传统喷雾干燥设备(来自于Buchi，Niro等供应商)喷雾干燥，生成大体无定形的颗粒产品。
干胰素粉应主要由在要求尺寸范围之内的胰岛素颗粒组成，基本不含其它任何生物活性物质，药物载体等。这种“纯净”制剂可能包括一些微量成份，如防腐剂，它存在的量很少，一般低于重量的10％，通常低于重量的5％。使用这种纯净制剂，即使是大剂量所需的吸入次收也可以大大减少，通常仅需一次呼吸。
本发明的胰岛素粉末可任意地与适于呼吸和肺部给药的药物载体或赋形剂组合。当想要降低用于病人的粉末中的胰岛素浓度时，这些载体可能仅起填充剂的作用，但它同样也可以起到增加胰岛素组合物的稳定性和改善粉末在粉末分散器中的分散性，从而提供更为有效、更易重现的胰岛素释放；以及改善胰岛素的工艺性能如流动性和稠度，以易于生产和粉末填充的作用。
适宜的载体材料可以是无定形粉末，结晶粉末，或者无定形与结晶粉末的组合。适宜的材料包括(a)糖：如果糖、半乳糖、葡萄糖、D-甘露糖、山梨糖等的单糖；像乳糖、海藻糖、纤维素二糖等二糖；环糊精：如2-羟丙基-β环糊精；像棉子糖、麦芽糖糊精、葡聚糖等多糖；(b)氨基酸：如甘氨酸、精氨酸、天冬氨酸、甘氨酸、半胱氨酸、赖氨酸等。(c)由有机酸及有机碱制备的有机盐：如柠檬酸钠、抗坏血酸钠、葡萄糖酸镁、葡萄糖酸钠，氨基丁三醇盐酸盐等。(d)多肽和蛋白：如天冬酰苯氨酸甲酯人血清白蛋白、明胶及此类。(e)alditols，如甘露糖醇、木糖醇等。优选的载体组群包括乳糖、海藻糖、棉子糖、麦芽糖糊精、甘氨酸、柠檬酸钠、氨基丁三醇盐酸盐、人血清白蛋白及甘露糖醇。
这些载体材料可以与胰岛素在喷雾干燥前组合，也就是将载体材料加入到准备进行喷雾干燥的缓冲溶液中。在这种方法中，载体材料将作为胰岛素颗粒的一部分与其同时形成。一般地，当载体材料经喷雾干燥与胰岛素一起形成时，在各颗粒中胰岛素的含量将占重量百分比的5％到95％，优选从20％到80％。颗粒的其余部分主要是载体材料(一般占重量比的5％到95％，通常是20％到80％)，但也含缓冲剂，不可能包括上面所述的其他成份。已经发现，分散到肺泡区的颗粒(也就是那些小于10μm，在要求尺寸范围内的颗粒)中含有载体材料并不显著干扰机体对胰岛素的吸收。
此外，也可以将载体单独制成干粉形式并经混合与胰岛素组合在一起。单独制造的粉末载体通常是结晶(以防止吸水)，但在一些情况下也可以是无定形的或是结晶与无定形体的混合物。需对载体颗粒的大小进行选择以改善胰岛素粉的流动性，一般在20μm到100μm的范围内。在此尺寸范围内的载体颗粒通常并不进入肺泡区内，经常在吸入之前在给药装置内就与胰岛素相分离。因此，进入到肺泡区的颗粒主要包括胰岛素和缓冲剂。优选的载体材料是尺寸在上述范围内的甘露糖醇晶体。
本发明的干胰岛素粉也可以与其它活性物质组合。例如，在干胰岛素粉末中加入少量糊精或活性糊精类似物有利于改善对糖尿病的治疗。糊精是由正常(非糖尿病的)个体的胰腺β细胞与胰岛素同时分泌的一种激素。人们确信糊精在体内调节胰岛素的活性，而且有人提出将糊精与胰岛素同时给药可以加强对血糖的控制。将干粉糊精与本发明的组合物中的胰岛素组合，可以提供达到这种同时给药的非常方便的产品。糊精可以按重量比从0.1％到10％与胰岛素混合(基于药物中的胰岛素的总重量)，优选从重量比的0.5％到2.5％。糊精可以从供应商处买到(例如AniylinCorporation，San Diego，California)，并很容易调配到本发明的组合物中。例如，糊精可以与胰岛素、载体一起溶于水溶液或其它合适的溶液中，将该溶液喷雾干燥制得粉末产品。
本发明的干粉胰岛素组合物优选用常用的方法将其分散在流动的空气中或其它生理上可接受的气流中来烟雾化。在共同未决的申请号为07/910048，公开号为WO93/00951的申请中描述了一个适用于这种分散的系统，其所有公开内容在此以参考。参阅图1，将干的，自由流动的胰岛素粉末加入高速的空气或气体流中，得到的分散物入存储室10(holding Chamber)中。存储室10设有喷嘴12，喷嘴位于空气粉末分散物入口的对面。室10的体积要足够大的俘获合适的剂量，随需要还可以设置挡板和/或单向阀门的防止污染。在室10中俘获了一次剂量的胰岛素粉末后，病人P(图2)从喷嘴12吸气，把雾化的分散物吸入肺中。当病人P吸气时，补充空气从切向空气入口14进入，进入的空气接通常的旋涡方式流动，把雾化的胰岛素从小室中带入病人的肺中。室的体积及雾化剂量的大小要使病人可以完全吸入伴有足够空气的全部胰岛素以保证胰岛素到达肺泡区的深处。
这种雾化的胰岛素粉末在替代皮下注射速效胰岛素来治疗糖尿病或相关的胰岛素缺乏症时特别有用。令人惊奇的是，已经发现由于粉胰岛素的喷雾给药引起的胰岛素吸收和血糖反应比皮下注射所引起的要明显快多。因此，本发明的方法和组合物在用于病人需频繁地监测血糖水平并在需要时施用胰岛素来维持目的血清浓度的治疗方案中特别有价值，也可以用以需要进行机体胰岛素给药的任何时候。病人可以像刚才所述那样通过吸入适量的胰岛素来达到需要的剂量。通过刚才所述的方法进行机体胰岛素释放的效率一般在大约15％到30％，每一次的剂量(基于每一次的吸入)一般在大给0.5mg到10mg。通常，在一次呼吸给药中适宜的胰岛素总剂量在大约0.5mg到15mg。因此，病人可以通过一至四次的呼吸来达到需要的剂量。
提供下述实例是为了进行说明而不是进行限定。
                            实验部分
材料和方法
材料
结晶人胰岛素锌，26.3unit/mg(Lilly Lot # 784KK2，Eli Lilly and Company，Indianapolis，IN)反相HPLC检测，纯度大于99％。USP甘露糖醇(RoquetteCorporation，Gurnee，IL)。棉子糖(Pfanstiehl Laboratories，Waukegan，IL)。二水合柠檬酸钠，USP，ACS和一水合柠檬酸，USP(J.T.Baker，Phillipsburg，NJ)。
粉末的制备
胰岛素粉末的制备是将大块结晶胰岛素溶于含有赋形剂(甘露糖醇或棉子糖或不加)的柠檬酸钠缓冲溶液中，得到的最终固体浓度为7.5mg/ml，PH值为6.7±0.3。喷雾干燥器的操作在入口处的温度在110℃到120℃之间，供给液体速度为5ml/min，形成出口处的温度在70℃到80℃之间。然后将溶液滤过0.22μm的滤膜并在Buchi喷雾干燥器内喷雾干燥，形成良好的白色无定形粉末。生成的粉末在干燥环境中(相对＜温度10％)保存于盖紧盖子的容器内。
粉末分析
粉末的颗粒尺寸分布的测量是将粉末在Sedisperse A-11(Micromeritics，Norcross，GA)内分散后用液体离心沉积法在Horiba CAPA-700颗粒尺寸分析仪上进行。粉末的水分含量的测定是通过Karl Fischer法在三菱CA-06湿度计上进行。
在粉末制作过程前后的胰岛素完整性的测量是以人胰岛素标准品为参照，将称量过的部分粉末重新溶于蒸馏水中并将重新溶解的溶液与加入喷雾干燥器内的原始溶液进行比较。通过反相HPLC中的保留时间和峰面积来测定胰岛素分子是否在此过程中发生了化学修饰或降解。运用紫外吸收来测定胰岛素的浓度(278μm)以及是否存在不溶性聚合物(400μm)。此外还要测量开始时以及新配制的溶液的PH值。通过偏光显微镜来确证胰岛素粉末的无定性特性。大鼠的烟雾剂接触
大鼠实验在喷雾剂接触室内进行。雌性大鼠(280-300gm)禁食过夜。将动物(每次实验21至24只)放置于有机玻璃管内，然后封固于有48个气门、只露鼻子的(mose-only)烟雾剂接触室内(In-Tox产品，Albuquerque，NM)。到达呼吸区域的空气流量保持在7.2-9.8L/min，并通过真空将其移走，因此用magnahelic计测量时，在室内会有轻微的负压(约1.5cm H2O)。根据充入室内的粉末的多少，烟雾剂的接触时间在5到20分钟之间。用手将粉末加入到一个小的文丘里氏喷嘴中来分散粉末颗粒，形成良好的烟雾云。文氏喷嘴的操作压力超过15psig，空气流量设置在7.2l/min到9.8l/min。文氏喷嘴装在清晰的有机玻璃分散室的底部，通过它将烟雾剂加入到只露鼻子的接触室中。大鼠烟雾剂室的校准
呼吸区内的粉末浓度测定通过使用In-Tox过滤器在2l/min真空流量下收集呼吸区内大部分的计时过滤的样品，小室在有动物及没有动物时均进行了校准。粉末的质量用重量分析测定。呼吸区内粉末的颗粒大小通过设置在呼吸孔的阶式碰撞取样器(In Tox产品)在2l/min的流量下测定。每一级的粉末质量用重量分析测定。
每次实验使用21至24只大鼠，烟雾剂接触时间持续5到20分钟。在时间零点和烟雾剂接触结束后大约7、15、30、60、90、120、180和240分钟各杀死三只大鼠。将大鼠麻醉，打开其腹部，从腹主动脉抽取大量血液样品。然后用颈部脱位法处死动物。
血液在室温下凝集30分钟，然后用血清分离试管在3500rmp下离心20分钟。血清可以立即进行分析，也可以在-80℃下冷冻直至分析。在烟雾剂给药结束后尽快(0-7min)处死三只大鼠，抽取其血液并半它们的肺用5ml的灌洗6次。最终混合的灌洗样品中的胰岛素含量在计算生物利用度时作为大鼠的烟雾剂的剂量。灵长类接触系统
使用幼小的野生雄性Cynomolgus猴种的fascicularis弥猴2-5kg(Charles RiverPrimates，Inc.)进行灵长类烟雾剂研究(每组3-4只动物)。对动物皮下注射胰岛素(Eli Lilly，Indianapolis，Indiana)或让其接触胰岛素粉末烟雾剂。每只动物均关在只露头部的接触单元中，以适当的流速(7l/min)供给新鲜的实验气体的供给动物最少的氧气需要量。将动物固定在椅样的器具上使其处于直立的坐姿。罩子是清晰的，可以使动物完整地看到它们的周围环境。在(动物)腿上插上留置导管，从而可以在任意时间抽取血液样品。在整个过程中猴子完全清醒并表现得安静。灵长类的血液处理与大鼠相同(见上)。
灵长类类雾剂接触系统包括呼吸监测器，可以对每只猴子吸入的空气量进行定量。这个数值与测得的呼吸空气中的胰岛素浓度一起可以计算出每只动物确切吸入了多少胰岛素。
人体实验
对24个正常人分别用皮下注射和吸入雾化的干粉胰岛素进行胰岛素给药。每次皮下注射包括10.4单位的Humulin R，100u/ml(Eli Lilly，Indianapolis，Indiana)。干胰岛素粉是用上述的喷雾干燥的方法制备的无定形粉末，含有20％重量比的甘露糖醇赋形剂。将胰岛素干粉药物(5mg)在高速空气流中进行分散，形成良好的烟雾剂并将其俘获于小室中。每个个体对每一个烟雾剂团或每次“喷射”通过缓慢地深呼吸吸入烟雾剂粉末。粉末通过三次喷射给药(剂量为31.9单位)。如下所述，血清胰岛素及葡萄糖水平随时间进行测定。血清分析
大鼠、灵长类及人的血清胰岛素水平的测定应用适于人胰岛素的Coat-A-Count放射免疫分析仪(Diagnositc Products Corporation，Los Angeles，CA)。对每一组样品均做了标准曲线。分析的灵敏度大约为43pg/ml。评估内变化率(within assayvariability)＜5％(CV％)。葡萄糖分析由加利福尼亚兽医诊断公司(WestSacramento，CA)使用适于Boehringer Mannheim/Hitachi 747分析仪的葡萄糖/HK试剂系统包进行。评估内变化率(％CV)＜3％。
在大鼠实验中，烟雾剂的相对生物利用度的计算是通过将调整剂量的免疫活性胰岛素(IRI)浓度-时间曲线的曲线下面积(AUC)与由皮下注射所得到的进行比较。在大鼠中，用全部灌洗胰岛素的质量作为烟雾剂的剂量。一些胰岛素在肺部灌洗之前即被吸收，因此用这种方法估计的剂量可能稍微低估了沉积的总剂量。对这种推测的损失来进行校正。
在猴子实验中，除了用吸入的胰岛素的量代替肺灌洗胰岛素作为烟雾剂的剂量外，相对生物利用度的计算与上面大鼠的相似。在大鼠中，估算的剂量中只包括沉积于肺的物质，而不包括沉积于鼻腔和咽喉部位的胰岛素。在猴子中，估算的剂量中包括所有进入动物体内的胰岛素。大鼠胰岛素吸收结果
所有用于动物研究的胰岛素粉末的颗粒尺寸(集体平均直径)在1-3μ范围内，水份含量＜3％。用反相HPLC测得粉末中的胰岛素纯度＞97％。在图8C中显示了20％胰岛素制剂的代表性色谱图。粉末在重新溶于纯净水后得到澄清溶液，在400nm的紫外吸收小于0.01，pH值为6.7±0.3。在图9中显示了20％胰岛素制剂的代表性紫外图谱。
在In-Tox 48气门的接触室中，应用下面三种胰岛素粉末制剂作为烟雾剂进行了大鼠实验。
1.87.9％胰岛素；11.5％柠檬酸钠；0.6％柠檬酸。
2.20％胰岛素；66％甘露糖醇；12％柠檬酸钠，0.6％柠檬酸。
3.20％胰岛素；66％棉子糖；12.4％柠檬酸钠，0.6％柠檬酸。
表1列出了三次不同大鼠接触研究的主要测量结果，包括在小室操作条件下呼吸区域内烟雾剂的特性。由于在填加粉末过程中粉末的碰撞以及不完全分散引起的在墙壁上的损失，只有部分加入文氏喷嘴的粉末到达了大鼠的呼吸区域(34-67％)。然而在呼吸区域的烟雾剂颗粒的尺寸对于肺部沉积比较理想(1.3-1.9μm)，并且比原始制剂的颗粒尺寸(2.0-2.8μm)稍微小了些，这是由于在动物接触室内选择性丢失了大的颗粒。
表1.大鼠烟雾剂接触测量结果
  88％胰岛素    20％胰岛素甘露糖醇     20％胰岛素棉子糖
室内流速   7.2L/min   9.6L/min     9.8L/min
粉末集体平均直径(MMD)   2.2μm   2.8μm     2.0μm
加入室内的粉末   70mgs   255mgs     260mgs
粉末加入时间   5min   14min     20min
呼吸区的粉末   40mgs   171mgs     88mgs
呼吸区的胰岛素   35mgs   34mgs     18mgs
呼吸区粉末总量(％)   57％   67％     34％
集体平均空气动力学直径(MAD)   1.1mg/L   1.3mg/L     0.45mg/L
呼吸区颗粒大小   1.4μm   1.9μm     1.3μm
灌洗回收胰岛素量   30.7±5.2μg   12.7±6.9μg     31.6±12.9μg
血清胰岛素AUC(ng min/ml)   104   201     150
表2显示了三次烟雾剂以及一次皮下研究的大鼠血清胰岛素及葡萄糖结果。图3A和3B显示了三种经烟雾剂给药的制剂的血清免疫活性胰岛素(IRI)时-量曲线以及血清葡萄糖时-量曲线。
表3给出了不同研究的胰岛素tmax和葡萄糖tmin以及与皮下注射相比较烟雾剂的相对生物利用度。
表2.大鼠血清胰岛素和葡萄糖结果
        制剂     途径   时间(min)     血清胰岛素(pg/ml±1S.D)n＝3rats/timept     血清葡萄糖(pg/ml±1S.D)n＝3rats/timept
80％胰岛素   烟雾剂   0     230±184     106±12
(在5分钟   烟雾剂   12     1020±312     114±10
完成烟雾剂接触)   烟雾剂   21     165±768     81±10
平均剂量＝31μg/大鼠   烟雾剂   36     876±764     66±7
  烟雾剂   66     684±416     62±15
  烟雾剂   96     568±128     65±10
  烟雾剂   126     568±260     73±11
  烟雾剂   186     712±140     93±5
20％胰岛素-甘露糖醇   烟雾剂   0     476±56     165±18
(在14分钟   烟雾剂   22     1476±428     117±15
完成烟雾剂接触)   烟雾剂   35     2480±892     101±19
平均剂量＝13μg/大鼠   烟雾剂   57     1204±64     64±13
  烟雾剂   87     1084±396     63±17
  烟雾剂   117     664±180     105±38
  烟雾剂   147     1228±416     108±22
  烟雾剂   207     676±100     119±33
20％胰岛素-棉子糖   烟雾剂   0     426±97     157±37
(在20分钟   烟雾剂   27     2948±2816     139±46
完成烟雾剂接触)   烟雾剂   42     1504±592     181±11
平均剂量＝32μg/大鼠   烟雾剂   57     1272±496     124±45
  烟雾剂   87     852±164     128±17
  烟雾剂   117     604±156     124±9
  烟雾剂   147     532±172     172±12
  烟雾剂   207     556±100     218±34
20％胰岛素-甘露糖醇   皮下注射   0     360±140     107±5
剂量＝30μg胰岛素/大鼠   皮下注射   15     14200±3160     53±2
  皮下注射   30     10160±720     24±5
  皮下注射   60     11000±1080     28±6
  皮下注射   90     2440±1160     25±7
  皮下注射   120     3520±840     49±3
  皮下注射   180     1280±800     4017
  皮下注射   240     400±260     77±34
表3烟雾剂与皮下注射(SC)胰岛素在动物中的比较
  大鼠SC  大鼠88％胰岛素甘露糖醇烟雾剂  大鼠20％胰岛素甘露糖醇烟雾剂  大鼠20％胰岛素棉子糖烟雾剂   猴子SC  猴子20％胰岛素甘露糖烟雾剂
  胰岛素Max*   15min     16mm     21min     17min   15min     30min
  葡萄糖min*   30min     31min     43min     37min   45min     45min
  葡萄糖下降   77％     42％     62％     21％   45％     73％
  相对生物利用度   100％     10％**     44％**     14％**   100％     12％***
*T从烟雾剂接触结束计起
葡萄糖min＝在研究中观察到大于最大降低值的85％时的时间
**基于烟雾剂接触结束时从肺灌洗回收得到的胰岛素
***基于吸入的胰岛素，包括在鼻腔及咽喉内损失
所有三种制剂都对大鼠的机体循环提供了迅速吸收的胰岛素(图3A和3B)。20％胰岛素/甘露糖醇粉末的生物利用度及葡萄糖反应较高(表3)。不过没有进行许多重复实验，不能确定差别是否显著。灵长类结果
对4只猴子注射与人体实验相同的剂量(0.2u/kg，每只猴子约27μg)，得到皮下注射(SC)的数据与烟雾剂的结果进行比较(图4A和4B)。表4显示了猴子喷雾接触的数据，表5显示烟雾剂接触及皮下研究的平均血清胰岛素及葡萄糖(结果)。烟雾剂产生了很强的胰岛素及葡萄糖反应(高剂量)。图4显示了两次烟雾剂及一次皮下研究的平均血清胰岛素图形的比较。从这些图形的曲线下面积计算出烟雾剂胰岛素的相对生物利用度为12％。
表4猴子烟雾剂接触数据
    动物(ID)  重力过滤质量(mg)  平均烟雾剂浓度(μg/L)    吸入体积(L)   吸入烟雾剂量计算算值(μg)  吸入胰岛素质量计算值(μg)   体重(kg)    胰岛素剂量计算值(μg/kg)     AUC(μg min/ml)
  #1，23-46   1.07   178   8.96   1597     320   3.92   81.5     347
  #2，23-48   1.01   168   19.98   3363     673   3.81   176.6     1196
  #3，122-55   0.97   162   14.68   2373     475   4.1   115.7     739
    489±178
人体(实验)结果
下面的表5列出了呼吸给药与皮下注射的比较结果。呼吸烟雾剂给药的吸收(20分钟达峰)比皮下注射(60分钟达峰)快得多，引起的葡萄糖反应(60分钟达谷)也比皮下注射(90分钟达谷)快得多。胰岛素及葡萄糖反应在烟雾剂中的重现性与注射时至少同样的好。注射用的剂量根据体重做了仔细的调整，烟雾剂的剂量未调整。由葡萄糖反应得出的烟雾剂胰岛素的生物活性相对于注射为28-36％。由胰岛素曲线下面积得出的三次喷射给药组的烟雾剂胰岛素的生物利用度，相对于注射为22.8％。
               表5人体实验的血清胰岛素和葡萄糖结果胰岛素个体编号#S      剂量/注       个体内的    血清胰岛素    最大值的    基于胰岛素曲线下面
            射或发泡      剂量*      增加μU/ml    时间        积的相对生物利用度1-24(SC注射)    10.4U         10.4U       5.8-20.9      60min       100.0％7-24(喷射)      76.0U         31.9U       6.1-28.5      20min       22.8％葡萄糖个体编号#S     平均血清葡萄糖  mg/dl下降量   最小值的   ％SC       基于胰岛素AUC
           的下降mg/dl                   时间                  的相对生物利用度1-24(SC注射)   93.6-64.9       287           90min      100％      100％7-24(喷射)     91.8-67.6       24.2          60min      84.3％     27.4％*仪器效率＝42％
在图5A-5B中进一步显示了人体实验的结果。图5A显示皮下注射(○)及吸入(三次喷射，●)的平均血清胰岛素浓度随时间的变化。在图5B中的相似的方式显示了平均血清葡萄糖水平。在图6A和6B中分别显示了胰岛素的峰值与葡萄糖的谷值，在图7A和7B中分别显示了胰岛素与葡萄糖的个体间差异。
此外，在烟雾剂接触过程中，猴子的浅呼吸(潮式呼吸)不是用于肺部深处沉积的优选呼吸方式。如预期的那样，当使用最佳的呼吸方式，同时用嘴而不是用鼻子吸入烟雾剂团时，在人体实验中观察到了较高的生物利用度。
虽然前述的发明为达到使理解清楚的目的，以说明和实例的方式对某些细节做了描述，但那些可能实施的改变和修饰显然在附加的权利要求书的范围内。

Claims (24)

1.雾化胰岛素制剂的方法，所述方法包括：
提供干粉胰岛素；
将一定数量的所述干粉分散在气体流中形成烟雾剂；并且
将烟雾剂俘获在设有供患者随后吸入的喷嘴的小室中。
2.如权利要求1所述的方法，其中的干粉不含增透剂。
3.如权利要求1所述的方法，其中的胰岛素附着于干粉载体上，重量浓度在5％至99％范围内。
4.如权利要求3所述的方法，其中的粉末载体包括糖、有机盐、氨基酸、多肽或蛋白质。
5.如权利要求1所述的方法，其中的胰岛素干粉包含平均尺寸小于10μm的颗粒。
6.如权利要求1所述的方法，其中的干粉包含含有胰岛素及载体两者的独立颗粒。
7.如权利要求6所述的方法，其中各个颗粒的胰岛素含量为从重量比的5％至99％。
8.胰岛素干粉在制备用于改进胰岛素呼吸(道)释放的药物的用途，其中的改进包括释放胰岛素干粉。
9.如权利要求8所述的用途，其中的胰岛素不含增透剂。
10.如权利要求8所述的用途，其中的胰岛素附着于干粉载体上，重量浓度在10％至99％范围内。
11.如权利要求10所述的用途，其中粉末载体包括糖、有机盐、氨基酸、多肽或蛋白质。
12.如权利要求8所述的用途，其中的胰岛素干粉包括平均尺寸小于10μm的颗粒。
13.如权利要求8所述的用途，其中的干粉包含有胰岛素及载体两者的独立颗粒。
14.如权利要求13所述的用途，其中各个颗粒胰岛素含量为从重量比5％至99％。
15.制备稳定的干粉胰岛素组合物的方法，所述方法包括：
将胰岛素溶于缓冲水溶液中形成溶液；以及
将溶液喷雾干燥制得平均尺寸小于10μm的大体无定形颗粒。
16.如权利要求15所述的方法，其中的胰岛素与药物载体一起溶于缓于水溶液中，其中在喷雾干燥中制得各个颗粒的胰岛素含量为从重量比5％至99％的干粉。
17.如权利要求16所述的方法，其中的药物载体是可以在喷雾干燥中产生粉末的糖、有机盐、氨基酸、多肽或蛋白质。
18.如权利要求17所述的方法，其中的糖选自甘露糖醇、棉子糖、乳糖、麦芽糖糊精和海藻糖。
19.如权利要求17所述的方法，其中的有机盐选白柠檬酸钠、乙酸钠、抗坏血酸钠。
20.用于肺部释放的胰岛素组合物，所述组合物包含附着于药物载体材料上的、胰岛素含量为重量比5％至99％，并且尺寸低于10μm的独立颗粒，其中的组合物不含增透剂。
21.如权利要求20所述的胰岛素组合物，其中的药物载体材料包括糖，该糖选自甘露糖醇、棉子糖、乳糖、麦芽糖糊精和海藻糖。
22.如权利要求20所述的胰岛素组合物，其中的药物载体材料包括选自柠檬酸钠、葡萄糖酸钠、抗坏血酸钠的有机盐。
23.由权利要求15的方法制得的胰岛素组合物。
24.由权利要求15的方法制备的胰导素组合物，由平均颗粒尺寸小于10μm的干粉胰岛素组成的胰岛素组合物。
CN95191910A 1994-03-07 1995-02-07 用于胰岛素肺部给药的方法和组合物 Expired - Fee Related CN1098679C (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US20747294A 1994-03-07 1994-03-07
US08/207,472 1994-03-07
US38347595A 1995-02-01 1995-02-01
US08/383,475 1995-02-01

Publications (2)

Publication Number Publication Date
CN1152867A CN1152867A (zh) 1997-06-25
CN1098679C true CN1098679C (zh) 2003-01-15

Family

ID=26902263

Family Applications (1)

Application Number Title Priority Date Filing Date
CN95191910A Expired - Fee Related CN1098679C (zh) 1994-03-07 1995-02-07 用于胰岛素肺部给药的方法和组合物

Country Status (23)

Country Link
US (6) US6685967B1 (zh)
EP (3) EP1462096B1 (zh)
JP (2) JPH10501519A (zh)
KR (1) KR100419037B1 (zh)
CN (1) CN1098679C (zh)
AT (2) ATE416755T1 (zh)
AU (1) AU689217B2 (zh)
BR (1) BR9507023A (zh)
CA (1) CA2183577C (zh)
CZ (1) CZ295827B6 (zh)
DE (2) DE69535897D1 (zh)
DK (1) DK0748213T3 (zh)
ES (2) ES2218543T3 (zh)
FI (1) FI116195B (zh)
HU (1) HUT75676A (zh)
IL (1) IL112618A (zh)
MX (1) MX9603936A (zh)
MY (1) MY124282A (zh)
NO (1) NO316661B1 (zh)
NZ (1) NZ281112A (zh)
PL (1) PL179443B1 (zh)
PT (1) PT748213E (zh)
WO (1) WO1995024183A1 (zh)

Families Citing this family (301)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6582728B1 (en) 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
CA2145418A1 (en) * 1992-09-29 1994-04-14 John S. Patton Pulmonary delivery of active fragments of parathyroid hormone
US6024090A (en) * 1993-01-29 2000-02-15 Aradigm Corporation Method of treating a diabetic patient by aerosolized administration of insulin lispro
US7448375B2 (en) * 1993-01-29 2008-11-11 Aradigm Corporation Method of treating diabetes mellitus in a patient
US6632456B1 (en) 1993-06-24 2003-10-14 Astrazeneca Ab Compositions for inhalation
US20010003739A1 (en) * 1993-06-24 2001-06-14 Astrazeneca Ab Systemic administration of a therapeutic preparation
TW402506B (en) * 1993-06-24 2000-08-21 Astra Ab Therapeutic preparation 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
ES2218543T3 (es) 1994-03-07 2004-11-16 Nektar Therapeutics Procedimiento y preparacion para la administracion de insulina por via pulmonar.
US6051256A (en) 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
US20030113273A1 (en) * 1996-06-17 2003-06-19 Patton John S. Methods and compositions for pulmonary delivery of insulin
JPH10500672A (ja) * 1994-05-18 1998-01-20 インヘイル セラピューティック システムズ，インコーポレイティド インターフェロンの乾燥粉末製剤に関する方法及び組成物
US6165976A (en) 1994-06-23 2000-12-26 Astra Aktiebolag Therapeutic preparation for inhalation
US6290991B1 (en) * 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
US6586006B2 (en) 1994-08-04 2003-07-01 Elan Drug Delivery Limited Solid delivery systems for controlled release of molecules incorporated therein and methods of making same
US5863563A (en) * 1994-10-20 1999-01-26 Alphagene Inc. Treatment of pulmonary conditions associated with insufficient secretion of surfactant
MX9704550A (es) 1994-12-22 1997-10-31 Astra Ab Formulaciones de medicamentos en aerosol.
JPH10511090A (ja) * 1994-12-22 1998-10-27 アストラ・アクチエボラーグ 副甲状腺ホルモン，ｐｔｈ含有吸入用治療製剤
US6524557B1 (en) 1994-12-22 2003-02-25 Astrazeneca Ab Aerosol formulations of peptides and proteins
US6309671B1 (en) * 1995-04-14 2001-10-30 Inhale Therapeutic Systems Stable glassy state powder formulations
US6258341B1 (en) * 1995-04-14 2001-07-10 Inhale Therapeutic Systems, Inc. Stable glassy state powder formulations
US6428771B1 (en) 1995-05-15 2002-08-06 Pharmaceutical Discovery Corporation Method for drug delivery to the pulmonary system
GB9515182D0 (en) † 1995-07-24 1995-09-20 Co Ordinated Drug Dev Improvements in and relating to powders for use in dry powder inhalers
DE19539574A1 (de) 1995-10-25 1997-04-30 Boehringer Mannheim Gmbh Zubereitungen und Verfahren zur Stabilisierung biologischer Materialien mittels Trocknungsverfahren ohne Einfrieren
UA59358C2 (uk) 1996-01-24 2003-09-15 Бик Гулден Ломберг Хеміше Фабрік Гмбх Спосіб приготування порошкоподібного пульмонологічного порошкоподібного препарату та препарат, одержаний в такий спосіб
AU1729297A (en) † 1996-02-09 1997-08-28 Quadrant Holdings Cambridge Limited Solid formulations containing trehalose
US5874064A (en) * 1996-05-24 1999-02-23 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
US6503480B1 (en) 1997-05-23 2003-01-07 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
USRE37053E1 (en) 1996-05-24 2001-02-13 Massachusetts Institute Of Technology Particles incorporating surfactants for pulmonary drug delivery
US5855913A (en) * 1997-01-16 1999-01-05 Massachusetts Instite Of Technology Particles incorporating surfactants for pulmonary drug delivery
US6254854B1 (en) 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
US20020052310A1 (en) 1997-09-15 2002-05-02 Massachusetts Institute Of Technology The Penn State Research Foundation Particles for inhalation having sustained release properties
AUPO269996A0 (en) * 1996-10-01 1996-10-24 Walter And Eliza Hall Institute Of Medical Research, The A method of prophylaxis and treatment
US20030203036A1 (en) 2000-03-17 2003-10-30 Gordon Marc S. Systems and processes for spray drying hydrophobic drugs with hydrophilic excipients
WO1998029140A1 (en) * 1996-12-31 1998-07-09 Inhale Therapeutic Systems Processes and compositions for spray drying hydrophobic drugs in organic solvent suspensions of hydrophilic excipients
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
CA2283705A1 (en) * 1997-03-20 1998-10-01 Novo Nordisk A/S Zinc free insulin crystals for use in pulmonary compositions
US20030035778A1 (en) * 1997-07-14 2003-02-20 Robert Platz Methods and compositions for the dry powder formulation of interferon
PT901786E (pt) 1997-08-11 2007-08-07 Pfizer Prod Inc Disperções farmacêuticas sólidas com biodisponibilidade melhorada
US7052678B2 (en) 1997-09-15 2006-05-30 Massachusetts Institute Of Technology Particles for inhalation having sustained release properties
US6309623B1 (en) * 1997-09-29 2001-10-30 Inhale Therapeutic Systems, Inc. Stabilized preparations for use in metered dose inhalers
US6565885B1 (en) * 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
US20060165606A1 (en) * 1997-09-29 2006-07-27 Nektar Therapeutics Pulmonary delivery particles comprising water insoluble or crystalline active agents
ZA989744B (en) * 1997-10-31 2000-04-26 Lilly Co Eli Method for administering acylated insulin.
WO1999055310A1 (en) 1998-04-27 1999-11-04 Altus Biologics Inc. Stabilized protein crystals, formulations containing them and methods of making them
US6451349B1 (en) 1998-08-19 2002-09-17 Quadrant Healthcare (Uk) Limited Spray-drying process for the preparation of microparticles
GB9814172D0 (en) * 1998-06-30 1998-08-26 Andaris Ltd Formulation for inhalation
UA73924C2 (en) 1998-10-09 2005-10-17 Nektar Therapeutics Device for delivering active agent formulation to lungs of human patient
US20060171899A1 (en) * 1998-12-10 2006-08-03 Akwete Adjei Water-stabilized aerosol formulation system and method of making
US7087215B2 (en) * 1998-12-21 2006-08-08 Generex Pharmaceuticals Incorporated Methods of administering and enhancing absorption of pharmaceutical agents
WO2000047203A1 (en) * 1999-02-12 2000-08-17 Mqs, Inc. Formulation and system for intra-oral delivery of pharmaceutical agents
EP1165050B1 (en) * 1999-04-05 2006-03-29 Mannkind Corporation Methods for fine powder formation
US7001892B1 (en) 1999-06-11 2006-02-21 Purdue Research Foundation Pharmaceutical materials and methods for their preparation and use
US6858199B1 (en) 2000-06-09 2005-02-22 Advanced Inhalation Research, Inc. High efficient delivery of a large therapeutic mass aerosol
US9006175B2 (en) * 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
PT1196430E (pt) 1999-06-29 2012-04-18 Mannkind Corp Purificação e estabilização de péptidos e proteínas em agentes farmacêuticos
GB9916316D0 (en) * 1999-07-12 1999-09-15 Quadrant Holdings Cambridge Dry powder compositions
WO2001010903A2 (en) * 1999-08-09 2001-02-15 Incyte Genomics, Inc. Proteases and protease inhibitors
US6586008B1 (en) * 1999-08-25 2003-07-01 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles during spray drying
US7678364B2 (en) 1999-08-25 2010-03-16 Alkermes, Inc. Particles for inhalation having sustained release properties
US6749835B1 (en) * 1999-08-25 2004-06-15 Advanced Inhalation Research, Inc. Formulation for spray-drying large porous particles
US7252840B1 (en) 1999-08-25 2007-08-07 Advanced Inhalation Research, Inc. Use of simple amino acids to form porous particles
WO2001018042A2 (en) * 1999-09-10 2001-03-15 Incyte Genomics, Inc. Apoptosis proteins
US6761909B1 (en) * 1999-12-21 2004-07-13 Rxkinetix, Inc. Particulate insulin-containing products and method of manufacture
AU2729101A (en) 1999-12-21 2001-07-03 Rxkinetix, Inc. Particulate drug-containing products and method of manufacture
FI20002217A (fi) * 1999-12-30 2001-07-01 Orion Yhtymae Oyj Inhalaatiopartikkelit
JP2003519175A (ja) * 1999-12-30 2003-06-17 カイロン コーポレイション インターロイキン−２の肺送達のための方法
EP2133098A1 (en) 2000-01-10 2009-12-16 Maxygen Holdings Ltd G-CSF conjugates
US6540982B1 (en) * 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation
US6596261B1 (en) * 2000-01-25 2003-07-22 Aeropharm Technology Incorporated Method of administering a medicinal aerosol formulation
US6585957B1 (en) 2000-01-25 2003-07-01 Aeropharm Technology Incorporated Medicinal aerosol formulation
JP2003524646A (ja) * 2000-01-25 2003-08-19 エアロファーム テクノロジー インコーポレイテッド 医薬エアゾール製剤
US6540983B1 (en) * 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation
CA2401454A1 (en) * 2000-03-03 2001-09-13 Incyte Genomics, Inc. G-protein coupled receptors
JP4711520B2 (ja) * 2000-03-21 2011-06-29 日本ケミカルリサーチ株式会社 生理活性ペプチド含有粉末
US6447750B1 (en) * 2000-05-01 2002-09-10 Aeropharm Technology Incorporated Medicinal aerosol formulation
GB0010709D0 (en) * 2000-05-03 2000-06-28 Vectura Ltd Powders for use a in dry powder inhaler
US8404217B2 (en) * 2000-05-10 2013-03-26 Novartis Ag Formulation for pulmonary administration of antifungal agents, and associated methods of manufacture and use
ES2525087T5 (es) 2000-05-10 2018-06-28 Novartis Ag Polvos basados en fosfolípidos para administración de fármacos
US7871598B1 (en) * 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
GB0011807D0 (en) * 2000-05-16 2000-07-05 Quadrant Holdings Cambridge Formulation for inhalation
EP2093293A3 (en) 2000-06-16 2010-07-07 Incyte Corporation G-Protein coupled receptors
US7575761B2 (en) * 2000-06-30 2009-08-18 Novartis Pharma Ag Spray drying process control of drying kinetics
WO2002009674A2 (en) * 2000-07-28 2002-02-07 Inhale Therapeutic Systems, Inc. Methods and compositions to upregulate, redirect or limit immune responses to bioactive compounds
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
US6613308B2 (en) 2000-09-19 2003-09-02 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US7608704B2 (en) 2000-11-08 2009-10-27 Incyte Corporation Secreted proteins
CA2430318C (en) * 2000-11-29 2009-10-27 Itoham Foods Inc. Powder formulation and method for producing the same
ES2689704T3 (es) * 2000-11-30 2018-11-15 Vectura Limited Partículas para usar en una composición farmacéutica
ES2474199T3 (es) 2000-11-30 2014-07-08 Vectura Limited Composiciones farmacéuticas para inhalaci�n
US20020106331A1 (en) * 2000-12-08 2002-08-08 Joan Rosell Use of electrolytes (ions in solution) to suppress charging of inhalation aerosols
US20020141946A1 (en) * 2000-12-29 2002-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
EP1345629A2 (en) * 2000-12-29 2003-09-24 Advanced Inhalation Research, Inc. Particles for inhalation having sustained release properties
EP1797902A3 (en) * 2000-12-29 2007-10-03 Advanced Inhalation Research, Inc. Particles for inhalation having sustained release properties
IL156059A0 (en) 2001-02-27 2003-12-23 Maxygen Aps NEW INTERFERON beta-LIKE MOLECULES
US7905230B2 (en) 2001-05-09 2011-03-15 Novartis Ag Metered dose inhaler with lockout
US9994853B2 (en) 2001-05-18 2018-06-12 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
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
TW553752B (en) 2001-06-20 2003-09-21 Inhale Therapeutic Syst Powder aerosolization apparatus and method
NZ519403A (en) * 2001-06-21 2005-03-24 Pfizer Prod Inc Use of insulin in a medicament to reduce weight gain in a diabetic patient who is using exogenous insulin to control blood sugar levels
GB0208742D0 (en) 2002-04-17 2002-05-29 Bradford Particle Design Ltd Particulate materials
PT1429731E (pt) * 2001-09-19 2007-04-30 Elan Pharma Int Ltd Formulações de insulina nanoparticulada
US7231919B2 (en) 2001-09-28 2007-06-19 Kurve Technology, Inc. Particle dispersion device for nasal delivery
EP1446104B2 (en) * 2001-11-01 2011-08-03 Novartis AG Spray drying methods
KR20040073438A (ko) 2001-11-19 2004-08-19 벡톤 디킨슨 앤드 컴퍼니 입자 형태의 약제학적 조성물
PT1455755E (pt) 2001-11-20 2013-06-18 Civitas Therapeutics Inc Composições particuladas melhoradas para distribuição pulmonar
WO2003047553A1 (en) * 2001-12-07 2003-06-12 Eiffel Technologies Limited Synthesis of small particles
ES2364636T3 (es) 2001-12-19 2011-09-08 Novartis Ag Administración pulmonar de aminoglucósidos.
JP4739672B2 (ja) 2001-12-21 2011-08-03 ネクター セラピューティクス 湿気のバリアを有するカプセルパッケージ
US9657294B2 (en) 2002-02-20 2017-05-23 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
US9181551B2 (en) 2002-02-20 2015-11-10 Sirna Therapeutics, Inc. RNA interference mediated inhibition of gene expression using chemically modified short interfering nucleic acid (siNA)
AU2003222225A1 (en) * 2002-02-20 2003-09-09 Incyte Corporation Receptors and membrane-associated proteins
EP1894591B1 (en) 2002-03-20 2013-06-26 MannKind Corporation Cartridge for an inhalation apparatus
US20050163725A1 (en) * 2002-03-20 2005-07-28 Blizzard Charles D. Method for administration of growth hormone via pulmonary delivery
US7008644B2 (en) * 2002-03-20 2006-03-07 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
JP2005520843A (ja) 2002-03-20 2005-07-14 アドバンスト インハレーション リサーチ，インコーポレイテッド 呼吸用持続性治療製剤
EP1485073A2 (en) * 2002-03-20 2004-12-15 Advanced Inhalation Research, Inc. Method for administration of growth hormone via pulmonary delivery
US7754242B2 (en) * 2002-03-20 2010-07-13 Alkermes, Inc. Inhalable sustained therapeutic formulations
HUE031167T2 (hu) 2002-03-20 2017-07-28 Civitas Therapeutics Inc A levodopa pulmonális bejuttatása
AU2003226603A1 (en) 2002-04-19 2003-11-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem Beta-agonist compounds comprising nitric oxide donor groups and reactive oxygen species scavenger groups and their use in the treatment of respiratory disorders
AU2003263024A1 (en) * 2002-04-23 2003-11-10 Christopher Mcconville Process of forming and modifying particles and compositions produced thereby
GB0216562D0 (en) 2002-04-25 2002-08-28 Bradford Particle Design Ltd Particulate materials
US9339459B2 (en) 2003-04-24 2016-05-17 Nektar Therapeutics Particulate materials
AU2003249623A1 (en) * 2002-05-09 2003-12-12 Kurve Technology, Inc. Particle dispersion chamber for nasal nebulizer
US6941980B2 (en) 2002-06-27 2005-09-13 Nektar Therapeutics Apparatus and method for filling a receptacle with powder
EP1531794B1 (en) 2002-06-28 2017-05-10 Civitas Therapeutics, Inc. Inhalable epinephrine
AU2003265431A1 (en) * 2002-08-13 2004-02-25 Incyte Corporation Cell adhesion and extracellular matrix proteins
US20070219353A1 (en) * 2002-09-03 2007-09-20 Incyte Corporation Immune Response Associated Proteins
AU2003279829A1 (en) * 2002-10-04 2004-05-04 Incyte Corp Protein modification and maintenance molecules
US20050164275A1 (en) * 2002-10-18 2005-07-28 Incyte Corporation Phosphodiesterases
US20070009886A1 (en) * 2002-11-12 2007-01-11 Incyte Corporation Carbohydrate-associated proteins
WO2004044165A2 (en) * 2002-11-13 2004-05-27 Incyte Corporation Lipid-associated proteins
US20040105818A1 (en) 2002-11-26 2004-06-03 Alexza Molecular Delivery Corporation Diuretic aerosols and methods of making and using them
WO2004048550A2 (en) * 2002-11-26 2004-06-10 Incyte Corporation Immune response associated proteins
US7516741B2 (en) 2002-12-06 2009-04-14 Novartis Ag Aerosolization apparatus with feedback mechanism
WO2004054606A1 (en) * 2002-12-13 2004-07-01 Pfizer Products Inc. Method of decreasing hepatic glucose output in diabetic patients
US20050236296A1 (en) * 2002-12-30 2005-10-27 Nektar Therapeutics (Formerly Inhale Therapeutic Systems, Inc.) Carry case for aerosolization apparatus
AU2003302329B2 (en) 2002-12-30 2010-01-07 Novartis Ag Prefilming atomizer
US7669596B2 (en) 2002-12-31 2010-03-02 Novartis Pharma Ag Aerosolization apparatus with rotating capsule
PL1615689T3 (pl) 2003-04-09 2016-06-30 Novartis Ag Urządzenie do aerozolizacji z prowadnicą wyrównującą do przebijania kapsułki
ES2383367T5 (es) 2003-04-09 2021-03-31 Novartis Ag Aparato de pulverización en forma de aerosol con protección de entrada de aire
US8869794B1 (en) 2003-04-09 2014-10-28 Novartis Pharma Ag Aerosolization apparatus with capsule puncturing member
US7829682B1 (en) 2003-04-30 2010-11-09 Incyte Corporation Human β-adrenergic receptor kinase nucleic acid molecule
US7683029B2 (en) * 2003-05-07 2010-03-23 Philip Morris Usa Inc. Liquid aerosol formulations containing insulin and aerosol generating devices and methods for generating aerosolized insulin
CA2526222A1 (en) * 2003-05-16 2004-12-02 Arriva Pharmaceuticals, Inc. Treatment of respiratory disease associated with matrix metalloprotease inhibitors
US7338171B2 (en) * 2003-10-27 2008-03-04 Jen-Chuen Hsieh Method and apparatus for visual drive control
CN101027082A (zh) * 2004-01-12 2007-08-29 曼恩坎德公司 降低2型糖尿病患者血清胰岛素原水平的方法
US20050191360A1 (en) * 2004-02-10 2005-09-01 Advanced Inhalation Research, Inc. Particles for inhalation having rapid release properties
WO2005089722A1 (en) * 2004-03-12 2005-09-29 Biodel, Inc. Rapid acting drug delivery compositions
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
US7625865B2 (en) 2004-03-26 2009-12-01 Universita Degli Studi Di Parma Insulin highly respirable microparticles
US20060039985A1 (en) * 2004-04-27 2006-02-23 Bennett David B Methotrexate compositions
JP2007536273A (ja) * 2004-05-07 2007-12-13 プレジデント・アンド・フェロウズ・オブ・ハーバード・カレッジ 肺マラリアワクチン
US10508277B2 (en) 2004-05-24 2019-12-17 Sirna Therapeutics, Inc. Chemically modified multifunctional short interfering nucleic acid molecules that mediate RNA interference
US7481219B2 (en) * 2004-06-18 2009-01-27 Mergenet Medical, Inc. Medicine delivery interface system
US8513204B2 (en) 2004-06-21 2013-08-20 Novartis Ag Compositions comprising amphotericin B, mehods and systems
WO2006002140A2 (en) 2004-06-21 2006-01-05 Nektar Therapeutics Compositions comprising amphotericin b
RU2393168C2 (ru) * 2004-07-19 2010-06-27 Биокон Лимитед Инсулин-олигомерные конъюгаты, их препараты и применения
CN101010305B (zh) 2004-08-20 2010-08-11 曼金德公司 二酮哌嗪合成的催化反应
PL2322180T3 (pl) 2004-08-23 2015-10-30 Mannkind Corp Sole diketopiperazyny do dostarczania leków
US7115561B2 (en) * 2004-09-22 2006-10-03 Patterson James A Medicament composition and method of administration
SE0402345L (sv) * 2004-09-24 2006-03-25 Mederio Ag Uppmätt läkemedelsdos
RU2007119721A (ru) 2004-10-29 2008-12-10 Президент Энд Феллоуз Оф Гарвард Колледж (Us) Частицы для лечения легочной инфекции
US20060115468A1 (en) * 2004-11-26 2006-06-01 Kara Morrison Dietary supplement for treating and preventing gastrointestinal disorders
CN101094651B (zh) 2004-12-30 2011-03-09 多贝尔有限公司 含有胶原凝集素家族蛋白质或者其变体的喷雾干燥的组合物和其制备方法
US20080206342A1 (en) * 2005-01-10 2008-08-28 Rosemary Kovelesky Compositions and Methods For Increasing the Bioavailability of Pulmonarily Administered Insulin
CN100431634C (zh) * 2005-04-04 2008-11-12 陈庆堂 干粉气溶胶化吸入器
UA95446C2 (ru) * 2005-05-04 2011-08-10 Іллюміджен Байосайєнсіз, Інк. Мутаци в генах oas1
CN101184522B (zh) 2005-05-18 2011-12-21 尼克塔治疗公司 用于支气管内治疗的阀、设备和方法
US20070031342A1 (en) * 2005-06-22 2007-02-08 Nektar Therapeutics Sustained release microparticles for pulmonary delivery
JP2009500163A (ja) * 2005-07-07 2009-01-08 ナノセラピューティクス・インコーポレイテッド 粉末を製粉および調製する方法及びそれにより得られる組成物
CN104324362B (zh) 2005-09-14 2018-04-24 曼金德公司 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
US8084420B2 (en) 2005-09-29 2011-12-27 Biodel Inc. Rapid acting and long acting insulin combination formulations
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
US20070123449A1 (en) * 2005-11-01 2007-05-31 Advanced Inhalation Research, Inc. High load particles for inhalation having rapid release properties
GB0524194D0 (en) * 2005-11-28 2006-01-04 Univ Aston Respirable powders
TWI299993B (en) * 2005-12-15 2008-08-21 Dev Center Biotechnology Aqueous inhalation pharmaceutical composition
US9012605B2 (en) 2006-01-23 2015-04-21 Amgen Inc. Crystalline polypeptides
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
ES2622493T3 (es) 2006-02-24 2017-07-06 Rigel Pharmaceuticals, Inc. Composiciones y métodos para la inhibición de la ruta de JAK
AU2007238114B2 (en) 2006-04-12 2010-10-14 Biodel, Inc. Rapid acting and long acting insulin combination formulations
US20080170996A1 (en) * 2006-07-28 2008-07-17 The Board Of Regents Of The University Of Texas System Compositions and Methods for Stimulation of Lung Innate Immunity
ES2542146T3 (es) 2006-07-31 2015-07-31 Novo Nordisk A/S Insulinas extendidas PEGiladas.
GB0616299D0 (en) * 2006-08-16 2006-09-27 Cambridge Consultants Drug Capsules for dry power inhalers
US20080063722A1 (en) * 2006-09-08 2008-03-13 Advanced Inhalation Research, Inc. Composition of a Spray-Dried Powder for Pulmonary Delivery of a Long Acting Neuraminidase Inhibitor (LANI)
WO2008034881A1 (en) 2006-09-22 2008-03-27 Novo Nordisk A/S Protease resistant insulin analogues
ES2538082T3 (es) 2007-02-11 2015-06-17 Map Pharmaceuticals Inc Método de administración terapéutica de DHE para permitir el rápido alivio de migraña mientras que se minimiza el perfil de efectos secundarios
ES2563038T3 (es) 2007-04-30 2016-03-10 Novo Nordisk A/S Método para secar una composición proteica, una composición proteica seca y una composición farmacéutica que comprende la proteína seca
US8747872B2 (en) 2007-05-02 2014-06-10 The Regents Of The University Of Michigan Nanoemulsion therapeutic compositions and methods of using the same
KR101234540B1 (ko) * 2007-10-16 2013-02-19 바이오콘 리미티드 경구 투여가능한 고형 약제학적 조성물 및 그 제조방법
WO2011163272A1 (en) 2010-06-21 2011-12-29 Mannkind Corporation Dry powder drug delivery system and methods
US8785396B2 (en) 2007-10-24 2014-07-22 Mannkind Corporation Method and composition for treating migraines
AU2008317307A1 (en) * 2007-10-25 2009-04-30 Novartis Ag Powder conditioning of unit dose drug packages
EP2060268A1 (en) * 2007-11-15 2009-05-20 Novo Nordisk A/S Pharmaceutical compositions for pulmonary or nasal delivery of peptides
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
US9260502B2 (en) 2008-03-14 2016-02-16 Novo Nordisk A/S Protease-stabilized insulin analogues
US8691759B2 (en) 2008-03-18 2014-04-08 Novo Nordisk A/S Protease stabilized, acylated insulin analogues
DK2293833T3 (en) 2008-06-13 2016-05-23 Mannkind Corp DRY POWDER INHALER AND MEDICINAL ADMINISTRATION SYSTEM
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
KR101628410B1 (ko) 2008-06-20 2016-06-08 맨카인드 코포레이션 흡입 활동에 관한 실시간 프로파일링을 위한 대화형 장치 및 방법
TWI494123B (zh) 2008-08-11 2015-08-01 Mannkind Corp 超快起作用胰島素之用途
US20110105383A1 (en) * 2008-09-10 2011-05-05 Magnus Hook Methods and compositions for stimulation of mammalian innate immune resistance to pathogens
AU2009292643B2 (en) 2008-09-19 2016-02-18 Nektar Therapeutics Polymer conjugates of therapeutic peptides
JP5722782B2 (ja) * 2008-09-26 2015-05-27 ナノバイオ コーポレーション ナノエマルジョン治療用組成物及びその使用方法
WO2010043566A2 (de) 2008-10-17 2010-04-22 Sanofi-Aventis Deutschland Gmbh Kombination von einem insulin und einem glp-1-agonisten
EP2894165B1 (en) 2008-11-10 2023-01-04 Alexion Pharmaceuticals, Inc. Methods and compositions for treating complement-associated disorders
EP2376089B1 (en) 2008-11-17 2018-03-14 The Regents of the University of Michigan Cancer vaccine compositions and methods of using the same
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
EP2388040A4 (en) 2009-01-19 2013-12-25 Mitsubishi Gas Chemical Co METHOD OF ACTIVE INJECTION INTO A LIVING BODY BY ELECTROSPRAY AND DEVICE THEREFOR
JP5341532B2 (ja) 2009-01-19 2013-11-13 第一電子工業株式会社 １対の誤嵌合防止キー及び該キーを用いた電気コネクタ
DK2389372T3 (en) 2009-01-23 2015-12-14 Rigel Pharmaceuticals Inc COMPOSITIONS AND METHODS FOR INHIBITION OF JAK pathway
US8889213B2 (en) 2009-01-26 2014-11-18 Teva Pharmaceutical Industries Ltd. Processes for coating a carrier with microparticles
US9060927B2 (en) * 2009-03-03 2015-06-23 Biodel Inc. Insulin formulations for rapid uptake
AU2010221254B2 (en) 2009-03-04 2014-04-03 Mannkind Corporation An improved dry powder drug delivery system
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
DK2405963T3 (da) 2009-03-11 2013-12-16 Mannkind Corp Apparat, system og fremgangsmåde til at måle modstand i en inhalator
WO2010107964A1 (en) 2009-03-18 2010-09-23 Pleiades Cardio-Therapeutics, Inc. Unit doses, aerosols, kits, and methods for treating heart conditions by pulmonary administration
PL2411521T3 (pl) 2009-03-25 2015-08-31 Univ Texas Kompozycje do stymulacji wrodzonej odporności immunologicznej na patogeny u ssaków
PT3130396T (pt) 2009-03-27 2021-05-12 Bend Res Inc Processo de secagem por pulverização
WO2010135459A2 (en) * 2009-05-19 2010-11-25 Mount Sinai School Of Medicine Of New York University Brain delivery of insulin to treat systemic inflammation
WO2010142017A1 (en) 2009-06-09 2010-12-16 Defyrus, Inc . Administration of interferon for prophylaxis against or treatment of pathogenic infection
BRPI1013154B1 (pt) 2009-06-12 2020-04-07 Mannkind Corp Micropartículas de dicetopiperazina com áreas de superfície específicas definidas, pó seco compreendendo as referidas micropartículas, método para formação das referidasmicropartículas e formação de micropartículas de fumaril diacetopiperazina, uso das referidas micropartículas e sistema de inalação
WO2010151526A1 (en) 2009-06-23 2010-12-29 Alexion Pharmaceuticals, Inc. Bispecific antibodies that bind to complement proteins
GB0918450D0 (en) 2009-10-21 2009-12-09 Innovata Ltd Composition
EP2496295A1 (en) 2009-11-03 2012-09-12 MannKind Corporation An apparatus and method for simulating inhalation efforts
AU2010317994B2 (en) 2009-11-13 2014-03-06 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
PL2498802T3 (pl) 2009-11-13 2015-06-30 Sanofi Aventis Deutschland Kompozycja farmaceutyczna zawierająca agonistę GLP-1, insulinę i metioninę
US10842951B2 (en) 2010-01-12 2020-11-24 Aerami Therapeutics, Inc. Liquid insulin formulations and methods relating thereto
US20160243199A1 (en) 2015-02-25 2016-08-25 Dance Biopharm, Inc. Liquid insulin formulations and methods relating thereto
US9180261B2 (en) 2010-01-12 2015-11-10 Dance Biopharm Inc. Preservative free insulin formulations and systems and methods for aerosolizing
EP2528601A1 (en) 2010-01-26 2012-12-05 Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. Compositions and methods for prevention and treatment of pulmonary hypertension
CA2797856C (en) 2010-04-30 2018-09-18 Alexion Pharmaceuticals, Inc. Anti-c5a antibodies and methods for using the antibodies
AU2011202239C1 (en) 2010-05-19 2017-03-16 Sanofi Long-acting formulations of insulins
US20130059916A1 (en) 2010-05-26 2013-03-07 Stephane Rocchi Biguanide compounds and its use for treating cancer
AU2010360116B2 (en) 2010-08-30 2014-06-26 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the manufacture of a medicament for the treatment of diabetes mellitus type 2
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
EP2611529B1 (en) 2010-09-03 2019-01-23 Bend Research, Inc. Spray-drying method
PT2611530T (pt) 2010-09-03 2019-05-09 Bend Res Inc Aparelho de secagem por pulverização e métodos de utilização do mesmo
US9248584B2 (en) 2010-09-24 2016-02-02 Bend Research, Inc. High-temperature spray drying process and apparatus
EP3327125B1 (en) 2010-10-29 2020-08-05 Sirna Therapeutics, Inc. Rna interference mediated inhibition of gene expression using short interfering nucleic acids (sina)
SG194034A1 (en) 2011-04-01 2013-11-29 Mannkind Corp Blister package for pharmaceutical cartridges
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
CA2754237A1 (en) 2011-05-27 2012-11-27 The Regents Of The University Of California Cyanoquinoline compounds having activity in correcting mutant-cftr processing and increasing ion transport and uses thereof
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
WO2013030160A1 (en) 2011-08-29 2013-03-07 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
AR087744A1 (es) 2011-09-01 2014-04-16 Sanofi Aventis Deutschland Composicion farmaceutica para uso en el tratamiento de una enfermedad neurodegenerativa
AU2012328885B2 (en) 2011-10-24 2017-08-31 Mannkind Corporation Methods and compositions for treating pain
KR20140103939A (ko) 2011-12-16 2014-08-27 노파르티스 아게 흡입 프로파일-비의존적 약물 전달을 위한 에어로졸화 장치
US9421248B2 (en) 2011-12-30 2016-08-23 Grifols, S.A. Alpha 1-proteinase inhibitor for delaying the onset or progression of pulmonary exacerbations
US9770192B2 (en) * 2012-03-19 2017-09-26 Richard C. Fuisz Method and system to amplify and measure breath analytes
US8877967B2 (en) 2012-03-23 2014-11-04 Oxigene, Inc. Compositions and methods for inhibition of cathepsins
AU2013247047A1 (en) 2012-04-11 2014-10-23 Novo Nordisk A/S Insulin formulations
CN108057154B (zh) * 2012-07-12 2021-04-16 曼金德公司 干粉药物输送系统和方法
WO2014066856A1 (en) 2012-10-26 2014-05-01 Mannkind Corporation Inhalable influenza vaccine compositions and methods
US20140179597A1 (en) * 2012-11-16 2014-06-26 Steven Lehrer Method for the treatment and prevention of Alzheimer's disease and central nervous system dysfunction
ES2928365T3 (es) 2013-03-15 2022-11-17 Mannkind Corp Composiciones de dicetopiperazina microcristalina, métodos de preparación y uso del mismo
JP6457484B2 (ja) 2013-04-03 2019-01-23 サノフイＳａｎｏｆｉ インスリンの長時間作用型製剤による糖尿病の治療
EP3021834A1 (en) 2013-07-18 2016-05-25 MannKind Corporation Heat-stable dry powder pharmaceutical compositions and methods
WO2015012758A1 (en) * 2013-07-22 2015-01-29 Inhalation Sciences Sweden Ab Apparatus and method for generating an aerosol
CN105517607A (zh) 2013-08-05 2016-04-20 曼金德公司 吹入设备和方法
BR112016007166A2 (pt) 2013-10-07 2017-09-12 Novo Nordisk As derivado de um análogo de insulina
NZ631007A (en) 2014-03-07 2015-10-30 Alexion Pharma Inc Anti-c5 antibodies having improved pharmacokinetics
US10307464B2 (en) 2014-03-28 2019-06-04 Mannkind Corporation Use of ultrarapid acting insulin
WO2016007682A1 (en) 2014-07-08 2016-01-14 Amphastar Pharmaceuticals Inc. Micronized insulin, micronized insulin analogues, and methods of manufacturing the same
WO2016044839A2 (en) 2014-09-19 2016-03-24 The Board Of Regents Of The University Of Texas System Compositions and methods for treating viral infections through stimulated innate immunity in combination with antiviral compounds
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
EP3204039B1 (en) 2014-10-10 2022-06-08 The Regents Of The University Of Michigan Nanoemulsion compositions for preventing, suppressing or eliminating allergic and inflammatory disease
EP3212169B1 (en) 2014-10-31 2021-01-13 Bend Research, Inc. Process for forming active domains dispersed in a matrix
HUE062573T2 (hu) 2014-12-12 2023-11-28 Sanofi Aventis Deutschland Glargin inzulin/lixiszenatid rögzített arányú készítmény
TWI748945B (zh) 2015-03-13 2021-12-11 德商賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患治療
TW201705975A (zh) 2015-03-18 2017-02-16 賽諾菲阿凡提斯德意志有限公司 第２型糖尿病病患之治療
US10322168B2 (en) 2016-01-07 2019-06-18 Amphastar Pharmaceuticals, Inc. High-purity inhalable particles of insulin and insulin analogues, and high-efficiency methods of manufacturing the same
CN114847965A (zh) 2016-02-01 2022-08-05 英凯达治疗公司 电子监测联合吸入药理学疗法管理心律失常
CA3043480A1 (en) 2016-11-09 2018-05-17 The Board Of Regents Of The University Of Texas System Methods and compositions for adaptive immune modulation
PE20191205A1 (es) 2016-12-16 2019-09-10 Novo Nordisk As Composiciones farmaceuticas que contienen insulina
EP3554503B1 (en) 2016-12-16 2023-10-04 The Board of Regents of The University of Texas System Inhibitors of bromodomain-containing protein 4 (brd4)
JP2020519628A (ja) 2017-05-10 2020-07-02 インカーダ セラピューティクス， インコーポレイテッド 肺投与によって心臓の状態を処置するための単位用量、エアロゾル、キットおよび方法
EP3638312B1 (en) * 2017-06-12 2024-02-21 Elgan Pharma Ltd. Multiparticulate granulate comprising insulin
PT3658184T (pt) 2017-07-27 2023-11-29 Alexion Pharma Inc Formulações de anticorpo anti-c5 de elevada concentração
WO2019126536A1 (en) 2017-12-20 2019-06-27 Alexion Pharmaceuticals Inc. Humanized anti-cd200 antibodies and uses thereof
US10744087B2 (en) 2018-03-22 2020-08-18 Incarda Therapeutics, Inc. Method to slow ventricular rate
US11389433B2 (en) 2018-06-18 2022-07-19 Board Of Regents, The University Of Texas System BRD4 inhibitor treatment of IgE-mediated diseases
US20220000880A1 (en) 2018-11-01 2022-01-06 Rigel Pharmaceuticals, Inc. Method and composition embodiments for treating acute myeloid leukemia
US20220023282A1 (en) 2018-12-13 2022-01-27 Mannkind Corporation Compositions of Bedaquiline, Combinations Comprising Them, Processes for Their Preparation, Uses and Methods of Treatment Comprising Them
EP3976050A1 (en) 2019-05-24 2022-04-06 Stichting Radboud universitair medisch centrum Improved administration of glycylcyclines by inhalation
US20200377518A1 (en) 2019-05-29 2020-12-03 Rigel Pharmaceuticals, Inc. Method of preventing and treating thrombosis
US11007185B2 (en) 2019-08-01 2021-05-18 Incarda Therapeutics, Inc. Antiarrhythmic formulation
CA3147443A1 (en) 2019-08-08 2021-02-11 Rigel Pharmaceuticals, Inc. Compounds and method for treating cytokine release syndrome
MX2022001890A (es) 2019-08-14 2022-04-26 Rigel Pharmaceuticals Inc Metodo para bloquear o mejorar el sindrome de liberacion de citocinas.
TW202228792A (zh) 2020-10-09 2022-08-01 殷漢生技股份有限公司 吸入用奈米載體製劑
CN114712336B (zh) * 2020-12-22 2023-11-07 黄嘉若 一种用于肺部给药的水性气溶胶、制备方法和用途
EP4304582A1 (en) 2021-03-12 2024-01-17 Alvarius Pharmaceuticals Ltd. Compositions and methods for treating addictions comprising 5-meo-dmt
CN117460525A (zh) * 2021-04-11 2024-01-26 爱儿安制药有限公司 多种胰岛素制剂及其在多个早产儿中使用的多种方法
WO2023183377A1 (en) 2022-03-23 2023-09-28 Rigel Pharmaceuticals, Inc. Pyrimid-2-yl-pyrazole compounds as irak inhibitors

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520748A1 (en) * 1991-06-26 1992-12-30 Pafra Limited Storage of materials
CN1129904A (zh) * 1993-06-24 1996-08-28 阿斯特拉公司 供吸入的治疗学制剂

Family Cites Families (250)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US558085A (en) * 1896-04-14 And william c
US979993A (en) 1910-03-24 1910-12-27 Joseph Francis O'byrne Projectile.
US1855591A (en) 1926-02-03 1932-04-26 Wallerstein Co Inc Invertase preparation and method of making the same
US2598525A (en) 1950-04-08 1952-05-27 E & J Mfg Co Automatic positive pressure breathing machine
DE1812574U (de) 1960-04-05 1960-06-02 Felix Duerst Betonmischer.
NL113394C (zh) 1960-04-07
US3300474A (en) 1964-02-12 1967-01-24 Pharmacia Ab Sucrose ether copolymerizates
US3362405A (en) 1964-04-06 1968-01-09 Hamilton O. Hazel Method and apparatus for admixing gas with solid particles
BR6570825D0 (pt) 1964-07-04 1973-08-16 Shiryo Kogyo Co Inc Nippon Processo para produzir granulos cristalizados a partir de solucoes de acucares e outros cristaloides
US3314803A (en) 1966-01-26 1967-04-18 Gen Foods Corp Mannitol fixed flavor and method of making same
US3674901A (en) 1966-07-26 1972-07-04 Nat Patent Dev Corp Surgical sutures
US3425600A (en) 1966-08-11 1969-02-04 Abplanalp Robert H Pressurized powder dispensing device
US3554768A (en) 1967-08-01 1971-01-12 Gen Foods Corp Carbohydrate fixed acetaldehyde
US3620776A (en) 1968-06-28 1971-11-16 Nestle Sa Spray drying process
US3619294A (en) 1968-07-15 1971-11-09 Penick & Ford Ltd Method of combining crystalline sugar with impregnating agents and products produced thereby
US3555717A (en) 1968-10-24 1971-01-19 Victor Comptometer Corp Artificial fishing lure
DE1812574A1 (de) 1968-12-04 1970-06-11 Riedel De Haen Ag Verfahren zur Herstellung biozider Granulate
US3632357A (en) 1969-07-29 1972-01-04 Standard Brands Inc Method of producing hard candy
US3655442A (en) 1969-08-27 1972-04-11 California & Hawaiian Sugar Method of making sugar and sugar products
US3666496A (en) 1969-09-03 1972-05-30 Firmenich Inc Water soluble,powdered,terpene-containing flavors
US3937668A (en) * 1970-07-15 1976-02-10 Ilse Zolle Method for incorporating substances into protein microspheres
US3764716A (en) 1970-11-16 1973-10-09 American Potato Co Preparation of dehydrated mashed potatoes
US3745682A (en) 1971-09-28 1973-07-17 Pneu Dart Inc Gun for propelling a drug or medicine projectile
US4069819A (en) 1973-04-13 1978-01-24 Societa Farmaceutici S.P.A. Inhalation device
US3971852A (en) 1973-06-12 1976-07-27 Polak's Frutal Works, Inc. Process of encapsulating an oil and product produced thereby
GB1479283A (en) 1973-07-23 1977-07-13 Bespak Industries Ltd Inhaler for powdered medicament
FR2257351A1 (en) 1974-01-11 1975-08-08 Obert Jean Claude Aerosol device for solid vaccines - feed and breaker screws deliver material sideways into blower chamber
IT1016489B (it) 1974-03-18 1977-05-30 Isf Spa Inalatore
DE2415159A1 (de) 1974-03-29 1975-10-09 Hoechst Ag Alkalialkansulfonathaltige spruehprodukte und verfahren zu ihrer herstellung
US3948263A (en) 1974-08-14 1976-04-06 Minnesota Mining And Manufacturing Company Ballistic animal implant
JPS5134879A (en) 1974-09-19 1976-03-24 Eisai Co Ltd Bishochukuryushinoseizoho
US3964483A (en) 1975-01-13 1976-06-22 Syntex Puerto Rico, Inc. Inhalation device
US4005711A (en) 1975-01-13 1977-02-01 Syntex Puerto Rico, Inc. Inhalation device
FR2299011A1 (fr) 1975-01-29 1976-08-27 Obert Jean Claude Generateur d'aerosols de part
US4102999A (en) 1975-02-10 1978-07-25 Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai Process for producing stable macromomycin powder
US3991304A (en) 1975-05-19 1976-11-09 Hillsman Dean Respiratory biofeedback and performance evaluation system
US4153689A (en) 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
GB1527605A (en) 1975-08-20 1978-10-04 Takeda Chemical Industries Ltd Insulin preparation for intranasal administration
US3994421A (en) 1975-09-29 1976-11-30 American Cyanamid Company Unitary therapeutic aerosol dispenser
US4109019A (en) 1975-11-18 1978-08-22 William Percy Moore Process for improved ruminant feed supplements
NL7704348A (nl) 1977-04-21 1978-10-24 Philips Nv Werkwijze voor het bereiden van een geattenueer- de transmissible gastroenteritis(tge)-virusstam voor toepassing in levende vaccins.
US4180593A (en) 1977-04-29 1979-12-25 Cohan Allan N Process for producing round spherical free flowing blown bead food products of controlled bulk density
US4127502A (en) 1977-06-10 1978-11-28 Eastman Kodak Company Stabilizers for reconstituted, lyophilized samples
US4211769A (en) * 1977-08-24 1980-07-08 Takeda Chemical Industries, Ltd. Preparations for vaginal administration
DE2748132A1 (de) 1977-10-27 1979-05-03 Behringwerke Ag Stabilisator fuer polysaccharid
NL7712041A (en) 1977-11-01 1979-05-03 Handelmaatschappij Voorheen Be Suction equipment for powdery material - incorporates ejector type suction pump and cyclone type separator
US4244949A (en) 1978-04-06 1981-01-13 The Population Council, Inc. Manufacture of long term contraceptive implant
DE2960616D1 (en) 1978-05-03 1981-11-12 Fisons Plc Inhalation device
US4158544A (en) 1978-07-17 1979-06-19 Beckman Instruments, Inc. Process for preparing a biological composition for use as a reference control in diagnostic analysis
US4253468A (en) 1978-08-14 1981-03-03 Steven Lehmbeck Nebulizer attachment
US4588744A (en) 1978-09-19 1986-05-13 Mchugh John E Method of forming an aqueous solution of 3-3-Bis(p-hydroxyphenyl)-phthalide
US4503035B1 (en) 1978-11-24 1996-03-19 Hoffmann La Roche Protein purification process and product
GB2037735B (en) 1978-12-21 1983-11-09 Standard Telephones Cables Ltd Glass composition
SU1003926A1 (ru) 1979-01-24 1983-03-15 Всесоюзный Научно-Исследовательский И Конструкторский Институт Автогенного Машиностроения Порошковый питатель
EP0015123B1 (en) 1979-02-21 1982-12-22 Imperial Chemical Industries Plc A process for the extraction of poly-3-hydroxy-butyric acid from microbial cells
IT1116047B (it) 1979-04-27 1986-02-10 Sigma Tau Ind Farmaceuti Dispositivo per la rapida inalazione di farmaci in polvere da parte di persone sofferenti di asma
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
WO1981001243A1 (en) 1979-10-30 1981-05-14 Riker Laboratories Inc Breath actuated devices for administering powdered medicaments
US4294624A (en) 1980-03-14 1981-10-13 Veltman Preston Leonard Drying co-mingled carbohydrate solution and recycled product by dielectric heating
ZA811942B (en) 1980-03-25 1983-02-23 H Malem Nebulising apparatus
JPS56138110A (en) * 1980-03-28 1981-10-28 Teijin Ltd Suppository containing citric acid or salt thereof
EP0111216A3 (en) 1980-03-31 1985-01-16 Takeda Chemical Industries, Ltd. Method for enzyme immunoassay and peptide-enzyme conjugate, its lyophilizate, antibody and kit therefor
US4423079A (en) 1980-07-14 1983-12-27 Leo Kline Growth promoting compositions for Lactobacillus sanfrancisco and method of preparation
US4326524A (en) 1980-09-30 1982-04-27 Minnesota Mining And Manufacturing Company Solid dose ballistic projectile
US4327076A (en) 1980-11-17 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4371557A (en) 1981-01-21 1983-02-01 General Foods Corporation Maintenance of protein quality in foods containing reducing sugars
US4327077A (en) 1981-05-29 1982-04-27 Life Savers, Inc. Compressed chewable antacid tablet and method for forming same
US4484577A (en) 1981-07-23 1984-11-27 Key Pharmaceuticals, Inc. Drug delivery method and inhalation device therefor
GB2105189B (en) 1981-07-24 1985-03-20 Fisons Plc Inhalation drugs
US5260306A (en) 1981-07-24 1993-11-09 Fisons Plc Inhalation pharmaceuticals
EP0072046B1 (en) 1981-07-24 1986-01-15 FISONS plc Inhalation drugs, methods for their production and pharmaceutical formulations containing them
DE3141498A1 (de) 1981-10-20 1983-04-28 Bayer Ag, 5090 Leverkusen Arzneimittel enthaltend kallikrein und verfahren zu seiner herstellung
NL193099C (nl) 1981-10-30 1998-11-03 Novo Industri As Gestabiliseerde insuline-oplossing.
US4713249A (en) 1981-11-12 1987-12-15 Schroeder Ulf Crystallized carbohydrate matrix for biologically active substances, a process of preparing said matrix, and the use thereof
SE8204244L (sv) * 1982-07-09 1984-01-10 Ulf Schroder Kristalliserad kolhydratsmatris for biologiskt aktiva substanser
JPS58154548A (ja) 1982-03-09 1983-09-14 Nippon Shinyaku Co Ltd アズレン誘導体の安定化方法
US4659696A (en) * 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4823784A (en) 1982-04-30 1989-04-25 Cadema Medical Products, Inc. Aerosol inhalation apparatus
US4599311A (en) 1982-08-13 1986-07-08 Kawasaki Glenn H Glycolytic promotersfor regulated protein expression: protease inhibitor
US4457916A (en) 1982-08-31 1984-07-03 Asahi Kasei Kogyo Kabushiki Kaisha Method for stabilizing Tumor Necrosis Factor and a stable aqueous solution or powder containing the same
US4591552A (en) 1982-09-29 1986-05-27 New York Blood Center, Inc. Detection of hepatitis B surface antigen (or antibody to same) with labeled synthetic peptide
US4778054A (en) 1982-10-08 1988-10-18 Glaxo Group Limited Pack for administering medicaments to patients
SE458824B (sv) 1982-10-08 1989-05-16 Glaxo Group Ltd Anordning foer att tillfoera laekemedel till patienter
US4559298A (en) 1982-11-23 1985-12-17 American National Red Cross Cryopreservation of biological materials in a non-frozen or vitreous state
ES519619A0 (es) 1983-02-08 1984-03-16 Gandariasbeitia Aguirreche Man Procedimiento continuo para la produccion de enzimas proteoliticas y aminoliticas a partir de microorganismos vegetales.
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
JPS6035263A (ja) 1983-08-05 1985-02-23 Wako Pure Chem Ind Ltd 不溶性担体に固定化された免疫活性物質の安定化法及び該物質を構成単位として含む生理活性物質測定用試薬
US4649911A (en) 1983-09-08 1987-03-17 Baylor College Of Medicine Small particle aerosol generator for treatment of respiratory disease including the lungs
DE3345722A1 (de) 1983-12-17 1985-06-27 Boehringer Ingelheim KG, 6507 Ingelheim Inhalator
US4534343A (en) 1984-01-27 1985-08-13 Trutek Research, Inc. Metered dose inhaler
US4820534A (en) 1984-03-19 1989-04-11 General Foods Corporation Fixation of volatiles in extruded glass substrates
US4758583A (en) 1984-03-19 1988-07-19 The Rockefeller University Method and agents for inhibiting protein aging
US4927763A (en) 1984-03-21 1990-05-22 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
DD238305A3 (de) 1984-04-23 1986-08-20 Maisan Werke Barby Veb Verfahren zur herstellung von d-glucose und staerkehydrolysaten
US4617272A (en) 1984-04-25 1986-10-14 Economics Laboratory, Inc. Enzyme drying process
US4956295A (en) 1984-05-21 1990-09-11 Chr. Hansen's Laboratory, Inc. Stabilization of dried bacteria extended in particulate carriers
US4620847A (en) 1984-06-01 1986-11-04 Vsesojuzny Nauchno-Issledovatelsky Institut Meditsinskikh Polimerov Device for administering powdered substances
JPS60258195A (ja) 1984-06-05 1985-12-20 Ss Pharmaceut Co Ltd α．α―トレハロース脂肪酸ジエステル誘導体
JPS60258125A (ja) 1984-06-06 1985-12-20 Hayashibara Biochem Lab Inc 蛋白性生理活性物質を含有する水溶性乾燥物
US4721709A (en) 1984-07-26 1988-01-26 Pyare Seth Novel pharmaceutical compositions containing hydrophobic practically water-insoluble drugs adsorbed on pharmaceutical excipients as carrier; process for their preparation and the use of said compositions
US4624251A (en) 1984-09-13 1986-11-25 Riker Laboratories, Inc. Apparatus for administering a nebulized substance
NZ209900A (en) 1984-10-16 1989-08-29 Univ Auckland Automatic inhaler
IE58110B1 (en) * 1984-10-30 1993-07-14 Elan Corp Plc Controlled release powder and process for its preparation
DE3445010A1 (de) 1984-12-10 1986-06-19 Boehringer Mannheim Gmbh Kontroll- bzw. eichserum fuer die lipid-diagnostik
FR2575678B1 (fr) 1985-01-04 1988-06-03 Saint Gobain Vitrage Ejecteur pneumatique de poudre
US4857319A (en) 1985-01-11 1989-08-15 The Regents Of The University Of California Method for preserving liposomes
FR2575923B1 (fr) 1985-01-15 1988-02-05 Jouveinal Sa Composition laxative a base de lactulose, et son procede de fabrication
US4830858A (en) 1985-02-11 1989-05-16 E. R. Squibb & Sons, Inc. Spray-drying method for preparing liposomes and products produced thereby
US4942544A (en) 1985-02-19 1990-07-17 Kenneth B. McIntosh Medication clock
JPS61194034A (ja) 1985-02-25 1986-08-28 Teijin Ltd 経鼻投与用粉末状組成物
US4946828A (en) * 1985-03-12 1990-08-07 Novo Nordisk A/S Novel insulin peptides
GB8508173D0 (en) 1985-03-28 1985-05-01 Standard Telephones Cables Ltd Controlled delivery device
IL78342A (en) 1985-04-04 1991-06-10 Gen Hospital Corp Pharmaceutical composition for treatment of osteoporosis in humans comprising a parathyroid hormone or a fragment thereof
JPS63500175A (ja) 1985-05-22 1988-01-21 リポソ−ム　テクノロジ−，インコ−ポレイテツド リポソ−ム吸入法および吸入システム
DE229810T1 (de) 1985-07-09 1987-11-05 Quadrant Bioresources Ltd., Soulbury, Leighton Buzzard, Bedfordshire, Gb Beschuetzung von proteinen und aehnlichem.
US4847079A (en) 1985-07-29 1989-07-11 Schering Corporation Biologically stable interferon compositions comprising thimerosal
GB2178965B (en) 1985-07-30 1988-08-03 Glaxo Group Ltd Devices for administering medicaments to patients
US4719762A (en) 1985-11-21 1988-01-19 Toshiba Heating Appliances Co., Ltd. Stored ice detecting device in ice making apparatus
US4680027A (en) 1985-12-12 1987-07-14 Injet Medical Products, Inc. Needleless hypodermic injection device
JPS62174094A (ja) 1985-12-16 1987-07-30 Ss Pharmaceut Co Ltd α．α―トレハロース誘導体
JPH0710344B2 (ja) 1985-12-26 1995-02-08 株式会社林原生物化学研究所 無水グリコシルフルクト−スによる含水物の脱水方法
SE453566B (sv) 1986-03-07 1988-02-15 Draco Ab Anordning vid pulverinhalatorer
US4897353A (en) 1986-03-13 1990-01-30 University Of Southwestern Louisiana Cryogenic protection of phosphofructokinase using amino acids and zinc ions
US4806343A (en) * 1986-03-13 1989-02-21 University Of Southwestern Louisiana Cryogenic protectant for proteins
US5017372A (en) * 1986-04-14 1991-05-21 Medicis Corporation Method of producing antibody-fortified dry whey
US4739754A (en) 1986-05-06 1988-04-26 Shaner William T Suction resistant inhalator
US4762857A (en) 1986-05-30 1988-08-09 E. I. Du Pont De Nemours And Company Trehalose as stabilizer and tableting excipient
US4926852B1 (en) 1986-06-23 1995-05-23 Univ Johns Hopkins Medication delivery system phase one
US4790305A (en) 1986-06-23 1988-12-13 The Johns Hopkins University Medication delivery system
US5042975A (en) * 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
WO1988001165A1 (en) 1986-08-11 1988-02-25 Innovata Biomed Limited Pharmaceutical formulations comprising microcapsules
DE3779221D1 (de) 1986-08-19 1992-06-25 Genentech Inc Einrichtung und dispersion zum intrapulmonalen eingeben von polypeptidwuchsstoffen und -zytokinen.
US4729754A (en) * 1986-10-15 1988-03-08 Rexnord Inc. Sealed bushing joint for chain
DE3636669C2 (de) 1986-10-28 2001-08-16 Siemens Ag Anordnung zur Zufuhr von Aerosol zu den Luftwegen und/oder Lungen eines Patienten
US5049388A (en) 1986-11-06 1991-09-17 Research Development Foundation Small particle aerosol liposome and liposome-drug combinations for medical use
US4833125A (en) 1986-12-05 1989-05-23 The General Hospital Corporation Method of increasing bone mass
NZ222907A (en) 1986-12-16 1990-08-28 Novo Industri As Preparation for intranasal administration containing a phospholipid absorption enhancing system
US4906463A (en) * 1986-12-22 1990-03-06 Cygnus Research Corporation Transdermal drug-delivery composition
US5114917A (en) 1986-12-24 1992-05-19 John Lezdey Treatment of inflammation using alpha 1-antichymotrypsin
JPS63186799A (ja) 1987-01-29 1988-08-02 不二製油株式会社 油脂粉末の製造方法
US5089181A (en) * 1987-02-24 1992-02-18 Vestar, Inc. Method of dehydrating vesicle preparations for long term storage
FR2611501B1 (fr) * 1987-03-04 1991-12-06 Corbiere Jerome Nouvelles compositions pharmaceutiques pour la voie buccale a base d'acetylsalielylate de lysine et leur procede d'obtention
US4855326A (en) 1987-04-20 1989-08-08 Fuisz Pharmaceutical Ltd. Rapidly dissoluble medicinal dosage unit and method of manufacture
US5387431A (en) * 1991-10-25 1995-02-07 Fuisz Technologies Ltd. Saccharide-based matrix
JP2656944B2 (ja) * 1987-04-30 1997-09-24 クーパー ラボラトリーズ タンパク質性治療剤のエアロゾール化
US4876241A (en) 1987-05-22 1989-10-24 Armour Pharmaceutical Company Stabilization of biological and pharmaceutical products during thermal inactivation of viral and bacterial contaminants
US4790824A (en) 1987-06-19 1988-12-13 Bioject, Inc. Non-invasive hypodermic injection device
GB8715238D0 (en) 1987-06-29 1987-08-05 Quadrant Bioresources Ltd Food process
US5059587A (en) * 1987-08-03 1991-10-22 Toyo Jozo Company, Ltd. Physiologically active peptide composition for nasal administration
US5139016A (en) 1987-08-07 1992-08-18 Sorin Biomedica S.P.A. Process and device for aerosol generation for pulmonary ventilation scintigraphy
IT1222509B (it) 1987-08-17 1990-09-05 Miat Spa Insufflatore per la somministrazione di farmaci sotto forma di polvere predosata in opercoli
GB8723846D0 (en) * 1987-10-10 1987-11-11 Danbiosyst Ltd Bioadhesive microsphere drug delivery system
US4968607A (en) 1987-11-25 1990-11-06 Immunex Corporation Interleukin-1 receptors
WO1989004838A1 (en) 1987-11-25 1989-06-01 Immunex Corporation Interleukin-1 receptors
US5081228A (en) 1988-02-25 1992-01-14 Immunex Corporation Interleukin-1 receptors
GB8801338D0 (en) 1988-01-21 1988-02-17 Quadrant Bioresources Ltd Preservation of viruses
IT1217890B (it) 1988-06-22 1990-03-30 Chiesi Farma Spa Dispositivo per l'inalazione di aerosol dosati
US4919962A (en) 1988-08-12 1990-04-24 General Foods Corporation Coffee flakes and process
EP0360340A1 (en) 1988-09-19 1990-03-28 Akzo N.V. Composition for nasal administration containing a peptide
EP0363060B1 (en) 1988-10-04 1994-04-27 The Johns Hopkins University Aerosol inhaler
US4984158A (en) 1988-10-14 1991-01-08 Hillsman Dean Metered dose inhaler biofeedback training and evaluation system
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
GB8824897D0 (en) 1988-10-24 1988-11-30 Ici Plc Biocatalysts
US4931361A (en) 1988-11-18 1990-06-05 California Institute Of Technology Cryoprotective reagents in freeze-drying membranes
US5225183A (en) * 1988-12-06 1993-07-06 Riker Laboratories, Inc. Medicinal aerosol formulations
US4906476A (en) * 1988-12-14 1990-03-06 Liposome Technology, Inc. Novel liposome composition for sustained release of steroidal drugs in lungs
US5006343A (en) * 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5011678A (en) 1989-02-01 1991-04-30 California Biotechnology Inc. Composition and method for administration of pharmaceutically active substances
GB8903593D0 (en) 1989-02-16 1989-04-05 Pafra Ltd Storage of materials
IT1228459B (it) 1989-02-23 1991-06-19 Phidea S R L Inalatore con svuotamento regolare e completo della capsula.
GB8904370D0 (en) 1989-02-25 1989-04-12 Cosmas Damian Ltd Liquid delivery compositions
SE466684B (sv) 1989-03-07 1992-03-23 Draco Ab Anordning vid en inhalator samt foerfarande foer att med anordningen registrera medicinering med inhalator
GB8909891D0 (en) 1989-04-28 1989-06-14 Riker Laboratories Inc Device
EP0470154B1 (en) * 1989-04-28 1996-06-05 Riker Laboratories, Inc. Dry powder inhalation device
IT1230313B (it) 1989-07-07 1991-10-18 Somova Spa Inalatore per medicamenti in capsule.
GB8918879D0 (en) 1989-08-18 1989-09-27 Danbiosyst Uk Pharmaceutical compositions
US5238920A (en) 1989-08-22 1993-08-24 Abbott Laboratories Pulmonary surfactant protein fragments
US5562608A (en) * 1989-08-28 1996-10-08 Biopulmonics, Inc. Apparatus for pulmonary delivery of drugs with simultaneous liquid lavage and ventilation
IT1237118B (it) 1989-10-27 1993-05-18 Miat Spa Inalatore multidose per farmaci in polvere.
GB2237510B (en) * 1989-11-04 1993-09-15 Danbiosyst Uk Small particle drug compositions for nasal administration
ES2075121T3 (es) * 1989-11-28 1995-10-01 Syntex Inc Nuevos compuestos triciclicos.
US5376386A (en) 1990-01-24 1994-12-27 British Technology Group Limited Aerosol carriers
GB9001635D0 (en) 1990-01-24 1990-03-21 Ganderton David Aerosol carriers
US5113855A (en) 1990-02-14 1992-05-19 Newhouse Michael T Powder inhaler
DE4004904A1 (de) 1990-02-16 1990-09-13 Gerhard Brendel Trommel-applikator
US5621094A (en) * 1990-05-14 1997-04-15 Quadrant Holdings Cambridge Limited Method of preserving agarose gel structure during dehydration by adding a non-reducing glycoside of a straight-chain sugar alcohol
IT1246350B (it) * 1990-07-11 1994-11-17 Eurand Int Metodo per ottenere una rapida sospensione in acqua di farmaci insolubili
IT1243344B (it) 1990-07-16 1994-06-10 Promo Pack Sa Inalatore plurimonodose per medicamenti in polvere
US5037912A (en) 1990-07-26 1991-08-06 The Goodyear Tire & Rubber Company Polymerization of 1,3-butadiene to trans-1,4-polybutadiene with organolithium and alkali metal alkoxide
US5230884A (en) 1990-09-11 1993-07-27 University Of Wales College Of Cardiff Aerosol formulations including proteins and peptides solubilized in reverse micelles and process for making the aerosol formulations
RU2095092C1 (ru) * 1990-09-12 1997-11-10 Бисгорд Ханс Ингаляторное устройство для вдыхания активного порошкообразного или жидкого вещества
US5200399A (en) 1990-09-14 1993-04-06 Boyce Thompson Institute For Plant Research, Inc. Method of protecting biological materials from destructive reactions in the dry state
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.
US5149543A (en) 1990-10-05 1992-09-22 Massachusetts Institute Of Technology Ionically cross-linked polymeric microcapsules
US5217004A (en) 1990-12-13 1993-06-08 Tenax Corporation Inhalation actuated dispensing apparatus
JPH06506455A (ja) * 1991-02-08 1994-07-21 ケンブリッジ・ニューロサイエンス・インコーポレイテッド 神経伝達物質放出調節剤としてのグアニジン置換体及びその誘導体ならびに神経伝達物質放出遮断物質を同定するための新規な方法
US5182097A (en) * 1991-02-14 1993-01-26 Virginia Commonwealth University Formulations for delivery of drugs by metered dose inhalers with reduced or no chlorofluorocarbon content
US5099833A (en) 1991-02-19 1992-03-31 Baxter International Inc. High efficiency nebulizer having a flexible reservoir
WO1992014449A1 (en) * 1991-02-20 1992-09-03 Nova Pharmaceutical Corporation Controlled release microparticulate delivery system for proteins
US5404871A (en) * 1991-03-05 1995-04-11 Aradigm Delivery of aerosol medications for inspiration
US5186164A (en) 1991-03-15 1993-02-16 Puthalath Raghuprasad Mist inhaler
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
EP0504459B1 (de) 1991-03-21 1996-06-05 PAUL RITZAU PARI-WERK GmbH Vernebler insbesondere zur Anwendung in Geräten für die Inhalationstherapie
GB9106648D0 (en) 1991-03-28 1991-05-15 Rhone Poulenc Rorer Ltd New inhaler
BR9106690A (pt) 1991-04-15 1993-06-29 Huhtamaeki Yhthymae Oy Disposicao para medir uma dose de medicamentos pulverulento para inalacao e aparelho de inalacao dotado do mesmo
US5206200A (en) 1991-04-22 1993-04-27 W. R. Grace & Co.-Conn. Tin catalysts for hydrolysis of latent amine curing agents
AU662919B2 (en) * 1991-07-02 1995-09-21 Inhale, Inc. Method and device for delivering aerosolized medicaments
US6681767B1 (en) * 1991-07-02 2004-01-27 Nektar Therapeutics Method and device for delivering aerosolized medicaments
GB9116610D0 (en) 1991-08-01 1991-09-18 Danbiosyst Uk Preparation of microparticles
US5161524A (en) 1991-08-02 1992-11-10 Glaxo Inc. Dosage inhalator with air flow velocity regulating means
US5253468A (en) 1991-09-03 1993-10-19 Robert Raymond Crop chopping machine
US6013638A (en) * 1991-10-02 2000-01-11 The United States Of America As Represented By The Department Of Health And Human Services Adenovirus comprising deletions on the E1A, E1B and E3 regions for transfer of genes to the lung
US5124162A (en) 1991-11-26 1992-06-23 Kraft General Foods, Inc. Spray-dried fixed flavorants in a carbohydrate substrate and process
DK0615438T3 (da) 1991-12-05 1996-11-11 Mallinckrodt Veterinary Inc En carbohydratglasmatrix til langvarig frigivelse af et terapeutisk middel
US5320094A (en) 1992-01-10 1994-06-14 The Johns Hopkins University Method of administering insulin
WO1993013752A1 (en) * 1992-01-21 1993-07-22 Sri International Improved process for preparing micronized polypeptide drugs
ATE204750T1 (de) * 1992-06-12 2001-09-15 Teijin Ltd Pharmazeutische zubereitung zur anwendung in den atemwegen
WO1993025198A1 (en) * 1992-06-12 1993-12-23 Teijin Limited Ultrafine powder for inhalation and production thereof
US5376359A (en) 1992-07-07 1994-12-27 Glaxo, Inc. Method of stabilizing aerosol formulations
US6509006B1 (en) * 1992-07-08 2003-01-21 Inhale Therapeutic Systems, Inc. Devices compositions and methods for the pulmonary delivery of aerosolized medicaments
US6582728B1 (en) * 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
US6673335B1 (en) * 1992-07-08 2004-01-06 Nektar Therapeutics Compositions and methods for the pulmonary delivery of aerosolized medicaments
CA2145418A1 (en) * 1992-09-29 1994-04-14 John S. Patton Pulmonary delivery of active fragments of parathyroid hormone
US5380473A (en) * 1992-10-23 1995-01-10 Fuisz Technologies Ltd. Process for making shearform matrix
US5558085A (en) 1993-01-29 1996-09-24 Aradigm Corporation Intrapulmonary delivery of peptide drugs
EP0681491B1 (en) 1993-01-29 2000-12-13 Aradigm Corporation Intrapulmonary delivery of hormones
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
US5354934A (en) 1993-02-04 1994-10-11 Amgen Inc. Pulmonary administration of erythropoietin
US5506203C1 (en) 1993-06-24 2001-02-06 Astra Ab Systemic administration of a therapeutic preparation
GB9314886D0 (en) * 1993-07-19 1993-09-01 Zeneca Ltd Production of a biological control agent
EP0655237A1 (de) * 1993-11-27 1995-05-31 Hoechst Aktiengesellschaft Medizinische Aerosolformulierung
ES2218543T3 (es) * 1994-03-07 2004-11-16 Nektar Therapeutics Procedimiento y preparacion para la administracion de insulina por via pulmonar.
US6051256A (en) 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
GB2288732B (en) * 1994-04-13 1998-04-29 Quadrant Holdings Cambridge Pharmaceutical compositions
WO1995030437A1 (en) * 1994-05-10 1995-11-16 American Home Products Corporation Improved modified live brsv vaccine
JPH10500672A (ja) * 1994-05-18 1998-01-20 インヘイル セラピューティック システムズ，インコーポレイティド インターフェロンの乾燥粉末製剤に関する方法及び組成物
US5591453A (en) * 1994-07-27 1997-01-07 The Trustees Of The University Of Pennsylvania Incorporation of biologically active molecules into bioactive glasses
US6290991B1 (en) * 1994-12-02 2001-09-18 Quandrant Holdings Cambridge Limited Solid dose delivery vehicle and methods of making same
US5512547A (en) * 1994-10-13 1996-04-30 Wisconsin Alumni Research Foundation Pharmaceutical composition of botulinum neurotoxin and method of preparation
US5705482A (en) * 1995-01-13 1998-01-06 Novo Nordisk A/S Pharmaceutical formulation
US6136346A (en) * 1995-04-14 2000-10-24 Inhale Therapeutic Systems Powdered pharmaceutical formulations having improved dispersibility
US6165463A (en) * 1997-10-16 2000-12-26 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
US6019968A (en) * 1995-04-14 2000-02-01 Inhale Therapeutic Systems, Inc. Dispersible antibody compositions and methods for their preparation and use
US6190859B1 (en) * 1995-04-17 2001-02-20 The United States Of America As Represented By The Secretary Of The Army Method and kit for detection of dengue virus
GB9508691D0 (en) * 1995-04-28 1995-06-14 Pafra Ltd Stable compositions
US5611344A (en) * 1996-03-05 1997-03-18 Acusphere, Inc. Microencapsulated fluorinated gases for use as imaging agents
WO1998029140A1 (en) * 1996-12-31 1998-07-09 Inhale Therapeutic Systems Processes and compositions for spray drying hydrophobic drugs in organic solvent suspensions of hydrophilic excipients
US20030035778A1 (en) * 1997-07-14 2003-02-20 Robert Platz Methods and compositions for the dry powder formulation of interferon
IL149085A0 (en) * 1999-10-29 2002-11-10 Inhale Therapeutic Syst A dry powder composition containing a di or tripeptide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0520748A1 (en) * 1991-06-26 1992-12-30 Pafra Limited Storage of materials
CN1129904A (zh) * 1993-06-24 1996-08-28 阿斯特拉公司 供吸入的治疗学制剂

Also Published As

Publication number Publication date
US7521069B2 (en) 2009-04-21
CA2183577C (en) 2007-10-30
AU1744995A (en) 1995-09-25
EP2036541A1 (en) 2009-03-18
WO1995024183A1 (en) 1995-09-14
JPH10501519A (ja) 1998-02-10
DE69535897D1 (de) 2009-01-22
NZ281112A (en) 1998-04-27
IL112618A (en) 1999-10-28
MX9603936A (es) 1997-05-31
MY124282A (en) 2006-06-30
BR9507023A (pt) 1997-09-23
US6685967B1 (en) 2004-02-03
AU689217B2 (en) 1998-03-26
US20040096401A1 (en) 2004-05-20
EP0748213A4 (en) 1998-03-04
NO316661B1 (no) 2004-03-22
ES2316917T3 (es) 2009-04-16
US20020192164A1 (en) 2002-12-19
ATE416755T1 (de) 2008-12-15
NO963745D0 (no) 1996-09-06
HUT75676A (en) 1997-05-28
CN1152867A (zh) 1997-06-25
KR970701534A (ko) 1997-04-12
EP1462096A1 (en) 2004-09-29
CZ260096A3 (en) 1997-04-16
EP0748213B1 (en) 2004-04-14
FI963468A0 (fi) 1996-09-04
DK0748213T3 (da) 2004-08-02
US20040096400A1 (en) 2004-05-20
KR100419037B1 (ko) 2004-06-12
FI963468A (fi) 1996-09-04
FI116195B (fi) 2005-10-14
JP2006077032A (ja) 2006-03-23
US20030053959A1 (en) 2003-03-20
US6737045B2 (en) 2004-05-18
US5997848A (en) 1999-12-07
CA2183577A1 (en) 1995-09-14
EP1462096B1 (en) 2008-12-10
ATE264096T1 (de) 2004-04-15
ES2218543T3 (es) 2004-11-16
IL112618A0 (en) 1995-06-29
DE69532884T2 (de) 2004-09-02
CZ295827B6 (cs) 2005-11-16
NO963745L (no) 1996-11-06
HU9602454D0 (en) 1996-11-28
DE69532884D1 (de) 2004-05-19
PT748213E (pt) 2004-08-31
EP0748213A1 (en) 1996-12-18
PL316199A1 (en) 1996-12-23
PL179443B1 (pl) 2000-09-29

Similar Documents

Publication Publication Date Title
CN1098679C (zh) 用于胰岛素肺部给药的方法和组合物
DE69631881T2 (de) Pulmonale verabreichung von medikamenten in aerosolform
KR100384353B1 (ko) 인터페론의건조분말제형을제조하기위한방법및조성물
US20090203576A1 (en) Methods and compositons for pulmonary delivery of insulin
KR20010075063A (ko) 건조 분말 활성제의 폐 전달
JPH10511090A (ja) 副甲状腺ホルモン，ｐｔｈ含有吸入用治療製剤
EP0327756A2 (en) Pharmaceutical compositions comprising a calcitonin and a glycyrrhizinate as absorption enhancer
US20030035778A1 (en) Methods and compositions for the dry powder formulation of interferon
RU2175556C2 (ru) Способы и композиции для легочной доставки инсулина
TW576750B (en) Pharmaceutical composition for respiratory/pulmonary delivery of insulin and preparation method thereof
KR20220154214A (ko) 흡입용 gm-csf의 액상 제제

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
ASS Succession or assignment of patent right

Owner name: INHALE THERAPEUTICS SYSTEMS, INC.

Free format text: FORMER OWNER: INHALATION THERAPY SYSTEM

Effective date: 20031114

C41 Transfer of patent application or patent right or utility model
C56 Change in the name or address of the patentee

Owner name: NEKTA MEDICINES INC

Free format text: FORMER NAME OR ADDRESS: INHALE THERAPEUTICS SYSTEMS, INC.

CP01 Change in the name or title of a patent holder

Patentee after: INHALE THERAPEUTIC SYSTEMS, Inc.

Patentee before: INHALE THERAPEUTIC SYSTEMS, Inc.

TR01 Transfer of patent right

Effective date of registration: 20031114

Patentee after: INHALE THERAPEUTIC SYSTEMS, Inc.

Patentee before: Inhale Therapeutic Systems

ASS Succession or assignment of patent right

Owner name: NOVARTIS INTERNATIONAL AG CO., LTD.

Free format text: FORMER OWNER: NEKTA MEDICINES INC.

Effective date: 20100513

Owner name: NOVARTIS AG

Free format text: FORMER OWNER: NOVARTIS INTERNATIONAL AG CO., LTD.

Effective date: 20100513

COR Change of bibliographic data

Free format text: CORRECT: ADDRESS; FROM: CALIFORNIA, U.S. TO: BASEL, SWITZERLAND

TR01 Transfer of patent right

Effective date of registration: 20100513

Address after: Basel, Switzerland

Patentee after: NOVARTIS AG

Address before: Basel, Switzerland

Patentee before: Nova pharmaceuticals

Effective date of registration: 20100513

Address after: Basel, Switzerland

Patentee after: Nova pharmaceuticals

Address before: California, USA

Patentee before: INHALE THERAPEUTIC SYSTEMS, Inc.

C17 Cessation of patent right
CF01 Termination of patent right due to non-payment of annual fee

Granted publication date: 20030115

Termination date: 20120207