CN102614131A - 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 - Google Patents

以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 Download PDF

Info

Publication number
CN102614131A
CN102614131A CN2012100686356A CN201210068635A CN102614131A CN 102614131 A CN102614131 A CN 102614131A CN 2012100686356 A CN2012100686356 A CN 2012100686356A CN 201210068635 A CN201210068635 A CN 201210068635A CN 102614131 A CN102614131 A CN 102614131A
Authority
CN
China
Prior art keywords
diketopiperazine
microgranule
active agent
amino butyl
insulin
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.)
Pending
Application number
CN2012100686356A
Other languages
English (en)
Inventor
凯斯·A·奥伯格
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.)
Mannkind Corp
Original Assignee
Mannkind Corp
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
Application filed by Mannkind Corp filed Critical Mannkind Corp
Publication of CN102614131A publication Critical patent/CN102614131A/zh
Pending 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
    • A61K9/14—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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/549—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame having two or more nitrogen atoms in the same ring, e.g. hydrochlorothiazide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • 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
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • 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
    • A61K38/26—Glucagons
    • 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
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • 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
    • 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
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • 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
    • 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
    • A61K9/1611—Inorganic compounds
    • 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
    • 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
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • 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
    • A61P5/18—Drugs for disorders of the endocrine system of the parathyroid hormones
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Endocrinology (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Otolaryngology (AREA)
  • Inorganic Chemistry (AREA)
  • Neurosurgery (AREA)
  • Obesity (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)

Abstract

本发明涉及以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法。提供结晶微粒表面对活性试剂的亲和力是通过改变微粒的表面性质以促进活性试剂缔合在微粒上来实现的。该方法所改变的表面性质包括静电性质、疏水性质和氢键合性质。

Description

以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法
本申请是申请日为2006年9月14日，申请号为200680033816.8，发明名称为“以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法”的发明专利申请的分案申请。
相关申请
本申请根据35U.S.C.§119(e)要求2005年9月14日递交的美国临时专利申请No.60/717524和2006年4月14日递交的美国临时专利申请No.60/744882的优先权，通过引用将上述文献全文结合在本文中。
技术领域
本发明一般性地涉及药物制剂领域，具体涉及在结晶微粒表面上包覆活性试剂的方法。
背景技术
治疗剂的输送已经成为一个主要问题。口腔给药因其简便性、患者依从性以及低成本而成为一种最常见的优选输送途经。然而，这种途经的缺点包括药效低或不稳定以及治疗剂吸附效率低。当待输送化合物在肠胃道条件下不稳定时尤为如此。本领域已开发了大量包覆和封装方法，但很少能够有效地解决上述问题。而且，有些治疗化合物在肠胃道条件下容易损失活性，因此为了以有效量吸收到血管中，必须以更大的剂量给药。
已经开发出大量药物配制体系来解决最佳药物输送的问题，这些方法是基于将药物结合到作为载体的基体中。药物配制需要考虑的因素包括体系应当对于待输送药物不具有毒性和反应性、制造成本低、所需组分易于获得并且与最终的组合物相容，还应当考虑物理特性，包括稳定性的释放速率。而且优选地，药物输送体系由容易通过常规生理过程从人体中移除的材料制成。
微粒药物制剂可用于各种给药途经，特别适用于肺部输送。通过肺部来输送具有全身效果的药剂的优点包括表面积大并且易于被粘膜表面吸收。美国专利No.6071497描述了一种基于形成二酮哌嗪微粒以及聚合物基微粒的肺部药物输送体系，通过引用将其结合于此。
发明内容
本发明提供了在结晶微粒上形成活性试剂包覆层的方法。一般地，将微粒的表面性质改性，以使活性试剂对微粒表面的亲合性高于对溶液中其它物质的亲合性，由此微粒被活性试剂包覆。
本发明提供了通过静电、疏水或氢键引起的缔合作用来用活性试剂(例如蛋自质)包覆结晶颗粒(例如富马酰基二酮哌嗪(FDKP)微粒)的改进方法。在本发明中，可选地，可通过过滤或干燥去除液体(用于回收经活性试剂包覆的微粒)，或通过交换一种不同的溶液介质来置换液体。在各种情况下，液体介质的去除都不是形成活性试剂-微粒复合体的必须步骤。本发明公开了一种包覆微粒的方法，该方法以改变结晶微粒的表面性质为基础，以使活性试剂吸附到微粒上。
在本发明的具体实施方式中，提供了一种在悬浮液中用活性试剂来包覆预先形成的结晶微粒的方法，包括：i)不依赖于是否去除溶剂，调节活性试剂与结晶微粒之间的能量相互作用；以及ii)容许活性试剂有时间吸附在微粒表面上。在某些实施方式中，所述在悬浮液中用活性试剂来包覆预先形成的结晶微粒的方法还可以包括如下步骤：在对活性试剂与微粒之间的相互作用不产生实质影响的条件下，去除或更换溶剂。
在本发明的其它具体实施方式中，用活性试剂包覆微粒的方法是通过改性微粒表面性质来实现的。微粒表面性质的改性通过改变溶液条件实现。这些条件包括但不限于改变pH。在本发明的其它实施方式中，通过以下方式来改性微粒表面性质：1)改变溶液的极性；2)添加单价或多价离子；以及3)微粒的化学衍生。
在另一种实施方式中，本发明还包括将活性试剂溶解在微粒悬浮液的液相中然后改变pH的步骤。这种将活性试剂溶解在液相中的步骤是指固体的溶解。此外，溶解活性试剂的步骤是指除了添加固体之外还添加一种更加浓缩的活性试剂溶液。
在另一种实施方式中，在添加活性试剂之前或之后，改变微粒悬浮液的pH条件以促进活性试剂与微粒之间的相互作用。
在其它实施方式中，活性试剂与微粒表面之间存在至少一种类型的能量方面有利的相互作用。
在本发明的另一种具体实施方式中，活性试剂为胰岛素或其类似物。
在本发明的其它具体实施方式中，在活性试剂与微粒之间形成有利的相互作用的表面性质选自静电性质、疏水性质和氢键合性质。
在本发明的另一种实施方式中，微粒是多孔的，并具有与溶液主体连通的内表面。在一种实施方式中，微粒包含二酮哌嗪，例如富马酰基二酮哌嗪，但不限于此。
在本发明的实施方式中，该包覆方法在微粒表面上形成单层。在本发明的其它实施方式中，所述单层是连续的。在本发明的其它实施方式中，单层中的活性试剂可以具有优选的取向。
在另一种实施方式中，提供了一种在悬浮液中用胰岛素包覆预先形成的结晶微粒的方法，包括：不依赖于是否去除溶剂，调节活性试剂与结晶微粒之间的能量相互作用；以及将胰岛素吸附在微粒表面上。
本文所用术语“溶剂”是指活性试剂和微粒浸在其中的流体介质。不应当认为，所有组分均为溶液形式。实际上，在许多情况下，“溶剂”是指微粒悬浮于其中的液体介质。
附图说明
以下附图构成本说明书的一部分，用于进一步说明本实施例的特定方面。通过以下附图，并结合具体实施方式的详细描述，可以更好地理解本发明。
图1示出了富马酰基二酮哌嗪(FDKP)悬浮液、FDKP颗粒和缓冲液组分的超声HCl滴定曲线。滴定曲线的超声速度变化的大小(图1，A区)反映出样品组分的可离子化羧基由于质子化所引起的水合作用变化。过量的超声衰减峰(图1，B区)是饱和点处质子交换反应中的快速松弛所造成的。频率(F)为15MHz，温度为25℃。
图2示出了FDKP颗粒+胰岛素和单独FDKP颗粒的超声冰醋酸滴定曲线。通过减去胰岛素的作用来计算超声速度，频率为8MHz，温度为25℃。图中还示出了作为所添加的冰醋酸的浓度的过量超声衰减。冰醋酸导致酸化的两个阶段与HCl滴定所观测到的类似。左侧插入图(A区)示出了pH大于约2.9时的活性试剂与FDKP微粒的缔合。右侧插入图(B区)示出了pH低于约2.9时活性试剂与微粒之间减弱的相互作用。
图3示出了根据本发明的可离子化的微粒上的蛋白质吸附。在pH调节之后将蛋白质加入微粒悬浮液，过滤掉未结合的蛋白质，并将微粒溶解以释放结合的蛋白质。
图4示出了pH对活性试剂到FDKP微粒的吸附的影响。图4A示出了胰岛素的吸附，图4B示出了抗-SSX-241-49单克隆抗体的吸附，图4C示出了甲状旁腺激素(PTH)的吸附，图4D示出了脑肠肽的吸附。
图5示出了pH对限制浓度的胰岛素到FDKP微粒的吸附的影响。
图6示出了用蛋白质(10mg/mL)逐步滴定FDKP微粒时的FDKP微粒悬浮液(11mg/mL)中的超声速度变化。游离蛋白质的作用以及FDKP微粒稀释液的影响已被扣除。温度为25℃。
图7示出了根据本发明活性试剂到FDKP微粒上的吸附饱和曲线。所示的活性试剂/FDKP微粒的加载曲线是pH为5.0时的活性试剂浓度的函数。图7A示出了胰高血糖素样肽-1(GLP-1)的吸附，图7B示出了PTH的吸附，图7C示出了抗-SSX-241-49单克隆抗体的吸附，图7D示出了抗-MOPC-21单克隆抗体的吸附。
图8示出了增大盐浓度对pH为5.0时的活性试剂到微粒的吸附的影响。在pH调节之后将活性试剂加入微粒悬浮液，过滤掉未结合的活性试剂，并将微粒溶解以释放结合的活性试剂。图8A示出了胰岛素的吸附，图8B示出了抗-SSX-241-49单克隆抗体的吸附，图8C示出了PTH的吸附，图8D示出了脑肠肽的吸附。
具体实施方式
待输送的试剂
包覆在结晶微粒上的物质在此被称为活性试剂。活性试剂的实例包括具有治疗、预防和/或诊断用途的药物组合物、合成化合物和有机大分子。
一般地，可以在结晶微粒表面上包覆任何形式的活性试剂。这些材料可以是有机大分子，包括核酸、合成有机化合物、多肽、肽、蛋白质、多糖和其它糖以及脂类。肽、蛋白质和多肽均为通过肽键连接的氨基酸链。肽一般被认为包含小于30个氨基酸残基，但也可以包含更多。蛋白质是可包含大于30个氨基酸残基的聚合物。如同本领域所知，术语“多肽”在本文中是指包含多个肽键的肽、蛋白质或任意长度的氨基酸链(通常包含至少10个氨基酸)。用于形成包覆层的活性试剂可以属于各种生物活性类别，例如血管活性试剂、神经活性试剂、激素、抗凝血剂、免疫调节剂、细胞毒素试剂、抗生素、抗病毒试剂、抗原和抗体。更具体地，活性试剂可以包括但不限于，胰岛素及其类似物、生长激素、甲状旁腺激素(PTH)、脑肠肽(ghrelin)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、胰高血糖素样肽-1(GLP-1)、Texas Red、炔、环胞霉素、clopiogrel和PPACK(D-苯丙氨酰基-L-脯氨酰基-L精氨酸氯甲基甲酮)、抗体及其片段，包括但不限于：人源化抗体或嵌合抗体；F(ab)、F(ab)2或单链抗体(单独的或结合到其它多肽上)；癌症抗原、细胞因子、传染性试剂、炎症介体、激素合细胞表面抗原的治疗性或诊断性单克隆抗体。肿瘤抗原的抗体的非限定性实例包括抗-SSX-241-49(滑膜肉瘤，X断裂点2)、抗-NY-ESO-1(食管肿瘤相关抗原)、抗-PRAME(黑色素瘤特异性抗原)、抗-PSMA(前列腺特异性膜抗原)、抗-Melan-A(黑色素瘤相关抗原)、抗-tyrosinase(黑色素瘤相关抗原)以及抗-MOPC-21(骨髓瘤血浆细胞蛋白)。
输送系统-结晶微粒
术语“微粒”基本上是指直径约为0.5-1000μm的颗粒，而与其确切的外部或内部结构无关。在广义上的微粒范围内，“微球”是指形状微均匀球形的微粒。本文使用结晶微粒是指下述微粒，所述微粒具有晶体的内部结构但不必须具有晶体的外部结构，并且在空间点阵中具有规则的原子排列。可离子化的结晶表面是指结晶微粒具有额外的能力来携带电荷。
优选地，构成结晶微粒的化学物质可与待输送活性试剂可逆地反应，并且至少对啮齿类动物和人类是无毒且不可代谢的。此外，优选的微粒的结晶结构在包覆活性试剂的过程中基本上不被破坏。结晶微粒的组成决定了可以例如何种类型的化学相互作用来促使活性试剂吸附在微粒表面上。
大量物质可被用于形成结晶微粒。微粒本身具有外表面，其性质可在包覆过程中被操控。可形成结晶微粒的代表性材料包括但不限于：芳族氨基酸，在规定的pH范围内具有有限的溶解度的盐，例如二酮哌嗪和吗啉硫酸盐。
美国专利No.5352461和5503852(通过引用将其整体结合于此)描述了一种药物输送系统，该系统基于由在低pH下稳定且在血液或小肠的pH下溶解的二酮哌嗪衍生物(例如3，6-二[N-富马酰-N-(正丁基)氨基]-2，5-二酮哌嗪，也称为富马酰二酮哌嗪或FDKP，即(E)-3，6-二[4-(N-羧基-2-丙烯基)酰胺丁基]-2，5-二酮哌嗪)来形成二酮哌嗪(DKP)微粒。如上述专利所公开，通过在药物(加载量)的存在下形成DKP微粒，使二酮哌嗪颗粒结合或负载待输送药物。基于二酮哌嗪结构元素或其一种取代衍生物(包括但不限于二酮吗啉和二酮二氧杂环己烷)的系统形成具有期望的尺寸分布和pH范围以及良好的加载容许量的微粒。通过对取代基进行适当的操控，可以得到大量稳定且可重复的特性。
可用于本发明的其它二酮哌嗪包括3，6-二(4-氨基丁基)-2，5-二酮哌嗪、3，6-二(琥珀酰-4-氨基丁基)-2，5-二酮哌嗪(琥珀酰二酮哌嗪或SDKP)、3，6-二(马来酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(戊二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰-4-氨基丁基)-2，5-二酮哌嗪及其衍生物。二酮哌嗪盐也可用于本发明，所述二酮哌嗪盐例如可以包括药学上可接受的盐，例如Na、K、Li、Mg、Ca、铵或一、二或三烷基铵(源自三乙胺、丁基胺、二乙醇胺、三乙醇胺或吡啶等)盐。所述盐可以是单盐、二盐或混合盐。还可以考虑二酮哌嗪的更高级别盐，在二酮哌嗪中，R基团包含一个以上酸基团。在本发明的其它方面，碱性试剂可以与二酮哌嗪混合以形成二酮哌嗪的药物盐，结果该药物是二酮哌嗪的反阳离子。
美国专利No.6444226和6652885(通过引用将其整体结合于此)描述了在含水悬浮液(向其中添加活性试剂溶液)中制备和提供DKP微粒，然后冷冻干燥该悬浮液以得到具有活性试剂包覆层的微粒的关键步骤。这种配制方法是基于通过冷冻干燥来去除液体介质从而在微粒上包覆活性试剂(还可参见美国专利No.6440463，通过引用将其整体结合于此)。与现有技术的教导相反，本发明提供了在去除溶剂之前调节活性试剂与微粒之间的结合的方法。因此，通过大多数物理方法(例如过滤或沉降)或蒸发方法(例如冷冻干燥或喷雾干燥)来去除溶剂，可以得到相当的加载量。
结晶微粒的受控包覆
受控包覆是指将活性试剂吸附在结晶微粒表面上的可控工艺。包覆工艺包括改变悬浮液中的结晶微粒的表面性质，这可以通过改变溶液条件(例如pH、温度、极性、离子强度和助溶剂)、与单价或多价离子复合或通过化学衍生来实现。在添加活性试剂之前或之后改变微粒的表面性质，可以影响其与活性试剂的化学相互作用，从而使活性试剂吸附到结晶微粒上。微粒与活性试剂之间的化学相互作用促进吸附并导致在微粒表面上形成活性试剂单层。一旦活性试剂分子被吸附，则该部分微粒表面不再受到进一步的相互作用，并且在该特定的表面点处不再吸附其它活性试剂。得到的单层可以是连续的(在吸附表面上，被吸附的活性试剂分子之间无间隙)，或者是非连续的(被吸附的活性试剂分子之间存在间隙，暴露出微粒表面)。
活性试剂到微粒表面的吸附
如上所述，将活性试剂吸附在微粒表面上，使得微粒上形成活性试剂单层(包覆层)。然而，关于在结晶微粒上吸附活性试剂(例如胰岛素)，存在不止一种机理：
在微粒上包覆活性试剂(例如胰岛素)的单层仅为将胰岛素到微粒上的加载过程的一个阶段而不一定是加载过程的最终结果，因为根据系统的能量学，既可以形成单个层可以形成多个层。
在容许的溶解度条件下(例如胰岛素浓度较低和/或pH较低(基本上低于5.0))，胰岛素与FDKP颗粒表面之间的吸引力远大于胰岛素的自缔合力。因此，胰岛素到微粒的包覆以单层方式发生并达到饱和，而不在微粒表面上聚集或形成多层(见实施例6)。随着溶解度接近饱和，由于胰岛素浓度较高和/或pH接近5.0(野生型胰岛素的最小溶解度)，胰岛素的自缔合在能量上变得更加有利。因此，包覆可以越过单层饱和点，并可在颗粒上附加其它层。存在两种类型的自缔合：多聚化和聚集。多聚化的特征在于特定的分子间相互作用和固定的化学计量。聚集的特征在于不特定的分子间相互作用和不确定的化学计量。一般来说，多聚活性试剂可以以多聚状态被吸附，或分解成单体或较低级的多聚体，并以该状态吸附到表面上。在这两种情况下，聚集均可调节活性试剂在微粒上形成层。根据本发明人目前的理解，在本文实施例中所用的一般条件(例如胰岛素溶解在醋酸中)下，随着非六聚胰岛素的聚集，产生了额外的胰岛素层的沉积。
包覆微粒的方法
用活性试剂包覆结晶微粒(例如预先形成的结晶微粒)的方法一般性地描述如下：将通过沉淀或其它方法预先形成的结晶微粒悬浮在液体介质(例如水)中；在添加活性试剂之前或之后调节介质以使颗粒表面改性。这时，活性试剂将吸附到微粒表面上，在一段时间间隔后(例如，＜1、1、2、3、4、5、6、7、8、9或10分钟，优选从小于1到至少5分钟)，加载过程完成。可以通过包括过滤、离心、冷冻干燥或喷雾干燥的任何方法来去除液体介质，或者通过介质交换来置换液体介质。可以通过以下实验方法来验证吸附：1)证实在滤出液或上层清液中不存在显著量的活性试剂，和/或2)证实在固体相中存在活性试剂，同时表明活性试剂在经历不存在微粒的相同过程时不沉淀。
操控微粒表面性质
如本文其它部分所公开，微粒的表面性质可以通过各种方法来操控。可以操控的微粒表面性质包括但不限于，静电性质、疏水性质和氢键合性质。在各种实施方式中，这些操控在存在或不存在活性试剂、或者在微粒与活性试剂混合之前或之后进行。当操控在活性试剂的存在下进行时(例如，通过改变溶液条件)，同时可以调整活性试剂对表面的亲合性。因此，在本发明的某些实施方式中，微粒的包覆可以包括操控表面的性质和调整活性试剂的性质。调整活性试剂性质的方法公开在名称为“METHODOF DRUG FORMULATION BASED ON INCREASING THE AFFINITY OFACTIVE AGENTS FOR CRYSTALLINE MICROPARTICLE SURFACES”共同待审的美国专利申请No.__/_______(代理人档案号No.51300-00035)中，该申请与本申请同日递交，通过引用将其整体结合于此。
静电相互作用是异性电荷之间的吸引力或同性电荷之间的排斥力，该力随着电荷彼此接近而增强。静电相互作用是理解离子溶液中带电体之间相互作用的关键。例如，通过考虑到排斥性静电相互作用与吸引性范德华相互作用的竞争，可以解释分散在溶剂中的胶体颗粒的稳定性。而且，微粒表面的化学官能团(例如但不限于COOH、NH等)可用作离子活性试剂的反离子，以使活性试剂/颗粒复合物形成盐。当考虑颗粒之间的相互作用和粘附性时，静电相互作用也很重要。
改变周围溶液体系的pH，可以改变悬浮液中可离子化的结晶微粒的静电性质。如实施例3所表明，改变溶液的pH使微粒的离子化发生变化，从而将活性试剂吸附到微粒表面。特别地，实施例4表明，由FDKP(3，6-二[N-富马酰-N-(正丁基)氨基]-2，5-二酮哌嗪)组成的微粒是可离子化的。当pH小于3.5时，微粒不溶于水，但溶解度在pH为3.5-5.0时迅速增大，这可能是由于羧基的离子化。FDKP微粒在pH为5时部分地离子化，然后在更高的pH下完全溶解，这可以通过超声频谱间接观察到。实施例5说明了蛋白质到FDKP微粒表面上的受控包覆。在一种实施方式中，二酮哌嗪微粒悬浮在酸性溶液中，活性试剂加入该悬浮液，然后在活性试剂与微粒混合后升高溶液的pH。升高的pH改变了微粒的表面性质，以使活性试剂对微粒的亲合性高于对溶剂的亲合性。
或者，可在升高微粒悬浮液的pH之后立即将活性试剂加入溶液。通过pH的变化来改变微粒的表面电荷性质，以使活性试剂对微粒的亲合性高于对溶液中其它物质的亲合性。
实施例6和7说明了通过操控pH条件将胰岛素加载到FDKP颗粒上。最后，实施例6中描述了微粒吸附蛋白质达到饱和以及单层的形成。
操控微粒表面的其它方法
除静电性质以外，还可以利用微粒表面的其它性质来控制活性试剂的吸附。可以操控具有如下官能团的化合物的微粒来使表面性质改性：咪唑、吡啶、Schiff碱、酮、羧酸生物电子等排体、酰胺或其它可以多种结构存在的官能团。
疏水相互作用是指非极性基团由于不溶于水而在水溶液中彼此缔合。疏水相互作用可以影响一系列分子过程，包括但不限于，结构稳定化(单个分子、两个或三个分子复合、或更大的组装)和动力学，还对蛋白质-蛋白质和蛋白质-配体结合过程有重要作用。还已知这些相互作用对蛋白质折叠前期有作用，并且参与了复合组装和自组装现象(例如，形成膜)。
可以通过改变由组氨酸组成的结晶微粒的质子化来操控疏水相互作用。组氨酸的质子化会降低结晶微粒的亲核性并赋予正电荷。
氢键合相互作用是指分子间极强的偶极-偶极力，极性键中的氢原子(例如，H-F、H-O或H-N)可以受到附近电负性分子或离子的吸引力，所述电负性分子或离子具有未成对电子(通常是另一个分子上的F、O或N原子)。氢键赋予了水独特的性质，并且对于生物分子组织十分重要，尤其会影响蛋白质和DNA的结构。
在本发明中，可以通过化学衍生来控制微粒表面的氢键合性质。可以以化学方式增加氢键供体/受体来改变微粒表面。例如，N-H键中的氢可以与C＝O键中的氧发生氢键合。如果N-H被N-CH3取代，则此特殊的氢键合相互作用消失。类似地，用C＝C基团取代C＝O基团也会消除此特殊的键合相互作用。
当可离子化的芳基被离子化时，具有包含该芳基的表面的微粒是极性的，而当该芳基未被离子化时，微粒是疏水的。通过将表面质子化并操控溶液条件来减少颗粒表面的离子化，可使疏水性或芳族活性试剂包覆在微粒表面上。
可以通过改变溶液极性来操控具有酮表面基团的微粒。通过降低溶剂极性(向水溶液中添加低极性的有机溶剂)，在颗粒表面上形成烯醇形式的主要物质。此烯醇形式是氢键供体，而酮形式为氢键受体。以此方式来促进含氮药物吸附在微粒表面上。
通过操控溶液条件还可以导致具有表面基团(进行pH或温度诱导的异构化)的微粒吸附药物分子。对于这些表面，异构化会使线性的表面基团出现扭结，这增大了微粒表面上的基团的移动性(流动性)。这使得表面与活性试剂形成更多的接触(与有序的表面相比)。如果与活性试剂的其它相互作用都是有利的，则净相互作用能量也有利于将药物吸附到微粒表面上。
液体介质去除技术
通过包括但不限于沉降、过滤或干燥的方法，可以在用活性试剂受控包覆结晶表面后将溶剂去除。干燥技术包括但不限于冷冻干燥和喷雾干燥。这些技术对本领域技术人员是已知的。在本发明的一种实施方式中，通过喷雾干燥来去除溶剂。对二酮哌嗪微粒进行喷雾干燥的方法例如公开在2006年2月22日递交的美国临时专利申请No.60/776605中，通过引用将其中与喷雾干燥二酮哌嗪微粒相关的内容结合于此。
表面性质改性分析
本发明采用超声频谱技术来分析悬浮液中结晶微粒的表面性质变化，这些变化促进或增强了活性试剂到结晶微粒的吸附。如本文其它部分所述，这些变化包括改变溶液条件(例如pH、温度、极性、离子强度和助溶剂)，这是通过复合到单价或多价离子、或者在添加活性试剂之前或之后通过化学衍生改变微粒的表面性质来实现的。
超声频谱技术是一种本领域技术人员已知的分析工具。简言之，超声频谱技术利用声波。特别地，超声频谱技术使用能够探测样品/材料中的分子间力的高频声波。超声波的振荡压缩(和减压)导致样品中的分子排列振动，这反映为分子间的吸引或排斥。
超声波穿过样品而损失能量(振幅减小)并改变速度。分析振幅的下降和速度的变化来作为样品的特征。因此，超声波的传播由超声速度和衰减来确定。
超声速度由介质的弹性和密度决定。固体的分子间相互作用最强，液体和气体次之，因此固体比液体和气体更具刚性。超声衰减是超声波穿过样品时的能量损失的度量。它表征了样品的超声透明度，并且可以表现为波幅的减小。
通过多频测定均匀体系中的超声衰减，可以分析快速化学反应，例如但不限于质子交换、结构转化(例如异构化)、自缔合(例如二聚合)、聚集、配体与大分子的结合等。
实施例
以下实施例用于说明本发明的实施方式。本领域技术人员应当理解，实施例中与本发明人发现的代表性技术一起公开的技术可以有效地用于实施本发明，因此这些技术被认为构成了实施本发明的优选方式。然而，根据本说明书，本领域技术人员应当认识到，在不脱离本发明的精神和范围的前提下，还可以对具体实施方式进行许多改变，同时获得相同或类似的效果。
实施例1
用活性试剂包覆微粒的一般过程
下表1为通过静电来包覆可离子化的结晶微粒(FDKP微粒)的实施例，该实施例采用pH控制吸附。在这些实验中，制备pH为2.0和4.5的FDKP微粒悬浮液。然后在各种悬浮液中添加蛋白质(生长激素)，得到最终条件：5mg/mL的FDKP颗粒和200μg/mL的蛋白质。搅拌之后，通过过滤将大部分液体从悬浮液中去除。然后将过滤器上截留的材料溶解并收集。通过HPLC来定量分析所有部分中的蛋白质浓度。
在低pH(2.0)下，蛋白质并未吸附到颗粒上，所有蛋白质存在于第一滤出液中。通过将pH升至4.5，改变颗粒的表面性质，使其对蛋白质具有较高的亲合性。在这些条件下，蛋白质与微粒相结合，而且并未在滤出液中观测到。为了确定与微粒缔合的蛋白质的量，在微粒溶解后回收蛋白质。无颗粒的对照实验表明，在所用的条件下，蛋白质本身并没有滞留在过滤器上，即蛋白质并未自缔合或聚集成尺寸大于过滤器滤孔的颗粒。
表1.使用FDKP微粒的吸附实验中的蛋白质浓度
Figure BSA00000685350500131
所示值根据过滤后溶液的HPLC定量分析获得
实施例2
通过操控pH来控制FDKP微粒的离子化
FDKP是在每一端具有羧酸官能团的棒状分子，该分子在羧酸被质子化时基本不溶于pH低于3.5的水，并且不带电荷。随着羧基的离子化，FDKP的溶解度在pH大于3.5时迅速增大。FDKP晶体(形成具有两个较大平坦表面和较窄边缘的平板状)的模型表明，棒状FDKP分子垂直于平板边缘排列，使得分子的羧酸末端排列在平板的较大表面上。根据理论，FDKP晶体的表面应当在大约5.0的pH下部分地离子化，这时溶解度约为1mg/mL，该pH刚好低于可以溶解10mg/mL的微粒悬浮液的pH。
使用超声频谱可以间接地观测到FDKP晶体表面的离子化。在图1中，示出了FDKP微粒和缓冲液的超声滴定曲线。在此实验中，分小份将含有200mM HCl的溶液加入FDKP微粒在20mM醋酸铵缓冲液中的10mg/mL的搅拌悬浮液中。初始pH为4.8。在每次添加HCl之后，使体系平衡并收集超声数据。
通过升高酸浓度(降低pH)观测到的超声速度的下降反映了体系中羧酸基团的质子化。随着该基团被质子化并变得不带电，其周围的水结构变松弛并且超声波传输变慢(超声速度降低)。由于FDKP微粒的羧酸盐表面与醋酸盐缓冲液中的羧酸盐基团在化学上十分相似，因此得到的曲线也类似。然而，差异是FDKP微粒所致。首先，FDKP微粒的速度变化的程度较大。这种差异是FDKP微粒表面上的离子化羧酸盐基团的质子化的结果。衰减曲线的峰值在完全质子化时附近出现，对于FDKP悬浮液，该峰值向着较高的酸浓度稍微偏移。最后，当pH从3.5降至2.3时，两个FDKP参数继续改变。这些变化表明了颗粒表面性质的其它改变，包括表面羧基的有序化或其它微观结构改变。
实施例3
通过表面性质的pH操控将蛋白质加载到FDKP微粒上
以两种方式，可以实现通过pH操控将蛋白质吸附到可离子化的微粒表面上。可以添加蛋白质然后调节pH，以使表面离子化同时吸附蛋白质。该过程是可逆的。或者，可以调节颗粒悬浮液的pH，从而在添加蛋白质之前将表面离子化。
图2所示的超声滴定数据表明了：当pH大于约2.9时，蛋白质(胰岛素)与FDKP微粒缔合，当pH低于约2.9时，相互作用减弱。
在20mM的醋酸铵缓冲液(pH为4.8)中制备FDKP微粒的悬浮液，然后与胰岛素原液混合，得到800μL的悬浮液，在最终的悬浮液中，FDKP微粒的浓度为10mg/mL，胰岛素浓度为1mg/mL。将该悬浮液引入超声频谱仪。一边轻微搅拌，一边以5μL的小份逐渐添加冰醋酸，从而降低pH。在滴定的每个步骤中，收集超声数据。
超声速度的变化与样品中的颗粒和/或大分子的表面积(结合水)的大小相关(成正比)。图2表明，当pH大于约2.9时(添加了10％v/v的醋酸)，微粒(单独的FDKP颗粒)的速度曲线与具有胰岛素的微粒(FDKP颗粒+胰岛素)的速度曲线重合。这说明体系(FDKP颗粒+胰岛素)的表面积基本上等于单独FDKP微粒的表面积。与微粒相比，胰岛素极小，因此胰岛素对表面积的贡献可忽略。当pH低于2.9时，FDKP颗粒的曲线与FDKP颗粒+胰岛素的曲线分离。FDKP颗粒+胰岛素曲线的超声速度此时较高，表明相比于单独的FDKP颗粒样品，有更多的表面积暴露于水。这种额外的表面积源自悬浮液中的游离胰岛素。当pH从约2.7升至约2.9时，胰岛素吸附到FDKP微粒表面上，导致胰岛素表面积损失，并且由于系统中不再存在游离的胰岛素，FDKP微粒+胰岛素曲线的较高值消失。
如上所述，通过pH而在颗粒上包覆蛋白质的方法是将颗粒悬浮在液体介质中，然后调节溶液条件以使颗粒表面离子化。然后可将蛋白质加入悬浮液，蛋白质分子将立即被吸附。图3示出了加入经pH调节的FDKP微粒悬浮液之后被吸附的蛋白质(胰岛素)的量。
制备5mg/mL的FDKP微粒悬浮液并添加过量的蛋白质(2mg/mL)(这里的“过量的蛋白质”是指，其量超过在FDKP微粒的可接触表面上形成覆盖单层所必须的量)。培养之后，通过过滤去除未吸附的蛋白质。将滞留在过滤器的固体(滞留物)溶解，并通过HPLC定量分析滞留在过滤器上的FDKP微粒和蛋白质的量。根据定量结果确定蛋白质/颗粒质量比。基于已知的这些颗粒的表面积以及蛋白质的分子尺寸，估计当质量比约为0.07时形成被吸附蛋白质的连续单层。基于这个估计，从此实施例可以看出，当pH为5.0时形成连续单层，当pH为3.5-4.5时形成非连续单层。
此外，将不同批量的干燥的经活性试剂包覆的FDKP微粒悬浮在酸溶液(最终pH约为2.0)中或水(最终pH约为4.5)中。如表2所述，不同的活性试剂包括胰岛素、生长激素和胰岛素aspart(一种速效胰岛素)。过滤掉这些悬浮液的溶剂，然后溶解滞留的颗粒并收集。通过HPLC定量分析全部样品中的活性试剂的量。结果示于表2。
对于每个样品，活性试剂均在酸性溶液中从颗粒上释放。因此，通过将微晶体表面质子化，可使活性试剂从晶体表面上解吸。颗粒再次悬浮在水中并不改变颗粒表面的离子化状态，因此这时蛋白质保持被吸附。表2.包覆在FDKP微粒上的活性试剂
表中各值为HPLC定量分析的积分峰面积(mAU*sec，215nm)
实施例4
通过pH将胰岛素吸附到FDKP微粒的表征
在pH控制过程中，通过将FDKP微粒的悬浮液与胰岛素水溶液混合，将胰岛素吸附(加载)到FDKP微粒上。为了描述pH对胰岛素与FDKP微粒结合的影响，制备不同pH值的5mg/mL的FDKP颗粒悬浮液。然后添加过量的溶解胰岛素，吸附约5分钟，然后过滤去除未结合的胰岛素。从过滤器(滞留物)回收具有被吸附的胰岛素的固体颗粒，将其溶解并收集。通过HPLC定量分析胰岛素和溶解的FDKP微粒的量。基于滞留物总质量计算被吸附的胰岛素的量。PH与胰岛素吸附量的关系示于图4A，胰岛素吸附量作为pH的函数增加。如图4B、4C和4D分别所示，对于SSX-241-49单克隆抗体、PTH和脑肠肽，得到类似的结果。
此外，将FDKP颗粒悬浮在不同pH的胰岛素溶液(10mg/mL)中。FDKP颗粒与胰岛素的质量比为10∶1。通过离心将上层清液与颗粒分离，然后通过HPLC确定上层清液中的未结合胰岛素的浓度。根据与初始胰岛素浓度的差异来确定胰岛素的结合。图5所示的数据说明，升高pH使得溶液中的胰岛素减少，并且FDKP颗粒上的胰岛素含量增加。
因此，随着pH从约3.0升至约5，结合到FDKP颗粒上的胰岛素增加。优选地，在pH为3.6时添加胰岛素溶液，在这些条件下，约75％的胰岛素从溶液中被吸附到颗粒上。当pH升至≥4.0时，结合的胰岛素增至＞95％。当pH约≥4.2、优选≥4.4时，胰岛素基本上完全结合。在pH大于5.0时，FDKP微粒开始溶解，并且不再保持结晶微粒的结构。
实施例5
用胰岛素加载FDKP微粒的描述
在生产规模方式(2-5kg)中，通过用醋酸沉淀来形成FDKP微粒并洗涤。向FDKP颗粒悬浮液中添加pH为3.6的胰岛素溶液。胰岛素原液包含10wt％的胰岛素和2.5wt％的醋酸(pH约为3.6)。用氢氧化铵将混合物的pH调节至4.5。表3示出了每千克用于制备包含约11.4wt％胰岛素的颗粒的制剂中的各种组分的量。聚山梨醇酯80可在形成颗粒时加入，它可以改善最终颗粒的操纵特性。容许胰岛素有时间吸附到FDKP颗粒上，并确保充分混合。然后将混合物逐滴加入液氮，以使悬浮液迅速冻结。通过冷冻干燥去除液体介质，从而制造FDKP颗粒/胰岛素主要药物产品。或者将混合物喷雾干燥。表4示出了去除溶剂后的主要产品中的各种组分的量。
表3.FDKP颗粒/胰岛素配方组成
表4.FDKP颗粒/胰岛素组成
Figure BSA00000685350500181
在表3和表4中，NF表示美国国家处方集(National Formulary)
*聚山梨醇酯80含量由HPLC/MS分析估算
**FDKP/胰岛素制剂在冷冻干燥后包含约1.2％的残余水，也可存在痕量的醋酸和氢氧化铵。
实施例6
蛋白质在微粒表面饱和(形成连续的单层)
在微粒表面包覆单层应当是可饱和的过程。即，微粒的可接触表面积和活性试剂分子的直径决定了微粒表面的容量。图6示出了这种饱和情况。
制备FDKP微粒的悬浮液，并将pH调节至3.0-3.5，在此pH下表面部分地离子化。在此过程中，不能使用更高的pH，因为这会引起活性试剂(胰岛素)的自缔合。将小部分的浓缩胰岛素溶液添加至搅拌悬浮液。在每次添加之后，使样品稳定，并收集超声数据。
图6表明，随着蛋白质浓度增大，观测到超声速度降低。超声速度的这种变化对于水溶液中的配体结合是常见的，并且说明活性蛋白质吸附到FDKP微粒表面上。速度降低是结合水从FDKP微粒和蛋白质表面上释放的结果。当结合水由于活性试剂的吸附而被取代时，其结构变松弛，并且超声速度在穿过样品时产生净减小。当FDKP微粒表面上的所有结合位点都已饱和时(即形成蛋白质单层)，曲线变平。图7A-7D的数据示出了各种活性试剂(GLP-1[图7A]；PTH[图7B]；抗-SSX-241-49单克隆抗体[图7C]；抗-MOPC-21单克隆抗体[图7D])在微粒上的附吸达到了饱和，因为活性试剂的浓度在恒定的FDKP浓度(5mg/mL)下增大，这些数据也表明形成了单层。这些研究在pH为5.0下进行，在此pH下，活性试剂到微粒上的吸附达到最优化。GLP-1无法在所用的浓度下自缔合(如美国临时专利申请No.60/744882所公开)。
实施例7
静电相互作用机理的证据
静电相互作用机理的证据是通过减弱静电相互作用来阻碍吸附的能力。这通过在离子化的颗粒/活性试剂体系中添加盐来说明。图8A-8D说明，增大活性试剂-FDKP微粒体系中的离子强度减少了活性试剂到微粒上的吸附。
当pH为5.0是，活性试剂到FDKP微粒表面上的吸附较强，在此pH下制备一系列样品。各个样品包含不同量的盐(氯化钠)，如图8A-8D的横坐标(单位为mM)所示。将活性试剂混入悬浮液，得到最终浓度为5mg/mL的FDKP微粒和0.75mg/mL的胰岛素(过量，图8A)。在短暂培养之后，过滤去除未结合的活性试剂并重新溶解吸附有活性试剂的颗粒。通过HPLC定量分析回收的活性试剂和颗粒的量，以质量比(加载百分比)表示。图8A-8D表明，增大活性试剂-FDKP微粒体系的离子强度降低了活性试剂的吸附程度，其中活性试剂包括抗-SSX-241-49单克隆抗体(0.2mg/mL；图8B)、脑肠肽(0.1mg/mL；图8C)和PTH(0.25mg/mL，图8D)，FDKP微粒为5mg/mL。
图8示出了加载悬浮液中的所测量的吸附与盐浓度之间的负相关关系。这可以解释为，盐和活性试剂竞争与颗粒表面相互作用。随着盐浓度增大，盐对表面结合位点的竞争力更强且更有效，并且基本上取代了颗粒表面的活性试剂。也可以推测，可能是德拜屏蔽效应导致了活性试剂与微粒结合的减少。
除非另有指明，本说明书和权利要求书中使用的表示成分数量，以及分子量、反应条件等性质的所有数字都应当被理解为：在所有情况下，用术语“约”加以了修饰。因此，除非有相反含义的说明，本说明书和所附权利要求书中示出的数量参数都是约数，它们可以根据本发明想要获得的性质而变动。至少，并且并非对权利要求书范围等同原则的应用加以限制，每个数量参数至少应按照报道的有效数字的数，以及应用普通的凑整技术来解释。虽然示出本发明宽广范围的数字范围和参数是约数，但是特别实施例中所示的数值却被尽可能地精确报道。但是，任何数值，必然含有一定误差，这是它们各自的检验测量方法中发现的标准偏差必然导致的。
除非本文另有指明，或与上下文明显矛盾，描述本发明的上下文中未明确提及数量的名词(用″a″，″an″修饰的)和使用的术语“该”、“所述”(″the″)和类似提法应当被理解为既包括单数又包括复数。本文中数值范围的叙述仅仅用作该范围内每个单独的值的速记方法。除非本文另有指明，每个单独的值被包括进说明书，这与在本文个别叙述一样。本文所述的所有方法都可以以任何合适的顺序来进行，除非本文另有指明，或与上下文明显矛盾。除非另有指明，本文提供的任何及所有例子，或者示例性的语言(例如，“例如”)仅用来更好地阐述本发明，而非对发明范围加以限制。说明书中任何语句都不应被解释为：表示对本发明的实践来说必要的、不要求保护的要素。
除非明确指出某个可选方式或可选方式之间互相排斥，尽管说明书支持某个可选方式和“和/或”的表述，但是权利要求中所用术语“或”是指“和/或”。
本文公开的本发明的替换性要素或实施方式的分组不应被理解为限制。每个组成员可被个别提到和被个别要求保护，或以与该组其它成员或本文中找到的其它要素的任何组合被提到和要求保护。可以预见到，为了方便和/或可专利性的理由，组中的一个或多个成员可被包括进一组或从中删除。当任何此类包括或删除发生时，说明书在本文中被看作为含有经过改动的组，因此满足说明书对所附权利要求书中所用的马库什组的支持。
本文中描述了本发明的优选实施方式，其包括发明人已知用来开展本发明的最佳方式。当然，在阅读前述说明书的基础上，对这些优选实施方式中的改动对于本领域普通技术人员来说将是明显的。本发明的发明人期待本领域技术人员合适地采用此类改动，发明人希望本发明以除了本文特别描述的方式之外的方式被实现。因此，只要适用法律允许，本发明包括对所附权利要求中提到的主题进行的所有改动和等同物。此外，所有可能的变化中，上面提到的要素的任何组合都被包括进本发明，除非本文另有指明，或与上下文明显矛盾。
此外，本说明书中提到了大量参考文献，包括专利和印刷公开物。上述参考文献和印刷公开物中的每种在此都通过引用被个别地整体包括进本文。
最后，应当理解，本文公开的本发明实施方式是为了阐述本发明的原理。可以进行的其它改动也落在本发明的范围内。因此，举例而言，而非限制，可按照本文的教导来使用本发明的替代性构造。因此，本发明不被限制为严格拘泥于本文所述和所示出的。

Claims (15)

1.一种微粒，所述微粒包含二酮哌嗪和聚山梨醇酯80。
2.权利要求1的微粒，还包含活性试剂。
3.权利要求2的微粒，其中所述活性试剂吸附在所述二酮哌嗪的结晶表面上。
4.权利要求3的微粒，其中所述活性试剂在所述结晶表面上形成单层。
5.权利要求4的微粒，其中所述单层是连续的。
6.权利要求5的微粒，其中所述活性试剂的吸附通过静电、极性、离子、疏水、氢键合或范德华相互作用介导。
7.权利要求1的微粒，其中所述二酮哌嗪选自3，6-二(4-氨基丁基)-2，5-二酮哌嗪、3，6-二(琥珀酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(马来酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(戊二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰-4-氨基丁基)-2，5-二酮哌嗪和3，6-二(富马酰-4-氨基丁基)-2，5-二酮哌嗪组成的组。
8.权利要求1的微粒，其包含约0.8％w/w的聚山梨醇酯80。
9.权利要求2或3的微粒，其中所述活性试剂选自由胰岛素或其类似物、生长激素、甲状旁腺激素(PTH)、脑肠肽、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、胰高血糖素样肽-1(GLP-1)、抗体及其片段和环孢霉素组成的组。
10.权利要求9的微粒，其中所述活性试剂包括胰岛素或其类似物。
11.一种制备二酮哌嗪粒子的方法，其包括：
通过向含有聚山梨醇酯80和二酮哌嗪的溶液中添加酸来沉淀含有聚山梨醇酯80的二酮哌嗪粒子，
其中所述二酮哌嗪在低pH下具有有限的溶解性。
12.权利要求11的方法，其中所述二酮哌嗪选自3，6-二(琥珀酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(马来酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(柠康酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(戊二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(丙二酰-4-氨基丁基)-2，5-二酮哌嗪、3，6-二(草酰-4-氨基丁基)-2，5-二酮哌嗪和3，6-二(富马酰-4-氨基丁基)-2，5-二酮哌嗪组成的组。
13.权利要求12的方法，其中所述二酮哌嗪是3，6-二(富马酰-4-氨基丁基)-2，5-二酮哌嗪。
14.权利要求12的方法，其中所述酸是乙酸。
15.一种在包含预形成的结晶微粒、活性试剂和溶剂的悬浮液中涂布所述预形成的结晶微粒的方法，所述方法包括：
改变悬浮条件以调节所述活性试剂与所述预形成的结晶微粒之间的能量相互作用，其中所述改变悬浮条件是改变所述溶剂的pH、添加单价或多价离子、改变所述溶剂的极性、或添加氢键供体或受体；
其中所述改变悬浮条件并不包括从所述悬浮液中去除溶剂；并且
其中所述改变悬浮条件使得所述活性试剂吸附在所述预形成的结晶微粒的表面上，从而涂布所述预形成的结晶微粒。
CN2012100686356A 2005-09-14 2006-09-14 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法 Pending CN102614131A (zh)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US71752405P 2005-09-14 2005-09-14
US60/717,524 2005-09-14
US74488206P 2006-04-14 2006-04-14
US60/744,882 2006-04-14

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
CN2006800338168A Division CN101262850B (zh) 2005-09-14 2006-09-14 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法

Publications (1)

Publication Number Publication Date
CN102614131A true CN102614131A (zh) 2012-08-01

Family

ID=37726824

Family Applications (3)

Application Number Title Priority Date Filing Date
CN201410508206.5A Active CN104324362B (zh) 2005-09-14 2006-09-14 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
CN201410508203.1A Active CN104324366B (zh) 2005-09-14 2006-09-14 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
CN2012100686356A Pending CN102614131A (zh) 2005-09-14 2006-09-14 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法

Family Applications Before (2)

Application Number Title Priority Date Filing Date
CN201410508206.5A Active CN104324362B (zh) 2005-09-14 2006-09-14 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
CN201410508203.1A Active CN104324366B (zh) 2005-09-14 2006-09-14 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

Country Status (16)

Country Link
US (15) US7799344B2 (zh)
EP (3) EP1928423B1 (zh)
JP (4) JP5465878B2 (zh)
KR (7) KR101643478B1 (zh)
CN (3) CN104324362B (zh)
AU (2) AU2006290227B2 (zh)
BR (2) BRPI0615819B8 (zh)
CA (2) CA2620758C (zh)
DK (3) DK1937219T3 (zh)
ES (3) ES2555310T3 (zh)
HK (2) HK1116088A1 (zh)
HU (2) HUE028623T2 (zh)
IN (1) IN2014DN09128A (zh)
MX (2) MX358592B (zh)
RU (3) RU2394550C2 (zh)
WO (2) WO2007033316A2 (zh)

Families Citing this family (71)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
WO2001000654A2 (en) * 1999-06-29 2001-01-04 Pharmaceutical Discovery Corporation Purification and stabilization of peptide and proteins in pharmaceutical agents
EP1894591B1 (en) 2002-03-20 2013-06-26 MannKind Corporation Cartridge for an inhalation apparatus
US20080260838A1 (en) * 2003-08-01 2008-10-23 Mannkind Corporation Glucagon-like peptide 1 (glp-1) pharmaceutical formulations
US8921311B2 (en) 2003-08-01 2014-12-30 Mannkind Corporation Method for treating hyperglycemia
DK1786784T3 (da) 2004-08-20 2011-02-14 Mannkind Corp Katalyse af diketopiperazinsyntese
CN104436170B (zh) 2004-08-23 2018-02-23 曼金德公司 用于药物输送的二酮哌嗪盐
HUE028623T2 (en) 2005-09-14 2016-12-28 Mannkind Corp Active substance formulation method based on increasing the affinity of the active ingredient for binding to the surface of crystalline microparticles
IN2015DN00888A (zh) * 2006-02-22 2015-07-10 Mannkind Corp
KR101438839B1 (ko) * 2006-04-14 2014-10-02 맨카인드 코포레이션 글루카곤 유사 펩타이드 1 （ｇｌｐ-1） 약제학적 제제
BRPI0818874A2 (pt) * 2007-10-24 2015-05-05 Mannkind Corp Liberação de agentes ativos
US8785396B2 (en) 2007-10-24 2014-07-22 Mannkind Corporation Method and composition for treating migraines
WO2009055740A2 (en) 2007-10-24 2009-04-30 Mannkind Corporation Method of preventing adverse effects by glp-1
ES2570400T3 (es) 2008-06-13 2016-05-18 Mannkind Corp Un inhalador de polvo seco y un sistema para el suministro de fármacos
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
JP5479465B2 (ja) 2008-06-20 2014-04-23 マンカインド コーポレイション 吸入努力をリアルタイムにプロファイルする対話式機器および方法
JP5841708B2 (ja) * 2008-07-01 2016-01-13 日東電工株式会社 表面被覆微粒子の医薬組成物
TWI532497B (zh) * 2008-08-11 2016-05-11 曼凱公司 超快起作用胰島素之用途
CA2742954C (en) 2008-11-07 2018-07-10 Massachusetts Institute Of Technology Aminoalcohol lipidoids and uses thereof
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
WO2010078373A1 (en) 2008-12-29 2010-07-08 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
JP5918539B2 (ja) 2009-01-08 2016-05-18 マンカインド コーポレイション Ｇｌｐ−１を用いる高血糖症の治療方法
EP2405963B1 (en) 2009-03-11 2013-11-06 MannKind Corporation Apparatus, system and method for measuring resistance of an inhaler
CN102458371B (zh) 2009-06-12 2015-08-05 曼金德公司 具有确定异构体含量的二酮哌嗪微粒
KR101875969B1 (ko) * 2009-06-12 2018-07-06 맨카인드 코포레이션 한정된 비표면적을 갖는 디케토피페라진 마이크로입자
WO2011017554A2 (en) 2009-08-07 2011-02-10 Mannkind Corporation Val (8) glp-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome
EP2496253B1 (en) 2009-11-02 2019-01-09 MannKind Corporation Apparatus and method for cryogranulating a pharmaceutical composition
SG10201406836SA (en) 2009-11-02 2014-12-30 Mannkind Corp Reactor For Producing Pharmaceutical Particles In A Precipitation Process
JP5784622B2 (ja) 2009-11-03 2015-09-24 マンカインド コーポレ−ション 吸入活動をシミュレートするための装置及び方法
EP2567219B1 (en) 2010-05-07 2019-09-18 MannKind Corporation Method and apparatus for determining weight percent of microparticles of diketopiperazine in suspension using raman spectroscopy
MX359281B (es) * 2010-06-21 2018-09-21 Mannkind Corp Sistema y metodos para suministrar un farmaco en polvo seco.
US10140619B2 (en) * 2010-06-22 2018-11-27 Sizmek Technologies, Inc. Dynamic creative creation and delivery
MX340112B (es) 2010-11-09 2016-06-27 Mannkind Corp Composicion que comprende un agonista de receptor de serotonina y una dicetopiperazina para el tratamiento de migrañas.
MX353285B (es) 2011-04-01 2018-01-05 Mannkind Corp Paquete de blister para cartuchos farmaceuticos.
CA3042808A1 (en) 2011-04-12 2012-10-18 Moerae Matrix, Inc. Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition
US9890200B2 (en) 2011-04-12 2018-02-13 Moerae Matrix, Inc. Compositions and methods for preventing or treating diseases, conditions, or processes characterized by aberrant fibroblast proliferation and extracellular matrix deposition
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
CN103945859A (zh) 2011-10-24 2014-07-23 曼金德公司 用于治疗疼痛的方法和组合物
CA3119789A1 (en) 2011-10-27 2013-05-02 Massachusetts Institute Of Technology Amino acid derivatives functionalized on the n-terminal capable of forming drug encapsulating microspheres
US20130261372A1 (en) * 2012-03-30 2013-10-03 Elwha LLC, a limited liability company of the State of Delaware Device, System, and Method for Delivery of Sugar Glass Stabilized Compositions
WO2014012069A2 (en) 2012-07-12 2014-01-16 Mannkind Corporation Dry powder drug delivery systems and methods
US20150231067A1 (en) * 2012-08-29 2015-08-20 Mannkind Corporation Method and composition for treating hyperglycemia
EP2895157A4 (en) * 2012-09-11 2016-07-13 Univ Massachusetts NETWORKED POLYMER NANOBAU GROUPS AND USES THEREOF
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
EP2911690A1 (en) 2012-10-26 2015-09-02 MannKind Corporation Inhalable influenza vaccine compositions and methods
CN104902920A (zh) 2012-12-21 2015-09-09 赛诺菲 作为glp1/gip双重激动剂或glp1/gip/胰高血糖素三重激动剂的毒蜥外泌肽-4衍生物
AU2014228415B2 (en) * 2013-03-15 2018-08-09 Mannkind Corporation Microcrystalline diketopiperazine compositions and methods
KR102321339B1 (ko) 2013-07-18 2021-11-02 맨카인드 코포레이션 열-안정성 건조 분말 약제학적 조성물 및 방법
US11446127B2 (en) 2013-08-05 2022-09-20 Mannkind Corporation Insufflation apparatus and methods
WO2015086729A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/gip receptor agonists
EP3080149A1 (en) 2013-12-13 2016-10-19 Sanofi Dual glp-1/glucagon receptor agonists
TW201609795A (zh) 2013-12-13 2016-03-16 賽諾菲公司 作為雙重ｇｌｐ－１／ｇｉｐ受體促效劑的艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物
WO2015086730A1 (en) 2013-12-13 2015-06-18 Sanofi Non-acylated exendin-4 peptide analogues
US10307464B2 (en) 2014-03-28 2019-06-04 Mannkind Corporation Use of ultrarapid acting insulin
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
US10336788B2 (en) 2014-04-17 2019-07-02 Moerae Matrix, Inc. Inhibition of cardiac fibrosis in myocardial infarction
ES2750686T3 (es) 2014-05-30 2020-03-26 Translate Bio Inc Lípidos biodegradables para la administración de ácidos nucleicos
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
PE20171238A1 (es) 2014-06-24 2017-08-24 Shire Human Genetic Therapies Composiciones enriquecidas estereoquimicamente para administracion de acidos nucleicos
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
BR112017010238A2 (pt) 2014-11-17 2018-02-06 Moerae Matrix, Inc. composições e métodos para prevenir ou tratar doenças, condições ou processos caracterizados por proliferação de fibroblastos e a deposição aberrante de matriz extracelular
AU2016229017A1 (en) 2015-03-12 2017-09-28 Moerae Matrix, Inc. Use of MK2 inhibitor peptide-containing compositions for treating non-small cell lung cancer with same
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
FI3310764T3 (fi) 2015-06-19 2023-07-18 Massachusetts Inst Technology Alkenyylillä substituoidut 2,5-piperatsiinidionit ja niiden käyttö koostumuksissa agenssin kuljettamiseksi subjektille tai soluun
AR105284A1 (es) 2015-07-10 2017-09-20 Sanofi Sa Derivados de exendina-4 como agonistas peptídicos duales específicos de los receptores de glp-1 / glucagón
IL260823B2 (en) * 2016-01-29 2024-08-01 Mannkind Corp Dry powder inhaler
JP7148605B2 (ja) 2017-10-12 2022-10-05 ノヴォ ノルディスク アー／エス 医学療法におけるセマグルチド
JP2021527058A (ja) * 2018-06-07 2021-10-11 マンカインド コーポレイション 吸入のための組成物および方法
CN114471750A (zh) * 2020-10-23 2022-05-13 南京工业大学 一种通过诱导液-液相分离可靠地合成纳米/亚微米液滴的方法及其应用

Family Cites Families (1114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB475440A (en) 1935-09-23 1937-11-19 Mine Safety Appliances Co Improvements in or relating to apparatus for determining the flow resistance of breathing apparatus elements
US2549303A (en) 1949-04-20 1951-04-17 Bristol Lab Inc Inhaler for crystalline pencilllin or the like
BE509861A (zh) 1952-03-13
US2754276A (en) 1953-02-12 1956-07-10 Du Pont Cellular compositions utilizing dinitrosopentamethylene-tetramine as the blowing agent
US3337740A (en) 1962-02-13 1967-08-22 Deering Milliken Res Corp Process for separating acrylic acid from impurities
US4187129A (en) 1962-05-14 1980-02-05 Aerojet-General Corporation Gelled mechanically stable high energy fuel composition containing metal platelets
FR1451293A (fr) 1964-05-18 1966-01-07 Entoleter Matière composite et son procédé de préparation
US3407203A (en) 1965-03-22 1968-10-22 Union Carbide Corp Novel process for the preparation of diketopiperazines
US3669113A (en) 1966-03-07 1972-06-13 Fisons Ltd Inhalation device
US3518340A (en) 1968-04-15 1970-06-30 Dow Corning Method of forming silicone rubber drug carriers
US3622053A (en) 1969-12-10 1971-11-23 Schering Corp Aerosol inhaler with flip-up nozzle
US3673698A (en) 1970-11-25 1972-07-04 Albert S Guerard Process for freeze drying with carbon dioxide
BE794951A (fr) 1972-02-03 1973-05-29 Parke Davis & Co Conditionnement soluble dans l'eau
US3873651A (en) 1972-05-12 1975-03-25 Atomic Energy Commission Freeze drying method for preparing radiation source material
US3823843A (en) 1972-10-26 1974-07-16 Lilly Co Eli Locking capsule
US3856142A (en) 1973-01-24 1974-12-24 Mine Safety Appliances Co Inhalant package
FR2224175B1 (zh) 1973-04-04 1978-04-14 Isf Spa
US3980074A (en) 1973-07-18 1976-09-14 Beecham Group Limited Device for the administration of powders
GB1479283A (en) 1973-07-23 1977-07-13 Bespak Industries Ltd Inhaler for powdered medicament
GB1459488A (en) 1974-03-19 1976-12-22 Wyeth John & Brother Ltd Piperazinedione derivatives
IT1017153B (it) 1974-07-15 1977-07-20 Isf Spa Apparecchio per inalazioni
US4018619A (en) 1974-09-23 1977-04-19 Iu Technology Corporation Highly activated mixtures for constructing load bearing surfaces and method of making the same
US4005711A (en) 1975-01-13 1977-02-01 Syntex Puerto Rico, Inc. Inhalation device
DE2502251A1 (de) 1975-01-17 1976-07-22 Schering Ag Vorrichtung zur inhalation pulverfoermiger feststoffe
US4040536A (en) 1975-05-05 1977-08-09 R. P. Scherer Corporation Locking hard gelatin capsule
LU75103A1 (zh) 1975-06-09 1977-01-24
US4153689A (en) 1975-06-13 1979-05-08 Takeda Chemical Industries, Ltd. Stable insulin preparation for nasal administration
US3998226A (en) 1975-09-22 1976-12-21 Edward G. Gomez Inhalation device for encapsulated concentrates
GB1509979A (en) 1975-11-28 1978-05-10 Fisons Ltd Pharmaceutical compositions containing aspirin or indomethacin
US4102953A (en) 1976-05-25 1978-07-25 The United States Of America As Represented By The Secretary Of The Navy Method for making extruded, solventless, composite-modified double base propellant
USD252707S (en) 1977-01-03 1979-08-21 Joel Besnard Inhaler
GB1598081A (en) 1977-02-10 1981-09-16 Allen & Hanburys Ltd Inhaler device for dispensing medicaments
US4171000A (en) 1977-03-23 1979-10-16 Uhle Klaus P Smoking device
IE46865B1 (en) 1977-04-29 1983-10-19 Allen & Hanburys Ltd Device for dispensing medicaments
US4148308A (en) 1977-05-31 1979-04-10 Sayer William J Mouthpiece with a tongue retractor
US4110240A (en) 1977-07-29 1978-08-29 Wyrough And Loser, Inc. Coprecipitation process
US4091077A (en) 1977-08-12 1978-05-23 The United States Of America As Represented By The United States Department Of Energy Process for recovering filler from polymer
US4211769A (en) 1977-08-24 1980-07-08 Takeda Chemical Industries, Ltd. Preparations for vaginal administration
US4268460A (en) 1977-12-12 1981-05-19 Warner-Lambert Company Nebulizer
CA1113044A (en) 1977-12-16 1981-11-24 J. Paul Leblond Personal repellant device
US4356167A (en) 1978-01-27 1982-10-26 Sandoz, Inc. Liposome drug delivery systems
US4175556A (en) 1978-04-07 1979-11-27 Freezer Winthrop J Inhaler with flow-through cap
US4196196A (en) 1978-06-19 1980-04-01 Tiholiz Ivan C Divalen/monovalent bipolar cation therapy for enhancement of tissue perfusion and reperfusion in disease states
US4168002A (en) 1978-08-03 1979-09-18 Crosby Leslie O Multiple-seed package card
US4272398A (en) 1978-08-17 1981-06-09 The United States Of America As Represented By The Secretary Of Agriculture Microencapsulation process
DE2840442C2 (de) 1978-09-16 1982-02-11 C.H. Boehringer Sohn, 6507 Ingelheim Verwendung des Diketopiperazins L-Leu-L-Trp als Geschmacksstoff für Getränke mit bitterer Geschmacksrichtung
DE2849493C2 (de) 1978-11-15 1982-01-14 Carl Heyer Gmbh, Inhalationstechnik, 5427 Bad Ems In der Hand zu haltender Aerosolspender
USD269463S (en) 1978-12-08 1983-06-21 Fisons Limited Container for a medicinal inhaler
JPS5837833Y2 (ja) 1979-04-27 1983-08-26 凸版印刷株式会社 アンプル収納容器
JPS6034925B2 (ja) 1979-07-31 1985-08-12 帝人株式会社 持続性鼻腔用製剤およびその製造法
US4407525A (en) 1979-10-04 1983-10-04 Gao Gesellschaft Fur Automation Und Organisation Mbh Identification card with hallmark for authentication by incident and transmitted light
GB2072536B (en) 1980-03-25 1983-12-07 Malem H Nebuliser
US4289759A (en) 1980-06-23 1981-09-15 Ortho Pharmaceutical Corporation Immunoregulatory diketopiperazine compounds
EP0055537B1 (en) 1980-12-12 1984-12-05 Combi Co., Ltd. Inhaler
US4900730A (en) 1981-01-14 1990-02-13 Toyo Jozo Co., Ltd. Preparation which promotes the absorption of peptides
GB2092136B (en) 1981-01-17 1985-06-05 Mitsui Toatsu Chemicals Production of n-substituted amide compounds
JPS58140026A (ja) 1982-01-14 1983-08-19 Toyo Jozo Co Ltd 吸収性良好な製剤
IT1220979B (it) 1981-06-04 1990-06-21 Lofarma Farma Lab Capsule contenenti un allergene e procedimento per la loro preparazione
SE438261B (sv) 1981-07-08 1985-04-15 Draco Ab Anvendning i dosinhalator av ett perforerat membran
CY1492A (en) 1981-07-08 1990-02-16 Draco Ab Powder inhalator
US5260306A (en) 1981-07-24 1993-11-09 Fisons Plc Inhalation pharmaceuticals
USD276654S (en) 1981-09-15 1984-12-04 Aktiebolaget Draco Medical aerosol inhalation device
KR890000664B1 (ko) 1981-10-19 1989-03-22 바리 안소니 뉴우샘 미분된 베클로메타손 디프로피오네이트 일수화물의 제조방법
US4659696A (en) 1982-04-30 1987-04-21 Takeda Chemical Industries, Ltd. Pharmaceutical composition and its nasal or vaginal use
US4483922A (en) 1982-05-14 1984-11-20 Amf Inc. Inactivation of enzymes
US4526804A (en) 1982-08-30 1985-07-02 Ball Corporation Method for providing sheet metal stock with finely divided powder
US4487327A (en) 1982-12-21 1984-12-11 Grayson Robert E Locking capsule
JPS59163313A (ja) 1983-03-09 1984-09-14 Teijin Ltd 経鼻投与用ペプチドホルモン類組成物
US4481139A (en) 1983-04-13 1984-11-06 Board Of Regents, The University Of Texas System Peptide antagonists of substance P
AU90762S (en) 1983-06-29 1985-08-15 Glaxo Group Ltd Inhaler
US4581020A (en) 1983-07-18 1986-04-08 Trimedyne, Inc. Medication delivery device and system for percutaneous administration of medication
GB8325529D0 (en) 1983-09-23 1983-10-26 Lilly Industries Ltd Medicinal forms
CH661878A5 (de) 1983-11-04 1987-08-31 Warner Lambert Co Kapsel-dosierungsformen.
US4671954A (en) 1983-12-13 1987-06-09 University Of Florida Microspheres for incorporation of therapeutic substances and methods of preparation thereof
USD295321S (en) 1984-03-13 1988-04-19 Glaxo Group Limited Inhaler container for a medical aerosol
JPS60248618A (ja) 1984-05-24 1985-12-09 Nippon Zoki Pharmaceut Co Ltd ジペプチドを含有する潰瘍治療剤
US4927555A (en) 1984-08-13 1990-05-22 Colgate-Palmolive Company Process for making thixotropic detergent compositions
USD288852S (en) 1984-08-29 1987-03-17 Aruman Co., Ltd. Disposable inhaler
US4757066A (en) 1984-10-15 1988-07-12 Sankyo Company Limited Composition containing a penem or carbapenem antibiotic and the use of the same
IE58468B1 (en) 1984-10-25 1993-09-22 Warner Lambert Co Method for sealing capsules and capsule
US4592348A (en) 1984-12-17 1986-06-03 Waters Iv William C Aerosol inhaler
US4946828A (en) 1985-03-12 1990-08-07 Novo Nordisk A/S Novel insulin peptides
SE448277B (sv) 1985-04-12 1987-02-09 Draco Ab Indikeringsanordning vid en doseringsanordning for lekemedel
JPS6320301Y2 (zh) 1985-04-18 1988-06-06
US5785989A (en) 1985-05-01 1998-07-28 University Utah Research Foundation Compositions and methods of manufacturing of oral dissolvable medicaments
US4615817A (en) 1985-05-17 1986-10-07 Mccoy Frederic C Additives containing polytetrafluoroethylene for making stable lubricants
CA1318730C (en) 1985-05-30 1993-06-01 C. Edward Capes Method of separating carbonaceous components from particulate coal containing inorganic solids and apparatus therefor
US5098590A (en) 1988-02-04 1992-03-24 Colgate Palmolive Co. Thixotropic aqueous automatic dishwasher detergent compositions with improved stability
GR861995B (en) 1985-07-30 1986-11-04 Glaxo Group Ltd Devices for administering medicaments to patients
AT384552B (de) 1985-08-01 1987-12-10 Hurka Wilhelm Inhalationsgeraet zur dosierung und verteilung von festkoerpern in die atemluft
US4624861A (en) 1985-09-05 1986-11-25 Gte Products Corporation Rare earth oxysulfide phosphors and processes for creating same
US4742156A (en) 1985-09-30 1988-05-03 Mcneilab, Inc. Peptide antagonists of neurokinin B and opthalmic solutions containing them
PT83613B (en) 1985-10-28 1988-11-21 Lilly Co Eli Process for the selective chemical removal of a protein amino-terminal residue
EP0248051A1 (en) 1985-11-29 1987-12-09 FISONS plc Pharmaceutical composition including sodium cromoglycate
LU86258A1 (fr) 1986-01-21 1987-09-03 Rech Dermatologiques C I R D S Composes benzamido aromatique,leur procede de preparation et leur utilisation en medecine humaine ou veterinaire et en cosmetique
SE453566B (sv) 1986-03-07 1988-02-15 Draco Ab Anordning vid pulverinhalatorer
US4849227A (en) 1986-03-21 1989-07-18 Eurasiam Laboratories, Inc. Pharmaceutical compositions
US6849708B1 (en) 1986-05-05 2005-02-01 The General Hospital Corporation Insulinotropic hormone and uses thereof
US5614492A (en) 1986-05-05 1997-03-25 The General Hospital Corporation Insulinotropic hormone GLP-1 (7-36) and uses thereof
US5118666A (en) 1986-05-05 1992-06-02 The General Hospital Corporation Insulinotropic hormone
US5120712A (en) 1986-05-05 1992-06-09 The General Hospital Corporation Insulinotropic hormone
US4926852B1 (en) 1986-06-23 1995-05-23 Univ Johns Hopkins Medication delivery system phase one
USD301273S (en) 1986-07-10 1989-05-23 Leonard G Darin Hand held fly suction device
JPS6320301A (ja) 1986-07-11 1988-01-28 Dainichi Color & Chem Mfg Co Ltd キトサン微小粒体
US5042975A (en) 1986-07-25 1991-08-27 Rutgers, The State University Of New Jersey Iontotherapeutic device and process and iontotherapeutic unit dose
JP2765700B2 (ja) 1986-08-11 1998-06-18 イノベータ・バイオメド・リミテツド マイクロカプセルを含有する医薬調合物
USRE35862E (en) 1986-08-18 1998-07-28 Emisphere Technologies, Inc. Delivery systems for pharmacological agents encapsulated with proteinoids
NL8720442A (nl) 1986-08-18 1989-04-03 Clinical Technologies Ass Afgeefsystemen voor farmacologische agentia.
ES2032831T5 (es) 1986-08-19 2001-02-16 Genentech Inc Dispositivo y dispersion para suministro intrapulmonar de factores de crecimiento polipeptidos y citoquinas.
DE3639836A1 (de) 1986-11-21 1988-06-01 Sigrid Bechter Mundstueck fuer ein inhalationsgeraet
KR890003520Y1 (ko) 1986-12-20 1989-05-27 주식회사 서흥캅셀 의약용 캅셀
US4861627A (en) 1987-05-01 1989-08-29 Massachusetts Institute Of Technology Preparation of multiwall polymeric microcapsules
US4981295A (en) 1987-05-11 1991-01-01 City Of Hope Respiratory training using feedback
US6645504B1 (en) 1987-06-24 2003-11-11 Autoimmune Inc. Bystander suppression of type I diabetes by oral administration of glucagon
US4913173A (en) 1987-06-25 1990-04-03 International Beauty Distributors, Inc. High efficiency wrap package, and process, for nails
DE3727894A1 (de) 1987-08-21 1989-03-02 Stephan Dieter Kapsel fuer pharmazeutisch wirksame inhaltsstoffe einer droge
GB8723846D0 (en) 1987-10-10 1987-11-11 Danbiosyst Ltd Bioadhesive microsphere drug delivery system
US4887722A (en) 1987-12-11 1989-12-19 Greenward Sr Edward H Method for beneficiating by carbonaceous refuse
DE3801326A1 (de) 1988-01-19 1989-07-27 Asea Brown Boveri Verfahren zur herstellung einer keramiksuspension
US4981625A (en) 1988-03-14 1991-01-01 California Institute Of Technology Monodisperse, polymeric microspheres produced by irradiation of slowly thawing frozen drops
CH675267A5 (zh) 1988-03-16 1990-09-14 Geberit Ag
GB8813338D0 (en) 1988-06-06 1988-07-13 Osprey Metals Ltd Powder production
USD316902S (en) 1988-09-02 1991-05-14 Hoelfing H Curt Meter hose inhaler reservoir
GB8821287D0 (en) 1988-09-12 1988-10-12 Ici Plc Device
EP0360340A1 (en) 1988-09-19 1990-03-28 Akzo N.V. Composition for nasal administration containing a peptide
USD321570S (en) 1988-09-30 1991-11-12 Blasdell Richard J Inhaler
EP0363060B1 (en) 1988-10-04 1994-04-27 The Johns Hopkins University Aerosol inhaler
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
JPH02115154A (ja) 1988-10-25 1990-04-27 Kao Corp イミド化合物及びその用途
USD326517S (en) 1988-10-27 1992-05-26 Glaxo Group Limited Inhalator
JP2692742B2 (ja) 1988-11-30 1997-12-17 株式会社ツムラ 新規なリグナン類
US5006343A (en) 1988-12-29 1991-04-09 Benson Bradley J Pulmonary administration of pharmaceutically active substances
US5075027A (en) 1989-02-06 1991-12-24 Colgate Palmolive Co. Thixotropic aqueous scented automatic dishwasher detergent compositions
US5514646A (en) 1989-02-09 1996-05-07 Chance; Ronald E. Insulin analogs modified at position 29 of the B chain
IT1228459B (it) 1989-02-23 1991-06-19 Phidea S R L Inalatore con svuotamento regolare e completo della capsula.
IT1228460B (it) 1989-02-23 1991-06-19 Phidea S R L Inalatore monouso con capsula pre-forata
US4983402A (en) 1989-02-24 1991-01-08 Clinical Technologies Associates, Inc. Orally administerable ANF
SE466684B (sv) 1989-03-07 1992-03-23 Draco Ab Anordning vid en inhalator samt foerfarande foer att med anordningen registrera medicinering med inhalator
US5358734A (en) 1989-03-30 1994-10-25 Gte Products Corporation Process for producing a blue emitting lamp phosphor
US5215739A (en) 1989-04-05 1993-06-01 Toko Yakuhin Kogyo Kabushiki Kaisha Spray gel base and spray gel preparation using thereof
US5067500A (en) 1989-04-24 1991-11-26 Philip Morris Incorporated Container for additive materials for smoking articles
US4991605A (en) 1989-04-24 1991-02-12 Philip Morris Incorporated Container for additive materials for smoking articles
ES2087911T3 (es) 1989-04-28 1996-08-01 Riker Laboratories Inc Dispositivo de inhalacion de polvo seco.
GB8909891D0 (en) 1989-04-28 1989-06-14 Riker Laboratories Inc Device
DE69005800T2 (de) 1989-05-01 1994-05-19 Alkermes Inc Verfahren zur herstellung von kleinen partikeln von biologisch aktiven molekülen.
US5019400A (en) 1989-05-01 1991-05-28 Enzytech, Inc. Very low temperature casting of controlled release microspheres
US5017383A (en) 1989-08-22 1991-05-21 Taisho Pharmaceutical Co., Ltd. Method of producing fine coated pharmaceutical preparation
GB8919131D0 (en) 1989-08-23 1989-10-04 Riker Laboratories Inc Inhaler
US5270305A (en) 1989-09-08 1993-12-14 Glaxo Group Limited Medicaments
GB8921222D0 (en) 1989-09-20 1989-11-08 Riker Laboratories Inc Medicinal aerosol formulations
DK544589D0 (da) 1989-11-01 1989-11-01 Novo Nordisk As Manuel betjent apparat til dispensering af en forudbestemt maengde af et pulverformet stof
JPH0741428Y2 (ja) 1989-11-04 1995-09-27 アップリカ葛西株式会社 ベビーバス
EP0550436A1 (en) * 1989-11-06 1993-07-14 Alkermes Controlled Therapeutics, Inc. Protein microspheres and methods of using them
US5188837A (en) 1989-11-13 1993-02-23 Nova Pharmaceutical Corporation Lipsopheres for controlled delivery of substances
US5105291A (en) * 1989-11-20 1992-04-14 Ricoh Company, Ltd. Liquid crystal display cell with electrodes of substantially amorphous metal oxide having low resistivity
US5131539A (en) 1989-12-06 1992-07-21 Canon Kabushiki Kaisha Package for ink jet cartridge
USD331106S (en) 1989-12-30 1992-11-17 Ing. Erich Pfeiffer Gmbh & Co. Kg Single use inhaler
US5545618A (en) 1990-01-24 1996-08-13 Buckley; Douglas I. GLP-1 analogs useful for diabetes treatment
GB9001635D0 (en) 1990-01-24 1990-03-21 Ganderton David Aerosol carriers
US5201308A (en) 1990-02-14 1993-04-13 Newhouse Michael T Powder inhaler
UA26230A (uk) 1990-03-02 1999-07-19 Глексо Груп Лімітед Іhгалятор для спільhого використаhhя з лікувальhим блоком і лікувальhий блок
SK280968B6 (sk) 1990-03-02 2000-10-09 Glaxo Group Limited Balenie medikamentu na použite v inhalačnom prístroji
US6536427B2 (en) 1990-03-02 2003-03-25 Glaxo Group Limited Inhalation device
US5615670A (en) 1990-03-07 1997-04-01 Fisons Plc Powder inhaler with centrifugal force used to meter powder
IT1240750B (it) 1990-04-12 1993-12-17 Chiesi Farma Spa Dispositivo per la somministrazione di sostanze medicamentose in polvere
JPH05963A (ja) 1990-04-13 1993-01-08 Toray Ind Inc ポリペプチド類組成物
US5328464A (en) 1990-04-24 1994-07-12 Science Incorporated Closed drug delivery system
USD338268S (en) 1990-05-04 1993-08-10 Omron Corporation Heating inhaler
CA2081474A1 (en) 1990-05-08 1991-11-09 Manzer Durrani Direct spray-dried drug/lipid powder composition
IL98441A (en) 1990-06-14 1995-12-31 Rhone Poulenc Rorer Ltd Powder inhaler
DE4021263C2 (de) 1990-07-04 1996-04-11 Pfeiffer Erich Gmbh & Co Kg Austragvorrichtung für Medien
GB9015522D0 (en) 1990-07-13 1990-08-29 Braithwaite Philip W Inhaler
US5693338A (en) 1994-09-29 1997-12-02 Emisphere Technologies, Inc. Diketopiperazine-based delivery systems
US5443841A (en) 1992-06-15 1995-08-22 Emisphere Technologies, Inc. Proteinoid microspheres and methods for preparation and use thereof
US5578323A (en) 1992-06-15 1996-11-26 Emisphere Technologies, Inc. Proteinoid carriers and methods for preparation and use thereof
US5451410A (en) 1993-04-22 1995-09-19 Emisphere Technologies, Inc. Modified amino acids for encapsulating active agents
US5714167A (en) 1992-06-15 1998-02-03 Emisphere Technologies, Inc. Active agent transport systems
US5541155A (en) 1994-04-22 1996-07-30 Emisphere Technologies, Inc. Acids and acid salts and their use in delivery systems
US5447728A (en) 1992-06-15 1995-09-05 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US6331318B1 (en) 1994-09-30 2001-12-18 Emisphere Technologies Inc. Carbon-substituted diketopiperazine delivery systems
US5629020A (en) 1994-04-22 1997-05-13 Emisphere Technologies, Inc. Modified amino acids for drug delivery
JPH04103585A (ja) 1990-08-24 1992-04-06 Nisshin Flour Milling Co Ltd ピロリジン環を有する化合物
US5074418A (en) 1990-09-12 1991-12-24 Pitney Bowes Inc. Ink replenishing system transport and storage container
SE9002895D0 (sv) 1990-09-12 1990-09-12 Astra Ab Inhalation devices for dispensing powders i
ATE164525T1 (de) 1990-09-26 1998-04-15 Pharmachemie Bv Inhalator mit einem reservoir für mehrere dosierte inhalationsmittel, mit transportvorrichtung und mit wirbelkammer
US5170801A (en) 1990-10-02 1992-12-15 Glaxo Inc. Medical capsule device actuated by radio-frequency (rf) signal
FR2667509B1 (fr) 1990-10-04 1995-08-25 Valois Inhalateur a poudre, dispositif de conditionnement de microdoses de poudre sous forme de bandes adaptees a etre utilisees dans un inhalateur a poudre, et procede de fabrication de ces bandes.
IL99699A (en) 1990-10-10 2002-04-21 Autoimmune Inc Drug with the option of oral, intra-intestinal, or inhaled dosing for suppression of autoimmune response associated with type I diabetes
GB9024760D0 (en) 1990-11-14 1991-01-02 Riker Laboratories Inc Inhalation device and medicament carrier
US5124291A (en) 1990-11-15 1992-06-23 The Standard Oil Company Method for deagglomerating and re-exposing catalyst in a fluid bed reactor
GB9026191D0 (en) 1990-12-01 1991-01-16 Harris Pharma Ltd Breath actuated dispensing device
GB9027234D0 (en) 1990-12-15 1991-02-06 Harris Pharma Ltd An inhalation device
DE69127826T2 (de) 1990-12-17 1998-04-09 Minnesota Mining & Mfg Inhalationsgerät
US5145684A (en) 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
GB2253200A (en) 1991-02-01 1992-09-02 Harris Pharma Ltd Inhalation apparatus and fracturable capsule for use therewith
AU1442592A (en) 1991-02-20 1992-09-15 Nova Pharmaceutical Corporation Controlled release microparticulate delivery system for proteins
US5208998A (en) 1991-02-25 1993-05-11 Oyler Jr James R Liquid substances freeze-drying systems and methods
WO1994016759A1 (en) 1991-03-05 1994-08-04 Miris Medical Corporation An automatic aerosol medication delivery system and methods
US5394866A (en) 1991-03-05 1995-03-07 Aradigm Corporation Automatic aerosol medication delivery system and methods
US5404871A (en) 1991-03-05 1995-04-11 Aradigm Delivery of aerosol medications for inspiration
USD338062S (en) 1991-03-06 1993-08-03 Innovata Biomed Limited Inhaler
USD347057S (en) 1991-03-14 1994-05-17 Technosystem Limited Inhaler
JPH05273772A (ja) 1991-03-28 1993-10-22 Mita Ind Co Ltd ヒドラゾン系化合物およびそれを用いた感光体
US5797391A (en) 1991-03-28 1998-08-25 Rhone-Poulenc Rorer Limited Inhaler
US5413804A (en) 1991-04-23 1995-05-09 Cacique, Inc. Process for making whey-derived fat substitute product and products thereof
US5244653A (en) 1991-05-01 1993-09-14 Isp Chemicals Inc. Glycine anhydride dimethylol as a biocide and preservative
US5327883A (en) 1991-05-20 1994-07-12 Dura Pharmaceuticals, Inc. Apparatus for aerosolizing powdered medicine and process and using
US5492112A (en) 1991-05-20 1996-02-20 Dura Pharmaceuticals, Inc. Dry powder inhaler
US6055980A (en) 1991-05-20 2000-05-02 Dura Pharmaceuticals, Inc. Dry powder inhaler
US6060069A (en) 1991-05-20 2000-05-09 Dura Pharmaceuticals, Inc. Pulmonary delivery of pharmaceuticals
FR2676929B1 (fr) 1991-05-30 1994-02-11 Aerosols Bouchage Ste Fse Inhalateur de poudres.
AU653026B2 (en) 1991-06-07 1994-09-15 Teikoku Seiyaku Kabushiki Kaisha Physiologically active polypeptide-containing pharmaceutical composition
IT1248059B (it) 1991-06-14 1995-01-05 Miat Spa Insufflatore multidose per farmaci in polvere
JP3230056B2 (ja) 1991-07-02 2001-11-19 インヘイル・インコーポレーテッド 薬剤のエーロゾル化服用量を形成する装置
US6681767B1 (en) 1991-07-02 2004-01-27 Nektar Therapeutics Method and device for delivering aerosolized medicaments
US5203768A (en) 1991-07-24 1993-04-20 Alza Corporation Transdermal delivery device
US5337740A (en) 1991-08-01 1994-08-16 New England Pharmaceuticals, Inc. Inhalation devices
GB9116610D0 (en) 1991-08-01 1991-09-18 Danbiosyst Uk Preparation of microparticles
US5139878A (en) 1991-08-12 1992-08-18 Allied-Signal Inc. Multilayer film constructions
ES2089474T3 (es) 1991-08-16 1996-10-01 Sandoz Ltd Inhalador para la administracion de sustancias en polvo.
US5287850A (en) 1991-08-20 1994-02-22 Habley Medical Technology Corporation Timing and velocity controlled powered pharmaceutical inhaler
US6119688A (en) 1991-08-26 2000-09-19 3M Innovative Properties Company Powder dispenser
USD337636S (en) 1991-09-12 1993-07-20 Devilbiss Health Care, Inc. Ultrasonic medicament nebulizer
US5167506A (en) 1991-10-24 1992-12-01 Minnesota Mining And Manufacturing Company Inhalation device training system
USD348100S (en) 1991-10-29 1994-06-21 Fisons Plc Medicament inhaler
JPH0828037B2 (ja) 1991-10-31 1996-03-21 富士通株式会社 スピンドルシンク制御方式
USD350602S (en) 1991-11-01 1994-09-13 Rhone-Poulenc Rorer Limited Combined dry powder inhaler and cap
US6063910A (en) 1991-11-14 2000-05-16 The Trustees Of Princeton University Preparation of protein microparticles by supercritical fluid precipitation
USD350821S (en) 1991-11-18 1994-09-20 Smithkline Beecham P.L.C. Oral inhaler
SE9103572D0 (sv) 1991-11-29 1991-11-29 Astra Ab Organic salts of n,n'-diacetyl cystine
USD340975S (en) 1991-12-02 1993-11-02 Thayer Medical Corporation Combined expansion chamber metered dose inhaler dispenser and adaptor
US5338837A (en) 1991-12-13 1994-08-16 The Trustees Of Princeton University Glycosylated steroid derivatives for transport across biological membranes and process for making same
DE4211475A1 (de) 1991-12-14 1993-06-17 Asta Medica Ag Pulverinhalator
JP3121080B2 (ja) 1991-12-19 2000-12-25 アール・ピー・シーラー コーポレイション カプセル封入用溶液
GB2262452B (en) 1991-12-19 1995-12-20 Minnesota Mining & Mfg Inhalation device
US5363842A (en) 1991-12-20 1994-11-15 Circadian, Inc. Intelligent inhaler providing feedback to both patient and medical professional
US5525519A (en) 1992-01-07 1996-06-11 Middlesex Sciences, Inc. Method for isolating biomolecules from a biological sample with linear polymers
US5320094A (en) 1992-01-10 1994-06-14 The Johns Hopkins University Method of administering insulin
EP0621774B1 (en) 1992-01-21 1996-12-18 Sri International Improved process for preparing micronized polypeptide drugs
DE9209050U1 (de) 1992-02-13 1992-10-01 Schrader, Barthold von, 2400 Travemünde Inhalationseinrichtung
US5476093A (en) 1992-02-14 1995-12-19 Huhtamaki Oy Device for more effective pulverization of a powdered inhalation medicament
US5469971A (en) 1992-02-26 1995-11-28 Estee Lauder Inc. Method and apparatus for deagglomerating powder
EP0558879B1 (en) 1992-03-04 1997-05-14 Astra Aktiebolag Disposable inhaler
US5639441A (en) 1992-03-06 1997-06-17 Board Of Regents Of University Of Colorado Methods for fine particle formation
US5352461A (en) * 1992-03-11 1994-10-04 Pharmaceutical Discovery Corporation Self assembling diketopiperazine drug delivery system
DK36392D0 (da) 1992-03-19 1992-03-19 Novo Nordisk As Anvendelse af kemisk forbindelse
USD348929S (en) 1992-04-03 1994-07-19 Norton Healthcare Limited Medicament inhaler
CA2096302A1 (en) 1992-05-15 1993-11-16 David Kilis Air flow controller and recording system
USD344797S (en) 1992-06-11 1994-03-01 Schering Corporation Combined inhaler and cover
USD345013S (en) 1992-06-11 1994-03-08 Schering Corporation Combined inhaler and cover
USD350193S (en) 1992-06-11 1994-08-30 Schering Corporation Combined inhaler and cover
USD344796S (en) 1992-06-11 1994-03-01 Schering Corporation Combined inhaler and cover
WO1993025193A1 (en) 1992-06-12 1993-12-23 Teijin Limited Pharmaceutical preparation for intra-airway administration
US5792451A (en) 1994-03-02 1998-08-11 Emisphere Technologies, Inc. Oral drug delivery compositions and methods
US5811127A (en) 1992-06-15 1998-09-22 Emisphere Technologies, Inc. Desferrioxamine oral delivery system
US5394868A (en) 1992-06-25 1995-03-07 Schering Corporation Inhalation device for powdered medicaments
GB9213874D0 (en) 1992-06-30 1992-08-12 Fisons Plc Process to novel medicament form
US5785049A (en) 1994-09-21 1998-07-28 Inhale Therapeutic Systems Method and apparatus for dispersion of dry powder medicaments
US6509006B1 (en) 1992-07-08 2003-01-21 Inhale Therapeutic Systems, Inc. Devices compositions and methods for the pulmonary delivery of aerosolized medicaments
US6582728B1 (en) 1992-07-08 2003-06-24 Inhale Therapeutic Systems, Inc. Spray drying of macromolecules to produce inhaleable dry powders
GB9214819D0 (en) 1992-07-13 1992-08-26 Minnesota Mining & Mfg Valve assemblies
GB9216038D0 (en) 1992-07-28 1992-09-09 Bespak Plc Dispensing apparatus for powdered medicaments
GB2269992A (en) 1992-08-14 1994-03-02 Rh Ne Poulenc Rorer Limited Powder inhalation formulations
US5239993A (en) 1992-08-26 1993-08-31 Glaxo Inc. Dosage inhalator providing optimized compound inhalation trajectory
GB2270293A (en) 1992-09-05 1994-03-09 Medix Ltd Drug dispensing system
USD348928S (en) 1992-09-21 1994-07-19 Schering Corporation Inhaler
US5333106A (en) 1992-10-09 1994-07-26 Circadian, Inc. Apparatus and visual display method for training in the power use of aerosol pharmaceutical inhalers
AU5171293A (en) 1992-10-14 1994-05-09 Regents Of The University Of Colorado, The Ion-pairing of drugs for improved efficacy and delivery
HU217917B (hu) 1992-10-19 2000-05-28 Dura Pharmaceuticals Inc. Inhalálókészülék száraz porok inhalálásához
AU121578S (en) 1992-10-22 1994-09-20 Fisons Plc An inhalation device
USD359555S (en) 1992-11-18 1995-06-20 Nippon Glaxo Limited Nasal medicine inhaler
USD352107S (en) 1992-12-10 1994-11-01 Ciba-Geigy Corporation Inhaler
USD349572S (en) 1992-12-10 1994-08-09 Schering Corporation Aerosol inhaler
SE9203743D0 (sv) 1992-12-11 1992-12-11 Astra Ab Efficient use
US6250300B1 (en) 1992-12-11 2001-06-26 Ab Astra System for dispensing pharmaceutically active compounds
WO1994014492A2 (en) 1992-12-18 1994-07-07 Schering Corporation Inhaler for powdered medications
US5401516A (en) 1992-12-21 1995-03-28 Emisphere Technologies, Inc. Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof
US6105571A (en) 1992-12-22 2000-08-22 Electrosols, Ltd. Dispensing device
US6880554B1 (en) 1992-12-22 2005-04-19 Battelle Memorial Institute Dispensing device
US5896855A (en) 1992-12-24 1999-04-27 Rhone-Poulenc Rorer Limited Multi dose inhaler apparatus
FR2700279B1 (fr) 1993-01-14 1995-03-17 Valois Dispositif portatif pour projeter des doses d'une substance fluide à l'aide d'un flux d'air comprimé.
AU119600S (en) 1993-01-21 1994-03-07 Boehringer Ingelheim Kg Inhaler device
US6024090A (en) 1993-01-29 2000-02-15 Aradigm Corporation Method of treating a diabetic patient by aerosolized administration of insulin lispro
US5888477A (en) 1993-01-29 1999-03-30 Aradigm Corporation Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin
US6131567A (en) 1993-01-29 2000-10-17 Aradigm Corporation Method of use of monomeric insulin as a means for improving the reproducibility of inhaled insulin
US5364838A (en) 1993-01-29 1994-11-15 Miris Medical Corporation Method of administration of insulin
US7448375B2 (en) 1993-01-29 2008-11-11 Aradigm Corporation Method of treating diabetes mellitus in a patient
US5672581A (en) 1993-01-29 1997-09-30 Aradigm Corporation Method of administration of insulin
US5441060A (en) 1993-02-08 1995-08-15 Duke University Dry powder delivery system
IL108780A (en) 1993-02-27 1999-06-20 Fisons Plc inhaler
AU6360394A (en) * 1993-03-03 1994-09-26 Mayo Foundation For Medical Education And Research Vasonatrin peptide and analogs thereof
DE69413528T2 (de) 1993-04-06 1999-05-06 Minnesota Mining And Mfg. Co., Saint Paul, Minn. Vorrichtung zum deagglomerieren für trockenpulverinhalatoren
US5372128A (en) 1993-04-14 1994-12-13 Habley Medical Technology Corporation Fluidizing powder inhaler
DE69434418T2 (de) 1993-04-22 2005-12-22 Emisphere Technologies, Inc. Orale Dareichungsform
US5643957A (en) 1993-04-22 1997-07-01 Emisphere Technologies, Inc. Compounds and compositions for delivering active agents
ZA939608B (en) 1993-04-22 1994-08-24 Emisphere Tech Inc Modified hydrolyzed vegetable protein microspheres and methods for preparation and use thereof.
US5360614A (en) 1993-04-26 1994-11-01 The Estee Corporation Method of controlling the release of carbohydrates by encapsulation and composition therefor
AU679986B2 (en) 1993-04-28 1997-07-17 N.V. Organon Lyospheres comprising gonadotropin
JP3132830B2 (ja) 1993-05-12 2001-02-05 帝人株式会社 粉末状薬剤マルチドース施薬装置
US5424286A (en) 1993-05-24 1995-06-13 Eng; John Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same
US5533502A (en) 1993-05-28 1996-07-09 Vortran Medical Technology, Inc. Powder inhaler with aerosolization occurring within each individual powder receptacle
USD365876S (en) 1993-06-16 1996-01-02 Chawla Brindra P S Medicament inhaler
US5506203C1 (en) 1993-06-24 2001-02-06 Astra Ab Systemic administration of a therapeutic preparation
IS1796B (is) 1993-06-24 2001-12-31 Ab Astra Fjölpeptíð lyfjablanda til innöndunar sem einnig inniheldur eykjaefnasamband
US5747445A (en) 1993-06-24 1998-05-05 Astra Aktiebolag Therapeutic preparation for inhalation
US6794357B1 (en) 1993-06-24 2004-09-21 Astrazeneca Ab Compositions for inhalation
US6632456B1 (en) 1993-06-24 2003-10-14 Astrazeneca Ab Compositions for inhalation
TW402506B (en) 1993-06-24 2000-08-21 Astra Ab Therapeutic preparation for inhalation
US5562909A (en) 1993-07-12 1996-10-08 Massachusetts Institute Of Technology Phosphazene polyelectrolytes as immunoadjuvants
GB9314614D0 (en) 1993-07-14 1993-08-25 Minnesota Mining & Mfg Dry powder inhalers
US5371046A (en) 1993-07-22 1994-12-06 Taiwan Semiconductor Manufacturing Company Method to solve sog non-uniformity in the VLSI process
JPH0741428A (ja) 1993-07-30 1995-02-10 Teijin Ltd ペプチド、蛋白質性薬物経鼻・経肺製剤
DE69413989T2 (de) 1993-08-18 1999-04-08 Fisons Plc, Ipswich, Suffolk Inhalator mit atemstromregelung
US5306453A (en) 1993-08-18 1994-04-26 Edward Shulman Apparatus and method of making a non-woven fabric
US5524613A (en) 1993-08-25 1996-06-11 Habley Medical Technology Corporation Controlled multi-pharmaceutical inhaler
BE1007551A3 (nl) 1993-09-24 1995-08-01 Philips Electronics Nv Werkwijze voor het in een rekenmachine automatisch herstellen van consistentie in een hierarchische objektstruktuur na een interaktie door een gebruiker en rekenmachine voorzien van zo een systeem voor automatische consistentieherstelling.
US5477285A (en) 1993-10-06 1995-12-19 Thomson Consumer Electronics, Inc. CRT developing apparatus
GB9322014D0 (en) 1993-10-26 1993-12-15 Co Ordinated Drug Dev Improvements in and relating to carrier particles for use in dry powder inhalers
US5726156A (en) 1995-03-06 1998-03-10 Trega Biosciences, Inc. Cytokine regulatory agents and methods of use in pathologies and conditions associated with altered cytokine levels
JP3002702B2 (ja) 1993-11-16 2000-01-24 スカイファーム インコーポレーテッド 活性物質の制御放出を有する小胞
EP0655237A1 (de) 1993-11-27 1995-05-31 Hoechst Aktiengesellschaft Medizinische Aerosolformulierung
USD358880S (en) 1993-12-02 1995-05-30 Tenax Corporation Dry powder inhalator
US5705483A (en) 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
DE4422710C1 (de) 1994-06-29 1995-09-14 Boehringer Ingelheim Kg Inhalationsgerät mit einem Elektronikmodul zur Funktionsüberwachung
NZ277290A (en) 1993-12-18 1998-03-25 Merck Patent Gmbh Replacement cartridge for a powder inhalator has doses dispensed from helically arranged compartments
USD357603S (en) 1993-12-20 1995-04-25 Wolff Stephen H Base for displaying or holding items
US5415162A (en) 1994-01-18 1995-05-16 Glaxo Inc. Multi-dose dry powder inhalation device
US5484606A (en) 1994-01-24 1996-01-16 The Procter & Gamble Company Process for reducing the precipitation of difficulty soluble pharmaceutical actives
PT101450B (pt) 1994-02-02 1999-11-30 Hovione Produtos Farmaceuticos Novo dispositivo para inalacao
AU680727B2 (en) 1994-02-09 1997-08-07 Kinerton Limited Process for drying a material from solution
SE9400462D0 (sv) 1994-02-11 1994-02-11 Astra Ab Filling device
DK0748213T3 (da) 1994-03-07 2004-08-02 Nektar Therapeutics Fremgangsmåder og sammensætninger til pulmonal indgivelse af insulin
US6051256A (en) 1994-03-07 2000-04-18 Inhale Therapeutic Systems Dispersible macromolecule compositions and methods for their preparation and use
US5505194A (en) 1994-03-23 1996-04-09 Abbott Laboratories Aerosol inhalation device having slideably and rotatably connected elliptical cylinder portions
AU124387S (en) 1994-03-25 1995-08-11 Astra Ab Training device for an inhaler
US5839429A (en) 1994-03-25 1998-11-24 Astra Aktiebolag Method and apparatus in connection with an inhaler
ATE156677T1 (de) 1994-04-15 1997-08-15 Fissler Gmbh Gar- und/oder kochgerät, welches für eine bodenseitige zuführung von wärmeenergie durch wärmeleitung oder durch elektromagnetische induktion eingerichtet ist
US6395744B1 (en) 1994-04-22 2002-05-28 Queen's University At Kingston Method and compositions for the treatment or amelioration of female sexual dysfunction
FI942196A (fi) 1994-05-11 1995-11-12 Orion Yhtymae Oy Jauheinhalaattori
CA2190502A1 (en) 1994-05-18 1995-11-23 Robert M. Platz Methods and compositions for the dry powder formulation of interferons
WO1995031979A1 (en) 1994-05-19 1995-11-30 R.P. Scherer International Corporation Solutions of aryl or heteroaryl substituted alkanoic acids in lipophilic solvents and soft gelatin capsules containing such solutions
JP3372105B2 (ja) 1994-05-26 2003-01-27 株式会社日立ユニシアオートモティブ 吸入式投薬器
FR2720943B1 (fr) * 1994-06-09 1996-08-23 Applic Transferts Technolo Emulsions inverses stables à forte concentration en composé(s) fluoré(s) et leur utilisation pour l'administration pulmonaire de médicaments et pour la fabrication d'émulsions multiples.
US5483954A (en) 1994-06-10 1996-01-16 Mecikalski; Mark B. Inhaler and medicated package
IL110024A (en) 1994-06-15 1998-04-05 Yissum Res Dev Co Controlled release oral drug delivery system containing hydrogel- forming polymer
USD363775S (en) 1994-06-21 1995-10-31 Rhone-Poulenc Rorer Limited Multidose dry powder inhaler
USD362500S (en) 1994-06-28 1995-09-19 Thayer Medical Corporation Medication inhaler spacer
US5641510A (en) 1994-07-01 1997-06-24 Genentech, Inc. Method for treating capsules used for drug storage
US6039208A (en) 1994-07-29 2000-03-21 Ortho Pharmaceutical Corporation Variable day start tablet dispenser
US5562231A (en) 1994-07-29 1996-10-08 Ortho Pharmaceutical Corporation Variable day start tablet dispenser
US5623724A (en) 1994-08-09 1997-04-22 Northrop Grumman Corporation High power capacitor
GB9416884D0 (en) 1994-08-20 1994-10-12 Danbiosyst Uk Drug delivery compositions
USD359153S (en) 1994-08-25 1995-06-13 Viggiano Bernard J Muffin top
US5574008A (en) 1994-08-30 1996-11-12 Eli Lilly And Company Biologically active fragments of glucagon-like insulinotropic peptide
US5547929A (en) 1994-09-12 1996-08-20 Eli Lilly And Company Insulin analog formulations
ES2302332T3 (es) 1994-09-21 2008-07-01 Nektar Therapeutics Aparato y metodos para dispersar medicamentos en polvo seco.
FR2725626A1 (fr) 1994-10-18 1996-04-19 Sofab Dispositif pour l'inhalation de produits en poudre
AU4010395A (en) * 1994-10-27 1996-05-23 Amgen, Inc. Compositions for increased bioavailability of orally delivered therapeutic agents
SE9404140D0 (sv) 1994-11-29 1994-11-29 Astra Ab Dose indicating device
WO1996016947A1 (fr) 1994-12-01 1996-06-06 Toyama Chemical Co., Ltd. Nouveau derive de 2,3-dicetopiperazine ou sel de celui-ci
SE9404439D0 (sv) 1994-12-21 1994-12-21 Astra Ab Inhalation device
AR002009A1 (es) 1994-12-22 1998-01-07 Astra Ab Composicion farmaceutica, procedimiento para la manufactura de un polvo de proliposoma como el utilizado en dicha composicion, procedimiento para lamanufactura de dicha composicion, uso de dicha composicion farmaceutica en la manufactura de un medicamento y dispositivo inhalador de polvo seco.
US6485726B1 (en) 1995-01-17 2002-11-26 The Brigham And Women's Hospital, Inc. Receptor specific transepithelial transport of therapeutics
PT805696E (pt) 1995-01-23 2000-08-31 Direct Haler A S Inalador
USD368364S (en) 1995-02-02 1996-04-02 Reitano Joseph R Inhaler case
US5901703A (en) 1995-02-06 1999-05-11 Unisia Jecs Corporation Medicine administering device for nasal cavities
US5660835A (en) 1995-02-24 1997-08-26 East Carolina University Method of treating adenosine depletion
JPH11501892A (ja) 1995-03-10 1999-02-16 ミネソタ マイニング アンド マニュファクチャリング カンパニー エアロゾルバルブ
US5653961A (en) 1995-03-31 1997-08-05 Minnesota Mining And Manufacturing Company Butixocort aerosol formulations in hydrofluorocarbon propellant
US5542539A (en) 1995-04-04 1996-08-06 Ethicon Endo-Surgery, Inc. Container for quick release packages for surgical instruments
USD377215S (en) 1995-04-13 1997-01-07 Glaxo Group Limited Inhaler
US6309671B1 (en) 1995-04-14 2001-10-30 Inhale Therapeutic Systems Stable glassy state powder formulations
US5990077A (en) 1995-04-14 1999-11-23 1149336 Ontario Inc. Glucagon-like peptide-2 and its therapeutic use
US5645051A (en) 1995-04-21 1997-07-08 Dura Pharmaceuticals, Inc. Unit dose dry powder inhaler
US5921237A (en) 1995-04-24 1999-07-13 Dura Pharmaceuticals, Inc. Dry powder inhaler
US5622166A (en) 1995-04-24 1997-04-22 Dura Pharmaceuticals, Inc. Dry powder inhaler delivery system
US6428771B1 (en) 1995-05-15 2002-08-06 Pharmaceutical Discovery Corporation Method for drug delivery to the pulmonary system
US5922253A (en) 1995-05-18 1999-07-13 Alkermes Controlled Therapeutics, Inc. Production scale method of forming microparticles
US5809997A (en) 1995-05-18 1998-09-22 Medtrac Technologies, Inc. Electronic medication chronolog device
US5924419A (en) 1995-05-22 1999-07-20 Kotliar; Igor K. Apparatus for passive hypoxic training and therapy
DE19519840A1 (de) 1995-05-31 1996-12-05 Kaewert Klaus Gelantinekapsel
AU128811S (en) 1995-06-06 1996-12-03 Orion Yhtymae Oy A protective cover for example a moisture protective cover for a powder inhaler
US5714007A (en) 1995-06-06 1998-02-03 David Sarnoff Research Center, Inc. Apparatus for electrostatically depositing a medicament powder upon predefined regions of a substrate
US5641861A (en) 1995-06-07 1997-06-24 Torrey Pines Institute For Molecular Studies μopioid receptor ligands: agonists and antagonists
US5610271A (en) 1995-06-07 1997-03-11 Torrey Pines Institute For Molecular Studies Kappa receptor selective opioid peptides
US5919897A (en) 1995-06-07 1999-07-06 Torrey Pines Institute For Molecular Studies MU opioid receptor ligands: agonists and antagonists
US6193844B1 (en) 1995-06-07 2001-02-27 Mclaughlin John R. Method for making paper using microparticles
US5824345A (en) 1995-06-07 1998-10-20 Emisphere Technologies, Inc. Fragrances and flavorants
US6357442B1 (en) 1995-06-08 2002-03-19 Innovative Devices, Llc Inhalation actuated device for use with metered dose inhalers (MDIS)
US6672304B1 (en) 1995-06-08 2004-01-06 Innovative Devices, Llc Inhalation actuated device for use with metered dose inhalers (MDIs)
SI9620081B (en) 1995-06-21 2001-06-30 Asta Medica Ag Pharmaceutical powder cartridge with integrated metering device and inhaler for powdered medicaments
GB9513218D0 (en) 1995-06-29 1995-09-06 Fisons Plc Inhalation device and method
DE19523516C1 (de) 1995-06-30 1996-10-31 Asta Medica Ag Inhalator zum Verabreichen von Medikamenten aus Blisterpackungen
AU131838S (en) 1995-07-01 1997-10-21 Glaxo Group Ltd Inhalation device
JP3098401B2 (ja) 1995-07-12 2000-10-16 株式会社エルティーティー研究所 経鼻投与用製剤
US5758638A (en) 1995-07-24 1998-06-02 Kreamer; Jeffry W. Indicator for a medicament inhaler
US5642727A (en) 1995-07-25 1997-07-01 David Sarnoff Research Center, Inc. Inhaler apparatus using a tribo-electric charging technique
WO1997004747A1 (en) 1995-07-27 1997-02-13 Dunn James M Drug delivery systems for macromolecular drugs
US6209538B1 (en) 1995-08-02 2001-04-03 Robert A. Casper Dry powder medicament inhalator having an inhalation-activated flow diverting means for triggering delivery of medicament
SE9502799D0 (sv) 1995-08-10 1995-08-10 Astra Ab Device in inhalers
SE9502800D0 (sv) 1995-08-10 1995-08-10 Astra Ab Disposable inhaler
JP3317823B2 (ja) 1995-08-11 2002-08-26 株式会社ユニシアジェックス 投薬器
US5746197A (en) 1995-08-18 1998-05-05 Williams; Jeffery W. Extension for metered dose inhaler
US5690910A (en) 1995-08-18 1997-11-25 Baker Norton Pharmaceuticals, Inc. Method for treating asthma
US5980865A (en) 1995-08-18 1999-11-09 Baker Norton Pharmaceuticals, Inc. Method for treating late phase allergic reactions and inflammatory diseases
US6852690B1 (en) 1995-08-22 2005-02-08 Amylin Pharmaceuticals, Inc. Method and composition for enhanced parenteral nutrition
FR2738153B1 (fr) 1995-09-04 1998-01-02 Valois Appareil d'inhalation destine a distribuer des doses precises et reproductibles de produit pulverulent
US5617844A (en) 1995-09-21 1997-04-08 King; Russell W. Aerosol medication delivery system
KR0124764Y1 (ko) 1995-09-23 1998-09-15 양주환 의약 및 식품용 하드 공 캅셀
SE9503344D0 (sv) 1995-09-27 1995-09-27 Astra Ab Inhalation device
US5766620A (en) 1995-10-23 1998-06-16 Theratech, Inc. Buccal delivery of glucagon-like insulinotropic peptides
US5849322A (en) 1995-10-23 1998-12-15 Theratech, Inc. Compositions and methods for buccal delivery of pharmaceutical agents
DK0861089T3 (da) 1995-11-13 2002-10-07 Medtronic Minimed Inc Metoder og sammensætninger til indgivelse af monomere proteiner
DE19545257A1 (de) 1995-11-24 1997-06-19 Schering Ag Verfahren zur Herstellung von morphologisch einheitlichen Mikrokapseln sowie nach diesem Verfahren hergestellte Mikrokapseln
DE59605366D1 (de) 1995-12-07 2000-07-06 Jago Pharma Ag Muttenz Inhalator zur mehrfachen dosisweisen abgabe eines pharmakologischen trockenpulvers
US7131441B1 (en) 1995-12-07 2006-11-07 Skyepharma Ag Inhaler for multiple dosed administration of a pharmacological dry powder
JP2000503565A (ja) 1996-01-03 2000-03-28 グラクソ、グループ、リミテッド 吸入装置
US6026809A (en) 1996-01-25 2000-02-22 Microdose Technologies, Inc. Inhalation device
US6470884B2 (en) 1996-01-29 2002-10-29 Aventis Pharma Limited Capsule opening arrangement for use in a powder inhaler
JPH09208485A (ja) 1996-01-31 1997-08-12 Teijin Ltd ペプチド・蛋白質性薬物の水難溶性組成物
EP0880562B1 (en) 1996-02-06 2000-12-06 E.I. Du Pont De Nemours And Company Treatment of deagglomerated particles with plasma-activated species
USD381416S (en) 1996-02-08 1997-07-22 Astra Aktiebolag Unit dose inhaler
USD377861S (en) 1996-02-21 1997-02-11 Medport, Inc. Inhaler carrying case
NZ331361A (en) 1996-02-21 2000-01-28 Schering Corp Powder inhaler including swirl means for changing the flow direction of the powder and chimney means for reversing the flow direction
KR100568436B1 (ko) 1996-02-27 2007-04-25 데이진 가부시키가이샤 분말상경비투여조성물
US6509313B1 (en) 1996-02-28 2003-01-21 Cornell Research Foundation, Inc. Stimulation of immune response with low doses of cytokines
US5699789A (en) 1996-03-11 1997-12-23 Hendricks; Mark R. Dry powder inhaler
JP3328132B2 (ja) 1996-03-21 2002-09-24 株式会社ユニシアジェックス 吸入式投薬器
GB9606188D0 (en) 1996-03-23 1996-05-29 Danbiosyst Uk Pollysaccharide microspheres for the pulmonary delivery of drugs
USD395499S (en) 1996-04-08 1998-06-23 Dura Pharmaceuticals, Inc. Dry powder inhaler
US5875776A (en) 1996-04-09 1999-03-02 Vivorx Pharmaceuticals, Inc. Dry powder inhaler
US5858099A (en) 1996-04-09 1999-01-12 Sarnoff Corporation Electrostatic chucks and a particle deposition apparatus therefor
ES2205210T3 (es) 1996-04-29 2004-05-01 Quadrant Technologies Ltd. Procedimientos de inhalacion de polvos secos.
US5817343A (en) 1996-05-14 1998-10-06 Alkermes, Inc. Method for fabricating polymer-based controlled-release devices
AU132977S (en) 1996-05-17 1998-02-17 Astrazeneca Ab Container for inhaling apparatus
US5985309A (en) 1996-05-24 1999-11-16 Massachusetts Institute Of Technology Preparation of particles for inhalation
USRE37053E1 (en) 1996-05-24 2001-02-13 Massachusetts Institute Of Technology Particles incorporating surfactants for pulmonary drug delivery
US5874064A (en) * 1996-05-24 1999-02-23 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US6503480B1 (en) 1997-05-23 2003-01-07 Massachusetts Institute Of Technology Aerodynamically light particles for pulmonary drug delivery
US6254854B1 (en) 1996-05-24 2001-07-03 The Penn Research Foundation Porous particles for deep lung delivery
JPH1053765A (ja) 1996-06-04 1998-02-24 Denso Corp スメクチック液晶組成物及び液晶セル
JP2000512280A (ja) 1996-06-05 2000-09-19 ラポポート，バジル ヒト甲状腺刺激ホルモンレセプター組成物およびその使用
US5871010A (en) 1996-06-10 1999-02-16 Sarnoff Corporation Inhaler apparatus with modified surfaces for enhanced release of dry powders
AUPO066096A0 (en) 1996-06-26 1996-07-18 Peptide Delivery Systems Pty Ltd Oral delivery of peptides
US5769276A (en) 1996-07-10 1998-06-23 Terronics Development Corporation Powder atomizer
US5783556A (en) 1996-08-13 1998-07-21 Genentech, Inc. Formulated insulin-containing composition
AU133903S (en) 1996-08-19 1998-05-29 Orion Yhtymae Oy Inhaler device
US6006753A (en) 1996-08-30 1999-12-28 Eli Lilly And Company Use of GLP-1 or analogs to abolish catabolic changes after surgery
US6277819B1 (en) 1996-08-30 2001-08-21 Eli Lilly And Company Use of GLP-1 or analogs in treatment of myocardial infarction
JP3890099B2 (ja) 1996-09-30 2007-03-07 キヤノン株式会社 パターン認識装置及びその方法、及びそのプログラムを記憶した記憶媒体
JP3020141B2 (ja) 1996-10-07 2000-03-15 株式会社富士薬品 経鼻投与用製剤
US6532437B1 (en) 1996-10-23 2003-03-11 Cornell Research Foundation, Inc. Crystalline frap complex
UA65549C2 (uk) 1996-11-05 2004-04-15 Елі Ліллі Енд Компані Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція
US6441172B1 (en) 1996-11-07 2002-08-27 Torrey Pines Institute For Molecular Studies Diketodiazacyclic compounds, diazacyclic compounds and combinatorial libraries thereof
ATE366584T1 (de) 1996-11-12 2007-08-15 Novo Nordisk As Verwendung von glp-1 peptiden
DE19647947A1 (de) 1996-11-20 1998-05-28 Pfeiffer Erich Gmbh & Co Kg Austragvorrichtung für Medien
US5868774A (en) 1996-11-21 1999-02-09 Reil; Vladimir Unique cartridge and earring stud gun system
US6159360A (en) 1996-11-22 2000-12-12 Heinkel Industriezentrifugen Gmbh & Co. Invertible filter centrifuge including a solids drier
ATE215403T1 (de) 1996-12-11 2002-04-15 Earth Sciences Ltd Verfahren und vorrichtung zur verarbeitung und behandlung von partikelförmigem material
USD390651S (en) 1996-12-12 1998-02-10 Inhale Therapeutics Systems Medicament inhaler housing
GB9626233D0 (en) 1996-12-18 1997-02-05 Chawla Brinda P S Medicament packaging and deliveery device
GB9626263D0 (en) 1996-12-18 1997-02-05 Innovata Biomed Ltd Powder inhaler
GB2320489A (en) 1996-12-20 1998-06-24 Norton Healthcare Ltd Inhaler dose counter
AU6014098A (en) 1996-12-31 1998-07-31 Inhale Therapeutic Systems Aerosolized hydrophobic drug
USD397435S (en) 1997-01-03 1998-08-25 GGU Gesellschaft fuer Gesundheits-und Umweltforschung mbH Combined inhaler and cover
US5794613A (en) 1997-01-09 1998-08-18 Sepracor, Inc. Multiple-dose dispenser for dry powder inhalers
USD389238S (en) 1997-01-24 1998-01-13 Healthscan Products, Inc. Inhaler mask
US6884435B1 (en) * 1997-01-30 2005-04-26 Chiron Corporation Microparticles with adsorbent surfaces, methods of making same, and uses thereof
DE69829139T2 (de) 1997-01-30 2006-04-06 Hitachi, Ltd. Medikator vom ansaugtyp
SE9700423D0 (sv) 1997-02-07 1997-02-07 Astra Ab Disposable inhaler
SE9700422D0 (sv) 1997-02-07 1997-02-07 Astra Ab Single dose inhaler II
SE9700424D0 (sv) 1997-02-07 1997-02-07 Astra Ab Powder inhaler
SE9700421D0 (sv) 1997-02-07 1997-02-07 Astra Ab Single dose inhaler I
JP3011898B2 (ja) 1997-02-20 2000-02-21 フォルテ グロウ メディカル株式会社 吸引器
DE19708406A1 (de) 1997-03-03 1998-09-10 Alfred Von Schuckmann Gerät zur dosierten Ausgabe von Substanzen
USD390653S (en) 1997-03-04 1998-02-10 Blasdell Richard J Inhaler
SE9700935D0 (sv) 1997-03-14 1997-03-14 Astra Ab Inhalation device
SE9700937D0 (sv) 1997-03-14 1997-03-14 Astra Ab Powder inhaler I
SE9700936D0 (sv) 1997-03-14 1997-03-14 Astra Ab Inhalation device
SE9700948D0 (sv) 1997-03-14 1997-03-14 Astra Ab Powder inhaler X
SE9700938D0 (sv) 1997-03-14 1997-03-14 Astra Ab Powder inhaler II and a method of construction thereof
SE9700940D0 (sv) 1997-03-14 1997-03-14 Astra Ab Powder inhaler IV
TW469832U (en) 1997-03-14 2001-12-21 Astra Ab Inhalation device
SE9700943D0 (sv) 1997-03-14 1997-03-14 Astra Ab Powder inhaler V
US6006747A (en) 1997-03-20 1999-12-28 Dura Pharmaceuticals, Inc. Dry powder inhaler
US6043214A (en) 1997-03-20 2000-03-28 Novo Nordisk A/S Method for producing powder formulation comprising an insulin
US8391104B2 (en) 1997-03-28 2013-03-05 Carlos De La Huerga Interactive medication container labeling
US5904139A (en) 1997-03-28 1999-05-18 Hauser; Stephen G. Breath coordinated inhaler
JP2002510193A (ja) 1997-03-31 2002-04-02 イーライ・リリー・アンド・カンパニー グルカゴン様ペプチド−１類似体
US6155423A (en) 1997-04-01 2000-12-05 Cima Labs Inc. Blister package and packaged tablet
TR199903240T2 (xx) 1997-04-02 2000-05-22 Purdue Research Foundation A��z yoluyla proteinlerin verilmesi i�in y�ntem
PT101988B (pt) 1997-04-04 2004-02-27 Hovione Farmaciencia Sa Sistema de orientacao e posicionamento de um objecto
USD410541S (en) 1997-06-30 1999-06-01 Novartis Ag Inhaler
SE9702796D0 (sv) 1997-07-25 1997-07-25 Pharmacia & Upjohn Ab A device at a pharmaceutical container or inhaler
CA2212430A1 (en) 1997-08-07 1999-02-07 George Volgyesi Inhalation device
GB2327895B (en) 1997-08-08 2001-08-08 Electrosols Ltd A dispensing device
US5855564A (en) 1997-08-20 1999-01-05 Aradigm Corporation Aerosol extrusion mechanism
US5846447A (en) 1997-08-26 1998-12-08 E. I. Du Pont De Nemours And Company Process for forming a dispersion of polytetrafluoroethylene
USD416085S (en) 1997-09-05 1999-11-02 Pharmacia & Upjohn Inhaler
USD417271S (en) 1997-09-10 1999-11-30 Medic-Aid Limited Drug delivery device
ATE273996T1 (de) 1997-09-12 2004-09-15 Pharis Biotec Gmbh Zusammensetzung zur therapie von diabetes mellitus und fettsucht
US5848589A (en) 1997-09-18 1998-12-15 Welnetz; Robert J. Altitude mask simulator
AU135340S (en) 1997-09-24 1998-10-12 Innovata Biomed Ltd An inhaler
US6394085B1 (en) 1997-09-25 2002-05-28 Norton Healthcare Ltd. Inhaler spacer
US6073629A (en) 1997-09-25 2000-06-13 Norton Healthcare Ltd. Inhaler spacer
USD463544S1 (en) 1997-09-26 2002-09-24 1263152 Ontario Inc. Aerosol medication delivery inhaler
US6565885B1 (en) 1997-09-29 2003-05-20 Inhale Therapeutic Systems, Inc. Methods of spray drying pharmaceutical compositions
ES2293875T3 (es) 1997-10-01 2008-04-01 Novadel Pharma Inc. Aerosol bucal no polar.
US6228394B1 (en) 1997-10-14 2001-05-08 Boehringer Ingelheim Pharmaceuticals, Inc. Supercritical fluid extraction of mould lubricant from hard shell capsules
NZ504021A (en) 1997-10-17 2003-04-29 Systemic Pulmonary Delivery Lt Method and apparatus for delivering aerosolized medication having air discharged through air tube directly into plume of aerosolized medication
USD398992S (en) 1997-10-21 1998-09-29 Schering-Plough Healthcare Products, Inc. Nasal inhaler
ZA989744B (en) 1997-10-31 2000-04-26 Lilly Co Eli Method for administering acylated insulin.
IN188720B (zh) 1997-11-06 2002-11-02 Panacea Biotec Ltd
AU135120S (en) 1997-11-14 1998-09-21 Astrazeneca Ab Inhaler
SE9704184D0 (sv) 1997-11-14 1997-11-14 Astra Ab Inhalation device
USD412978S (en) 1997-12-02 1999-08-17 Dura Pharmaceuticals, Inc. Inhaler
US6116238A (en) 1997-12-02 2000-09-12 Dura Pharmaceuticals, Inc. Dry powder inhaler
USD418600S (en) 1997-12-04 2000-01-04 Charmaine Haerle Inhaler clip
EP1049486A4 (en) 1997-12-05 2006-01-04 Lilly Co Eli GLP-1 FORMULATIONS
US6192876B1 (en) 1997-12-12 2001-02-27 Astra Aktiebolag Inhalation apparatus and method
US6380357B2 (en) 1997-12-16 2002-04-30 Eli Lilly And Company Glucagon-like peptide-1 crystals
US5965701A (en) 1997-12-23 1999-10-12 Ferring Bv Kappa receptor opioid peptides
US6077940A (en) 1997-12-24 2000-06-20 Genentech, Inc. Free solution ligand interaction molecular separation method
US6358058B1 (en) 1998-01-30 2002-03-19 1263152 Ontario Inc. Aerosol dispensing inhaler training device
JP3530004B2 (ja) 1998-02-06 2004-05-24 株式会社日立ユニシアオートモティブ 吸入式投薬器
US6158431A (en) 1998-02-13 2000-12-12 Tsi Incorporated Portable systems and methods for delivery of therapeutic material to the pulmonary system
USD421800S (en) 1998-02-19 2000-03-21 Pierre Fabre Medicament Powder and compressed-air inhaler
USD412979S (en) 1998-02-27 1999-08-17 Diemolding Corporation Metered dose inhaler spacer
US7143764B1 (en) 1998-03-13 2006-12-05 Astrazeneca Ab Inhalation device
PL343276A1 (en) 1998-03-16 2001-08-13 Inhale Therapeutic Syst Aerosolized active agent delivery
US6998387B1 (en) 1998-03-19 2006-02-14 Amylin Pharmaceuticals, Inc. Human appetite control by glucagon-like peptide receptor binding compounds
SE9801078D0 (sv) 1998-03-27 1998-03-27 Shl Medical Ab Inhalator
AU138848S (en) 1998-03-30 1999-11-22 Astra Ab Inhaler with cap
AU138849S (en) 1998-03-30 1999-11-22 Astra Ab Inhaler with cap
AU138847S (en) 1998-03-30 1999-11-22 Astra Ab Inhaler with cap
IL138687A0 (en) 1998-04-08 2001-10-31 Lilly Co Eli Pulmonary and nasal delivery of raloxifene
CA2340340A1 (en) 1998-04-09 1999-10-21 Axiva Gmbh Particulate excipients for pulmonary administration
FR2777283B1 (fr) 1998-04-10 2000-11-24 Adir Nouveaux composes peptidiques analogues du glucagon-peptide- 1 (7-37), leur procede de preparation et les compositions pharmaceutiques qui les contiennent
US6578571B1 (en) 1998-04-20 2003-06-17 Infamed Ltd. Drug delivery device and methods therefor
GB9810126D0 (zh) 1998-05-13 1998-07-08 Glaxo Group Ltd
US6257233B1 (en) 1998-06-04 2001-07-10 Inhale Therapeutic Systems Dry powder dispersing apparatus and methods for their use
SE9802080D0 (sv) 1998-06-11 1998-06-11 Hellstroem Pharmaceutical composition for the treatment of functional dyspepsia and/or irritable bowel syndrome and new use of substances therein
TR200100079T2 (tr) 1998-06-12 2001-06-21 Bionebraska, Inc. Glikoza karşı ß-hücre tepkisini arttıran glukagon benzeri peptid-1
US6152130A (en) 1998-06-12 2000-11-28 Microdose Technologies, Inc. Inhalation device with acoustic control
USD412572S (en) 1998-06-19 1999-08-03 Gray Gene W Nasal inhaler adaptor for left and right nostril
EP1089783B1 (de) 1998-06-22 2004-09-29 AstraZeneca AB Vorrichtung zum leersaugen pulverenthaltender kavitäten
CA2336682C (en) * 1998-07-07 2006-10-10 Transdermal Technologies, Inc. Compositions for rapid and non-irritating transdermal delivery of pharmaceutically active agents and methods for formulating such compositions and delivery thereof
DE19831525A1 (de) 1998-07-14 2000-01-20 Pfeiffer Erich Gmbh & Co Kg Spender für Medien
US6703381B1 (en) 1998-08-14 2004-03-09 Nobex Corporation Methods for delivery therapeutic compounds across the blood-brain barrier
US6087334A (en) 1998-08-21 2000-07-11 Amylin Pharmaceuticals, Inc. Anti-diabetic peptides
CN1160127C (zh) 1998-08-26 2004-08-04 帝人株式会社 粉状经鼻组合物
WO2000012116A1 (en) 1998-08-28 2000-03-09 Eli Lilly And Company Method for administering insulinotropic peptides
US6720407B1 (en) 1998-08-28 2004-04-13 Eli Lilly And Company Method for administering insulinotropic peptides
US20020088458A1 (en) 1998-09-24 2002-07-11 Astrazeneca Ab Inhaler
CN1320056A (zh) 1998-09-24 2001-10-31 阿斯特拉曾尼卡有限公司 吸入器
GB9820886D0 (en) 1998-09-26 1998-11-18 Glaxo Group Ltd Inhalation device
GB9820937D0 (en) 1998-09-26 1998-11-18 Glaxo Group Ltd Inhalation device
US6187291B1 (en) 1998-09-28 2001-02-13 Robert Weinstein Method and device for facilitating combined aerosol and oral treatments for diabetes mellitus
USD411005S (en) 1998-09-29 1999-06-15 Pharmadesign Inc. Arthritic aid for metered dose inhaler
UA73924C2 (en) 1998-10-09 2005-10-17 Nektar Therapeutics Device for delivering active agent formulation to lungs of human patient
US6279511B1 (en) 1998-10-23 2001-08-28 Instech Laboratories, Inc. Powered multichannel infusion and monitoring system
US6263871B1 (en) 1998-10-29 2001-07-24 Richard I. Brown Mouthpiece with coupler
US6235725B1 (en) 1998-10-30 2001-05-22 Baker Norton Pharmaceuticals, Inc. Methods and compositions for the prevention of tolerance to medications
JP3747134B2 (ja) 1998-11-04 2006-02-22 キヤノン株式会社 インクジェット記録ヘッドカートリッジの保管容器
US6261594B1 (en) 1998-11-25 2001-07-17 The University Of Akron Chitosan-based nitric oxide donor compositions
US6540672B1 (en) 1998-12-09 2003-04-01 Novo Nordisk A/S Medical system and a method of controlling the system for use by a patient for medical self treatment
GB9827145D0 (en) 1998-12-09 1999-02-03 Co Ordinated Drug Dev Improvements in or relating to powders
US6375975B1 (en) 1998-12-21 2002-04-23 Generex Pharmaceuticals Incorporated Pharmaceutical compositions for buccal and pulmonary application
US6552024B1 (en) 1999-01-21 2003-04-22 Lavipharm Laboratories Inc. Compositions and methods for mucosal delivery
SE9900215D0 (sv) 1999-01-26 1999-01-26 Pharmacia & Upjohn Ab New use
JP2000217917A (ja) 1999-01-27 2000-08-08 Unisia Jecs Corp 吸入式投薬器
US6248363B1 (en) 1999-11-23 2001-06-19 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
ATE363892T1 (de) 1999-03-05 2007-06-15 Chiesi Farma Spa Verbesserte pulverformulierungen zur inhalation
IT1309592B1 (it) 1999-03-05 2002-01-24 Chiesi Farma Spa Particelle veicolo modificate da utilizzarsi nella preparazione diformulazioni farmaceutiche sotto forma di polimeri per inalazione e
US6632258B1 (en) 1999-03-16 2003-10-14 The United States Of America As Represented By The United States Department Of Energy Coal beneficiation by gas agglomeration
US6803044B1 (en) 1999-03-24 2004-10-12 Zengen, Inc. Antimicrobial and anti-inflammatory peptides for use in human immunodeficiency virus
US6630169B1 (en) 1999-03-31 2003-10-07 Nektar Therapeutics Particulate delivery systems and methods of use
DK1165050T3 (da) 1999-04-05 2006-05-01 Mannkind Corp Fremgangsmåde til dannelse af fint pulver
USD441859S1 (en) 1999-04-06 2001-05-08 Istituto Biochimico Pavese Pharma S.P.A. Disposable dry-powder inhaler
CA2370506C (en) 1999-05-07 2008-04-15 Imerys Pigments, Inc. A method of treating an aqueous suspension of kaolin
US6417920B1 (en) 1999-05-11 2002-07-09 Shimadzu Corporation Particle size analyzer based on laser diffraction method
US6514500B1 (en) 1999-10-15 2003-02-04 Conjuchem, Inc. Long lasting synthetic glucagon like peptide {GLP-!}
GB9911388D0 (en) 1999-05-18 1999-07-14 Glaxo Group Ltd Dispenser
BR0010823A (pt) * 1999-05-20 2002-03-05 Pharmasol Gmbh Adjuvante de estabilidade, biocompatibilidade otimizada (sba) para realçar a resposta imune humoral e celular
US6395300B1 (en) 1999-05-27 2002-05-28 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
US7919119B2 (en) 1999-05-27 2011-04-05 Acusphere, Inc. Porous drug matrices and methods of manufacture thereof
DE19924277A1 (de) 1999-05-27 2000-11-30 Beiersdorf Ag Zubereitungen von Emulsionstyp W/O mit erhöhtem Wassergehalt mit einem Gehalt an mittelpolaren Lipiden und Siliconemulgatoren und gegebenenfalls kationischen Polymeren
EP1060741B1 (en) * 1999-06-14 2003-09-03 Baxter International Inc. Sustained release microspheres
US6644315B2 (en) 1999-06-18 2003-11-11 Saeed Ziaee Nasal mask
SE516826C2 (sv) 1999-06-18 2002-03-05 Shl Medical Ab Anordning i en inhalator med organ för aktivering och avaktivering av en kanister som svar på ett luftflöde
US7169889B1 (en) 1999-06-19 2007-01-30 Biocon Limited Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin
WO2000078333A2 (en) 1999-06-21 2000-12-28 Eli Lilly And Company Synergetic use of thiazolidinediones with glucagon-like peptide-1 and agonists thereof to treat non-insulin dependant diabetes
US6858199B1 (en) 2000-06-09 2005-02-22 Advanced Inhalation Research, Inc. High efficient delivery of a large therapeutic mass aerosol
GB2353222B (en) 1999-06-23 2001-09-19 Cambridge Consultants Inhalers
USD444226S1 (en) 1999-06-24 2001-06-26 Novo Nordisk A/S Inhaler
WO2001000654A2 (en) * 1999-06-29 2001-01-04 Pharmaceutical Discovery Corporation Purification and stabilization of peptide and proteins in pharmaceutical agents
US9006175B2 (en) 1999-06-29 2015-04-14 Mannkind Corporation Potentiation of glucose elimination
US6606992B1 (en) 1999-06-30 2003-08-19 Nektar Therapeutics Systems and methods for aerosolizing pharmaceutical formulations
ITMI991582A1 (it) 1999-07-16 2001-01-16 Chiesi Farma Spa Polveri costituite da particelle aventi la superficie perfettamente levigata da utilizzare come veicoli per la preparazione di miscele inala
IL147756A (en) 1999-07-22 2005-12-18 Aventis Pharma Inc Preserved pharmaceutical formulations
US7305986B1 (en) 1999-07-23 2007-12-11 Mannkind Corporation Unit dose capsules for use in a dry powder inhaler
DE60030862T2 (de) 1999-07-23 2007-09-06 Mannkind Corp., Valencia Trockenpulverinhalator
US7464706B2 (en) 1999-07-23 2008-12-16 Mannkind Corporation Unit dose cartridge and dry powder inhaler
US20010036481A1 (en) 1999-08-25 2001-11-01 Advanced Inhalation Research, Inc. Modulation of release from dry powder formulations
CN1175961C (zh) 1999-09-17 2004-11-17 株式会社新王磁材 稀土合金的切割方法和切割装置
USD438612S1 (en) 1999-09-27 2001-03-06 G-Intek Co., Ltd. Snivel inhaler
DK1220700T3 (da) 1999-10-06 2003-08-04 Eckardt Angela Åndedrætskontrolleret inhalationsapparat til tørpulver
HU229310B1 (en) 1999-10-29 2013-10-28 Nektar Therapeutics Dry powder compositions having improved dispersivity
SE9903990D0 (sv) 1999-11-02 1999-11-02 Shl Medical Ab Inhalator with aerosolizing unit
GB9928311D0 (en) 1999-11-30 2000-01-26 Novartis Ag Organic compounds
IT1308581B1 (it) 1999-12-03 2002-01-08 Medel Italiana Srl Apparato per nebulizzare un liquido, in particolare per uso medico.
SE9904706D0 (sv) 1999-12-21 1999-12-21 Astra Ab An inhalation device
CO5270018A1 (es) 1999-12-11 2003-04-30 Glaxo Group Ltd Distribuidor de medicamento
US7022674B2 (en) 1999-12-16 2006-04-04 Eli Lilly And Company Polypeptide compositions with improved stability
US7204250B1 (en) 1999-12-16 2007-04-17 Compumedics Limited Bio-mask
DE19961300A1 (de) 1999-12-18 2001-06-21 Asta Medica Ag Vorratssystem für Arzneimittel in Pulverform und damit ausgestatteter Inhalator
US6669960B2 (en) 1999-12-21 2003-12-30 Rxkinetix, Inc. Particulate drug-containing products and method of manufacture
US7080642B2 (en) 1999-12-22 2006-07-25 3M Innovative Properties Company Refillable device with counting means
CN100333790C (zh) 1999-12-30 2007-08-29 希龙公司 含白细胞介素－2的药物组合物在制药中的应用
WO2001051071A2 (en) 2000-01-11 2001-07-19 Novo Nordisk A/S Transepithelial delivery of glp-1 derivatives
US6894026B1 (en) 2000-01-11 2005-05-17 Atossa Healthcare, Inc. Long-acting oxytocin analogues for the treatment and prevention of breast cancer and psychiatric disorders
DK1248594T3 (da) 2000-01-19 2006-02-06 Mannkind Corp Formulering med multi-spidsfrigivelse til indgivelse af lægemidler
US7833549B2 (en) 2000-01-19 2010-11-16 Mannkind Corporation Dry powder formulations of antihistamine for nasal administration
US6540983B1 (en) 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation
US6540982B1 (en) 2000-01-25 2003-04-01 Aeropharm Technology Incorporated Medical aerosol formulation
US6443307B1 (en) 2000-01-25 2002-09-03 Michael D. Burridge Medication dispenser with an internal ejector
EP1257577B1 (en) 2000-01-27 2004-04-21 Eli Lilly And Company Process for solubilizing glucagon-like peptide 1 (glp-1) compounds
US6427688B1 (en) 2000-02-01 2002-08-06 Dura Pharmaceuticals, Icn. Dry powder inhaler
US7171965B2 (en) 2000-02-01 2007-02-06 Valois S.A.S. Breath actuated dry powder inhaler and tape dose strip
USD439325S1 (en) 2000-02-08 2001-03-20 Baker Norton Pharmaceuticals, Inc. Cover for a nasal inhaler
EP1129705A1 (en) 2000-02-17 2001-09-05 Rijksuniversiteit te Groningen Powder formulation for inhalation
GB0004456D0 (en) 2000-02-26 2000-04-19 Glaxo Group Ltd Medicament dispenser
CA2401288A1 (en) 2000-02-28 2001-09-07 Vectura Limited Improvements in or relating to the delivery of oral drugs
USD439656S1 (en) 2000-03-06 2001-03-27 Astrazeneca Uk Limited Inhaler
US6443151B1 (en) 2000-03-08 2002-09-03 Aradigm Corporation Fluid velocity-sensitive trigger mechanism
EP1267969B1 (en) 2000-03-10 2007-07-04 University Of North Carolina At Chapel Hill Dry powder inhaler devices, multi-dose dry powder drug packages, control systems, and associated methods
US6608038B2 (en) 2000-03-15 2003-08-19 Novartis Ag Methods and compositions for treatment of diabetes and related conditions via gene therapy
GB2360218A (en) 2000-03-18 2001-09-19 Astrazeneca Uk Ltd Inhaler
US6823863B2 (en) 2000-03-18 2004-11-30 Astrazeneca Ab Inhaler
GB0006525D0 (en) 2000-03-18 2000-05-10 Astrazeneca Uk Ltd Inhaler
GB2360216A (en) 2000-03-18 2001-09-19 Astrazeneca Uk Ltd Inhaler
SE0000935D0 (sv) 2000-03-21 2000-03-21 Astrazeneca Ab An inhalation device
USD449684S1 (en) 2000-03-24 2001-10-23 Astrazeneca Ab Inhaler
US6432383B1 (en) 2000-03-30 2002-08-13 Generex Pharmaceuticals Incorporated Method for administering insulin
AU5173701A (en) 2000-04-03 2001-10-15 Iep Pharmaceutical Devices Inc Method for improving lung delivery of pharmaceutical aerosols
US6998137B2 (en) 2000-04-07 2006-02-14 Macromed, Inc. Proteins deposited onto sparingly soluble biocompatible particles for controlled protein release into a biological environment from a polymer matrix
DE60114393T2 (de) 2000-04-11 2006-04-27 Trudell Medical International, London Aerosolspender mit einer möglichkeit für positiven ausatemdruck
DE10019879A1 (de) 2000-04-20 2001-10-25 Degussa Verfahren zur Herstellung von 2,5-Diketopiperazinen, neue 2,5-Diketopiperazine und deren Verwendung
MY136453A (en) 2000-04-27 2008-10-31 Philip Morris Usa Inc "improved method and apparatus for generating an aerosol"
US6468507B1 (en) 2000-05-01 2002-10-22 Aeropharm Technology, Inc. Non-aqueous aerosol formulation comprising rosiglitazone maleate, a non-aqueous carrier, and an amino acid stabilizer
US6447750B1 (en) 2000-05-01 2002-09-10 Aeropharm Technology Incorporated Medicinal aerosol formulation
USD442685S1 (en) 2000-05-02 2001-05-22 Salter Labs Medication inhaler spacer
US20010039442A1 (en) 2000-05-06 2001-11-08 Sal Gorge Headache relief device
US6948494B1 (en) 2000-05-10 2005-09-27 Innovative Devices, Llc. Medicament container with same side airflow inlet and outlet and method of use
US20020000225A1 (en) 2000-06-02 2002-01-03 Carlos Schuler Lockout mechanism for aerosol drug delivery devices
CN1141974C (zh) 2000-06-07 2004-03-17 张昊 结肠定位释放的口服生物制剂
DK1695983T3 (da) 2000-06-16 2009-05-18 Lilly Co Eli Glucagon-lignende peptid-1 analoger
RU2181297C2 (ru) 2000-06-20 2002-04-20 Эпштейн Олег Ильич Способ лечения патологического синдрома и лекарственное средство
GB0015043D0 (en) 2000-06-21 2000-08-09 Glaxo Group Ltd Medicament dispenser
GB0015034D0 (en) 2000-06-21 2000-08-09 Glaxo Group Ltd Inhalation device
AR028746A1 (es) 2000-06-23 2003-05-21 Norton Health Care Ltd Cartucho de dosis previamente medidas para inhalador de polvo seco accionado por la respiracion, el inhalador y un metodo de provision de dosis previamente medidas de polvo seco
TWI224512B (en) 2000-06-23 2004-12-01 Norton Healthcare Ltd Reservoir pressure system for medicament inhaler
US6562807B2 (en) 2000-06-23 2003-05-13 Novo Nordisk A/S Glucagon antagonists/inverse agonists
PE20020067A1 (es) 2000-06-23 2002-02-05 Norton Healthcare Ltd Desaglomerador para inhalador de polvo seco accionado por la respiracion
USD450117S1 (en) 2000-06-29 2001-11-06 Innovata Biomed Limited Inhaler
USD452910S1 (en) 2000-06-29 2002-01-08 Innovata Biomend Limited Inhaler
AU6895801A (en) 2000-07-04 2002-01-14 Novo Nordisk As Heterocyclic compounds, which are inhibitors of the enzyme dpp-iv
US6363932B1 (en) 2000-07-06 2002-04-02 Clinical Technologies, Inc. Aerosol enhancement device
US6951215B1 (en) 2000-07-14 2005-10-04 Tufts University Drug delivery device for animals
US6360929B1 (en) 2000-07-17 2002-03-26 Mccarthy Madeleine Medicinal atomizing inhaler pouch/retainer
GB2364919A (en) 2000-07-21 2002-02-13 Cambridge Consultants Inhalers
SE516555C2 (sv) 2000-08-04 2002-01-29 Microdrug Ag Elektropulver
CA2774959C (en) 2000-08-04 2016-05-31 Dmi Biosciences, Inc. Method of using diketopiperazines and composition containing them
WO2002012201A1 (en) 2000-08-04 2002-02-14 Dmi Biosciences, Inc. Method of synthesizing diketopiperazines
BRPI0113042B8 (pt) 2000-08-05 2021-05-25 Glaxo Group Ltd composto da fórmula ou um seu solvato fisiologicamente aceitável, uso do mesmo, composição farmacêutica, formulação farmacêutica, método para o tratamento de um indivíduo humano ou animal com uma condição inflamatória e/ou alérgica, e, processo para preparar um composto ou um seu solvato
JP2004515467A (ja) 2000-08-07 2004-05-27 ネクター セラピューティックス 吸入可能な、噴霧乾燥した、最少の凝集物を有する４−ヘリックスバンドルタンパク質粉末
WO2002013897A2 (en) 2000-08-14 2002-02-21 Advanced Inhalation Research, Inc. Inhalation device and method
US6704255B2 (en) 2000-08-22 2004-03-09 Ricoh Company, Ltd. Lens actuator
US6514482B1 (en) 2000-09-19 2003-02-04 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
US6613308B2 (en) 2000-09-19 2003-09-02 Advanced Inhalation Research, Inc. Pulmonary delivery in treating disorders of the central nervous system
USD460173S1 (en) 2000-09-20 2002-07-09 P.A. Knowledge Limited Inhaler device
CA2422941A1 (en) 2000-09-20 2003-03-19 Franco Del Bon Inhalator and pertaining atomizer
SE517225C2 (sv) 2000-09-21 2002-05-14 Microdrug Ag Optimering av en elektrostatiskt doserad inhalator för torrt pulver
SE517226C2 (sv) 2000-09-25 2002-05-14 Microdrug Ag Inhalator med luftbroms för torrt pulver
SE517228C2 (sv) 2000-09-25 2002-05-14 Microdrug Ag Inhalator för torrt pulver med andningsaktivering
GB0023653D0 (en) 2000-09-27 2000-11-08 Cambridge Consultants Device for dispensing particulate material
WO2002026300A1 (en) 2000-09-29 2002-04-04 Pa Knowledge Limited Pressure-responsive means and associated method of manufacture
US6756062B2 (en) * 2000-11-03 2004-06-29 Board Of Regents University Of Texas System Preparation of drug particles using evaporation precipitation into aqueous solutions
ATE420630T1 (de) 2000-11-29 2009-01-15 Itoham Foods Inc Pulverzubereitungen und verfahren zu ihrer herstellung
GB0029562D0 (en) 2000-12-04 2001-01-17 Novartis Ag Organic compounds
USD455208S1 (en) 2000-12-05 2002-04-02 Clinical Designs Limited Inhaler
WO2002047716A2 (en) 2000-12-13 2002-06-20 Eli Lilly And Company Chronic treatment regimen using glucagon-like insulinotropic peptides
EP1351704B1 (en) 2000-12-21 2007-03-07 Nektar Therapeutics Storage stable powder compositions of interleukin-4 receptor
US7077130B2 (en) 2000-12-22 2006-07-18 Chrysalis Technologies Incorporated Disposable inhaler system
US6799572B2 (en) 2000-12-22 2004-10-05 Chrysalis Technologies Incorporated Disposable aerosol generator system and methods for administering the aerosol
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
US6626173B2 (en) 2001-01-08 2003-09-30 Iep Pharmaceutical Devices Inc. Dry powder inhaler
US6644309B2 (en) 2001-01-12 2003-11-11 Becton, Dickinson And Company Medicament respiratory delivery device and method
FI20010144A0 (fi) 2001-01-24 2001-01-24 Valtion Teknillinen Menetelmä ja laite aerosolilähteiden tutkimiseksi
AUPR272901A0 (en) * 2001-01-25 2001-02-22 Gainful Plan Limited Method of preparing biological materials and preparations produced using same
US20040022861A1 (en) 2001-01-30 2004-02-05 Williams Robert O. Process for production of nanoparticles and microparticles by spray freezing into liquid
WO2002067995A1 (en) 2001-02-26 2002-09-06 Council Of Scientific And Industrial Research Carrier systems comprising vitamin b12 - biodegradable micro particulate conju gates for peroral delivery of drugs, peptides/proteins and vaccines
EP1238680B1 (en) 2001-03-05 2003-12-10 Ivo Pera Inhaling device for dispersing powdered medicaments contained in a capsule through the respiratory tract
US6523536B2 (en) 2001-03-12 2003-02-25 Birdsong Medical Devices, Inc. Dual-canister inhaler having a spacer and easy to operate lever mechanism
US6698422B2 (en) 2001-03-12 2004-03-02 Birdsong Medical Devices, Inc. Canister inhaler having a spacer and easy to operate lever mechanism and a flexible, elastic mouthpiece
USD453264S1 (en) 2001-03-30 2002-02-05 Benjamin Acevedo, Jr. Pouch for medical inhaler
GB0108213D0 (en) 2001-04-02 2001-05-23 Glaxo Group Ltd Medicament dispenser
US6652838B2 (en) 2001-04-05 2003-11-25 Robert E. Weinstein Method for treating diabetes mellitus
SE0101233L (sv) 2001-04-05 2002-10-01 Microdrug Ag Förfarande och anordning för frigörande av pulver och inhalatoranordning för administrering av medicinskt pulver
AU2002254567B2 (en) 2001-04-11 2007-10-11 Bristol-Myers Squibb Company Amino acid complexes of C-aryl glucosides for treatment of diabetes and method
US6766799B2 (en) 2001-04-16 2004-07-27 Advanced Inhalation Research, Inc. Inhalation device
US6447751B1 (en) 2001-04-18 2002-09-10 Robert E. Weinstein Method and device for facilitating combined aerosol and oral treatments for diabetes mellitus
EP1387656B1 (en) 2001-04-19 2009-12-23 Technology Innovation Limited Medicament container
USD451597S1 (en) 2001-04-24 2001-12-04 G-Intek Co.,Ltd Snivel inhaler
US7232897B2 (en) 2001-04-24 2007-06-19 Harvard University, President And Fellows Of Harvard College Compositions and methods for modulating NH2-terminal Jun Kinase activity
JP4663906B2 (ja) 2001-04-26 2011-04-06 富士フイルム株式会社 セルロースアシレートフイルム
JP2005506855A (ja) 2001-05-10 2005-03-10 ベクトゥラ デリバリー デバイシーズ リミテッド 吸入器
NZ529572A (en) 2001-05-21 2006-02-24 Nektar Therapeutics Pulmonary administration of chemically modified insulin
SE0101825D0 (sv) 2001-05-22 2001-05-22 Astrazeneca Ab An Inhalation device
AU2002308706A1 (en) 2001-06-01 2002-12-16 Eli Lilly And Company Glp-1 formulations with protracted time action
US7035294B2 (en) 2001-06-04 2006-04-25 Calix Networks, Inc. Backplane bus
EG24184A (en) 2001-06-15 2008-10-08 Otsuka Pharma Co Ltd Dry powder inhalation system for transpulmonary
FI20011317A0 (fi) 2001-06-20 2001-06-20 Orion Corp Jauheinhalaattori
US20030010794A1 (en) 2001-06-22 2003-01-16 3M Innovative Properties Company Metering valve for a metered dose inhaler having improved flow
US6681768B2 (en) 2001-06-22 2004-01-27 Sofotec Gmbh & Co. Kg Powder formulation disintegrating system and method for dry powder inhalers
US6614197B2 (en) 2001-06-30 2003-09-02 Motorola, Inc. Odd harmonics reduction of phase angle controlled loads
DE10136555A1 (de) 2001-07-27 2003-02-13 Boehringer Ingelheim Int Optimierte Verfahren zur Bestimmung der Aerosol-Partikelgrößenverteilung und Vorrichtung zur Durchführung derartiger Verfahren
US7414720B2 (en) 2001-07-27 2008-08-19 Herbert Wachtel Measuring particle size distribution in pharmaceutical aerosols
GB0120018D0 (en) 2001-08-16 2001-10-10 Meridica Ltd Pack containing medicament and dispensing device
NZ531292A (en) 2001-08-22 2005-08-26 Aventis Pharma Gmbh Combination products of aryl-subsituted propanolamine derivatives with other active ingredients and the use thereof
HUP0501192A3 (en) 2001-08-23 2006-06-28 Lilly Co Eli Glucagon-like peptide-1 analogs
WO2003020201A2 (en) 2001-08-28 2003-03-13 Eli Lilly And Company Pre-mixes of glp-1 and basal insulin
GB0121709D0 (en) 2001-09-07 2001-10-31 Imp College Innovations Ltd Food inhibition agent
AU2002333644A1 (en) 2001-09-17 2003-04-01 Glaxo Group Limited Dry powder medicament formulations
CA2460904C (en) 2001-09-19 2011-03-22 Advent Pharmaceuticals Pty Ltd An inhaler for delivering metered doses of powdered medicament
US6640050B2 (en) 2001-09-21 2003-10-28 Chrysalis Technologies Incorporated Fluid vaporizing device having controlled temperature profile heater/capillary tube
US6568390B2 (en) 2001-09-21 2003-05-27 Chrysalis Technologies Incorporated Dual capillary fluid vaporizing device
AU2002340083A1 (en) 2001-09-28 2003-04-07 Kurve Technology, Inc Nasal nebulizer
WO2003030974A1 (en) 2001-10-08 2003-04-17 Eli Lilly And Company Portable medication inhalation kit
NZ532694A (en) 2001-10-16 2005-03-24 Internat Non Toxic Composites High density non-toxic composites comprising tungsten, another metal and polymer powder
USD461239S1 (en) 2001-10-18 2002-08-06 Anna L. Cassidy Inhaler sleeve with spring clip
US7179788B2 (en) 2001-10-19 2007-02-20 Eli Lilly And Company Biphasic mixtures of GLP-1 and insulin
WO2003035030A1 (en) 2001-10-24 2003-05-01 Pari Gmbh Kit for the preparation of a pharmaceutical composition
USD473298S1 (en) 2001-11-01 2003-04-15 Astrazeneca Ab Inhaler refill
DE60238864D1 (de) 2001-11-07 2011-02-17 Mankind Corp Für epitope von antigenen kodierende expressionsvektoren und verfahren zu deren konzeption
MXPA04005865A (es) 2001-12-19 2004-09-13 Nektar Therapeutics Suministro de aminoglucosidos a los pulmones.
US6994083B2 (en) 2001-12-21 2006-02-07 Trudell Medical International Nebulizer apparatus and method
GB0130857D0 (en) 2001-12-22 2002-02-06 Glaxo Group Ltd Medicament dispenser
USD469866S1 (en) 2002-01-07 2003-02-04 Aerogen, Inc. Inhaler for dispensing medication
US20030198666A1 (en) 2002-01-07 2003-10-23 Richat Abbas Oral insulin therapy
USD479745S1 (en) 2002-01-07 2003-09-16 Aerogen, Inc. Inhaler for dispensing medications
USD471273S1 (en) 2002-01-07 2003-03-04 Aerogen, Inc. Inhaler for dispensing medication
USD474536S1 (en) 2002-01-07 2003-05-13 Aerogen, Inc. Inhaler for dispensing medications
ITMI20020078A1 (it) 2002-01-16 2003-07-16 Fabrizio Niccolai Dispositivo utilizzabile nel tratamento di affezzioni delle vie respiratorie
US6991779B2 (en) 2002-01-18 2006-01-31 Mannkind Corporation Compositions for treatment or prevention of bioterrorism
US7105489B2 (en) 2002-01-22 2006-09-12 Amylin Pharmaceuticals, Inc. Methods and compositions for treating polycystic ovary syndrome
US7258118B2 (en) 2002-01-24 2007-08-21 Sofotec Gmbh & Co, Kg Pharmaceutical powder cartridge, and inhaler equipped with same
NZ534125A (en) 2002-02-20 2006-11-30 Emisphere Tech Inc A formulation comprising a GLP-1 compound and a delivery agent
US6591832B1 (en) 2002-02-21 2003-07-15 Saint-Gobain Calmar Inc. Dry powder dispenser
US6830149B2 (en) 2002-03-08 2004-12-14 Musculoskeletal Transplant Foundation Package with insert for holding allograft implant to preclude lipid transfer
US7008644B2 (en) 2002-03-20 2006-03-07 Advanced Inhalation Research, Inc. Method and apparatus for producing dry particles
EP1894591B1 (en) 2002-03-20 2013-06-26 MannKind Corporation Cartridge for an inhalation apparatus
UA80123C2 (en) 2002-04-09 2007-08-27 Boehringer Ingelheim Pharma Inhalation kit comprising inhalable powder of tiotropium
US20030235538A1 (en) 2002-04-09 2003-12-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Method for the administration of an anticholinergic by inhalation
US20030194420A1 (en) 2002-04-11 2003-10-16 Richard Holl Process for loading a drug delivery device
USD475133S1 (en) 2002-04-18 2003-05-27 Mcluckie Lynne E. Luminescent-colored inhaler
US7316748B2 (en) 2002-04-24 2008-01-08 Wisconsin Alumni Research Foundation Apparatus and method of dispensing small-scale powders
US6830046B2 (en) 2002-04-29 2004-12-14 Hewlett-Packard Development Company, L.P. Metered dose inhaler
US20040151059A1 (en) 2002-05-01 2004-08-05 Roberts Ii William Leroy Deagglomerator apparatus and method
USD478983S1 (en) 2002-05-01 2003-08-26 Chrysalis Technologies Incorporated Inhaler
WO2003094951A1 (en) 2002-05-07 2003-11-20 Novo Nordisk A/S Soluble formulations comprising insulin aspart and insulin detemir
US7998923B2 (en) * 2002-05-07 2011-08-16 The Regents Of The University Of California Bioactivation of particles
US6889690B2 (en) 2002-05-10 2005-05-10 Oriel Therapeutics, Inc. Dry powder inhalers, related blister devices, and associated methods of dispensing dry powder substances and fabricating blister packages
USD473640S1 (en) 2002-05-13 2003-04-22 Iep Pharmaceutical Devices Inc. Breath actuated inhaler
USD492769S1 (en) 2002-05-24 2004-07-06 Glaxosmithkline K.K. Lens for an inhaler
USD477665S1 (en) 2002-06-12 2003-07-22 Microdrug Ag Inhaler
US8003179B2 (en) 2002-06-20 2011-08-23 Alcan Packaging Flexible France Films having a desiccant material incorporated therein and methods of use and manufacture
AU154760S (en) 2002-06-20 2004-03-02 Astrazeneca Ab Inhaler
ES2638987T3 (es) 2002-06-28 2017-10-25 Civitas Therapeutics, Inc. Epinefrina inhalable
US20060003316A1 (en) 2002-07-15 2006-01-05 John Simard Immunogenic compositions derived from poxviruses and methods of using same
GB0217198D0 (en) 2002-07-25 2002-09-04 Glaxo Group Ltd Medicament dispenser
GB0217382D0 (en) 2002-07-26 2002-09-04 Pfizer Ltd Process for making orally consumable dosage forms
ES2359576T5 (es) 2002-07-31 2020-03-03 Chiesi Farm Spa Inhalador de polvo
USD489448S1 (en) 2002-07-31 2004-05-04 Advanced Inhalations Revolutions, Inc. Vaporization apparatus
US20080260838A1 (en) 2003-08-01 2008-10-23 Mannkind Corporation Glucagon-like peptide 1 (glp-1) pharmaceutical formulations
JP4828940B2 (ja) * 2002-08-01 2011-11-30 マンカインド コーポレイション 細胞輸送組成物およびこれらの使用
US20150283213A1 (en) 2002-08-01 2015-10-08 Mannkind Corporation Method for treating hyperglycemia with glp-1
US20040038865A1 (en) 2002-08-01 2004-02-26 Mannkind Corporation Cell transport compositions and uses thereof
DE10235168A1 (de) 2002-08-01 2004-02-12 Aventis Pharma Deutschland Gmbh Verfahren zur Reinigung von Preproinsulin
GB0315791D0 (en) 2003-07-07 2003-08-13 3M Innovative Properties Co Two component molded valve stems
US20040121964A1 (en) 2002-09-19 2004-06-24 Madar David J. Pharmaceutical compositions as inhibitors of dipeptidyl peptidase-IV (DPP-IV)
USD509296S1 (en) 2002-09-21 2005-09-06 Aventis Pharma Limited Inhaler
US7322352B2 (en) 2002-09-21 2008-01-29 Aventis Pharma Limited Inhaler
JP2004121061A (ja) * 2002-10-01 2004-04-22 Sanei Gen Ffi Inc 粉末組成物の製造方法
BR0306930A (pt) 2002-10-11 2004-11-09 Otsuka Pharma Co Ltd Inalador de pó
CN1176649C (zh) 2002-10-16 2004-11-24 上海医药工业研究院 舒马普坦干粉吸入剂及其制备方法
ITMO20020297A1 (it) 2002-10-16 2004-04-17 Roberto Oliva Inalatore per preparati monodose in capsule.
AU2003286796A1 (en) 2002-10-31 2004-06-07 Umd, Inc. Therapeutic compositions for drug delivery to and through covering epithelia
GB0225621D0 (en) 2002-11-02 2002-12-11 Glaxo Group Ltd Medicament carrier
AU2003276447A1 (en) 2002-11-04 2004-06-07 Cambridge Consultants Limited Inhalers
USD493220S1 (en) 2002-11-06 2004-07-20 Merck Patent Gmbh Inhaler
US20080015457A1 (en) 2002-11-07 2008-01-17 Silva Carlos D Device for Monitoring Respiratory Movements
USD483860S1 (en) 2002-11-12 2003-12-16 Pari Gmbh Spezialisten Fur Effektive Inhalation Electronic inhaler and control unit
US6904907B2 (en) 2002-11-19 2005-06-14 Honeywell International Inc. Indirect flow measurement through a breath-operated inhaler
GB0227128D0 (en) 2002-11-20 2002-12-24 Glaxo Group Ltd A capsule
US7913688B2 (en) 2002-11-27 2011-03-29 Alexza Pharmaceuticals, Inc. Inhalation device for producing a drug aerosol
US20040138099A1 (en) 2002-11-29 2004-07-15 Draeger Eberhard Kurt Insulin administration regimens for the treatment of subjects with diabetes
MXPA05005864A (es) 2002-12-02 2005-11-16 Univ Alberta Dispositivo y metodo para desaglomeracion de polvo para inhalacion.
US7284553B2 (en) 2002-12-12 2007-10-23 Boehringer Ingelheim Pharma Gmbh & Co. Kg Powder inhaler comprising a chamber for a capsule for taking up a non-returnable capsule being filled with an active ingredient
AU2003285776A1 (en) 2002-12-13 2004-07-09 Otsuka Pharmaceutical Co., Ltd. FREEZE-DRIED INTERFERON-Gamma COMPOSITION FOR TRANSPULMONARY ADMINISTRATION AND INHALATION SYSTEM THEREFOR
AR042452A1 (es) 2002-12-13 2005-06-22 Otsuka Pharma Co Ltd Dispositivo de inhalacion para la administrcion transpulmonar
AU2003299722A1 (en) 2002-12-17 2004-07-14 Mdrna, Inc. Compositions and methods for enhanced mucosal delivery of y2 receptor-binding peptides and methods for treating and preventing obesity
US6941947B2 (en) 2002-12-18 2005-09-13 Quadrant Technologies Limited Unit dose dry powder inhaler
US6962006B2 (en) 2002-12-19 2005-11-08 Acusphere, Inc. Methods and apparatus for making particles using spray dryer and in-line jet mill
US7185650B2 (en) 2002-12-19 2007-03-06 Arie Huber Systems and methods for determining a minimum effective dose of an inhaled drug for an individual patient at a given time
WO2004060387A1 (en) 2002-12-27 2004-07-22 Diobex, Inc. Compositions and methods for the prevention and control of insulin-induced hypoglycemia
DE10300032B3 (de) 2003-01-03 2004-05-27 E. Braun Gmbh Pulverinhalator
GB0309154D0 (en) 2003-01-14 2003-05-28 Aventis Pharma Inc Use of insulin glargine to reduce or prevent cardiovascular events in patients being treated for dysglycemia
US20040187869A1 (en) 2003-01-17 2004-09-30 Schering Corporation Training device for medicament inhalers
ATE330351T1 (de) * 2003-01-29 2006-07-15 I & T Innovation Tech Entw Abisolieren von flachleitern
EP1605916A4 (en) 2003-02-12 2012-02-22 R & P Korea Co Ltd SOLUBENT SOLVENT SYSTEM WITH SOLUBLE PEEL WITH IMPROVED ELUTION RATE
GB0303870D0 (en) 2003-02-20 2003-03-26 Norton Healthcare Ltd Pre-metered dose magazine for breath-actuated dry powder inhaler
US20040171518A1 (en) 2003-02-27 2004-09-02 Medtronic Minimed, Inc. Compounds for protein stabilization and methods for their use
DE602004029630D1 (de) * 2003-03-04 2010-12-02 Technology Dev Co Ltd Injizierbare Insulinzubereitung mit Langzeitwirkung und Verfahren zur dessen Herstellung und Verwendung
KR101124007B1 (ko) 2003-03-04 2012-03-23 노턴 헬스케어 리미티드 약제흡입기조립체
EP1605895A4 (en) 2003-03-06 2011-08-24 Emisphere Tech Inc ORAL INSULIN THERAPY AND PROTOCOL
CA2458288A1 (en) 2003-03-11 2004-09-11 Institut De Cardiologie De Montreal / Montreal Heart Institute Method and compound to reduce the incidence of diabetes in a subject with chronic heart failure
USD499802S1 (en) 2003-04-01 2004-12-14 Chiesi Farmaceutici S.P.A. Powder inhaler
PL1615689T3 (pl) 2003-04-09 2016-06-30 Novartis Ag Urządzenie do aerozolizacji z prowadnicą wyrównującą do przebijania kapsułki
US20040204439A1 (en) 2003-04-14 2004-10-14 Staniforth John Nicholas Composition, device, and method for treating sexual dysfunction via inhalation
EP1468935A1 (de) 2003-04-16 2004-10-20 Alcan Technology & Management Ltd. Blisterverpackung
AU155845S (en) 2003-05-15 2004-07-13 Glaxo Group Ltd A dispensing device for example an inhaler device
CN103191409A (zh) 2003-05-15 2013-07-10 Dmi生物科学公司 T-细胞介导的疾病的治疗
US20070006876A1 (en) 2003-05-16 2007-01-11 University Of Alberta Add-on spacer design concept for dry-powder inhalers
AU155633S (en) 2003-05-16 2004-06-01 Henkel Kgaa Blister pack
GB0312007D0 (en) 2003-05-24 2003-07-02 Innovata Biomed Ltd Container
US9107831B2 (en) * 2003-06-02 2015-08-18 Novartis Vaccines And Diagonstics, Inc. Immunogenic compositions containing microparticles comprising adsorbed toxoid and polysaccharide-containing antigens
WO2004112702A2 (en) 2003-06-13 2004-12-29 Advanced Inhalation Research, Inc. Low dose pharmaceutical powders for inhalation
US20050008908A1 (en) 2003-06-27 2005-01-13 Ultracell Corporation Portable fuel cartridge for fuel cells
US7001622B1 (en) 2003-06-30 2006-02-21 Robert Berndt Composition and method for treatment and prevention of pruritis
GB0315509D0 (en) 2003-07-02 2003-08-06 Meridica Ltd Dispensing device
AU158576S (en) 2003-07-05 2006-08-22 Clinical Designs Ltd Inhaler
US7462367B2 (en) 2003-07-11 2008-12-09 Boehringer Ingelheim International Gmbh Anticholinergic powder formulations for inhalation
US8921311B2 (en) 2003-08-01 2014-12-30 Mannkind Corporation Method for treating hyperglycemia
USD569967S1 (en) 2003-08-06 2008-05-27 Meridica Limited Inhaler
US20050043247A1 (en) 2003-08-18 2005-02-24 Boehringer Ingelheim International Gmbh Spray-dried amorphous BIBN 4096, process for preparing and the use thereof as inhalative
DE10338402A1 (de) 2003-08-18 2005-03-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Sprühgetrocknetes, amorphes BIBN 4096, Verfahren zu dessen Herstellung sowie dessen Verwendung als Inhalativum
US20050056535A1 (en) 2003-09-15 2005-03-17 Makoto Nagashima Apparatus for low temperature semiconductor fabrication
DE10343668A1 (de) 2003-09-18 2005-04-14 Boehringer Ingelheim Pharma Gmbh & Co. Kg Arzneimittelblister
GB2398065A (en) 2003-10-16 2004-08-11 Bespak Plc Dispensing apparatus
EP1675822A2 (en) 2003-10-16 2006-07-05 Cara Therapeutics, Inc. Amide or thioamide derivatives and their use in the treatment of pain
US20050187749A1 (en) 2003-10-24 2005-08-25 Judy Singley Method, system, and computer program for performing carbohydrate/insulin calculation based upon food weight
USD511208S1 (en) 2003-10-24 2005-11-01 Valois Sas Metered dose inhaler
US7377277B2 (en) 2003-10-27 2008-05-27 Oriel Therapeutics, Inc. Blister packages with frames and associated methods of fabricating dry powder drug containment systems
US7451761B2 (en) 2003-10-27 2008-11-18 Oriel Therapeutics, Inc. Dry powder inhalers, related blister package indexing and opening mechanisms, and associated methods of dispensing dry powder substances
WO2005044173A1 (en) 2003-10-27 2005-05-19 Oriel Therapeutics, Inc. Blister packages and associated methods of fabricating dry powder drug containment systems
US20050147581A1 (en) 2003-11-19 2005-07-07 The Board Of Trustees Of The University Of Illinois Macromolecular drug complexes having improved stability and therapeutic use of the same
SE0303269L (sv) 2003-12-03 2005-06-04 Microdrug Ag Medicinsk produkt
GB0329884D0 (en) 2003-12-23 2004-01-28 Glaxo Group Ltd Method
EP1701714A2 (en) 2004-01-07 2006-09-20 Nektar Therapeutics Improved sustained release compositions for pulmonary administration of insulin
ES2584867T3 (es) * 2004-01-12 2016-09-29 Mannkind Corporation Un método que reduce los niveles séricos de proinsulina en diabéticos de tipo 2
US20070027063A1 (en) 2004-01-12 2007-02-01 Mannkind Corporation Method of preserving the function of insulin-producing cells
AU2005209199B2 (en) 2004-01-16 2008-09-11 Biodel Inc. Sublingual drug delivery device
DE102004006450B4 (de) 2004-02-05 2012-09-27 Ing. Erich Pfeiffer Gmbh Dosiervorrichtung
USD512777S1 (en) 2004-02-19 2005-12-13 Chrysalis Technologies Incorporated Inhaler
DE102004008141A1 (de) 2004-02-19 2005-09-01 Abbott Gmbh & Co. Kg Guanidinverbindungen und ihre Verwendung als Bindungspartner für 5-HT5-Rezeptoren
BRPI0507910B8 (pt) 2004-02-24 2021-06-22 Microdose Therapeutx Inc dispositivo para inalação de ar para administração de um medicamento
RU2379062C2 (ru) 2004-02-24 2010-01-20 Майкродоуз Терапьютикс, Инк. Способ и устройство для доставки медикамента на основе синтезирующей струи
ES2398318T3 (es) 2004-03-12 2013-03-15 Biodel, Inc. Composiciones de suministro de fármacos de acción rápida
ITMO20040060A1 (it) 2004-03-18 2004-06-18 Roberto Oliva Inalatore per preparati in polvere
USD515696S1 (en) 2004-03-19 2006-02-21 Innovata Biomed Limited Inhaler
WO2005092301A1 (en) 2004-03-26 2005-10-06 Universita' Degli Studi Di Parma Insulin highly respirable microparticles
EP1733231B1 (en) 2004-04-05 2011-05-04 Université Bordeaux 2 Peptides and peptidomimetics binding to cd23
USD533268S1 (en) 2004-04-18 2006-12-05 Bahram Olfati Inhaler
CA2562386C (en) 2004-04-21 2014-11-18 Innovata Biomed Limited Inhaler
WO2005102428A1 (en) 2004-04-23 2005-11-03 The Governors Of The University Of Alberta Enhanced drug delivery for inhaled aerosols
AU2005238962B2 (en) 2004-04-23 2011-05-26 Philip Morris Products S.A. Aerosol generators and methods for producing aerosols
GB0410712D0 (en) 2004-05-13 2004-06-16 Novartis Ag Organic compounds
USD527817S1 (en) 2004-05-13 2006-09-05 Novartis Ag Inhaler
US20050265927A1 (en) 2004-05-17 2005-12-01 Yale University Intranasal delivery of nucleic acid molecules
PA8633401A1 (es) 2004-05-19 2006-09-08 Cipla Ltd Dispositivo inhalador de medicamentos
USD529604S1 (en) 2004-05-28 2006-10-03 Quadrant Technologies Limited Dry powder inhaler
USD548833S1 (en) 2004-05-28 2007-08-14 Quadrant Technologies Limited Dry powder inhaler
SE528190C2 (sv) 2004-06-07 2006-09-19 Mederio Ag Inhalator
WO2005120616A1 (en) 2004-06-07 2005-12-22 Mederio Ag Securing dose quality of inhalable drug
RU2006145886A (ru) 2004-06-25 2008-06-27 Такеда Фармасьютикал Компани Лимитед (Jp) Производные метастина и их применение
US20060000469A1 (en) 2004-07-02 2006-01-05 Tseng Daniel C Nebulizing apparatus for medical use with improved nozzle positioning structure
CA2574642A1 (en) 2004-07-23 2006-01-26 Intercure Ltd. Apparatus and method for breathing pattern determination using a non-contact microphone
CA2574398C (en) 2004-07-26 2010-05-18 1355540 Ontario Inc. Powder inhaler featuring reduced compaction
WO2006017688A2 (en) 2004-08-03 2006-02-16 Biorexis Pharmaceutical Corporation Combination therapy using transferrin fusion proteins comprising glp-1
DK1786784T3 (da) 2004-08-20 2011-02-14 Mannkind Corp Katalyse af diketopiperazinsyntese
EP1781254A2 (en) 2004-08-23 2007-05-09 Mannkind Corporation Pulmonary delivery of inhibitors of phosphodiesterase type 5
CN104436170B (zh) 2004-08-23 2018-02-23 曼金德公司 用于药物输送的二酮哌嗪盐
GB0419849D0 (en) 2004-09-07 2004-10-13 Pfizer Ltd Pharmaceutical combination
WO2006031775A2 (en) 2004-09-13 2006-03-23 Oriel Therapeutics, Inc. Dry powder inhalers that inhibit agglomeration, related devices and methods
WO2006031712A2 (en) 2004-09-13 2006-03-23 Oriel Therapeutics, Inc. Tubular dry powder drug containment systems, associated inhalers and methods
USD537522S1 (en) 2004-09-15 2007-02-27 Glaxo Group Limited Telescopic strap, particularly for a dust cap of a metered dose inhaler
USD537936S1 (en) 2004-09-15 2007-03-06 Glaxo Group Limited Cap with an extension, particularly for a dust cap of a metered dose inhaler
USD518170S1 (en) 2004-09-28 2006-03-28 Vectura, Ltd. Inhaler
EA200700743A1 (ru) 2004-10-06 2007-10-26 Бёрингер Ингельхайм Интернациональ Гмбх Устройство для распыления порошка, устройство для хранения порошка и способ распыления порошка
US7469696B2 (en) 2004-10-13 2008-12-30 Hewlett-Packard Development Company, L.P. Thermal drop generator
USD515924S1 (en) 2004-11-01 2006-02-28 Warner-Lambert Company Llc Blister card
DE102005033398A1 (de) 2004-11-10 2006-05-11 Alfred Von Schuckmann Inhalier-Gerät
WO2006059939A1 (en) 2004-12-03 2006-06-08 Mederio Ag A medical product comprising a glucagon-like peptide medicament intended for pulmonary inhalation
SE0402976L (sv) 2004-12-03 2006-06-04 Mederio Ag Medicinsk produkt
GB0427028D0 (en) 2004-12-09 2005-01-12 Cambridge Consultants Dry powder inhalers
US20060130838A1 (en) 2004-12-20 2006-06-22 Lee Yong Y Data logger for monitoring asthmatic conditions
BRPI0519241A2 (pt) 2004-12-22 2009-01-06 Centocor Inc agonistas, composiÇÕes, mÉtodos e usos de glp-1
CA2592776A1 (en) 2005-01-10 2006-08-17 Mannkind Corporation Methods and compositions for minimizing accrual of inhalable insulin in the lungs
US20060165756A1 (en) 2005-01-27 2006-07-27 Catani Steven J Method for weight management
USD538423S1 (en) 2005-02-04 2007-03-13 Berube-White Panda bear inhaler
GB0503738D0 (en) 2005-02-23 2005-03-30 Optinose As Powder delivery devices
US20060219242A1 (en) 2005-03-30 2006-10-05 Boehringer Ingelheim International Method for the Administration of an Anticholinergic by Inhalation
JP4656397B2 (ja) 2005-03-31 2011-03-23 株式会社吉野工業所 粉体用容器
CN100431634C (zh) 2005-04-04 2008-11-12 陈庆堂 干粉气溶胶化吸入器
US7762953B2 (en) 2005-04-20 2010-07-27 Adidas Ag Systems and methods for non-invasive physiological monitoring of non-human animals
US7694676B2 (en) 2005-04-22 2010-04-13 Boehringer Ingelheim Gmbh Dry powder inhaler
MX2007013356A (es) * 2005-04-27 2008-03-26 Baxter Int Microparticulas modificadas en la superficie y metodos de formacion y uso de las mismas.
US7219664B2 (en) 2005-04-28 2007-05-22 Kos Life Sciences, Inc. Breath actuated inhaler
KR20080005938A (ko) 2005-05-02 2008-01-15 아스트라제네카 아베 공동을 개봉하기 위한 장치 및 방법, 약제 팩, 및 분배장치
USD544093S1 (en) 2005-06-02 2007-06-05 Bang & Olufsen A/S Inhaler
PL2656860T3 (pl) 2005-06-17 2021-11-08 Wisconsin Alumni Research Foundation Preparaty środka zwężającego naczynia i sposoby ochrony komórek podczas chemioterapii i radioterapii przeciwnowotworowej
WO2007007110A1 (en) 2005-07-13 2007-01-18 Cipla Limited Inhaler device
US8763605B2 (en) 2005-07-20 2014-07-01 Manta Devices, Llc Inhalation device
USD550835S1 (en) 2005-07-22 2007-09-11 Omron Healthcare Co., Ltd. Atomizer for inhaler
ES2439455T3 (es) 2005-08-01 2014-01-23 Mannkind Corporation Procedimiento de preservar la función de las células productoras de insulina
US8062670B2 (en) 2005-08-05 2011-11-22 3M Innovative Properties Company Compositions exhibiting improved flowability
EP1934805A4 (en) 2005-08-25 2017-01-11 Oriel Therapeutics, Inc. Drug containment systems with sticks, related kits, dry powder inhalers and methods
WO2008048234A2 (en) 2005-08-26 2008-04-24 North Carolina State University Inhaler system for targeted maximum drug-aerosol delivery
US7678363B2 (en) 2005-08-26 2010-03-16 Braincells Inc Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs
JP2007061281A (ja) 2005-08-30 2007-03-15 Hitachi Ltd 吸入量測定システム
WO2007030706A1 (en) 2005-09-08 2007-03-15 New England Medical Center Hospitals, Inc. Fragments of the glucagon-like peptide-i and uses thereof
HUE028623T2 (en) 2005-09-14 2016-12-28 Mannkind Corp Active substance formulation method based on increasing the affinity of the active ingredient for binding to the surface of crystalline microparticles
USD540671S1 (en) 2005-09-21 2007-04-17 The Procter & Gamble Company Cap for product dispenser
US20070086952A1 (en) 2005-09-29 2007-04-19 Biodel, Inc. Rapid Acting and Prolonged Acting Inhalable Insulin Preparations
US20070074989A1 (en) 2005-09-30 2007-04-05 Musculoskeletal Transplant Foundation Container for lyophilization and storage of tissue
GB0520794D0 (en) 2005-10-12 2005-11-23 Innovata Biomed Ltd Inhaler
ITMI20051999A1 (it) 2005-10-21 2007-04-22 Eratech S R L Formulazioni inalatorie di farmaci in fora di polvere secca per somministrazione come tale o con nebulizzatore e dotate di elevata erogabilita' respirabilita' e stabilita'
USD566549S1 (en) 2005-10-26 2008-04-15 Reckitt Benckiser (Uk) Limited Cap
US8039432B2 (en) 2005-11-09 2011-10-18 Conjuchem, Llc Method of treatment of diabetes and/or obesity with reduced nausea side effect
AR058289A1 (es) 2005-12-12 2008-01-30 Glaxo Group Ltd Colector para ser usado en dispensador de medicamento
AR058290A1 (es) 2005-12-12 2008-01-30 Glaxo Group Ltd Dispensador de medicamento
US8293869B2 (en) 2005-12-16 2012-10-23 Nektar Therapeutics Polymer conjugates of GLP-1
BRPI0706947B8 (pt) 2006-01-24 2021-05-25 Ansun Biopharma Inc método de preparação de uma composição de micropartícula
USD557798S1 (en) 2006-01-25 2007-12-18 Valois S.A.S. Inhaler
US7390949B2 (en) 2006-02-01 2008-06-24 Wanne, Inc. Saxophone and clarinet mouthpiece cap
GB0602897D0 (en) 2006-02-13 2006-03-22 Jagotec Ag Improvements In Or Relating To Dry Powder Inhaler Devices
WO2007094833A1 (en) 2006-02-14 2007-08-23 Battelle Memorial Institute Accurate metering system
IN2015DN00888A (zh) 2006-02-22 2015-07-10 Mannkind Corp
EP2471811B1 (en) 2006-02-22 2015-09-16 Merck Sharp & Dohme Corp. Oxyntomodulin derivatives
DE102006010089A1 (de) 2006-02-24 2007-10-18 Aha-Kunststofftechnik Gmbh Trockenpulver-Inhalator
USD541151S1 (en) 2006-03-20 2007-04-24 The Procter & Gamble Company Cap for product dispenser
US8037880B2 (en) 2006-04-07 2011-10-18 The University Of Western Ontario Dry powder inhaler
EP2012817A2 (en) 2006-04-12 2009-01-14 Biodel, Inc. Rapid acting and long acting insulin combination formulations
EP1844809A1 (de) 2006-04-13 2007-10-17 Boehringer Ingelheim Pharma GmbH & Co. KG Medikamentenmagazin für einen Inhalator, sowie Mehrdosispulverinhalator
EP1844806A1 (de) 2006-04-13 2007-10-17 Boehringer Ingelheim Pharma GmbH Medikamenten-Ausgabevorrichtung, Medikamentenmagazin dafür, und Verfahren zur Entnahme eines Medikaments aus einer Medikamentenkammer
KR101438839B1 (ko) 2006-04-14 2014-10-02 맨카인드 코포레이션 글루카곤 유사 펩타이드 1 （ｇｌｐ-1） 약제학적 제제
US20070243216A1 (en) 2006-04-14 2007-10-18 Stanley Kepka Stable solutions of prostaglandin and uses of same
GR1005620B (el) 2006-05-09 2007-09-03 Βελτιωση συσκευης εισπνοων ξηρης σκονης
WO2007129515A1 (ja) 2006-05-10 2007-11-15 S.K.I. Net, Inc. 小動物用麻酔システム
DE102006021978A1 (de) 2006-05-10 2007-11-15 Robert Bosch Gmbh Vorrichtung und Verfahen zum Verstärken eines Blisters
PT103481B (pt) 2006-05-16 2008-08-01 Hovione Farmaciencia S A Inalador de uso simples e método de inalação
GB0611656D0 (en) 2006-06-13 2006-07-19 Cambridge Consultants Dry powder inhalers
GB0611659D0 (en) 2006-06-13 2006-07-19 Cambridge Consultants Dry powder inhalers
CA2655477C (en) 2006-06-16 2015-05-05 Cipla Limited Vibration assisted release of encapsulated inhalable powder
WO2008001132A1 (en) 2006-06-27 2008-01-03 Brintech International Limited Inhaler
US8251059B2 (en) 2006-06-27 2012-08-28 Otsuka Pharmaceutical Co., Ltd. Powder inhaler
GB0613161D0 (en) 2006-06-30 2006-08-09 Novartis Ag Organic Compounds
CN2917673Y (zh) 2006-07-06 2007-07-04 兴安药业有限公司 一种胶囊型干粉吸入器
US20090250058A1 (en) 2006-07-14 2009-10-08 Astrazeneca Ab Inhalation System and Delivery Device for the Administration of a Drug in the Form of Dry Powder
JP2009544716A (ja) 2006-07-27 2009-12-17 ノバルティス アクチエンゲゼルシャフト 肺送達のためのインスリン含有エアロゾル化可能製剤
EP2046778B1 (en) 2006-08-04 2013-12-04 Manus Pharmaceuticals (Canada) Ltd. Multifunctional bioactive compounds
GB0616299D0 (en) 2006-08-16 2006-09-27 Cambridge Consultants Drug Capsules for dry power inhalers
US20080066739A1 (en) 2006-09-20 2008-03-20 Lemahieu Edward Methods and systems of delivering medication via inhalation
US20080108574A1 (en) 2006-09-27 2008-05-08 Braincells, Inc. Melanocortin receptor mediated modulation of neurogenesis
US8236766B2 (en) 2006-11-10 2012-08-07 Cara Therapeutics, Inc. Uses of synthetic peptide amides
US7713937B2 (en) 2006-11-10 2010-05-11 Cara Therapeutics, Inc. Synthetic peptide amides and dimeric forms thereof
US7842662B2 (en) 2006-11-10 2010-11-30 Cara Therapeutics, Inc. Synthetic peptide amide dimers
BRPI0718651B8 (pt) 2006-11-10 2021-05-25 Cara Therapeutics Inc amidas peptídicas sintéticas
BRPI0718694A2 (pt) 2006-11-10 2013-12-31 Proveris Scient Corp Teste automatizado de bomba de atomização nasal.
US7824014B2 (en) 2006-12-05 2010-11-02 Canon Kabushiki Kaisha Head substrate, printhead, head cartridge, and printing apparatus
USD548618S1 (en) 2006-12-06 2007-08-14 Eveready Battery Company, Inc. Zinc-air hearing aid battery package
USD549111S1 (en) 2006-12-06 2007-08-21 Eveready Battery Company, Inc. Zinc-air hearing aid battery package
USD548619S1 (en) 2006-12-06 2007-08-14 Eveready Battery Company, Inc. Zinc-air hearing aid battery package
CA2673553C (en) 2006-12-22 2014-06-17 Laboratorios Almirall, S.A. Breath actuated metering slide for a powder inhaler
WO2008092864A1 (en) 2007-01-29 2008-08-07 Novo Nordisk A/S Method and devices for aerosolizing a drug formulation
US8172817B2 (en) 2007-01-31 2012-05-08 Allegiance Corporation Liquid collection system and related methods
CA2677932A1 (en) 2007-02-15 2008-08-21 Indiana University Research And Technology Corporation Glucagon/glp-1 receptor co-agonists
US8196576B2 (en) 2007-02-28 2012-06-12 Microdose Therapeutx, Inc. Inhaler
WO2009005546A1 (en) 2007-03-05 2009-01-08 Board of Governors for Higher Education, State of Rhode Island and the Providence Plantations High efficiency mouthpiece/adaptor for inhalers
JP2008212436A (ja) 2007-03-06 2008-09-18 Canon Inc 吸入装置
US8146745B2 (en) 2007-03-09 2012-04-03 Cardpak, Inc. Environmentally separable packaging device with attaching base
GB0704928D0 (en) 2007-03-14 2007-04-25 Cambridge Consultants Dry powder inhalers
US8688184B2 (en) 2007-04-11 2014-04-01 Starr Life Sciences Corporation Noninvasive photoplethysmographic sensor platform for mobile animals
JP4417400B2 (ja) 2007-04-16 2010-02-17 アンリツ株式会社 はんだ検査ライン集中管理システム、及びそれに用いられる管理装置
PT2157967E (pt) 2007-04-23 2013-04-03 Intarcia Therapeutics Inc Formulações de suspensões de péptidos insulinotrópicos e suas utilizações
US20100215588A1 (en) 2007-04-26 2010-08-26 Rami Skaliter Therapeutic delivery of inhibitory nucleic acid molecules to the respiratory system
USD583463S1 (en) 2007-04-30 2008-12-23 Sun Pharma Advanced Research Company Limited Inhaler
USD577815S1 (en) 2007-04-30 2008-09-30 Sun Pharma Advanced Research Company Limited Inhaler
WO2009008001A2 (en) 2007-04-30 2009-01-15 Sun Pharma Advanced Research Company Limited Inhalation device
EP1992378A1 (en) 2007-05-16 2008-11-19 Boehringer Ingelheim Pharma GmbH & Co. KG Dispensing device
WO2008144439A1 (en) 2007-05-16 2008-11-27 Mystic Pharmaceuticals, Inc. Combination unit dose dispensing containers
USD579549S1 (en) 2007-06-07 2008-10-28 Novartis Ag Inhaler
CN101820896A (zh) 2007-06-08 2010-09-01 麻省理工学院 用于治疗雷特综合征和突触病症的igf
WO2008157751A2 (en) 2007-06-21 2008-12-24 Cara Therapeutics, Inc. Substituted imidazoheterocycles
DK2898914T3 (en) 2007-07-06 2018-09-03 Manta Devices Llc INHALATION DEVICES FOR STORAGE AND DELIVERY OF MEDICINES
US20090084379A1 (en) 2007-10-02 2009-04-02 Baxter International Inc. Dry powder inhaler
EP2048112A1 (en) 2007-10-09 2009-04-15 Kemira Kemi AB Use of a nozzle for manufacturing sodium percarbonate
WO2009055740A2 (en) 2007-10-24 2009-04-30 Mannkind Corporation Method of preventing adverse effects by glp-1
US8785396B2 (en) 2007-10-24 2014-07-22 Mannkind Corporation Method and composition for treating migraines
BRPI0818874A2 (pt) 2007-10-24 2015-05-05 Mannkind Corp Liberação de agentes ativos
KR20100098610A (ko) 2007-10-25 2010-09-08 노파르티스 아게 단위 투여량의 약물 포장물의 분말 컨디셔닝
GB0721394D0 (en) 2007-10-31 2007-12-12 Vectura Group Plc Compositions for trating parkinson's disease
US8430097B2 (en) 2007-11-06 2013-04-30 3M Innovative Properties Company Medicinal inhalation devices and components thereof
CN101317821B (zh) 2007-11-15 2012-01-04 陈晓东 适用于肺部给药的超细干粉颗粒及其制备方法
EP2060268A1 (en) 2007-11-15 2009-05-20 Novo Nordisk A/S Pharmaceutical compositions for pulmonary or nasal delivery of peptides
EP2534958A1 (en) 2007-12-14 2012-12-19 AeroDesigns, Inc Delivering aerosolizable food products
USD594753S1 (en) 2007-12-14 2009-06-23 The Procter & Gamble Company Blister card
JP2011507593A (ja) 2007-12-20 2011-03-10 アストラゼネカ・アクチエボラーグ 粉末８５４を脱凝集解体する装置ならびに方法
US7584846B2 (en) 2007-12-21 2009-09-08 S.C. Johnson & Son, Inc. Shaped packaging for a refill
WO2009095684A1 (en) 2008-02-01 2009-08-06 Vectura Limited Pulmonary formulations of triptans
GB0802028D0 (en) 2008-02-05 2008-03-12 Dunne Stephen T Powder inhaler flow regulator
USD614045S1 (en) 2008-02-22 2010-04-20 Ima Safe S.R.L. Blister packaging
DK2254629T3 (en) 2008-03-27 2016-01-25 Mannkind Corp The dry powder inhalation
AU2008354530B2 (en) 2008-04-07 2014-02-27 Indian Institute Of Science Compositions useful for the treatment of diabetes and other chronic disorder
DE102008023376A1 (de) 2008-05-13 2009-11-19 Alfred Von Schuckmann Spender für in einer gesonderten Verpackung enthaltenen, pulverförmigen Massen
AU2009246217B2 (en) 2008-05-15 2013-01-10 Novartis Ag Pulmonary delivery of a fluoroquinolone
USD598785S1 (en) 2008-05-22 2009-08-25 Wm. Wrigley Jr. Company Blister card
USD597418S1 (en) 2008-05-22 2009-08-04 Wm. Wrigley Jr. Company Blister card
USD605753S1 (en) 2008-06-13 2009-12-08 Mannkind Corporation Cartridge for a dry powder inhaler
USD597657S1 (en) 2008-06-13 2009-08-04 Mannkind Corporation Dry powder inhaler
USD604833S1 (en) 2008-06-13 2009-11-24 Mannkind Corporation Dry powder inhaler
USD605752S1 (en) 2008-06-13 2009-12-08 Mannkind Corporation Dry powder inhaler
USD604832S1 (en) 2008-06-13 2009-11-24 Mannkind Corporation Cartridge for a dry powder inhaler
USD614760S1 (en) 2008-06-13 2010-04-27 Mannkind Corporation Dry powder inhaler
US8485180B2 (en) 2008-06-13 2013-07-16 Mannkind Corporation Dry powder drug delivery system
ES2570400T3 (es) 2008-06-13 2016-05-18 Mannkind Corp Un inhalador de polvo seco y un sistema para el suministro de fármacos
USD613849S1 (en) 2008-06-13 2010-04-13 Mannkind Corporation Cartridge for a dry powder inhaler
USD635241S1 (en) 2008-06-13 2011-03-29 Mannkind Corporation Dry powder inhaler
JP5479465B2 (ja) 2008-06-20 2014-04-23 マンカインド コーポレイション 吸入努力をリアルタイムにプロファイルする対話式機器および方法
TWI532497B (zh) 2008-08-11 2016-05-11 曼凱公司 超快起作用胰島素之用途
USD629505S1 (en) 2008-12-01 2010-12-21 Mannkind Corporation Dry powder inhaler
USD635242S1 (en) 2008-12-01 2011-03-29 Mannkind Corporation Dry powder inhaler
USD629887S1 (en) 2008-12-01 2010-12-28 Mannkind Corporation Dry powder inhaler
USD629888S1 (en) 2008-12-01 2010-12-28 Mannkind Corporation Dry powder inhaler
USD629506S1 (en) 2008-12-01 2010-12-21 Mannkind Corporation Dry powder inhaler
USD629886S1 (en) 2008-12-01 2010-12-28 Mannkind Corporation Dry powder inhaler
USD635243S1 (en) 2008-12-01 2011-03-29 Mannkind Corporation Dry powder inhaler
WO2010078373A1 (en) 2008-12-29 2010-07-08 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
US8314106B2 (en) 2008-12-29 2012-11-20 Mannkind Corporation Substituted diketopiperazine analogs for use as drug delivery agents
JP5918539B2 (ja) 2009-01-08 2016-05-18 マンカインド コーポレイション Ｇｌｐ−１を用いる高血糖症の治療方法
US8550074B2 (en) 2009-01-15 2013-10-08 Manta Devices, Llc Delivery device and related methods
AU2010221254B2 (en) 2009-03-04 2014-04-03 Mannkind Corporation An improved dry powder drug delivery system
EP2405963B1 (en) 2009-03-11 2013-11-06 MannKind Corporation Apparatus, system and method for measuring resistance of an inhaler
SG174345A1 (en) 2009-03-18 2011-11-28 Mannkind Corp Inhaler adaptor for a laser diffraction apparatus and method for measuring particle size distribution
GB0907425D0 (en) 2009-04-29 2009-06-10 Glaxo Group Ltd Compounds
USD626836S1 (en) 2009-04-30 2010-11-09 Bryce Lien Bottle cap
USD628090S1 (en) 2009-05-07 2010-11-30 Mccormick & Company, Incorporated Seasoning package
USD620375S1 (en) 2009-05-11 2010-07-27 Mcneil-Ppc, Inc. Blister
MX2011012265A (es) 2009-05-21 2012-04-11 Microdose Therapeutx Inc Sistema de casete rotatorio para inhalador de polvo seco.
AU2010253776B2 (en) 2009-05-29 2015-01-22 Pearl Therapeutics, Inc. Compositions for pulmonary delivery of long-acting muscarinic antagonists and long-acting B2 adrenergic receptor agonists and associated methods and systems
CN102458371B (zh) 2009-06-12 2015-08-05 曼金德公司 具有确定异构体含量的二酮哌嗪微粒
KR101875969B1 (ko) 2009-06-12 2018-07-06 맨카인드 코포레이션 한정된 비표면적을 갖는 디케토피페라진 마이크로입자
US9180263B2 (en) 2009-07-01 2015-11-10 Microdose Therapeutx, Inc. Laboratory animal pulmonary dosing device
WO2011017554A2 (en) 2009-08-07 2011-02-10 Mannkind Corporation Val (8) glp-1 composition and method for treating functional dyspepsia and/or irritable bowel syndrome
WO2011031564A2 (en) 2009-08-27 2011-03-17 Stc.Unm Methods and systems for dosing and coating inhalation powders onto carrier particles
IT1395945B1 (it) 2009-09-30 2012-11-02 Oliva Inalatore perfezionato per preparati in polvere
USD647195S1 (en) 2009-10-09 2011-10-18 Vectura Delivery Devices Limited Inhaler having cover
USD647196S1 (en) 2009-10-09 2011-10-18 Vectura Delivery Devices Limited Inhaler having cover
JP5784622B2 (ja) 2009-11-03 2015-09-24 マンカインド コーポレ−ション 吸入活動をシミュレートするための装置及び方法
USD650295S1 (en) 2009-11-13 2011-12-13 Avidiamed Gmbh Blister pack for pharmaceuticals
WO2011079310A1 (en) 2009-12-23 2011-06-30 Map Pharmaceuticals,Inc. Enhanced eductor design
CN102111798A (zh) 2009-12-29 2011-06-29 中兴通讯股份有限公司 一种td-scdma模拟测试信号的生成方法和装置
CA2786066A1 (en) 2009-12-31 2011-07-07 Stealth Peptides International, Inc. Methods for performing a coronary artery bypass graft procedure
AU332056S (en) 2010-01-08 2010-08-04 Teva Pharma Ireland Inhaler
USD641076S1 (en) 2010-03-26 2011-07-05 Oriel Therapeutics, Inc. Dry powder inhaler
GB201006901D0 (en) 2010-04-26 2010-06-09 Sagentia Ltd Device for monitoring status and use of an inhalation or nasal drug delivery device
PT105065B (pt) 2010-04-26 2012-07-31 Hovione Farmaciencia S A Um inalador simples de cápsulas
USD645954S1 (en) 2010-05-21 2011-09-27 Consort Medical Plc Mechanical dosage counter apparatus
USD636868S1 (en) 2010-06-14 2011-04-26 Mannkind Corporation Dry powder inhaler
USD636869S1 (en) 2010-06-14 2011-04-26 Mannkind Corporation Dry powder inhaler
USD636867S1 (en) 2010-06-14 2011-04-26 Mannkind Corporation Dry powder inhaler
CN101851213A (zh) 2010-06-21 2010-10-06 于清 3，6-双(4-双反丁烯二酰基氨丁基)-2，5-二酮哌嗪及其盐取代物的合成方法
MX359281B (es) 2010-06-21 2018-09-21 Mannkind Corp Sistema y metodos para suministrar un farmaco en polvo seco.
WO2012022771A2 (en) 2010-08-19 2012-02-23 Sanofi-Aventis Deutschland Gmbh Method and system for determining information related to a drug reservoir using an electronic sensor
USD643308S1 (en) 2010-09-28 2011-08-16 Mannkind Corporation Blister packaging
DK2621488T3 (en) 2010-09-29 2019-03-04 Pulmatrix Operating Co Inc CATIONIC DRY POWDER
MX340112B (es) 2010-11-09 2016-06-27 Mannkind Corp Composicion que comprende un agonista de receptor de serotonina y una dicetopiperazina para el tratamiento de migrañas.
CA140810S (en) 2010-12-01 2012-05-23 Teva Pharma Inhaler cap
USD642483S1 (en) 2010-12-03 2011-08-02 Mccormick & Company, Incorporated Seasoning package
KR20140027937A (ko) 2011-02-10 2014-03-07 맨카인드 코포레이션 Ｎ­보호된 비스­３，６­（４­아미노알킬）­２，５，디케토피페라진의 생성
MX353285B (es) 2011-04-01 2018-01-05 Mannkind Corp Paquete de blister para cartuchos farmaceuticos.
WO2012174472A1 (en) 2011-06-17 2012-12-20 Mannkind Corporation High capacity diketopiperazine microparticles
PL2739268T3 (pl) 2011-08-01 2019-07-31 Monash University Sposób i formulacja do inhalacji
USD674893S1 (en) 2011-10-20 2013-01-22 Mannkind Corporation Inhaler device
CN103945859A (zh) 2011-10-24 2014-07-23 曼金德公司 用于治疗疼痛的方法和组合物
CN102436238B (zh) 2011-11-03 2014-04-16 广东轻工职业技术学院 基于生产线数据采集及信息管理系统的数据采集方法
AU2013252901B2 (en) 2012-04-27 2017-11-30 Mannkind Corp Methods for the synthesis of ethylfumarates and their use as intermediates
WO2014012069A2 (en) 2012-07-12 2014-01-16 Mannkind Corporation Dry powder drug delivery systems and methods
US20150231067A1 (en) 2012-08-29 2015-08-20 Mannkind Corporation Method and composition for treating hyperglycemia
EP2911690A1 (en) 2012-10-26 2015-09-02 MannKind Corporation Inhalable influenza vaccine compositions and methods
CN103110611A (zh) 2012-12-11 2013-05-22 苏州惠仁生物科技有限公司 吸入剂及其制备方法与普鲁兰糖作为吸入剂载体的应用
USD711740S1 (en) 2013-01-22 2014-08-26 H204K9, Inc. Bottle cap
AU2014228415B2 (en) 2013-03-15 2018-08-09 Mannkind Corporation Microcrystalline diketopiperazine compositions and methods
KR102321339B1 (ko) 2013-07-18 2021-11-02 맨카인드 코포레이션 열-안정성 건조 분말 약제학적 조성물 및 방법
US11446127B2 (en) 2013-08-05 2022-09-20 Mannkind Corporation Insufflation apparatus and methods
GB201319265D0 (en) 2013-10-31 2013-12-18 Norton Waterford Ltd Medicament inhaler
US10307464B2 (en) 2014-03-28 2019-06-04 Mannkind Corporation Use of ultrarapid acting insulin
US10561806B2 (en) 2014-10-02 2020-02-18 Mannkind Corporation Mouthpiece cover for an inhaler
USD771237S1 (en) 2014-10-02 2016-11-08 Mannkind Corporation Mouthpiece cover
IL260823B2 (en) 2016-01-29 2024-08-01 Mannkind Corp Dry powder inhaler
CA3024721A1 (en) 2016-05-19 2017-11-23 Mannkind Corporation Apparatus, system and method for detecting and monitoring inhalations

Also Published As

Publication number Publication date
RU2010109856A (ru) 2011-09-27
RU2008114306A (ru) 2009-10-20
AU2006290870A1 (en) 2007-03-22
US7803404B2 (en) 2010-09-28
DK2656836T3 (en) 2017-10-23
US20160151287A1 (en) 2016-06-02
US9089497B2 (en) 2015-07-28
US20100278924A1 (en) 2010-11-04
US9283193B2 (en) 2016-03-15
ES2555310T3 (es) 2015-12-30
BRPI0615819A2 (pt) 2011-05-24
BRPI0616071B8 (pt) 2021-05-25
CN104324366A (zh) 2015-02-04
RU2008114361A (ru) 2009-10-20
US8420604B2 (en) 2013-04-16
DK1937219T3 (en) 2016-02-15
US20210353544A1 (en) 2021-11-18
KR101486829B1 (ko) 2015-01-29
JP6080926B2 (ja) 2017-02-15
DK1928423T3 (en) 2016-02-29
US8729019B2 (en) 2014-05-20
KR20140014322A (ko) 2014-02-05
CN104324366B (zh) 2016-10-05
HUE028623T2 (en) 2016-12-28
US20070059373A1 (en) 2007-03-15
WO2007033316A2 (en) 2007-03-22
KR20140026637A (ko) 2014-03-05
AU2006290227B2 (en) 2012-08-02
HK1116088A1 (zh) 2008-12-19
EP2656836B1 (en) 2017-07-26
KR20080043372A (ko) 2008-05-16
US20170281549A1 (en) 2017-10-05
US20190029961A1 (en) 2019-01-31
US9717689B2 (en) 2017-08-01
KR20140026638A (ko) 2014-03-05
US20190290586A1 (en) 2019-09-26
JP2016029064A (ja) 2016-03-03
RU2394550C2 (ru) 2010-07-20
US10143655B2 (en) 2018-12-04
AU2006290870B2 (en) 2013-02-28
KR101643478B1 (ko) 2016-07-27
US20100247661A1 (en) 2010-09-30
US9066881B2 (en) 2015-06-30
JP2009507929A (ja) 2009-02-26
CA2621806A1 (en) 2007-03-22
US20230390206A1 (en) 2023-12-07
BRPI0615819B8 (pt) 2021-05-25
KR20080043387A (ko) 2008-05-16
US20150359744A1 (en) 2015-12-17
CN104324362A (zh) 2015-02-04
EP1928423A2 (en) 2008-06-11
WO2007033316A3 (en) 2007-05-31
US9446001B2 (en) 2016-09-20
HK1117768A1 (zh) 2009-01-23
EP1937219B1 (en) 2015-11-11
US20160346212A1 (en) 2016-12-01
MX358592B (es) 2018-08-27
KR20160022404A (ko) 2016-02-29
US20070059374A1 (en) 2007-03-15
AU2006290227A1 (en) 2007-03-22
CN104324362B (zh) 2018-04-24
EP1928423B1 (en) 2015-12-09
KR101557502B1 (ko) 2015-10-06
RU2390325C2 (ru) 2010-05-27
CA2620758A1 (en) 2007-03-22
IN2014DN09128A (zh) 2015-07-10
HUE028691T2 (en) 2016-12-28
US20140308358A1 (en) 2014-10-16
US10357459B2 (en) 2019-07-23
WO2007033372A3 (en) 2007-05-10
EP1937219A2 (en) 2008-07-02
JP5859481B2 (ja) 2016-02-10
RU2443414C2 (ru) 2012-02-27
BRPI0615819B1 (pt) 2020-10-06
JP5465878B2 (ja) 2014-04-09
CA2621806C (en) 2016-08-02
US11013692B2 (en) 2021-05-25
JP5167133B2 (ja) 2013-03-21
US20130189365A1 (en) 2013-07-25
BRPI0616071B1 (pt) 2020-03-17
JP2013177414A (ja) 2013-09-09
US11103459B2 (en) 2021-08-31
MX2019012598A (es) 2019-12-16
EP2656836A1 (en) 2013-10-30
JP2009507931A (ja) 2009-02-26
ES2640282T3 (es) 2017-11-02
US20110003004A1 (en) 2011-01-06
WO2007033372A2 (en) 2007-03-22
BRPI0616071A2 (pt) 2011-06-07
ES2559677T3 (es) 2016-02-15
CA2620758C (en) 2016-06-21
KR101486397B1 (ko) 2015-01-28
KR101384456B1 (ko) 2014-04-10
KR20120060245A (ko) 2012-06-11
US7799344B2 (en) 2010-09-21

Similar Documents

Publication Publication Date Title
CN102614131A (zh) 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法
CN101262850B (zh) 以提高结晶微粒表面对活性试剂的亲和力为基础的药物配制方法
AU2014271222B2 (en) Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents
AU2012244328B2 (en) Method of drug formulation based on increasing the affinity of crystalline microparticle surfaces for active agents

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication
RJ01 Rejection of invention patent application after publication

Application publication date: 20120801