Method of preventing adverse effects by glp-1

A technology of GLP-1 and preparations, which can be used in pharmaceutical formulas, medical preparations containing active ingredients, metabolic diseases, etc., and can solve problems such as toxicity to patients

Inactive Publication Date: 2011-02-09
MANNKIND CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In some cases, metabolites can be toxic to patients, or can produce unwanted side effects

Method used

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  • Method of preventing adverse effects by glp-1
  • Method of preventing adverse effects by glp-1
  • Method of preventing adverse effects by glp-1

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0116] Administration of GLP-1 to healthy adult males in the form of an inhalable dry powder

[0117] GLP-1 has been shown to control elevated blood glucose in humans when given by intravenous (iv) or subcutaneous (sc) infusion or by multiple subcutaneous injections. Due to the extremely short half-life of the hormone, continuous subcutaneous infusions or multiple daily subcutaneous injections are required to achieve clinical efficacy. None of these routes is practical for prolonged clinical use. The applicant has found in animal experiments that therapeutic levels can be achieved when GLP-1 is administered by inhalation. The results of these studies can be found, for example, in US Patent Application No. 11 / 735,957, the disclosure of which is incorporated herein by reference.

[0118] In healthy individuals, several effects of GLP-1, including decreased gastric emptying, increased satiety and suppression of inappropriate glucagon secretion, appear to be related to the bur...

Embodiment 2

[0147] Comparison of pulmonary administration of GLP-1 and Exented to male Zucker diabetic obese rats for and subcutaneous administration of Exented

[0148] Considerable effort has been expended in developing GLP-1 analogs with longer circulating half-lives that would lead to clinically useful treatments. As demonstrated herein, pulmonary administration of GLP-1 also provided clinically meaningful activity. It is therefore of interest to compare these two pathways.

[0149] Preparation of FDKP particles

[0150] Fumaryl diketopiperazine (FDKP) and polysorbate 80 were dissolved in dilute ammonia water to obtain a solution containing 2.5 wt% FDKP and 0.05 wt% polysorbate 80. The FDKP solution was then mixed with an acetic acid solution containing polysorbate 80 to form granules. The particles were washed and concentrated by tangential flow filtration to achieve about 11% solids by weight.

[0151] Preparation of GLP-1 stock solution .

[0152] A 10 wt% GLP-1 stock ...

Embodiment 3

[0166] Oxyntomodulin / FDKP Powder Preparation

[0167] Oxyntomodulin (also known as glucagon-37) is a peptide consisting of 37 amino acid residues. This peptide is manufactured by and obtained from American Peptide Company, Inc. of Sunnyvale, CA. FDKP particles in suspension were mixed with oxyntomodulin solution, then snap-frozen into pellets in liquid nitrogen, and lyophilized to produce sample powders.

[0168] Six powders were prepared with target peptide contents between 5% and 30%. The actual peptide content determined by HPLC was between 4.4% and 28.5%. The aerodynamic properties of powders containing 10% peptide were analyzed using cascade impact.

[0169] The FDKP solution was then mixed with a polysorbate 80-containing acetic acid solution to form granules. The particles were washed and concentrated by tangential flow filtration to achieve about 11% solids by weight.

[0170] The FDKP particle suspension (1885 mg x 11.14% solids = 210 mg FDKP particles) was weigh...

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Abstract

A method for preventing or reducing adverse effects such as profuse sweating, nausea and vomiting, which normally are associated with subcutaneous and intravenous administration of glucagon-like peptide 1 (GLP-1 ) therapy is provided. In particular, the method comprises the rapid administration of a GLP-1 formulation into the pulmonary circulation such as by inhalation, directly into pulmonary alveolar capillaries using a dry powder drug delivery system.

Description

[0001] Cross References to Related Applications [0002] This application is based on U.S. Provisional Application No. 60 / 982,368 filed October 24, 2007; U.S. Provisional Application No. 60 / 985,620 filed November 5, 2007; 35 U.S.C. § 119(e) requirements; U.S. Provisional Application No. 61 / 033,740, filed May 4; priority to U.S. Provisional Application No. 61 / 052,127, filed May 9, 2008. The entire contents of each of these applications are incorporated herein by reference. technical field [0003] Disclosed herein are methods of preventing or reducing adverse effects (eg, profuse sweating, nausea, and vomiting) commonly associated with subcutaneous and intravenous administration of glucagon-like peptide 1 (GLP-1 ) therapy. In particular, the method involves rapid administration of GLP-1 into the pulmonary circulation using a dry powder drug delivery system, eg, by inhalation into the alveolar capillaries. Background of the invention [0004] Drug delivery systems for intro...

Claims

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Application Information

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IPC IPC(8): A61K31/495A61K38/26A61K9/14
CPCA61K45/06A61K31/495A61K38/28A61K38/26A61M15/00A61P43/00A61P5/50A61P3/10A61K2300/00A61K9/14A61K9/00
Inventor 彼得·理查森罗伯特·A·鲍格曼唐纳德·科斯特洛
Owner MANNKIND CORP
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