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Glucagon-like peptide 1(glp-1) pharmaceutical formulations

A GLP-1, drug technology, applied in the field of pulmonary delivery pharmaceutical preparations, dry powder preparations, and pharmaceutical preparations for the treatment of diseases, can solve problems such as unavoidable side effects such as weight gain

Inactive Publication Date: 2009-06-10
MANNKIND CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] However, despite these pathways / advancements in GLP-1 therapy, none of the drugs currently available to diabetics are able to achieve their goals (HbA1c, fasting blood glucose, glucose bias) in all patients, and none of them avoid side effects such as toxicity , low blood sugar, weight gain, nausea, and stress from vomiting

Method used

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  • Glucagon-like peptide 1(glp-1) pharmaceutical formulations
  • Glucagon-like peptide 1(glp-1) pharmaceutical formulations
  • Glucagon-like peptide 1(glp-1) pharmaceutical formulations

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0118] Biophysical and analytical analysis of GLP-1 structure

[0119] To analyze the structure and behavior of GLP-1, a large number of biophysical and analytical techniques are used. These techniques include far-ultraviolet circular dichroism (far-UV CD), near-ultraviolet circular dichroism (near-UV CD), internal fluorescence, Fourier transform infrared spectroscopy (FTIR), high-pressure liquid chromatography (HPLC), and mass spectrometry (MS); all of which are well known to those of ordinary skill in the art. The effects of concentration, ionic strength, temperature, pH, oxidative stress, agitation and multiple freeze-thaw cycles on GLP-1 peptides were studied using a wide range of conditions; all described in more detail below. These assays were also used to characterize major pathways of degradation and to establish conditions for manipulating the peptide structure of GLP-1 to achieve a certain GLP-1 / DKP formulation.

[0120] Experimental procedure

[0121] GLP-1 w...

Embodiment 2

[0144] GLP-1 / FDKP Adsorption Study

[0145] The interaction of GLP-1 with diketopiperazine (DKP) particles in suspension was evaluated by performing adsorption studies. Variables in adsorption studies explored the effects of electrostatics, hydrogen bonding, water structure, protein flexibility, and specific salt-pairing interactions on GLP-1 / DKP interactions. In addition, the effect of several common protein stabilizers on the surface adsorption of GLP-1 and DKP was tested.

[0146]Using preformed DKP suspension particles (ie, FDKP), the conditions under which GLP-1 adsorbed to the surface of preformed DKP particles were investigated. The FDKP particle suspension (where the FDKP particles were pre-formed) was combined with a solution of 3X pH buffer and 3X additive or excipient. The final solution had a FDKP concentration of 5, mg / ml and a GLP-1 concentration of 0.25, mg / ml (5% w / w). Unbound GLP-1 in the supernatant was filtered from the suspension. FDKP particles were ...

Embodiment 3

[0168] Integrity Analysis of GLP-1 / FDKP Preparations

[0169] Based on the results from the experiments in Examples 1 and 2, a series of GLP-1 preparations with the characteristics described in Table 1 were selected for the cell viability assays discussed herein. Most of the formulations contained GRAS ("Generally Regarded As Safe") excipients, but some were selected to allow studies of the relationship between stability and adsorption.

[0170] Table 1. GLP-1 / FDKP selected for Integrity Phase Analysis.

[0171]

[0172] Additionally, based on the results obtained in Examples 1 and 2, a series of formulations were also selected for Phase II integrity studies of GLP-1 / FDKP. Table 2 below shows the six GLP-1 formulations selected for Phase II integrity. After powders were prepared, they were blended with blank FDKP to produce similar amounts of GLP-1 peptide and FDKP in each formulation.

[0173] Table 2. GLP-1 / FDKP formulations selected for phase II integrity. Formulat...

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Abstract

A composition is disclosed comprising glucagon- like peptide 1 (GLP-I) particles in combination with diketopiperazine (DKP) that is stable both in vitro and in vivo. The composition has utility as a pharmaceutical formulation for treating diseases such as diabetes, cancers, and obesity but is not limited to such diseases or conditions. In particularly, the composition has utility as a pharmaceutical formulation for pulmonary delivery.

Description

[0001] Cross References to Related Applications [0002] This application is a continuation-in-part of U.S. Application No. 10 / 632,878, filed July 22, 2003, and is filed April 14, 2006 under 35 U.S.C. § 119(e) Priority of Provisional Application No. 60 / 744,882. Each of the above priority applications is hereby incorporated by reference in its entirety. technical field [0003] The present invention relates to the field of pharmaceutical preparations. The present invention discloses a dry powder formulation comprising diketopiperazine (DKP) particles combined with Glucagon-Like Peptide 1 (GLP-1). The present invention is useful as a pharmaceutical formulation for the treatment of diseases such as, but not limited to, diabetes, cancer and obesity. The invention is more particularly useful as a pharmaceutical formulation for pulmonary delivery. Background technique [0004] Glucagon-like peptide 1 (GLP-1), disclosed in the literature, is a 30 or 31 amino acid incretin that...

Claims

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Application Information

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IPC IPC(8): A61K9/16A61K38/26
CPCA61K9/0019A61K9/145A61K9/143A61K9/08A61K38/26A61K9/0075A61K45/06A61P1/00A61P1/04A61P1/18A61P3/00A61P3/04A61P3/06A61P3/10A61P9/00A61P9/10A61P25/00A61P25/28A61P35/00A61P37/06A61P43/00A61K9/0073A61K9/16A61K9/1611A61K9/1682A61K9/19A61K31/496
Inventor 斯蒂芬尼·戈恩大卫·布兰特柯哈瓦·盖尔伯马克·金韦曼·温蒂尔·师特汉姆凯斯·奥伯格安德里亚·勒龙-贝马克·J·豪肯森玛丽·法瑞斯
Owner MANNKIND CORP
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