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Compositions for treatment with glucagon-like peptide, and methods of making and using the same

a technology of glucagon and peptide, which is applied in the field of compositions for treatment with glucagonlike peptide, and methods of making and using the same, can solve the problems of short biological half-lives of peptides and proteins with low molecular mass, loss of solubility, and associated disadvantages of quality of life and potential intravenous administration, so as to reduce undesirable immunogenicity, prolong the biological half-life of peptides, and reduce glomerular filtration

Inactive Publication Date: 2005-11-24
PHARMAIN CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a drug delivery system that uses metal bridges to connect a carrier and a biological active peptide or protein. This system has several advantages, including protecting the active agent from other molecules and cells, decreasing immunogenicity, and prolonging the biological half-life of the active agent in vivo. The system can also use a metal binding domain to connect the active agent to the carrier, which can reversibly dissociate from the carrier. The invention also involves the use of a polymer carrier to which the active agent can bind, and the metal binding domain can be attached to the carrier through a chelated metal ion. The invention can be used in various drug delivery systems, such as polymer micelles, liposomes, and emulsions.

Problems solved by technology

In addition, peptides and proteins that have low molecular masses tend to have short biological half-lives due to their efficient removal from systemic circulation via kidneys.
This strategy is proven efficient in clinical practice but may be impractical for outpatients requiring high levels of mobility, associated disadvantages of quality of life and potential intravenous (I.V.) line infections.
Due to limited volume of these capsules, peptides and proteins are often used in a concentrated formulation, which leads to a loss of solubility due to aggregation and potential loss of specific activity.
The annual economic cost of diabetes in the US is estimated to be as much as $100 billion, making the disease an important clinical and public health problem.
While high blood sugar can be controlled in Type II diabetes by lifestyle changes and oral anti-hyperglycemic agents, the only standard treatment for Type I diabetes, however, is strict control of blood glucose levels by insulin therapy by injection, with the associated risk of serious hypoglycemic events.
However, this treatment still suffers from a short half life for GLP-1 due to proteolysis.

Method used

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  • Compositions for treatment with glucagon-like peptide, and methods of making and using the same
  • Compositions for treatment with glucagon-like peptide, and methods of making and using the same
  • Compositions for treatment with glucagon-like peptide, and methods of making and using the same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Synthesis of MPEG-PL

[0287] Poly-L-lysine, hydrobromide (Sigma, mol mass. 48000, d.p. 200), Ig was dissolved in 175 ml of 0.1 M Na2CO3, pH 8.7. An aliquot of this solution was removed for NH2-groups determination by TNBS titration (final concentration of NH2-groups, 25 mM). Methoxy polyethylene glycol succinate (MPEGS9.6 g, 1.9 mmol) was dissolved in 25 ml of water, degassed, and N-hydroxy(sulfo)succinimide (500 mg, 2.3 mmol) was added, followed by 1 g, 5 mmol of EDC in 2 ml of water. This solution was incubated for 10 min at room temperature and added drop-wise to the solution of poly-1-lysine, final pH 7.7. The mixture was incubated for six hours. The product was purified using ultrafiltration on a cartridge with a cut-off of 100 kD (UFP-100 A / G Technology) to remove unconjugated MPEGS and other reactants.

example 2

Synthesis of MPEG-PL-NTA

[0288] The product obtained as described in Example 1 (MPEGsuccinyl-poly-L-Lys (m.w. 340000) was succinylated using 10-fold molar excess of succinic anhydride over the concentration of TNBS-reactive free aminogroups in the co-polymer in 0.5 M sodium carbonate pH 8.0, 4 hours room temperature. Succinylated co-polymer (MPEGs-PL-Suc) was purified using dialysis against water.

[0289] 100 mg Lyophilized MPEGs-PL-Suc was dissolved in 2 ml water at 28 μmol succinate / ml, treated with 30 mg ethyl-diaminopropyl carbodiimide (EDC) in the presence of 20 mg Sulfo-NHS for 10 min at room temperature. A solution of activated MPEGs-PL-Suc was added to a solution of N_,N_-Bis(carboxymethyl)-L-lysine Hydrate (BCMLys) in 1 ml sodium bicarbonate, pH 8.7. Final pH 7.6, incubated 24 hours at 4° C. The resultant product MPEGs-PL-Suc-NTA was purified using ultrafiltration on YM50 membrane (Amicon) by diluting to 100 ml and concentrating to 5 ml volume four times. A solution of MPEGs...

example 3

Synthesis of MPEGs-PL-NiNTA

[0290] A solution of product MPEGs-PL-Suc-NTA was dialysed against IL of 10 mM Ni acetate / 20 mM citric acid, pH 6 for 24 hours at 4° C. and purified by dialysing against 2 L water (2 changes). Binding of Ni was measured by spectrophotometry at 625 nm using Ni-citrate as a standard.

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Abstract

In part, the present invention is directed to compositions comprising a carrier with a metal binding domain, a metal ion, and GLP-1.

Description

RELATED APPLICATIONS [0001] This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 60 / 564,710, filed Apr. 23, 2004.INTRODUCTION [0002] The development of new drugs, formulations and other systems for administration of physiologically active peptides and proteins and other therapeutics and materials is driven by the need to provide these peptides or proteins or other materials to achieve the desirable physiological effects. With respect to peptides and proteins, many of them have been observed to be unstable in the gastro-intestinal tract and therefore may need to be stabilized or protected or delivered via systemic circulation. In addition, peptides and proteins that have low molecular masses tend to have short biological half-lives due to their efficient removal from systemic circulation via kidneys. For example, a fraction of these peptides and proteins can also be removed via reticulo-endothelial uptake due to recognition by monocyte / macro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K9/107A61K9/127A61K9/51A61K38/16A61K38/26A61K47/10A61K47/34A61K47/42
CPCA61K9/0019A61K38/26A61K47/10A61K47/48315A61K47/42A61K47/48215A61K47/34A61K47/60A61K47/645
Inventor BOLOTIN, ELIJAH M.
Owner PHARMAIN CORP
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