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Method for administering glp-1 molecules

Inactive Publication Date: 2005-07-07
NOVO NORDISK NORTH AMERICA OPERATIONS AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011] The present invention also encompasses a method of stimulating the GLP-1 receptor in a subject in need of such stimulation, said method comprising the step of administering to

Problems solved by technology

Type 2 diabetics generally still make insulin, but the insulin cannot be used effectively by the body's cells.
This is primarily because the amount of insulin produced in response to rising blood sugar levels is not sufficient to allow cells to efficiently take up glucose and thus, reduce blood sugar levels.
However, development of a GLP-1 therapeutic has been extremely difficult.
This is primarily due to the instability of the peptide during manufacturing processes, in solution formulations, and in vivo.
Many type 2 diabetics or obese patients desiring to lose weight will not be willing to undertake a treatment regimen that may involve several injections per day.
Unfortunately, there are numerous barriers to effective oral delivery of peptides.
Further, many peptides cannot effectively traverse the cells of the epithelial membrane in the small intestine to reach the bloodstream.
Finally, many drugs become insoluble at the low pH levels encountered in the digestive tract and, thus, are not absorbed effectively.
The fact that GLP-1 compounds are relatively unstable in solution formulations, only remain in solution under a fairly narrow set of conditions, and have a relatively short in vivo half-life when administered as a solution formulation, suggested that these compounds could not be effectively delivered through the oral route.
Further, numerous parameters impact whether a particular class of compounds can be effectively delivered in combination with one or more classes of delivery agents.

Method used

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  • Method for administering glp-1 molecules
  • Method for administering glp-1 molecules
  • Method for administering glp-1 molecules

Examples

Experimental program
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Effect test

example 1

Insulinotropic Activity Determination

[0331] A collagenase digest of pancreatic tissue is separated on a Ficoll gradient (27%, 23%, 20.5%, and 11% in Hank's balanced salt solution, pH 7.4). The islets are collected from the 20.50% / 11% interface, washed and handpicked free of exocrine and other tissue under a stereomicroscope. The islets are incubated overnight in RPMI 1640 medium supplemented with 10% fetal bovine plasma and containing 11 mM glucose at 37° C. and 95% air / 5% CO2. The GLP-1 compound to be studied is prepared at a range of concentrations, preferably 3 nanomolar to 30 nanomolar in RPMI medium containing 10% fetal bovine plasma and 16.7 mM glucose. About 8 to 10 isolated islets are then transferred by pipette to a total volume of 250 μL of the GLP-1 compound containing medium in 96-well microtiter dishes. The islets are incubated in the presence of the GLP-1 compound at 37° C., 95% air, 5% CO2 for 90 minutes. Then aliquots of islet-free medium are collected and 100 μl t...

example 2

Glp-1 Stability in the Presence of Dpp IV

[0332] The stability of each GLP-1 molecule can be determined by incubation of the GLP-1 molecule in human plasma. Plasma (800 μL), obtainable from healthy human volunteers, is incubated at 37° C. with 300 pmol / L of a GLP-1 molecule for up to six hours. This is followed by reversed phase HPLC and RIA according to Deacon, et al., in J. Clin. Endocrinol. Metab. 80: 952-957 (1995).

example 3

Formulation of Delivery Agent Number 15

[0333] Approximately 600 mg of delivery agent number 15 was weighed into Type I glass vials to which 3 mL of base (0.1 N NaOH, pH 12.7) was added to achieve a final concentration of 200 mg / mL. The pH was adjusted to 7.1 and the concentration was estimated to be 171 mg / mL. Delivery agent number 15 was then diluted to 150 mg / mL with Milli-Q® water.

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Abstract

The invention encompasses formulations that demonstrate the feasibility of oral absorption comprising GLP-1 compounds and specified delivery agents.

Description

FIELD OF THE INVENTION [0001] The present invention relates to a formulation useful for the oral administration comprising a glucagon-like peptide-1 (GLP-1) compound and a specified delivery agent. Oral administration of the formulations can be used to treat type 2 diabetes as well as a variety of other conditions. BACKGROUND OF THE INVENTION [0002] Over the past several decades, continuous strides have been made to improve the treatment of diabetes mellitus. Approximately 90% of people with diabetes have type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM). Type 2 diabetics generally still make insulin, but the insulin cannot be used effectively by the body's cells. This is primarily because the amount of insulin produced in response to rising blood sugar levels is not sufficient to allow cells to efficiently take up glucose and thus, reduce blood sugar levels. [0003] A large body of pre-clinical and clinical research data suggests that glucagon-like pepti...

Claims

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Application Information

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IPC IPC(8): A61K9/08A61K9/00A61K38/00A61K38/17A61K38/22A61K38/26A61K47/12A61K47/18A61K47/20A61K47/22A61P1/00A61P3/04A61P3/10A61P5/48A61P43/00C07K14/605
CPCA61K9/0095A61K9/08A61K47/183A61K47/18A61K38/26A61K47/20A61P1/00A61P3/04A61P3/10A61P5/48A61P9/10A61P43/00A01N37/18
Inventor KHAN, MOHAMMED
Owner NOVO NORDISK NORTH AMERICA OPERATIONS AS
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