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Oral GLP-1 formulations

a technology of oral glp-1 and formulation, which is applied in the field of oral glp-1 formulations, can solve the problems of reducing blood sugar levels, glp-1 may encounter difficulty in traversing the epithelial membrane cells, and the development of oral glp-1 therapeutics is extremely difficult, so as to facilitate the oral delivery of glp-1 and facilitate the bioavailability of glp-1

Inactive Publication Date: 2006-12-21
NOVO NORDISK NORTH AMERICA OPERATIONS AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0008] The present invention provides pharmaceutical compositions comprising at least one delivery agent and GLP-1. These pharmaceutical compositions facilitate the oral delivery of GLP-1, providing an improved (e.g. increased) bioavailability of GLP-1 compared to administration of GLP-1 without a delivery agent. The delivery agent may be selected from the following, including salts thereof: TABLE 1Deliv-eryAgentNo.Compound 1 2 3 4 5 6 7 8 91011121314151617181920212223242526272829 According to one embodiment, the pharmaceutical composition includes an effective amount of a GLP-1 compound, for example, to treat NIDDM or obesity.
[0009] The delivery agents enable the oral delivery of macromolecules, providing an increased or improved bioavailability of GLP-1 compared to administration of GLP-1 without a delivery agent.

Problems solved by technology

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.
Development of an oral GLP-1 therapeutic has been extremely difficult.
This is primarily due to the in vivo instability of the peptide.
Further, GLP-1 may encounter difficulty in traversing the cells of the epithelial membrane in the small intestine to reach the bloodstream.
In light of the above difficulties, oral administration of GLP-1 compounds has not been feasible.
Because patients are generally adverse to injections and time consuming infusions, patient compliance with GLP-1 administration regimens will be low.

Method used

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Examples

Experimental program
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Effect test

example 1

Preparation of Dosing Solutions

[0166] GLP-1 was obtained from Bachem (Torrance, Calif.) as a bulk powder. To prepare stock solutions, GLP-1 was dissolved in deionized water (pH6.5) to obtain a concentration of 8 mg / ml. Stock solutions were kept frozen at −20° C. in 0.5-ml aliquots until used. For dosing solutions, delivery agent was dissolved in deionized water to obtain a final concentration of 200 mg / ml (oral dosing) or 100 mg / ml (intracolonic dosing). The free acid form of delivery agent was converted to the sodium salt by adding one equivalent of sodium hydroxide. Solutions were vortexed, sonicated, and heated, and if necessary, additional sodium hydroxide was added in μl quantities to achieve uniform solubility. A specified quantity of GLP-1 stock was then added to the delivery agent solution to obtain a final concentration of 1 or 0.3 mg / ml (oral) or 0.6 mg / ml (intracolonic). After solubilization and drug addition, solutions were brought to final volume by the addition of dei...

example 2

Preparation of Deliver Agent No. 24 in Published International Application No. 03 / 072195

Preparation of 4-dimethylamino-benzoyl chloride

[0171] To a 1000 mL round bottomed flask was added 4-dimethylamino-benzoic acid (50.0 g, 1.0 eq) and THF (600 mL). A solution of thionyl chloride (44.16 mL, 2.0 eq) in tetrahydrofuran was added and the resulting mixture heated to reflux for 4 hours. The excess thionyl chloride and solvent were removed under reduced pressure to yield 4-dimethylamino-benzoyl chloride as a solid, which was used without further purification in the preparation of compound 560.

[0172] Preparation of delivery agent 24: To a 1000 mL round bottomed flask was added chlorotrimethylsilane (15.48 mL, 2 eq) in methylene chloride (250 ml). 4-aminobutyric acid (10.0 g, 1 equivalent) was added and the mixture was heated to reflux for 1.5 hours. The resulting solution was cooled to 0° C. (ice bath) and triethylamine (27.21 mL, 3 equivalents) was added drop-wise. A solution of 4-dime...

example 3

Preparation of Deliver Agent No. 8 in Published International Application No. 03 / 072195

[0173]

[0174] Step 1. 4,N-Dimethylbenzenesulphonamide was reacted with ethyl-8-bromooctanoate in DMF under the influence of sodium hydride to obtain 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid ethyl ester

[0175] Step 2. The ester of 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid ethyl ester was hydrolyzed in aqueous sodium hydroxide to obtain 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid

[0176] Step 3. The sulphonamide of 8-[Methyl-(toluene-4-sulfonyl)-amino]-octanoic acid was removed under reductive conditions and the resulting amine reacted with hydrogen chloride to obtain (7-Carboxy-heptyl)-methylammonium hydrochloride.

[0177] Step 4. The carboxylic acid of (7-Carboxy-heptyl)-methylammonium hydrochloride was protected in-situ with chlorotrimethylsilane. The resulting trimethylsilyl ester was reacted with 0-acetylsalicyloyl chloride. The protecting groups were removed with ...

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Abstract

The present invention provides phamaceutical compositions comprising at least one delivery agent and GLP-1. These pharmaceutical compositions facilitate the oral delivery of GLP-1, providing improved (e.g. increased) bioavailability of GLP-1 compared to administration of GLP-1 without a delivery agent.

Description

[0001] This application claims the benefit of U.S. Provisional Application No. 60 / 552,116, filed Mar. 10, 2004, and U.S. Provisional Application No. 60 / 530,931, filed Dec. 19, 2003. Both of these applications are hereby incorporated by reference in their entirety.FIELD OF THE INVENTION [0002] The present invention relates to a formulation comprising a delivery agent and a glucagon-like peptide 1 or a glucagon-like peptide 1 analog compound (collectively “GLP-1”). These formulations are useful as oral medicaments for the treatment of type 2 diabetes and obesity as well as other conditions known to be treated with GLP-1. BACKGROUND OF THE INVENTION [0003] Type 2 diabetes, also known as non-insulin dependent diabetes mellitus (NIDDM), is a condition in which patients generate 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 effici...

Claims

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Application Information

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IPC IPC(8): A61K38/26
CPCA61K38/26
Inventor SARUBBI, DONALD
Owner NOVO NORDISK NORTH AMERICA OPERATIONS AS
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