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Stable Formulation of Modified GLP-1

a technology of glp-1 and stable formulation, which is applied in the direction of inorganic non-active ingredients, extracellular fluid disorder, metabolic disorder, etc., can solve the problems of glp-1 being prone to instability, glp-1 being found to be almost ineffective in niddm, and little is known about their physico-chemical and solution structural properties, etc., to achieve improved stability, suitable for invasiveness, and physical stability increased significantly

Inactive Publication Date: 2009-04-30
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The formulation achieves significant physical stability, extending shelf life from seconds to months and maintaining biological activity, making it suitable for various administration routes, including invasive and non-invasive methods.

Problems solved by technology

Furthermore, as an insulinotropic hormone, GIP was found to be almost ineffective in NIDDM.
While much attention has been focused on the pharmacological properties of acylated GLP-1 compounds, hitherto little is known about their physico-chemical and solution structural properties.
It is an important technical challenge to ensure prolonged stability during storage (shelf life) of many protein based drug products due to the inherent lability of macromolecules.
GLP-1 is known to be prone to instability due to aggregation.
Both degradation pathways may ultimately lead to loss of biological activity of the protein drug.
However, solubility limitations and the low stability against the actions of endogenous diaminopeptidyl peptidase limits the usefulness of these compounds, and thus there still is a need for improvements in this field.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0238]Preservative, isotonic agent and buffer were dissolved and pH was adjusted to the specified pH. Hereafter the Compound 1 or GLP1(7-37) was dissolved under slow stirring. The pH was adjusted to the specified using Sodium Hydroxide and / or Hydrochloric Acid. Finally, the formulation was sterilised by filtration through a 0.22 μm sterile filter.

Visual inspectionTurbidityatmeasurementsIsotonic5° C. (visualat 5° C.CompoundAmountpHBufferagentPreservativescore)(NTU)Arg34,Lys26(Nε-3 mg / ml7.9DisodiumMannitolPhenol1.5 0.9(γ-Glu(NUα-hydrogen36.9 mg / ml5 mg / ml(12 weeks)(6 weeks)hexadecanoyl)))phosphateGLP-1 (7-37).GLP1(7-37)3 mg / ml7.9DisodiumMannitolPhenol3364hydrogen36.9 mg / ml5 mg / ml(1 day)(1 day)phosphate

[0239]It is seen that a formulation with GLP1(7-37) is physically unstable after just 1 day as it has a visual score corresponding to 3 and a turbidity of 364 NTU, whereas a formulation with Compound 1 is physically stable for more than 12 weeks.

example 2

[0240]Buffer was dissolved and pH was adjusted to the specified pH. Hereafter the Compound 1 was dissolved under slow stirring. The pH was adjusted to the specified using Sodium Hydroxide and / or Hydrochloric Acid. Finally, the formulation was sterilised by filtration through a 0.22 μm sterile filter.

[0241]The physical stability is evaluated by visual inspection and Turbidity measurements in NTU as described in Example 1.

VisualTurbidityAmount ofinspection at 5° C.measurementscompound 1PHBuffer(visual score)at 5° C. (NTU)80 mg / ml7.4Disodium14.7hydrogen (8 months)(10 months)phosphate80 mg / ml7.4Disodium14.9hydrogen(22 months)(22 months)phosphate

[0242]It is seen that the formulation is physically stable for more than 22 months.

example 3

[0243]Preservative and buffer was dissolved and pH was adjusted to the specified pH. Hereafter the Compound 1 was dissolved under slow stirring. The pH was adjusted to the specified using Sodium Hydroxide and / or Hydrochloric Acid. Finally, the formulation was sterilised by filtration through a 0.22 μm sterile filter.

[0244]The physical stability is evaluated by visual inspection and Turbidity measurements in NTU as described in Example 1.

Visual inspectionTurbidity measurementsAmount ofat 5° C. (visualat 5° C.compound 1PHBufferPreservativescore)(NTU)80 mg / ml7.4DisodiumPhenol14.3hydrogen10 mg / ml (8 months)(10 months)phosphate80 mg / ml7.4DisodiumPhenol15.3hydrogen10 mg / ml(22 months)(22 months)phosphate

[0245]It is seen that the formulation is physically stable for more than 10 months and even for more than 22 months.

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Abstract

Pharmaceutical formulations of GLP-1 compounds and methods for preparation thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. application Ser. No. 10 / 185,923 filed Jun. 27, 2002, which claims priority to Danish Patent Application Number PA 2001 01010, filed Jun. 28, 2001, and Danish Patent Application Number PA 2001 01011 filed Jun. 28, 2001 and Danish Patent Application No. PA 2001 01052 filed Jul. 4, 2001 and Danish Patent Application No. PA 2001 01053 filed Jul. 4, 2001 and Danish Patent Application No. PA 2002 00093 filed Jan. 18, 2002, which claims priority to U.S. Provisional Application No. 60 / 308,325 filed Jul. 27, 2001 and U.S. Provisional Application No. 60 / 308,297 filed Jul. 27, 2001, the contents of each of which is incorporated herein in its entirety.FIELD OF THE INVENTION[0002]The present invention relates to pharmaceutical formulations comprising GLP-1 compounds, uses thereof and methods for preparing said formulations.BACKGROUND OF THE INVENTION[0003]Peptides are widely used in medical practice, and sinc...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/26A61P3/10A61K47/18A61K38/00A61K47/22A61K47/30A61P3/04C07K14/605
CPCC07K14/605A61K38/26A61P1/04A61P3/00A61P3/10A61P3/04A61P7/12A61K9/08A61K9/0019A61K9/0073A61K9/0043A61K47/02A61K47/26A61K47/10A61K47/183
Inventor FLINK, JAMES M.LARSEN, SILKE MOLLERJENSEN, SIMON BJERREGAARDENGELUND, DORTHE KOT
Owner NOVO NORDISK AS
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