Stable formulation of modified GLP-1

Inactive Publication Date: 2008-07-10
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]We have discovered that certain modified GLP-1 or analogues thereof when formulated in aqueous solution together with a buffer, are physically stable at high concentrations of the modified GLP-1 or analogues thereof, when kept in the pH range from about 7 to about 10. The present formulations are physically stable within a given shelf life period at the recommended storage temperature (typically 2-3 years at 2-8° C.). Furthermore, the present formulations are physically stable during in-use (typically 1 month at accelerated temperatures e.g. 25° C. or 37° C.). The formulations of the

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

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0236]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 in-Turbidityspection atmeasure-IsotonicPreserva-5° C. (visualments at 5° C.CompoundAmountPHBufferagenttivescore)(NTU)Arg34,Lys26(Nε-3 mg / ml7.9DisodiumMannitolPhenol1.50.9(γ-Glu(Nα-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

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

[0237]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. The physical stability is evaluated by visual inspection and Turbidity measurements in NTU as described in Example 1.

Amount ofVisual inspectionTurbiditycompoundat 5° C.measurements1PHBuffer(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

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

example 3

[0238]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.

[0239]The physical stability is evaluated by visual inspection and Turbidity measurements in NTU as described in Example 1.

VisualinspectionTurbidityAmount ofat 5° C.measurementscompoundPreserva-(visualat 5° C.1PHBuffertivescore)(NTU)80 mg / ml7.4DisodiumPhenol14.3hydrogen10 mg / ml (8 months)(10 months)phosphate80 mg / ml7.4DisodiumPhenol15.3hydrogen10 mg / ml(22 months)(22 months)phosphate

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 on Jun. 27, 2002 and claims priority under 35 U.S.C. 119 of Danish Application No. PA 2001 01010 filed Jun. 28, 2001; Danish Application No. PA 2001 01011 filed Jun. 28, 2001; Danish Application No. PA 2001 01052 filed Jul. 4, 2001; Danish Application No. PA 2001 01053 filed Jul. 4, 2001; and Danish Application No. PA 2002 00093 filed Jan. 18, 2002; and US Provisional Applications No. 60 / 308,325 filed Jul. 27, 2001 and 60 / 308,297 filed Jul. 27, 2001, the contents of which are fully incorporated herein by reference.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 since they can be produced by recombinant DNA technology it can be expected that their importa...

Claims

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Application Information

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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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