Medicinal preparation containing exenatide

Abstract

The invention provides a medicinal preparation containing exenatide suitable for multi-administration, which contains exenatide, buffer solution, pharmaceutically acceptable accessory and preservative, wherein the buffer solution can keep the pH value of the preparation in an aqueous solution state at 3.0 to 7.0; the accessory may be one or combination of glucose, sucrose, methionine, mannitol or glycine; and the preservative is selected from benzoic acid, sodium benzoate, potassium sorbate or acetone chloroform. The medicinal preparation has the advantages that the stability of physicochemical and biological activities of the exenatide is enhanced by adding a few components capable of being accepted by the human body, and then a preparation suitable for clinical use, particularly injection use is prepared.

Description

field of invention

[0001] The invention relates to a stable pharmaceutical preparation of exenatide, which can be used for the treatment of diabetic patients. technical background

[0002] Exenatide (exenatide or exendin-4) was first isolated from the saliva secretion of giant monster lizard (Heloderm suspectum) (Eng, J. et al., J.Biol.Chem., 265:20259-62, 1990; Eng, J. et al., J.Biol.Chem., 267:7402-05, 1992), this is a 39-amino acid polypeptide whose amino acid sequence is similar to that of glucagon-like peptide-1 (GLP- 1) It has about 53% homology (Goke et al., J. Biol. Chem., 268:19650-55, 1993), and its amino acid sequence structure is as follows:

[0003] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-GIy-Ala-Pro-Pro-Pro-Ser

[0004] Pharmacological studies have found that exenatide has a similar effect to GLP-1, that is, it can stimulate pancreatic β cells to secrete insulin. Ex...

Examples

example 1

[0069] Example 1: Screening of preservatives

[0070] In order to study the stability of exenatide under the condition of adding different preservatives, the following experiment was carried out, the method is as follows: first prepare different preservative solutions, each solution contains 3% methionine and 20mM pH 4.5 Disodium hydrogen phosphate-citric acid buffer solution, then weigh exenatide, add it to different preservative solutions and dissolve it into an exenatide preparation solution of about 250 μg / ml, and then use NaOH or HCl to adjust the pH to 4.5. After the preparation, put it into a 25°C incubator for accelerated testing. Samples were taken every 2 weeks and tested by HPLC to observe the degradation of the samples. The specific results are shown in the table below.

[0071] Byetta prescription: Exenatide 250μg / ml + m-cresol 2.2mg / ml + 4% mannitol + 30mM acetate buffer

[0072] Table 6: Addition of different preservatives

[0073]

[0074] Table 7: Conten...

example 2

[0077] Example 2: Screening of different concentrations of sodium benzoate

[0078] First prepare sodium benzoate solutions containing different concentrations, each solution contains 3% methionine and 20mM pH 4.5 disodium hydrogen phosphate-citric acid buffer, then weigh exenatide, add it to different Dissolve in preservative solution to form about 250 μg / ml exenatide preparation solution, then adjust pH to 4.5 with NaOH or HCl. After the preparation, put it into a 25°C incubator for accelerated testing. Samples were taken every 2 weeks and tested by HPLC to observe the degradation of the samples. The specific results are shown in the table below.

[0079] Table 8: Periodic reverse-phase detection of the content of related substances

[0080]

[0081] Can get from above-mentioned result: the sodium benzoate of 0.005%-5% (especially 0.2%-2.0%) has antiseptic effect preferably, but considers that preservative generally has certain toxic effect to human body, therefore adopt...

field of invention

[0001] The invention relates to a stable pharmaceutical preparation of exenatide, which can be used for the treatment of diabetic patients. technical background

[0002] Exenatide (exenatide or exendin-4) was first isolated from the saliva secretion of giant monster lizard (Heloderm suspectum) (Eng, J. et al., J.Biol.Chem., 265:20259-62, 1990; Eng, J. et al., J.Biol.Chem., 267:7402-05, 1992), this is a 39-amino acid polypeptide whose amino acid sequence is similar to that of glucagon-like peptide-1 (GLP- 1) It has about 53% homology (Goke et al., J. Biol. Chem., 268:19650-55, 1993), and its amino acid sequence structure is as follows:

[0003] His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-GIy-Ala-Pro-Pro-Pro-Ser

[0004] Pharmacological studies have found that exenatide has a similar effect to GLP-1, that is, it can stimulate pancreatic β cells to secrete insulin. Ex...

Examples

example 1

[0069] Example 1: Screening of preservatives

[0070] In order to study the stability of exenatide under the condition of adding different preservatives, the following experiment was carried out, the method is as follows: first prepare different preservative solutions, each solution contains 3% methionine and 20mM pH 4.5 Disodium hydrogen phosphate-citric acid buffer solution, then weigh exenatide, add it to different preservative solutions and dissolve it into an exenatide preparation solution of about 250 μg / ml, and then use NaOH or HCl to adjust the pH to 4.5. After the preparation, put it into a 25°C incubator for accelerated testing. Samples were taken every 2 weeks and tested by HPLC to observe the degradation of the samples. The specific results are shown in the table below.

[0071] Byetta prescription: Exenatide 250μg / ml + m-cresol 2.2mg / ml + 4% mannitol + 30mM acetate buffer

[0072] Table 6: Addition of different preservatives

[0073]

[0074] Table 7: Conten...

example 2

[0077] Example 2: Screening of different concentrations of sodium benzoate

[0078] First prepare sodium benzoate solutions containing different concentrations, each solution contains 3% methionine and 20mM pH 4.5 disodium hydrogen phosphate-citric acid buffer, then weigh exenatide, add it to different Dissolve in preservative solution to form about 250 μg / ml exenatide preparation solution, then adjust pH to 4.5 with NaOH or HCl. After the preparation, put it into a 25°C incubator for accelerated testing. Samples were taken every 2 weeks and tested by HPLC to observe the degradation of the samples. The specific results are shown in the table below.

[0079] Table 8: Periodic reverse-phase detection of the content of related substances

[0080]

[0081] Can get from above-mentioned result: the sodium benzoate of 0.005%-5% (especially 0.2%-2.0%) has antiseptic effect preferably, but considers that preservative generally has certain toxic effect to human body, therefore adopt...

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