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Stabilized glucagon nanoemulsions

A technology of glucagon and nanoemulsion, which is applied in the field of glucagon nanoemulsion, and can solve the problems that acidic compositions are irritating and unsuitable for pump application

Inactive Publication Date: 2014-11-19
陈献
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although the invention of Kornfelt et al. addresses the physical and chemical stability of glucagon, the acidic composition is very irritating when injected subcutaneously and is not suitable for pump application because the patient will experience constant prolonged pain

Method used

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  • Stabilized glucagon nanoemulsions
  • Stabilized glucagon nanoemulsions
  • Stabilized glucagon nanoemulsions

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0223] Preparation of Physically Stable Glucagon-Containing Nanoemulsions

[0224] The emulsion compositions in Table 2 were prepared to dissolve glucagon. Each composition is coded with a unique "F" number.

[0225] Table 2

[0226]

[0227] *About 1mg / mL glucagon

[0228] **The aqueous phase contained 10% by weight sucrose and 0.0055% by weight edetyl disodium dihydrate in deionized water (DI-water). Ethylenediaminetetraethyl disodium dihydrate was added as an antimicrobial preservative.

[0229] Weigh out 10 g of sucrose and 5.5 mg of disodium ethylenediaminetetraacetic acid dihydrate, add deionized water to 100 g, and dissolve all the solids to obtain an aqueous phase.

[0230] The emulsion is prepared by the following steps:

[0231] 1. Weigh out egg lecithin, medium chain oil and glucagon in plastic vials;

[0232] 2. Add ethanol at 50% batch size;

[0233] 3. Mix to dissolve all solids;

[0234] 4. Use Speed ​​Vac to carry out vacuum drying to remove ethano...

Embodiment 2

[0247] HPLC method and determination of glucagon degradation products by HPLC

[0248] A reverse-phase HPLC method was established to detect glucagon and its degradation products in the nanoemulsions of the present invention. This method was used to evaluate the chemical stability of glucagon in nanoemulsions. The HPLC method conditions are as follows. The HPLC gradients are summarized in Table 4.

[0249] Column: 4.6x 250mm, C-8

[0250] Mobile phase A: 0.05 vol% trifluoroacetic acid in water

[0251] Mobile phase B: 0.05 vol% trifluoroacetic acid in water in acetonitrile

[0252] Column temperature: 35°C

[0253] Wavelength: 214nm

[0254] Autosampler temperature: 5°C

[0255] Table 4

[0256]

[0257] Freshly prepared glucagon ( Plate 1 ) and degraded glucagon ( Plate 2 ) is shown in Figure 3. This method enables the separation and quantification of the major glucagon degradation products, namely, various aspartate cleavage and glutamine deamidation degrad...

Embodiment 3

[0259] Improved Chemical Stability of Glucagon in Nanoemulsions at Neutral pH

[0260] A new batch of the F-3 nanoemulsion composition in Example 1 was prepared, divided into several small portions. Each part was adjusted to a pH value between pH 5 and pH 7.5 with NaOH, filled into glass vials and sealed, and placed at 40°C to accelerate the chemical degradation of glucagon. After 1, 11, 30 and 45 days, each composition was analyzed using the HPLC method described in Example 2 to detect glucagon. The average loss rate of glucagon was calculated and the results were used to reveal the relative stability of glucagon over the pH range studied. Table 5 below shows the loss rate of glucagon expressed in mg / mL / day at different pH values. The characteristic spectrum of pH vs. loss rate is in Figure 4 shown in (top panel).

[0261] table 5

[0262]

[0263] In the second study of pH versus loss rate, F-3 nanoemulsion compositions were prepared in a lower pH range (pH 2.4 to...

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Abstract

The present invention provides an oil-in-water nanoemulsion containing glucagon, an oily phase, and an aqueous phase, wherein the glucagon is physically and chemically stable and the nanoemulsion is suitable for administration by manual injection or by a pump to treat hypoglycemia.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Patent Application No. 61 / 581,610, filed December 29, 2011, which is hereby incorporated by reference in its entirety for all purposes. field of invention [0003] The present disclosure relates to stable glucagon nanoemulsions Background of the invention [0004] Glucagon is a hormone secreted by the pancreas, which is a single-chain polypeptide composed of 29 amino acids with a molecular weight of 3,485 Da. Synthetic and recombinant glucagon is available in suitable purity to enable its use as a pharmaceutical. Glucagon cannot be absorbed orally, so it is given by injection. [0005] Glucagon is used medically to treat hypoglycemia (characterized by lower than normal blood sugar concentrations). Hypoglycemia is common in people with type 1 diabetes and insulin users. Mild hypoglycemia causes anxiety, sweating, tremors, palpitations, nausea, and pallor. In severe...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/113A61K9/107A61K47/44A61K38/26
CPCA61K9/107A61K38/26A61K45/06A61K9/0019A61K9/1075A61K47/44A61K9/19A61K47/24A61P3/08A61P5/48A61K2300/00A61K47/20A61K47/26
Inventor 陈献诺曼·基思·奥丽达陈海靓豪·胡·丹格
Owner 陈献
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