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Salicylanilides enhance oral delivery of therapeutic peptides

A technology of salicylanilide and therapeutic peptides, applied in the direction of peptides, decapeptides, organic active ingredients, etc., can solve problems such as inconvenience to patients, discomfort, and disobedience of patients' treatment plans

Inactive Publication Date: 2009-09-02
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, injection and nasal mucosal administration are significantly less convenient and involve more patient discomfort than oral administration
This inconvenience or discomfort often results in actual patient non-compliance with the treatment regimen

Method used

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  • Salicylanilides enhance oral delivery of therapeutic peptides
  • Salicylanilides enhance oral delivery of therapeutic peptides
  • Salicylanilides enhance oral delivery of therapeutic peptides

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0435] Niclosamide improves the absorption / bioavailability of orally administered peptides

[0436] We previously reported that the amino acid sequence DWFKAFYDKVAE-KF-KEAF (SEQ ID NO: 5) with at least one protecting group (see, for example, U.S. Patent 6,933,279) when synthesized from all L-amino acids (L-4F) and reduced Rats degrade rapidly when administered orally without significantly changing the protective ability of HDL to inhibit LDL-induced monocyte chemotactic activity in cultures of human artery wall cells (Navab et al. (2002) Circulation 105: 290-292).

[0437] The surprising discovery of the present invention is that oral administration of L-4F together with niclosamide to mice results in a significant improvement in the ability of HDL of these mice to inhibit LDL-induced monocyte chemotactic activity. In contrast, oral administration of either agent alone is ineffective or significantly less effective.

[0438] Such as Figure 8 As shown, the combination of oral niclo...

Embodiment 2

[0453] Salicylanilide combined with L-4F enhances the formation of pre-βHDL

[0454] Niclosamide and L-4F lead to the formation of pre-βHDL in mice lacking apoE after oral administration (see, eg Figure 18 ). D-4F (free base) was dissolved in 0.1% Tween 20 in pH 7.0 ammonium bicarbonate buffer (ABCT). L-4F (free base) and niclosamide were dissolved in ABCT at a ratio of 1:10 (L-4F: niclosamide; weight: weight). Combine ABCT alone or contain L-4F or D-4F and niclosamide (their micrograms are such as Figure 18 ABCT shown on the middle x axis) was administered via a gastric tube in 100 μL to 8-month-old female apoE-deficient mice (n=8 per group) that had been fasted overnight. After 30 or 40 minutes, blood was taken from the mice, and the percentage of apolipoprotein A-I contained in the pre-β-1 HDL was determined by scanning in three parallel 2-dimensional gels. The data shown is the mean ± standard deviation.

[0455] It was also surprisingly found that oral co-administration of ni...

Embodiment 3

[0464] Niclosamide increases the absorption of L-4F in ApoE-deficient mice

[0465] use 14 C-L-4F determines the absorption of L-4F with and without niclosamide (BP-124). Fasted 6-month-old female apoE-deficient mice (n=4 per group) were administered via a gastric tube in 200 μL of pH 7.0 ammonium bicarbonate with or without 100 μg in 0.1% Tween 20 Niclosamide L-4F (21,000 dpm per mouse, containing 10 micrograms of L-4F). Continue fasting and stay Figure 27 Bleed the mice at the time points indicated on the middle x-axis and determine the dpm per mL of plasma. Figure 27 The area under the curve (AUC) for mice receiving L-4F+niclosamide is 4.4 times the AUC for mice receiving L-4F without niclosamide.

[0466] Data show that one of the mechanisms by which niclosamide enhances the biological activity of L-4F in vivo is by increasing the absorption of L-4F.

[0467] The above data (Examples 1, 2, and 3) show that the combination of niclosamide or other salicylanilides with L-4F and p...

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Abstract

This invention pertains to the surprising discovery that salicylanilides, e.g., niclosamide and / or niclosamide analogues when orally administered in conjunction with a peptide pharmaceutical (e.g., a class A amphipathic helical peptide as described herein) significantly increases the bioavailability of that peptide. Methods of peptide delivery using such ''delivery agents'' and pharmaceutical formulations are provided.

Description

[0001] Cross-references to related applications [0002] The present invention claims the priority of USSN 60 / 836,501 filed on August 8, 2006 and USSN 60 / 868,845 filed on December 6, 2006, for which the entire contents of both are incorporated herein by reference. [0003] Declaration of rights to inventions under research and development sponsored by the Federal Government [0004] This work was partially funded by USPHS Grant 2 P01 HL-030568. The U.S. government has certain rights in this invention. Technical field [0005] The present invention relates to oral peptide drugs, wherein the active compound includes a plurality of amino acids and at least one peptide bond in their molecular structure, and the present invention relates to a method for enhancing the bioavailability of such peptide compounds during oral administration. Background technique [0006] Many human hormones, neurotransmitters, or therapeutic antibodies are peptides or include peptides as an essential part of...

Claims

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Application Information

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IPC IPC(8): A61K38/00A61K31/165C07K7/00C07K14/00
Inventor 阿兰·M·福格尔曼莫哈马德·纳瓦布
Owner RGT UNIV OF CALIFORNIA
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