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Salicylanilide modified peptides for use as oral therapeutics

A technology of salicylanilide, a therapeutic peptide, applied in the field of enhancing the bioavailability of this peptide compound, which can solve problems such as discomfort, inconvenience to patients, and non-compliance of patient treatment plans

Inactive Publication Date: 2010-09-22
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 administration are significantly less convenient and patients experience more 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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  • Salicylanilide modified peptides for use as oral therapeutics
  • Salicylanilide modified peptides for use as oral therapeutics
  • Salicylanilide modified peptides for use as oral therapeutics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0455] Niclosamide increases uptake / bioavailability of orally administered peptides

[0456] We previously reported that the amino acid sequence D-W-F-K-A-F-Y-D-K-V-A-E-KF-K-E-A-F (SEQ ID NO: 5) (see, e.g., U.S. Patent 6,933,279) with at least one protecting group when synthesized from all L-amino acids (L-4F) and to small Rapidly degraded and did not significantly alter the protective ability of HDL to inhibit LDL-induced monocyte chemotactic activity in cultures of human arterial wall cells when administered orally to mice (Navab et al. (2002) Circulation 105:290-292).

[0457]The surprising finding of the present invention is that oral administration of L-4F to mice together with niclosamide resulted in a significant improvement in the ability of HDL to inhibit LDL-induced chemotactic activity of monocytes in these mice. In contrast, oral administration of either agent alone was ineffective or significantly less effective.

[0458] Such as Figure 8 As shown, the combinat...

Embodiment 2

[0473] Salicylanilide in combination with L-4F enhances the formation of pro-βHDL

[0474] Niclosamide plus L-4F results in the formation of pre-βHDL in apoE-null mice after oral administration (see, e.g. Figure 18 ). D-4F (free base) was dissolved in ammonium bicarbonate buffer pH 7.0 containing 0.1% Tween 20 (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 with Figure 18ABCT of micrograms of L-4F or D-4F indicated in the middle x-axis with or without niclosamide indicated in 100 μL by gastric tube to overnight fasted 8-month-old female apoE-deficient mice (n=8 per group) administration. Mice were bled 30 to 40 minutes later and the percentage of apolipoprotein A-I contained in pre-β-1 HDL was determined by scanning in triplicate 2-dimensional gels. Data shown are mean ± standard deviation.

[0475] It was also surprising to find that oral co-administration of niclosamide and L-...

Embodiment 3

[0484] Niclosamide enhances L-4F uptake in ApoE-deficient mice

[0485] use 14 C-L-4F Determines L-4F uptake with and without niclosamide (BP-124). Fasted 6-month-old female apoE-null mice (n=4 per group) were administered 100 μg chloride in 200 μL pH 7.0 ammonium bicarbonate, 0.1% Tween 20 with or without gastric tube Nisamide L-4F (contains 10 micrograms of L-4F per mouse at 21,000 dpm). continue fasting and Figure 27 Mice were bled at the time points indicated on the middle x-axis and the dpm per mL of plasma was determined. Figure 27 The area under the curve (AUC) for mice receiving L-4F+niclosamide was 4.4 times higher than for mice receiving L-4F without niclosamide.

[0486] The data suggest that one of the mechanisms by which niclosamide enhances the bioactivity of L-4F in vivo is by enhancing the uptake of L-4F.

[0487] The above data (Examples 1, 2 and 3) show that the combination of niclosamide or other salicylanilides with L-4F and presumably other therapeu...

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Abstract

This invention pertains to the surprising discovery that salicylanilides, e.g., niclosamide and / or niclosamide analogues can be reacted with a therapeutically active peptide to produce a modified peptide complex that shows increased resistance to proteolysis and that shows higher bioactivity when orally administered than the unmodified peptide.

Description

[0001] Cross References to Related Applications [0002] This application claims priority and benefit from USSN 60 / 968,815, filed August 29, 2007, the entire contents of which are hereby incorporated by reference. [0003] Statement of Rights in Inventions Made Under Federally Sponsored Research and Development [0004] This work was funded in part by USPHS Grant 2 P01 HL-030568. The US Government has certain rights in this invention. technical field [0005] The present invention relates to orally administered peptide pharmaceuticals, wherein active compounds comprise amino acids and at least one peptide bond in their molecular structure, and methods of enhancing the bioavailability of such peptide compounds upon oral administration. Background technique [0006] Many human hormones, neurotransmitters, or therapeutic antibodies are peptides or include peptides as an essential part of their molecular structure. A therapeutically effective amount of such a biologically rel...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/60A61K51/00
CPCC07K7/08C07K14/775A61K38/00A61K47/48023A61K47/54A61P3/10A61P9/10A61P11/00A61P11/06A61P13/12A61P19/10A61P25/28A61P29/00A61P31/12
Inventor 艾伦·M·福格尔曼莫哈梅德·内瓦布
Owner RGT UNIV OF CALIFORNIA
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