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Pharmaceutical combinations comprising mebendazole and strong or moderate cyp1a2 inhibitor

A CYP1A2, mebendazole technology, applied in the field of drug combinations comprising mebendazole and strong or moderate CYP1A2 inhibitors, can solve the problems of poor absorption, insufficient bioavailability, low systemic bioavailability and the like

Pending Publication Date: 2021-11-02
제파팜리미티드
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0021] The low systemic bioavailability of mebendazole limits the development of clinical treatments against proliferative diseases, including different types of cancer, as well as against parasites
In particular, mebendazole is believed to be primarily bioavailable because the absorption through the gastrointestinal tract is too poor (subsequently absorbed mebendazole is first-pass metabolized in the liver) to be unsuitable for the active drug mebendazole requiring therapeutic concentrations Treatment of systemic distribution of azoles such as proliferative diseases including different cancers and many parasitic and fungal diseases

Method used

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  • Pharmaceutical combinations comprising mebendazole and strong or moderate cyp1a2 inhibitor
  • Pharmaceutical combinations comprising mebendazole and strong or moderate cyp1a2 inhibitor
  • Pharmaceutical combinations comprising mebendazole and strong or moderate cyp1a2 inhibitor

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Embodiment approach

[0167] Certain embodiments of the invention are described in more detail below. Unless otherwise specified, the embodiments described below apply to each of the first to ninth aspects of the present invention.

[0168] The pharmaceutical composition comprises mebendazole or a pharmaceutically acceptable salt, solvate, hydrate, N-oxide, prodrug or active metabolite thereof and a strong or moderate CYP1A2 inhibitor.

[0169] In some embodiments:

[0170] - Strong or moderate CYP1A2 inhibitors are furofylline, thiabendazole, fluvoxamine, 8-phenylphylline, ciprofloxacin, enoxacin, or zafirlukast, or their pharmaceutically acceptable Salts, solvates, hydrates, N-oxides, prodrugs or active metabolites of .

[0171] In some embodiments:

[0172] - Mebendazole has an IC of 1 μM or less against neuroblastoma, sarcoma, renal or ovarian cancer derived cell lines in cell viability assays 50 ;and

[0173] - A strong or moderate CYP1A2 inhibitor is furofylline or a pharmaceutically acc...

Embodiment 1

[0204] Example 1: Investigation of whether mebendazole is a substrate of the human efflux transporters P-gp and BCRP in polarized Caco-2 cell monolayers

[0205] The aim of this study was to evaluate the potential of mebendazole as a substrate of the human efflux transporters P-gp and BCRP in polarized Caco-2 cell monolayers. Test compounds (10 μΜ in the absence and presence of reference inhibitors) were incubated with polarized cell monolayers for 120 min. Bidirectional apparent permeability of test compounds was quantified by LC-MS / MS and used to determine efflux ratio.

[0206] The efflux ratio of the positive control substrate in the absence and presence of the reference inhibitor was determined from incubations run with the test compound and demonstrated that the in vitro test system was able to detect the transported substrate. For the P-gp substrate assessment, the efflux ratios of tarilolol obtained in the absence (ER=52.2) and presence (ER=1.48) of the reference inhi...

Embodiment 2

[0217] Example 2: Investigation of whether mebendazole is a substrate of human SLC transporters OATP1B1 and OATP1B3 in transiently transfected HEK293 cells

[0218] The aim of this study was to evaluate the potential of mebendazole as a substrate of human SLC transporters (OATP1B1 and OATP1B3) in transfected HEK293 cells. Test compounds (1 and 10 μΜ) were incubated with HEK293 cells expressing SLC transporter and control (empty vector) HEK293 cells for 2 min. Absorption of test compounds was quantified by LC-MS / MS and used to determine absorbance ratio.

[0219] The uptake ratio of the positive control substrate was determined from incubations run with the test compound and demonstrated that the in vitro test system was able to detect the transported substrate. The absorbance ratios obtained for [3H]-estradiol 17β-D-glucuronide confirmed that the in vitro test system is capable of detecting substrates of OATP1B1. The calculated absorbance ratios of 1 μM and 10 μM mebendazole...

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Abstract

The invention relates to a pharmaceutical composition comprising mebendazole and a strong or moderate cytochrome P4501A2(CYP1A2) inhibitor, preferably fluvoxamine, thiabendazole or furafylline.

Description

[0001] field of invention [0002] The present invention relates to a drug combination comprising a benzimidazole compound mebendazole and a strong or moderate cytochrome P4501A2 isoenzyme (CYP1A2) inhibitor. [0003] Background of the invention [0004] Benzimidazoles represent a class of pharmacologically active compounds known to be active against biological targets relevant to the treatment of a variety of diseases. Known benzimidazoles, such as mebendazole, nocodazole, benomyl, carbendazim, oxbendazole (oxfendazole), albendazole, risbendazole (albendazole sulfoxide), thiabendazole, fenbendazole, triclabendazole and flubendazole have antiparasitic effects, including antihelminth and antiprotozoal activities and act as microtubule inhibitors. These microtubule-inhibiting benzimidazoles are active in animal cells as well as in parasites. Benzimidazoles have also been found to have additional mechanisms of action associated with all types of cancers / tumors and other prolifer...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4184A61K31/138A61K31/15A61K31/37A61K31/404A61K31/496A61K31/522A61P1/16A61P15/00A61P17/06A61P19/04A61P19/06A61P29/00A61P31/00A61P33/00
CPCA61K31/4184A61K31/522A61K31/496A61K31/15A61K31/404A61K31/37A61K31/138A61P35/00A61P31/00A61P33/00A61P1/16A61P19/06A61P19/04A61P17/06A61P15/00A61P29/00Y02A50/30A61K2300/00A61K31/427A61K45/06
Inventor 约翰·泰勒
Owner 제파팜리미티드
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