Pharmacologically optimized multimodal drug delivery system for nordihydroguiaretic acid (NDGA)
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Publication Number
US-9314437-B2
Publication Date
2016-04-19
Expiration Date
Abstract
The present invention relates generally to compositions and methods for oral delivery of nordihydroguaiaretic acid (NDGA). More particularly, the present invention relates to pharmacologically optimized multimodal drug delivery systems for orally administered NDGA and methods for preparation and use thereof.
Core Innovation
The invention provides an orally administered single dose of nordihydroguiaretic acid (NDGA) for treating metabolic diseases using a multimodal drug delivery system. The system is defined by multimodal NDGA delivery kinetics and includes a first portion and a second portion of NDGA with different pH-triggered release maxima. The first portion is releasable at a peak pH of 1 to 4 and the second portion is releasable at a peak pH of 5.0 to 7.5.
The multimodal drug delivery system imposes quantitative release relationships for the combined portions. Over 30% of a total portion of NDGA present in the drug delivery system is present in the second portion, and over 90% of the total portion of NDGA is releasable at a pH of 7.5 or lower. The document indicates a multimodal, including bimodal, absorption profile with intended release and absorption largely occurring before the large intestine to help avoid cecal/rectal toxicity.
The NDGA structure in the first portion or the second portion comprises Formula I, including pharmaceutically acceptable salts. The disclosed implementations include splitting the dose into tablet outer and inner portions, splitting into first and second bead formulations, and using heterogeneous biodegradable matrices. Further implementation approaches include differing water solubility between portions, including via polymer conjugation or different NDGA forms, to support the multimodal pH-dependent delivery kinetics.
Claims Coverage
The partial content identifies two independent claims. Each independent claim requires a multimodal oral NDGA delivery system with first and second portions releasable at distinct peak pH ranges, quantitative constraints on portion amounts and release at pH values, and NDGA structure defined by Formula I.
Orally administered single-dose multimodal NDGA delivery split by peak pH maxima
An orally administered single dose of NDGA for treating metabolic diseases comprising a multimodal drug delivery system having a first portion releasable at a peak pH of 1 to 4 and a second portion releasable at a peak pH of 5.0 to 7.5.
Quantitative portioning and release at pH 7.5 or lower
Over 30% of a total portion of NDGA is present in the second portion, and over 90% of the total portion of NDGA is releasable at a pH of 7.5 or lower.
NDGA structure comprises Formula I within first or second portions
The structure of the NDGA comprised in the first portion or the second portion comprises Formula I, including pharmaceutically acceptable salts.
Orally administered single-dose multimodal NDGA delivery with portion amount constraints
An orally administered single dose of NDGA for treating metabolic diseases comprising a multimodal drug delivery system having a first portion releasable at a peak pH of 1 to 4 and containing over 10% of a total portion of NDGA, and a second portion releasable at a peak pH of 5.0 to 7.5 and containing more than 30% of the total portion of NDGA.
The claim coverage centers on an oral single-dose NDGA multimodal system that splits NDGA into first and second portions with distinct peak pH release windows, requires substantial fractioning into the second portion, requires that over 90% of total NDGA is releasable at pH 7.5 or lower, and requires NDGA structure defined by Formula I.
Stated Advantages
A multimodal absorption kinetics profile, including a bimodal absorption profile.
Dose-sparing and reduced dosing frequency.
Improved glucose effects compared with triglyceride and fatty acid effects, described as an "one-two punch" effect.
Avoidance of cecal/rectal toxicity by largely releasing/absorbing NDGA before the large intestine.
Documented Applications
Treating metabolic diseases, including non-insulin-dependent diabetes mellitus (NIDDM)/hyperglycemia/insulin resistance.
Addressing hypertriglyceridemia.
Human pharmacokinetic comparison and evaluation of intended multimodal formulations, including Phase I human PK data described for comparison with an immediate-release unimodal PK formulation.
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