Methods of treating a patient afflicted with non-alcoholic steatohepatitis (NASH)
Inventors
Beeley, Nigel R. A. • Foulkes, J. Gordon • Mooney, Kieran George • Evans, Charles Rodney Greenaway • Johnson, Keith Arthur • Welgus, Howard G. • Jenkinson, Celia P.
Assignees
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Publication Number
US-11865113-B2
Publication Date
2024-01-09
Expiration Date
Abstract
Pharmaceutical carriers which provide an environment of physical and chemical stability comprising a therapeutically effective amount of an active pharmaceutical ingredient (API) compound of structure I, one or more antioxidants, one or more chelators and a vehicle base comprising water and one or more pharmaceutically acceptable non-aqueous solvents, one or more absorption enhancers, one or more gelling agents and one or more pH buffering agents are described.
Core Innovation
The invention relates to treating a patient afflicted with Non-alcoholic Steatohepatitis (NASH) by applying to a patient's skin a pharmaceutical composition effective to treat the patient and alleviate the patient's NASH. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound having the structure, or a pharmaceutically acceptable salt or ester of the compound, in an amount effective to treat the patient. The invention is directed to topical skin application through a carrier system intended to support therapeutic effect while limiting systemic exposure.
The pharmaceutically acceptable carrier provides an environment of physical and chemical stability, enables retention of the amount of the compound effective to treat the patient in the patient's skin, and permits only a low level of the compound to enter and accumulate in the patient's systemic circulation. The carrier comprises ethanol, phenoxyethanol, diethylene glycol mono-ethyl ether (DEGEE or Transcutol P®), propylene glycol, PEG400, carbomer homopolymer type C980, butylated hydroxytoluene (BHT), di-sodium EDTA, trolamine, and water, with specified concentrations or ranges.
The disclosed compound scope is defined by a Structure I class and related variants, including pharmaceutically acceptable salts, esters, and prodrugs, with broad substituent definitions and stereochemical possibilities. The partial content also includes examples and related structural embodiments, while a further disclosed compound embodiment is described as a substituted pyridine-linked piperidine carboxamide core with a substituted phenylpropanol side chain.
Claims Coverage
The consolidated claim coverage centers on one independent method claim for treating NASH by applying a skin-applied pharmaceutical composition. The inventive features combine a defined compound structure (or pharmaceutically acceptable salt or ester) with a pharmaceutically acceptable carrier that provides physical and chemical stability, retains the compound in skin, and limits systemic entry and accumulation; dependent claims refine carrier composition and compound concentration, and one item also identifies a substituted pyridine-linked piperidine carboxamide with substituted phenylpropanol side chain.
Skin-applied treatment of NASH with a defined compound
Applying to a patient's skin a pharmaceutical composition effective to treat the patient and alleviate Non-alcoholic Steatohepatitis (NASH), wherein the composition comprises a pharmaceutically acceptable carrier and a compound having the structure, or a pharmaceutically acceptable salt or ester of the compound, in an amount effective to treat the patient.
Carrier providing physical and chemical stability, skin retention, and limited systemic entry
The pharmaceutically acceptable carrier provides an environment of physical and chemical stability, enables retention of the amount of the compound effective to treat the patient in the patient's skin, and permits only a low level of the compound to enter and accumulate in the patient's systemic circulation.
Specified carrier components and concentrations
The carrier comprises ethanol, phenoxyethanol, diethylene glycol mono-ethyl ether (DEGEE or Transcutol P®), propylene glycol, PEG400, carbomer homopolymer type C980, butylated hydroxytoluene (BHT), di-sodium EDTA, trolamine sufficient to provide an apparent pH in the range 6.50 to 7.50, and water, with specified concentrations or ranges.
Compound concentration limits in the composition
The pharmaceutical composition contains the compound at concentrations up to 2.50% w/w, with discrete options of 0.25%, 0.75% or 1.75% w/w, including an exact 1.75% w/w option.
Substituted pyridine-linked piperidine carboxamide with substituted phenylpropanol side chain
A compound embodiment is described as a substituted pyridine-linked piperidine carboxamide core with a substituted phenylpropanol side chain.
Overall, the claims focus on topical NASH treatment using a defined compound class together with a carrier system specified by functional stability, skin retention, and low systemic entry characteristics, with dependent refinement of excipient composition and compound concentration.
Stated Advantages
Provides an environment of physical and chemical stability.
Enables retention of the amount of the compound effective to treat the patient in the patient's skin.
Permits only a low level of the compound to enter and accumulate in the patient's systemic circulation.
Effective to treat the patient and alleviate the patient's NASH.
Reduced C-4 impurity formation under photo-stability conditions for Modified TSAG3.
Maintains similar UVA profiles while improving photo-stability performance.
Improved physical stability via selection of trolamine to buffer apparent pH and stabilize viscosity.
Allows balance of flux and deposition for TSAG3 (Modified).
Deposition exceeds IC50 for SCD-1 inhibition while systemic exposure is limited.
Documented Applications
Treating a patient afflicted with Non-alcoholic Steatohepatitis (NASH) by applying to a patient's skin a pharmaceutical composition effective to treat the patient and alleviate the patient's NASH.
Evaluating photo-stability and physical stability of transdermal gel formulations under ICH visible and UVA conditions and in ICH tube studies.
Assessing Compound A release, permeation or flux, and deposition using Franz diffusion cells with human cadaver skin and artificial membranes.
Topical gel formulation application using TSAG3 and modified TSAG3, with stability evaluation and skin permeation and deposition.
Use of SCD1 inhibitor compounds in vitro, including inhibition of neutral lipid accumulation and effects on 14C-acetate incorporation in primary human sebocytes.
Cell-based applications including cytotoxicity across cancer and normal cell lines and modulation by oleic acid.
Biological application to melanogenesis and adipocyte differentiation assays.
Topical in vivo weight-loss studies for the SCD1 inhibitor compounds.
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