Di-isopropyl-phosphinoyl-alkanes as topical agents for the treatment of sensory discomfort
Inventors
Assignees
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Publication Number
US-10195217-B2
Publication Date
2019-02-05
Expiration Date
Abstract
The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to certain di-isopropyl-phosphinoyl-alkanes as described herein, DIPA-1-5, DIPA-1-6, DIPA-1-7, DIPA-1-8, and DIPA-1-9, collectively referred to herein as “DIPA compounds”, that are useful, for example, in the treatment of disorders (e.g., diseases) including: sensory discomfort (e.g., caused by irritation, itch, or pain); a skin dysesthesia; dermatitis; ocular pain and discomfort; heat discomfort; heat stress; flushing and/or night sweats (vasomotor symptoms); post-operative hypothermia; post-anaesthetic shivering; fatigue; tiredness; depression; cognitive dysfunction; and to enhance cognitive function. The applicant has found that localized delivery of DIPA compounds to the upper eyelid and/or facial skin has an alerting and enhancement effect on behavior and can be used to give a cosmetic refreshing look, to mental alertness, to reduce fatigue, and to improve work output. The present discovery also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example, in therapy, in diagnosis of neuropathic pain, and in study of TRPM8 function.
Core Innovation
The invention relates to diisopropyl-phosphinoyl-alkanes (DIPA-1-5 through DIPA-1-9; Formula 1) as topical agents. The compounds are described as penetrating keratinized skin, including the stratum corneum, to produce a dynamic cool sensation, especially for periorbital/eyelid application.
A therapeutic method is provided for treating skin dyesthesia or dysesthesia by topically applying a liquid or semi-liquid composition. The composition comprises a therapeutically effective amount of one or more Formula 1 compounds, with R defined as n-heptyl, n-octyl or n-nonyl, and includes a pharmaceutically acceptable carrier, diluent, or excipient. Following topical application, the composition penetrates the keratinized tissues of the skin.
The described biological characterization links the compounds to TRPM8-dependent effects. The document discusses TRPM8 calcium assay EC50/potency data, TRPM8-dependent anti-nociceptive activity in isolated mouse vagus, and an in vivo rat transdermal effect model using wet-dog shaking.
Claims Coverage
The provided content includes one independent claim directed to a therapeutic topical method using Formula 1 DIPA compounds applied to keratinized tissues, with composition penetration into the keratinized tissues. Dependent claims further define concentration and specified Formula 1 embodiments with an explicit therapeutically effective dosing range.
Topical application to keratinized tissues with Formula 1 compounds
A therapeutic method comprising topically applying a liquid or semi-liquid composition to keratinized tissues of the subject's skin, the composition comprising a therapeutically effective amount of one or more compounds having Formula 1, wherein R is n-heptyl, n-octyl or n-nonyl, and wherein the liquid or semi-liquid composition, following topical application, penetrates the keratinized tissues of the subject's skin.
Liquid or semi-liquid composition including a pharmaceutically acceptable carrier
The liquid or semi-liquid composition further comprises a pharmaceutically acceptable carrier, diluent, or excipient.
Defined concentration of Formula 1 compound in topical composition
The method uses the liquid or semi-liquid composition containing about 0.05 to 2% by weight of the Formula 1 compound.
Specified DIPA embodiments and therapeutically effective dosing range
The method uses the Formula 1 compound as DIPA-1-7, DIPA-1-8, and/or DIPA-1-9, administered at a therapeutically effective amount of 1–20 mg/ml.
The claims cover topical treatment of skin dyesthesia/dysesthesia using Formula 1 diisopropyl-phosphinoyl-alkanes that penetrate keratinized skin tissues, with the use of a pharmaceutically acceptable carrier and dependent constraints specifying concentration and particular DIPA embodiments with a therapeutically effective mg/ml range.
Stated Advantages
Produces a dynamic cool sensation after topical penetration of keratinized tissues.
Anti-fatigue effects and anti-sensory discomfort effects are described in connection with periorbital/eyelid topical use.
TRPM8-dependent anti-nociceptive activity is described.
Documented Applications
Treatment of skin dyesthesia/dysesthesia by topical application to keratinized skin tissues.
Ocular discomfort treatment, including dry eye syndrome, is described via a case study involving DIPA-1-9.
Transdermal treatment contexts are described for sensory discomfort, itch, and pain.
Applications are described for fatigue, heat stress, and vasomotor symptoms.
An application is described for cognitive enhancement.
A diagnostic use is described for cold allodynia.
A laboratory reagent application is described for TRPM8 selective laboratory reagents.
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