Other

University of California

Iview Therapeutics, Inc.

Highfive Technologies, Inc.

Wei, Edward Tak

Alveonix Ag

Edward Tak Wei

Holly A Thomas

Andrzej T Slominski

Guennady P Vlasov

Kurt Carlson

Jaw-Kang Chang

Nancy M Lee

Seong Jin Kim

Wolfgang Sad&eacute;e

Juliann G Kiang

Shantanu Sinha

Wolfgang Sadée

Jeremy Roy

Jaw Kang Chang

Toshimitsu Kishimoto

J Mark Quillan

Ohene Kwasi Ohene-Adu

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-1-7, DIPA-1-8, and DIPA-1-9, collectively referred to herein as 'DIPA compounds', that are useful, for example, in the treatment of dermatological disorders (e.g., diseases) including: sensory discomfort (e.g., caused by irritation, itch, or pain); a skin dysesthesia; atopic dermatitis; contact dermatitis; cholestatic itch; psoriasis; sebhorrheic dermatitis; milaria rubra; ocular pain and discomfort; heat discomfort; heat stress; flushing and/or night sweats (vasomotor symptoms); and pruritus of the elderly. The applicant has found that topical delivery of DIPA compounds to the skin alleviates skin discomfort. The present discovery pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example, in therapy of dermatological disorders.

Di-isopropyl-phosphinoyl-alkanes as topical agents for the treatment of sensory discomfort

The present invention pertains generally to the field of therapeutic compounds. More specifically the present invention 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; psoriasis; ocular discomfort; heat discomfort; heat stress; flushing and/or night sweats (vasomotor symptoms) in post-menopausal women; post-operative hypothermia; post-anaesthetic shivering; fatigue; tiredness; depression; cognitive dysfunction; and to enhance cognitive function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, for example, in therapy.

Di-isopropyl-phosphinoyl-alkanes (DAPA) compounds as topical agents for the treatment of sensory discomfort

The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to a particular 1-di-alkyl-phosphinoyl-alkane, 1-(Diisopropyl-phosphinoyl)-nonane, referred to herein as 'DIPA-1-9'. Surprisingly and unexpectedly, DIPA-1-9, is able to selectively treat (e.g., suppress) sensory discomfort arising from the lumenal epithelial lining of the pharynx and esophagus without side effects. Compared to structurally similar compounds, DIPA-1-9 did not have the problems of painful cold, stinging, or irritancy, or of adverse taste when applied in the oral cavity. To deliver the DIPA-1-9 to the lumenal epithelium of the pharynx and esophagus, an ideal formulation for delivery is a solution of DIPA-1-9 in syrup, at a concentration of 5 to 12 mg/mL and a delivery volume of less than 1 mL. The delivery unit can be a plastic vial with a design such that the syrup is poured onto the base of the tongue, next to the pillars of fauces. The DIPA-1-9 then reaches the nerve endings at the base of the epithelia and transduces signals of coolness and cold. Cooling of the pharyngeal and esophageal lining relieves discomfort and is useful for conditions such as throat irritation, pharyngitis, tonsillitis, cough, chronic cough, heartburn, chest pain, and esophagitis. Moreover, the elicitation of cooling in the pharynx and esophagus can be utilized to treat dysphagia, dyspepsia, and dyspnoea, and to enhance mucus expectoration in inflammatory airway disorders such as cystic fibrosis, asthma, and chronic obstructive pulmonary diseases (which includes bronchitis and bronchiectasis). A particularly preferred embodiment is DIPA-1-9 dissolved in a syrup vehicle in a delivery unit volume of less than 1 mL.

Treatment of upper aerodigestive tract disorders and cough

Wearing a face mask or a filtering facepiece respirator, especially in hot weather for more than one hour, causes discomfort. But, in a viral pandemic, a barrier to filter inhaled and exhaled air is necessary to protect against airborne pathogens. The sensations of heat abstraction, that is, coolness and cold, can be captured by the rational design of optimized molecules. The topical application of these molecules alleviates the discomfort of wearing a face mask covering. Several entities were identified by synthesis and experiment as having the ideal properties for achieving this purpose. The preferred embodiments are certain 1-diisopropyl-phosphinoyl-alkanes described as DIPA-1-7, DIPA-1-8, and DIPA-1-9, collectively referred to herein as 'DIPA compounds.' The applicant found that topical delivery of DIPA compounds to the facial skin, especially to the surface of the external nares (nostrils), alleviates face mask discomfort. From these studies, I hypothesize that the absence of cool air dynamics about the nostrils causes face mask discomfort, not just static heat accumulation or excess humidity. The present discovery pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions for relieving face mask discomfort.

Method to reduce face mask and respirator discomfort

Wearing a face mask or a filtering facepiece respirator, especially in hot weather for more than one hour, causes discomfort. But, in a viral pandemic, a barrier to filter inhaled and exhaled air is necessary to protect against airborne pathogens. The sensations of heat abstraction, that is, coolness and cold, can be captured by the rational design of optimized molecules called TRPM8 receptor agonists. The topical application of these molecules alleviates the discomfort of wearing a face mask covering. Several entities were identified by synthesis and experiment as having the ideal properties for achieving this purpose. The preferred embodiments are certain 1-diisopropyl-phosphinoyl-alkanes described as DIPA-1-5, DIPA-1-6, DIPA-1-7, DIPA-1-8, and DIPA-1-9, collectively referred to herein as 'DIPA compounds.' The applicant found that topical delivery of DIPA compounds to the facial skin, especially to the surface of the nares (nostrils), alleviates face mask discomfort. From these studies, it is hypothesized that it is the absence of cool air dynamics about the nostrils that causes face mask discomfort. The present discovery pertains to pharmaceutical compositions that relieve face mask discomfort.

The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to certain di-alkyl-phosphinoyl-alkanes as described herein, DIPA-1-8 and DIPA-1-9, and 2-6 and 2-7 that are collectively referred to herein as 'DAPA compounds', that are useful in the treatment of disorders (e.g., diseases) including: sensory discomfort (e.g., caused by inflammation, irritation, itch, or pain) in the nasal cavity. The applicant has found that localized delivery of DAPA compounds in combination with an intranasal steroid or an intranasal antihistamine immediately relieves nasal discomfort and enhances patient adherence to the use of the nasal medications.

Cooling adjunct for medications to treat disorders in the nasal cavity

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.

Heat abstraction from the body's surfaces causes sensations of cold from the skin, orbit, nose, mouth, throat, upper esophagus, airways, and anogenital surfaces. The detection of heat abstraction at these sites is via TRPM8, a neuronal protein linked to nerve membranes. Chemical agents that act on TRPM8 can also produce sensations of cold, but the surface of the lower gastrointestinal tract (LGIT) does not 'feel cold', yet it contains cells with TRPM8. The pharmacology of TRPM8 in the LGIT is an unexplored subject. Menthol has a relaxant effect on gut smooth muscle, but this action is not via TRPM8. Here, a class of selective TRPM8 agonists, called 1-Dialkyl-phosphinoyl-alkanes (Dapa) were synthesized, and the potency and selectivity on TRP channels were characterized. Certain Dapa molecules were shown to inhibit neural signals in isolated vagus nerve and to exert anti-inflammatory effects in a model of heat-injury. When applied to the human colon muscle, a Dapa embodiment inhibited contractions with a median inhibitory concentration of 8 &#x3bc;g/mL. Methods for coating and formulation of Dapa with excipients for delivery to the colonic mucosa are described. The preferred Dapa embodiments are believed useful in treating the muscle spasms and the inflammation of LGIT dysfunction.

Dialkyl-phosphinoyl-alkane (Dapa) compounds and compositions for treatment of lower gastrointestinal tract disorders

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; nasal congestion and nasal obstruction; pharyngeal and esophageal discomfort; 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.

The present discovery pertains to the discovery of certain amphiphilic compounds that may be useful for the management of sebum secretion in subjects with acne, oily skin, or seborrheic dermatitis. These compounds are 1-dialkylphosphorylalkanes with the longest alkyl group being seven or more carbons. Preferably, a compound is dissolved in a dermatologically acceptable vehicle, and delivered to the skin in a solution, gel, lotion, cream, or ointment. The method of application may be with the surface of the finger, or via an applicator. The decrease is sebum secretion in certain subjects may result in skin conditions that enhance cosmetic appearance and ameliorate skin disorders.

Chemical inhibitors of sebocyte function

The present discovery pertains generally to the field of therapeutic compounds. More specifically the present discovery pertains to certain di-alkyl-phosphinoyl-alkanes as described herein, DIPA-1-8 and DIPA-1-9, and 2-6 and 2-7 that are collectively referred to herein as 'DAPA compounds', that are useful in the treatment of disorders (e.g., diseases) including: sensory discomfort (e.g., caused by inflammation, irritation, itch, or pain) in the nasal cavity. The applicant has found that localized delivery of DAPA compounds with a swab to the Kiesselbach's area of the human nose will relieve the discomforts of rhinitis and other nasal cavity discomforts.

Topical agents for the treatment of sensory discomfort in the nasal cavity

A dynamic video communications system provides real time provisioning of a video communication session in a domain video network between a set of user devices. The real time provisioning is implemented by receiving an identifier of a video communication session from a user device, where the identifier includes a domain and a name, determining an authentication principle associated with the user device, where the authentication principle includes a domain of the user, checking whether the domain of the user matches a domain of the video communication session, and joining the user device with the video communication session.

Domain trusted video network

The present invention generally relates to refreshing, soothing, and cooling compounds that affect sensory processes. More particularly, the present invention pertains to certain N-alkylcarbonyl--Ala-esters compounds as described herein; compositions and articles comprising such compounds; and methods of treatment, for example, methods of reducing skin irritation, itch, and/or pain.

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Short-chain 2- to 3-carbon alcohols are used as solvents for cooling agents in the preparation of topical therapeutic and cosmetic formulations. Some of these alcohols, especially ethanol, inhibit the ability of the cooling agent to activate its target receptor. In one embodiment of this invention, (R)-1,2-propanediol is used as an alcoholic solvent for the topical delivery of cooling agents to biological surfaces. This propanediol enantiomer has a minimum inhibitory effect on cooling with respect to standard 2- to 3-carbon alcoholic solvents, and functions to substantially protect the agent's cooling activity from inhibition when in the presence of a short-chain alcohol.

The present invention generally relates to refreshing, soothing, and cooling compounds that affect sensory processes. More particularly, the present invention pertains to certain N-alkylcarbonyl-amino acid esters compounds as described herein; compositions and articles comprising such compounds; and methods of treatment, for example, methods of reducing cough and pharyngeal irritation, itch, and/or pain.

Growing community of inventors

Berkeley, CA, United States of America

Edward Tak Wei