USE OF ISOTHIOCYANATE FUNCTIONAL SURFACTANTS AS NRF2 INDUCERS TO TREAT EPIDERMOLYSIS BULLOSA SIMPLEX AND RELATED DISEASES

• US 20190330145A1
• Filed: 07/09/2019
• Published: 10/31/2019
• Est. Priority Date: 01/03/2011
• Status: Active Grant

• Current Assignee: The William M. Yarbrough Foundation
• Original Assignee: The William M. Yarbrough Foundation
• Inventors: Silver, Michael E.
• Granted Patent: US 10,640,464 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/145 having sulfur, e.g. thiurams (>N—C(S)—S—C(S)—N< and >N—C(S)—S—S—C(S)—N<), Sulfinylamines (—N=SO), Sulfonylamines (—N=SO2) isothiourea A61K31/155
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/26 Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/06 Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• CPC Class Codes: A61K 47/34 Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers A61K47/10 takes precedence
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/06 Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: C07C 331/20 of a saturated carbon skeleton

Abstract

The present invention relates to methods and compositions for the prevention and treatment of keratin-based skin diseases. In particular, the application describes compositions and methods of treating a patient suffering from skin blistering comprising the use of phase II enzyme inducers and/or activity modifiers.

Claims

1. A method for treating or preventing skin blistering in a patient in need thereof or at risk of developing skin blistering, comprising the step of administering to the patient a composition comprising a therapeutically effective amount of an Nrf2 inducer, wherein the Nrf2 inducer comprises an isothiocyanate functional surfactant.

2. The method according to claim 1, wherein the patient suffers from skin blistering.

3. The method according to claim 1, wherein the Nrf2 inducer is a phase II enzyme inducer.

4. The method according to claim 1, wherein the Nrf2 inducer causes the selective induction of K6, K16 or K17 in the keratinocytes in the skin of the patient.

5. The method according to claim 1, wherein the composition comprising the Nrf2 inducer is topically administered to the patient.

6. The method according to claim 5, wherein the amount of Nrf2 inducer in the composition topically administered to the patient is from about 0.5 nmol/cm2 to about 10 pmol/cm2.

7. The method according to claim 6, wherein the composition comprising the Nrf2 inducer is a topical preparation selected from the group consisting of ointment, cream, emulsion, lotion and gel.

8. The method according to claim 7, wherein the composition further comprises one or more pharmaceutical, biological or molecular biological active agents.

9. The method according to claim 1, wherein the patient is a mammal.

10. The method according to claim 9, wherein the mammal is a human.

11. The method according to claim 1, wherein the patient suffers from epidermolysis bullosa simplex.

12. The method according to claim 1, wherein the patient suffers from epidermolysis bullosa simplex-weber-cockayne type, epidermolysis bullosa simplex-koebner type, epidermolysis bullosa simplex with mottled pigmentation, epidermolysis bullosa simplex-dowling-Meara type, or epidermolysis bullosa simplex with muscular dystrophy.

13. The method according to claim 12, wherein the epidermolysis bullosa simplex is caused by a mutation at the K14 locus.

14. The method according to claim 1, wherein the isothiocyanate functional surfactant comprises at least one isothiocyanate functional group associated with an aliphatic and/or aromatic carbon atom of the isothiocyanate functional surfactant.

15. The method according to claim 1, wherein the isothiocyanate functional surfactant comprises a lysine derivative, wherein the lysine derivative comprises an α

-nitrogen and a ε

-nitrogen, and wherein an alkyl and/or alkanoyl substituent comprising at least approximately 8 carbon atoms is associated with the α

-nitrogen, and further wherein at least one isothiocyanate functional group is associated with the ε

-nitrogen.

16. The method according to claim 1, wherein the isothiocyanate functional surfactant is represented by the following chemical structure:

17. The method according to claim 1, wherein the protonated form of the isothiocyanate functional surfactant is represented by the following chemical structure:

18. The method according to claim 1, wherein the protonated form of the isothiocyanate functional surfactant is represented by the following chemical structure:

19. The method according to claim 1, wherein the protonated form of the isothiocyanate functional surfactant is represented by the following chemical structure:

20. The method according to claim 1, wherein the isothiocyanate functional surfactant is represented by the following chemical structure: