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EP-4739274-A1 - PHARMACEUTICAL COMPOSITIONS FOR USE IN REDUCING HYPERPIGMENTATION

EP4739274A1EP 4739274 A1EP4739274 A1EP 4739274A1EP-4739274-A1

Abstract

A method for reducing hyperpigmentation in a subject, comprising administering an effective amount of a pharmaceutical composition to a skin site of a subject in need thereof, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a stilbene compound, for example, a compound of Formula (I) (e.g., Formula (I-A)), or a pharmaceutically acceptable salt thereof.

Inventors

  • LING, Yufang

Assignees

  • Caliway Biopharmaceuticals Co. Ltd.

Dates

Publication Date
20260513
Application Date
20240703

Claims (20)

  1. A method for reducing hyperpigmentation in a subject, comprising administering an effective amount of a pharmaceutical composition to a skin site of a subject in need thereof, wherein the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein each of R 1 , R 2 , R 3 , R 4 , and R 8 independently, is H, halogen, thiol, hydroxyl, C1-4 alkyl, C2-4 alkenyl, OR 5 , COOR 6 , or -OC (=O) R 7 ; and wherein each of R 5 , R 6 , and R 7 are independently H, or C1-4 alkyl.
  2. The method of claim 1, wherein the compound of Formula (I) has following structure: wherein each of R 1 , R 2 , R 3 , and R 4 is set forth in claim 1.
  3. The method of claim 1 or claim 2, wherein at least one of R 1 , R 2 , R 3 , and R 4 is hydroxyl or methoxy.
  4. The method of claim 3, wherein at least three of R 1 , R 2 , R 3 , and R 4 are hydroxyl or methoxy.
  5. The method of claim 1 or claim 2, wherein at least one of R 1 , R 2 , R 3 , and R 4 is OC (=O) R 7 , in which R 7 is C1-4 alkyl, optionally methyl.
  6. The method of claim 5, wherein at least three of R 1 , R 2 , R 3 , and R 4 are OC (=O) R 7 , in which R 7 is C1-4 alkyl, optionally methyl.
  7. The method of any one of claims 1 and 3-6, wherein R 8 is hydroxyl.
  8. The method of claim 1, wherein the compound has one of the following structures:
  9. The method of any one of claims 1-8, wherein the pharmaceutically acceptable carrier comprises a non-ionic surfactant having a hydrophilic-lipophilic balance value (HLB value) greater than 5, a solvent, a buffer agent, an oil phase, or a combination thereof.
  10. The method of claim 9, wherein the non-ionic surfactant comprises polyoxyl castor oil, and/or polyoxyl hydrogenated castor oil.
  11. The method of claim 9 or claim 10, wherein the pharmaceutically acceptable carrier comprises the solvent, which is a polyol or a polymer thereof, acetone, dimelthyl sulfoxide, glycerol, alcohol, or a combination thereof; optionally wherein the polyol or polymer thereof is ethylene glycol, polyoxyethylene, polyethylene glycol, or propylene glycol.
  12. The method of any one of claims 9-11, wherein the pharmaceutically acceptable carrier comprises the oil phase, which comprises soybean oil and/or medium-chain triglycerides.
  13. The method of any one of claims 1-12, wherein the pharmaceutical composition comprises a plurality of nanoparticles formed by the pharmaceutically acceptable carrier and the compound of Formula (I) , or a pharmaceutically acceptable salt thereof.
  14. The method of claim 13, wherein the nanoparticles have an average particle size of up to 200 nm and a polydispersity index (PDI) value of up to 0.4.
  15. The method of claim 13 or claim 14, wherein the pharmaceutically acceptable carrier comprises the non-ionic surfactant and wherein the weight ratio between the compound of Formula (I) or the pharmaceutically acceptable salt thereof to the non-ionic surfactant ranges from 1: 1 to 1: 1000, optionally 1: 1 to 1: 500.
  16. The method of any one of claims 1-15, wherein the pharmaceutical composition is administered to the skin site via intradermal injection or topical application.
  17. The method of any one of claims 1-16, wherein the pharmaceutical composition further comprises an active agent for reducing hyperpigmentation, wherein the active agent is different from the compound or the pharmaceutically acceptable salt thereof.
  18. The method of any one of claims 1-17, wherein the method further comprises administering to the subject an active agent for reducing hyperpigmentation, wherein the active agent is different from the compound or the pharmaceutically acceptable salt thereof.
  19. The method of any one of claims 1-18, wherein the pharmaceutical composition further comprises an antioxidant.
  20. The method of any one of claims 1-18, wherein the pharmaceutical composition is free of water and/or an antioxidant.

Description

PHARMACEUTICAL COMPOSITIONS FOR USE IN REDUCING HYPERPIGMENTATION CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing dates of U.S. Provisional Application No. 63/512,421, filed July 7, 2023, the entire contents of which are incorporated by reference herein. BACKGROUND Hyperpigmentation causes patches of skin to become darker than the surrounding skin. It occurs when the skin produces excess melanin. Pigmentation of the skin results from the accumulation of melanin-containing melanosomes in the basal layer of the epidermis. Melanins are polymorphous and multifunctional biopolymers which are represented by eumelanin, pheomelanin and neuromelanin. An appropriate amount of melanin in the skin can absorb ultraviolet (UV) lights and maintain the skin’s body temperature, thereby protecting the skin from UV light. However, Excessive melanin can make the skin look dull, resulting in an unpleasant appearance. Further, the excess of melanin can lead to pigmented skin diseases such as skin melanization or spots and freckles, etc. Melanin production can also cause problems in other organs, e.g., animal skin, hair, eyes, ears, or brain. It is therefore of interest to develop compositions capable of modulating melanin levels, thereby reducing hyperpigmentation. Therefore, the ability to remove or lessen the appearance of hyperpigmentation (e.g., melasma, seborrheic keratosis, chloasma, freckles, sunburn, or aging skin) can be of interest to individuals desiring a uniform skin color and a more radiant complexion. Report on “2017-2022 Monitoring and Prospect Forecast of Chinese Whitening Market” issued by the Intelligence Research Group indicates that more than 80%of Chinese females have a demand for skin whitening for those between the ages of 20 to 50, and there is a nearly 66 billion whitening product market every year. Therefore, there is a significant market for a safe and effective product for controlling skin pigmentation. SUMMARY The present application is based, at least in part, on the surprising discovery that a stilbene-based compound (e.g., 4- [ (E) -2- (3, 5-dihydroxyphenyl) ethenyl] benzene-1, 3-diol) exhibited significant melanin-inhibiting activity, both in vitro and in vivo. Accordingly, such compounds are expected to be highly effective in reducing hyperpigmentation. Accordingly, provided herein is a method for reducing hyperpigmentation in a subject, comprising administering an effective amount of a pharmaceutical composition to a skin site of a subject in need thereof. In some embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable carrier and a stilbene compound, which may have the structure of Formula (I) or a pharmaceutically acceptable salt thereof: in which each of R1, R2, R3, R4, and R8 independently, is H, halogen, thiol, hydroxyl, C1-4 alkyl, C2-4 alkenyl, OR5, COOR6, or -OC (=O) R7. Each of R5, R6, and R7 are independently H, or C1-4 alkyl. In some examples, the stilbene compound disclosed herein may have the structural of Formula (I-A) : in which each of R1, R2, R3, and R4 is as defined herein. In some instances, at least one of R1, R2, R3, and R4 is hydroxyl. For example, three of R1, R2, R3, and R4 in the Formula (I) or Formula (I-A) compounds provided herein may be hydroxyl. In some instances, the other one can be hydrogen. In other examples, all of R1, R2, R3, and R4 may hydroxyl. In some instances, at least one of R1, R2, R3, and R4 is methoxy. For example, three of R1, R2, R3, and R4 in the Formula (I) or Formula (I-A) compounds provided herein may be methoxy. In some instances, the other one can be hydrogen. In other examples, all of R1, R2, R3, and R4 may methoxy. In some instances, at least one of R1, R2, R3, and R4 is OC (=O) R7, in which R7 is C1-4 alkyl (e.g., methyl) . For example, three of R1, R2, R3, and R4 in the Formula (I) or Formula (I-A) compounds provided herein may be OC (=O) R7, in which R7 is C1-4 alkyl (e.g., methyl) . In some instances, the other one can be hydrogen. In other examples, all of R1, R2, R3, and R4  OC (=O) R7, in which R7 is C1-4 alkyl (e.g., methyl) . Any of the Formula (I) compounds provided herein may hydroxyl at position R8. Exemplary stilbene compounds are provided below: (4- [ (E) -2- (3, 5-dihydroxyphenyl) ethenyl] benzene-1, 3-diol) , (5- [ (E) -2- (4-hydroxyphenyl) ethenyl] benzene-1, 3-diol) , (1, 2, 3-trimethoxy-5- [ (Z) -2-phenylethenyl] benzene) , (1- [ (E) -2- (2, 4-dimethoxyphenyl) ethenyl] -3, 5-dimethoxybenzene) , ( [4- [ (E) -2- (3, 5-diacetyloxyphenyl) ethenyl] phenyl] acetate) , and (5- [ (E) -2- (3-hydroxy-4-methoxyphenyl) ethenyl] benzene-1, 3-diol) . In some examples, the stilbene compound is not resveratrol. In some embodiments, the pharmaceutically acceptable carrier used in any of the pharmaceutical compositions described herein may comprise a non-ionic surfactant having a hydrophilic-lipophilic balance value (HLB value) greater than 5, a solvent (e.g.,