Formulation and Process for Modulating Wound Healing

Abstract

Methods and compounds are disclosed for wound healing by modulating autophagy. A formulation for modulating autophagy comprises a first modulating compound (FAM) selected from compounds having the general structure (I): wherein: L represents a linker selected from —C≡C—, (a tolan), —CH═CH— (a stilbene, preferably trans); or —CR a ═CR b — a stilbene derivative; where R a and R b are independently H or phenyl optionally substituted with —(R 3 ) p or —(R 4 ) q ; R 1 to R 4 are independent substituents at any available position of the phenyl rings, preferably at 3, 3′, 4, 4′, and/or 5, 5′; and m, n, p, and q are independently 0, 1, 2, or 3 representing the number of substituents of the rings, respectively, but at least one of m or n must be ≥1. Each R 1 to R 2 is independently selected from substituents described herein, including but not limited to hydroxyl, alkoxy, halo, halomethyl and glycosides. The formulation may also include an auxiliary autophagy modulating compound (AAM) as described herein. The formulation may include a hydrogel formed by the compounds themselves or otherwise and may include salts and/or complexes.

What is claimed is: 
     
         1 . A method for promoting wound healing in a patient having a wound or skin condition, comprising administering to a patient a therapeutically effective amount of a formulation comprising:
 a first autophagy modulating compound having the structure (I):   
       
         
           
           
               
               
           
         
         wherein L is a linker selected from the group consisting of: —C≡C— and —CR a ═CR b —; 
         R a  and R b  are independently H or phenyl optionally substituted with —(R 3 ) p  or —(R 4 ) q ; 
         R 1  to R 4  are independently substituents at any available position of the phenyl rings; 
         m, n, p, and q are, independently, 0, 1, 2, or 3, representing the number of substituents on the rings, respectively, and at least one of m or n must be ≥1; 
         wherein each R 1 , R 2 , R 3 , and R 4  is independently selected from:
 R 5 , wherein R 5  is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl; 
 
         optionally substituted with 1 to 3 substituents selected from —OH, —SH, -halo, —NH 2 , or NO 2 ;
 YR 6 , wherein Y is O, S, or NH; and R 6  is selected from H or R 5 ; 
 ZR 5 , wherein Z is —N(C═O)— or —O(C═O)—; 
 halo; 
 NO 2 ; 
 SO 3 Na; 
 azide; and 
 glycosides; 
 
         and salts thereof; 
         with the proviso that the first autophagy modulating compound is not resveratrol or 4,4′-(ethyne-1,2-diyl)diphenol (TOLECINE, also known as 4,4′-dihydroxytolan). 
       
     
     
         2 . The method of  claim 1 , wherein the first autophagy modulating compound is a hydroxylated tolan, having from 1 to 4 hydroxyl substituents. 
     
     
         3 . The method of  claim 1 , wherein the first autophagy modulating compound is selected from: 2,4,4′-trihydroxytolan; 4,3′,5′-trihydroxytolan; 2,2′,4,4′-tetrahydroxytolan; 3,3′,5,5′-tetrahydroxytolan; 4-hydroxy-4′-(trifluoro)methyltolan; 4,4′-dihydroxy-3-methoxytolan; 2,4,4′-trihydroxytolan-beta-D-glucoside; and 4-hydroxy-4′-methoxytolan. 
     
     
         4 . The method of  claim 1 , further comprising co-administering an auxiliary autophagy modulating compound. 
     
     
         5 . The method of  claim 4 , wherein the auxiliary autophagy modulator compound is administered at the same time as the first autophagy modulator compound. 
     
     
         6 . The method of  claim 4 , wherein the auxiliary autophagy modulator compound is administered prior to administering the first autophagy modulator compound. 
     
     
         7 . The method of  claim 4 , wherein the auxiliary autophagy modulating compound is selected from the group consisting of: substituted or unsubstituted parabenzoquinone, substituted or unsubstituted orthobenzoquinone, substituted or unsubstituted anthraquinone, an amino acid, an acidic monosaccharide, and a vitamin or a salt thereof. 
     
     
         8 . The method of  claim 7 , wherein the vitamin is an oxygen-containing vitamin or an isoprenoid-containing vitamin. 
     
     
         9 . The method of  claim 1 , wherein the first autophagy modulating compound upregulates autophagy activity. 
     
     
         10 . The method of  claim 1 , wherein the wound or skin condition is one or more selected from aging, autoimmune diseases with inflammation, avascular necrosis, bacterial infection, cancers, diabetic neuropathies, endometriosis, fungal infection, gout, hairloss, infectious arthritis, inflammation, inflammatory bowel, ischemia, Lyme disease, organ/tissue transplant, parasitic infection, psoriatic arthritis, psoriasis, pseudogout, rheumatoid arthritis, scleraderma, scurvy, sepsis, skin diseases, surgical scars, surgical adhesions, transfection procedures, ulcerative colitis, ulcers, viral infection, warts, surgical wounds, incisions, lacerations, cuts and scrapes, donor site wounds from skin transplants, traumatic wounds, infectious wounds, ischemic wounds, burns, bullous wounds, aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, subcutaneous wounds, chronic ulcers, gastric ulcers, skin ulcers, peptic ulcer, duodenal ulcer, gastric ulcer, gouty ulcer, hypertensive ischemic ulcer, stasis ulcer, sublingual ulcer, submucous ulcer, symptomatic ulcer, trophic ulcer, tropical ulcer, veneral ulcer, hyperkeratosis, photo-aging, psoriasis, skin rashes, sunburns, photoreactive processes, mouth sores and burns, post-extraction wounds, endodontic wounds, ulcers and lesions of bacterial or viral or autoimmunological origin, mechanical wounds, chemical wounds, thermal wounds, infectious and lichenoid wounds, herpes ulcers, stomatitis, aphthosa, acute necrotizing ulcerative gingivitis, burning mouth syndrome, corneal ulcers, radial keratotomy, corneal transplants, epikeratophakia, surgically induced wounds in the eye, hemorrhoids, pruritus, proctitis, anal fissures, dry cracked skin, seborrheic conditions, anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae, folliculitis, impetigo contagiosa, and impetigo bullosa. 
     
     
         11 . The method of  claim 1 , wherein the first autophagy modulating compound is dispersed in a hydrogel. 
     
     
         12 . The method of  claim 11 , wherein the hydrogel is a liquid crystalline hydrogel formed in part by the first autophagy modulating compound. 
     
     
         13 . The method of  claim 11 , wherein the hydrogel is an alginate. 
     
     
         14 . The method of  claim 11 , wherein the formulation comprises the first autophagy modulating compound combined with a cyclodextrin in a ratio of first autophagy modulating compound:cyclodextrin from about 1:1 to about 1:10. 
     
     
         15 . The method of  claim 11 , wherein the formulation comprises the first autophagy modulating compound combined in a complex with ascorbate and a cation. 
     
     
         16 . A method for promoting wound healing in a patient having a wound or skin condition, comprising administering to a patient a therapeutically effective amount of a formulation comprising:
 a first autophagy modulating compound having the structure (I):   
       
         
           
           
               
               
           
         
         wherein L is a linker comprising —CR a ═CR b —; 
         R a  and R b  are independently H or phenyl optionally substituted with —(R 3 ) p  or —(R 4 ) q ; 
         R 1  to R 4  are independently substituents at any available position of the phenyl rings; 
         m, n, p, and q are, independently, 0, 1, 2, or 3, representing the number of substituents on the rings, respectively, and at least one of m or n must be ≥1; 
         wherein each R 1 , R 2 , R 3 , and R 4  is independently selected from:
 R 5 , wherein R 5  is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl; optionally substituted with 1 to 3 substituents selected from —OH, —SH, -halo, —NH 2 , or NO 2 ; 
 YR 6 , wherein Y is O, S, or NH; and R 6  is selected from H or R 5 ; 
 ZR 5 , wherein Z is —N(C═O)— or —O(C═O)—; 
 halo; 
 NO 2 ; 
 SO 3 Na; 
 azide; and 
 glycosides 
 
         and salts thereof; 
         with the proviso that the first autophagy modulating compound is not resveratrol or 4,4′-(ethyne-1,2-diyl)diphenol (TOLECINE, also known as 4,4′-dihydroxytolan). 
       
     
     
         17 . The method of  claim 16 , wherein the first autophagy modulating compound is a trans-stilbene wherein L is —CH═CH—. 
     
     
         18 . The method of  claim 17 , wherein the stilbene is a hydroxylated stilbene, having from 1 to 4 hydroxyl substituents. 
     
     
         19 . A method for modulating autophagy in a patient in need of autophagy modulation, comprising administering to a patient a therapeutically effective amount of a formulation comprising:
 a first autophagy modulating compound having the structure (I):   
       
         
           
           
               
               
           
         
         wherein L is a linker selected from the group consisting of: —C≡C— and —CR a ═CR b —; 
         R a  and R b  are independently H or phenyl optionally substituted with —(R 3 ) p  or —(R 4 ) q ; 
         R 1  to R 4  are independently substituents at any available position of the phenyl rings; 
         m, n, p, and q are, independently, 0, 1, 2, or 3 representing the number of substituents on the rings, respectively, and at least one of m or n must be ≥1; 
         wherein each R 1 , R 2 , R 3 , and R 4  is independently selected from:
 R 5 , wherein R 5  is selected from (C 1 -C 6 )alkyl, (C 2 -C 6 )alkenyl, or (C 2 -C 6 )alkynyl; optionally substituted with 1 to 3 substituents selected from —OH, —SH, -halo, —NH 2 , or NO 2 ; 
 YR 6 , wherein Y is O, S, or NH; and R 6  is selected from H or R 5 ; 
 ZR 5 , wherein Z is —N(C═O)— or —O(C═O)—; 
 halo; 
 NO 2 ; 
 SO 3 Na; 
 azide; and 
 glycosides; 
 
         and salts thereof. 
       
     
     
         20 . The method of  claim 19 , wherein the patient suffers from a condition in need of autophagy upregulation, said condition comprising one or more of: wound healing, hair regrowth, bacterial infections, inflammation, viral infection, Parkinson's disease, neurodegenerative diseases, neuropathy, cardiovascular disease, heat failure, heart disease, aging, Alzheimer's disease, atherosclerosis, arterosclerosis, chronic obstructive pulmonary disease (COPD), Crohn's disease, inflammatory bowel, colitis, diabetes, diabetes type I or II, amyloidosis, bursitis, dermatitis, angitis, autoimmune diseases with inflammation, blood diseases, aplastic anemia, endometriosis, hepatitis, herpes, HIV, multiple sclerosis, retinal detachment, age-related macular degeneration, retinitis pigmentosa, Leber's congenital amaurosis, lysosomal storage diseases, arthritis, psoriasis, osteopenia, osteoporosis, surgical scars, surgical adhesions, space travel (bone density disorder), tendonitis, ulcerative colitis, aging, cancer, polycystic kidney and liver disease, kidney disease, liver disease, asthma, diabetic retinopathy, fibromyalgia, ankylosing spondylitis, celiac disease, Grave's disease, lupus, metabolic diseases, nephritis, rheumatoid arthritis, osteolysis, ischemia-reperfusion (I/R) injury, organ and tissue transplant, scleraderma, and sepsis.