Formulation and process for modulating wound healing

• US 10,045,950 B2
• Filed: 04/07/2016
• Issued: 08/14/2018
• Est. Priority Date: 04/08/2015
• Status: Active Grant

• Current Assignee: Biomendics, LLC
• Original Assignee: Biomendics, LLC
• Inventors: Tsai, Chun-che, McGuire, Karen M., Jamison, James M., Summers, Jack L.
• Primary Examiner(s): PACKARD, BENJAMIN J
• Application Number:
  US15/093,146
• Publication Number:
  US 20160296477A1
• Time in Patent Office: 859 Days
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/03 aromatic
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/085 having an ether linkage to aromatic ring nuclear carbon
• CPC Class Codes: A61K 31/09 having two or more such linkages
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/375 Ascorbic acid, i.e. vitamin C; Salts thereof
• CPC Class Codes: A61K 31/655 Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
• CPC Class Codes: A61K 31/7034 attached to a carbocyclic compound, e.g. phloridzin
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/36 Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
• CPC Class Codes: A61K 47/40 Cyclodextrins; Derivatives thereof
• CPC Class Codes: A61K 8/33 containing oxygen
• CPC Class Codes: A61K 8/347 Phenols
• CPC Class Codes: A61K 8/602 Glycosides, e.g. rutin
• CPC Class Codes: A61K 8/676 Ascorbic acid, i.e. vitamin C
• CPC Class Codes: A61K 8/70 containing perfluoro groups, e.g. perfluoroethers
• CPC Class Codes: A61K 8/733 Alginic acid; Salts thereof
• CPC Class Codes: A61K 8/738 Cyclodextrins
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• 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: A61K 9/08 : Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/19 : lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/04 : for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 : for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/06 : Antiasthmatics
• CPC Class Codes: A61P 13/12 : of the kidneys
• CPC Class Codes: A61P 15/00 : Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/00 : Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 : for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 : Antipsoriatics
• CPC Class Codes: A61P 17/14 : for baldness or alopecia
• CPC Class Codes: A61P 19/02 : for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 : for osteoporosis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 : Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/02 : Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/12 : Antivirals
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• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61Q 19/08 : Anti-ageing preparations
• CPC Class Codes: A61Q 7/00 : Preparations for affecting hair growth
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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 —(R³)_p or —(R⁴)_q;
  • R¹ to R⁴ 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 R¹ to R² 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.

Claims

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);

2. The method of claim 1 wherein the tolan is a hydroxylated tolan, having from 1 to 4 hydroxyl substituents.

3. The method of claim 2 wherein the tolan is selected from 2,4,4′

-trihydroxytolan;

4,3′

,5′

-trihydroxytolan;

2,2′

,4,4′

-tetrahydroxytolan;

3,3′

,5,5′

-tetrahydroxytolan; and

4-hydroxy-4′

-(trifluoro)methyltolan.

4. The method of claim 2 wherein the tolan is selected from 4,4′

-dihydroxy-3-methoxytolan;

2,4,4′

-trihydroxytolan-beta-D-glucoside; and

4-hydroxy-4′

-methoxytolan.

5. The method of claim 1, further comprising co-administering an auxiliary autophagy modulating compound.

6. The method of claim 5 wherein the auxiliary autophagy modulator compound is administered at the same time as the first autophagy modulator compound.

7. The method of claim 5 wherein the auxiliary autophagy modulator compound is administered prior to administering the first autophagy modulator compound.

8. The method of claim 5 wherein the auxiliary autophagy modulating compound is selected from the group consisting of substituted or unsubstituted parabenzoquinone;

substituted or unsubstituted orthobenzoquinone; and

substituted or unsubstituted anthraquinone.

9. The method of claim 5 wherein the auxiliary autophagy modulating compound is selected from the group consisting of an amino acid, an acidic monosaccharide, and a vitamin or a salt thereof.

10. The method of claim 9 wherein the vitamin is an oxygen-containing vitamin.

11. The method of claim 9 wherein the vitamin is an isoprenoid-containing vitamin.

12. The method of claim 1, wherein the first autophagy modulating compound upregulates autophagy activity.

13. The method of claim 12, 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 and veneral ulcer.

14. The method of claim 12, wherein the wound or skin condition is one or more dermatological disorders selected from hyperkeratosis, photo-aging, psoriasis, skin rashes, sunburns and photoreactive processes.

15. The method of claim 12, wherein the wound or skin condition is one or more selected from mouth sores and burns, post-extraction wounds, endodontic wounds, cysts, abscesses, ulcers and lesions of bacterial, viral or autoimmunological origin, mechanical, chemical, thermal, infectious and lichenoid wounds;

herpes ulcers, stomatitis aphthosa, acute necrotizing ulcerative gingivitis and burning mouth syndrome, such as is amenable to treatment in form of a mouth wash or spray.

16. The method of claim 12, wherein the wound or skin condition is one or more selected from corneal ulcers, radial keratotomy, corneal transplants, epikeratophakia and other surgically induced wounds in the eye, such as is amenable to treatment with opthalmological preparations.

17. The method of claim 12, wherein the wound or skin condition is one or more selected from anal pruritus, proctitis, anal fissures, and hemorrhoids, such as are amenable to treatment with anorectal cream or suppositories.

18. The method of claim 12, wherein the wound or skin condition is one or more selected from dry cracked skin;

severe dry skin, venous dermatitis, UV light damage and seborrheic conditions.

19. The method of claim 12, wherein the wound or skin condition is one or more selected from burns, anthrax, tetanus, gas gangrene, scalatina, erysipelas, sycosis barbae, folliculitis, impetigo contagiosa, and impetigo bullosa.

20. The method of claim 12, wherein the wound or skin condition is one or more associated with aging of the skin selected from elasticity of said skin, firmness of said skin, and the appearance of wrinkles or cellulite on the skin, and non-acne inflammation of the skin.

21. The method of claim 12, wherein the wound or skin condition is selected from oral and paraoral ulcers, resulting from radiation or chemotherapy, or both.

26. The method of claim 1, further comprising administering a first autophagy modulating compound having the structure (I) wherein at least one R¹ or at least one R² is methoxy.

22. 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);

23. The method of claim 22, wherein the patient suffers from a condition in need of autophagy upregulation, said condition comprising one or more of:

wound healing, hair regrowth, inflammation, Parkinson'"'"'s disease, neurodegenerative diseases, neuropathy, cardiovascular disease, heat failure, heart disease, aging, atherosclerosis, arterosclerosis, chronic obstructive pulmonary disease (COPD), Crohn'"'"'s disease, inflammatory bowel, colitis, diabetes, diabetes type I and II, amyloidosis, bursitis, dermatitis, angitis, autoimmune diseases with inflammation, blood diseases, aplastic anemia, endometriosis, hepatitis, HIV, multiple sclerosis, retinal detachment, age-related macular degeneration, retinitis pigmentosa, and Leber'"'"'s congenital amaurosis, lysosomal storage diseases, arthritis, psoriasis, osteopenia, osteoporosis, surgical scars, surgical adhesions, space travel (bone density disorder), tendonitis, and ulcerative colitis.

24. The method of claim 22, wherein the patient suffers from a condition in need of autophagy downregulation, said condition comprising one or more of:

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 (UR) injury, organ and tissue transplant, scleroderma, and sepsis.

25. The method of claim 22, further comprising administering a first autophagy modulating compound having the structure (I) wherein at least one R¹ or at least one R² is methoxy.