Patent Application: US-201414313338-A

Abstract:
a method for reducing scarring comprises applying into a wound a composition comprising resveratrol . the wound was formed at most one day before the applying , and no part of the skin surface of the wound is more than 3 cm from uninjured skin .

Description:
the present invention makes use of the discovery that compositions containing resveratrol , when applied into a wound soon after the initial injury , will greatly reduce scarring . in some cases , compositions containing resveratrol may even eliminate scarring altogether . also discovered is that these effects of resveratrol may be enhanced when combined with one or more additional active agents . it has been discovered that if a wound or incision is completely healed in less than 3 days , before fibroplasia begins , then no scar will be formed at the location of the wound or incision . therefore composition containing resveratrol will allow for scar free healing when applied to wounds or incisions that do not have any injured or missing tissue which is more than 3 cm from uninjured tissue . examples include almost all incisions purposefully created by a surgeon , because the surgeon is able to bring the edges of the skin at the location of the incision to well within 3 cm of each other . preferably , no part of the skin surface of the wound is more than 3 cm from uninjured skin , more preferably no part of the skin surface of the wound is more than 2 cm from uninjured skin , even more preferably no part of the skin surface of the wound is more than 1 cm from uninjured skin , and most preferably no part of the skin surface of the wound is more than 0 . 5 cm from uninjured skin . compositions containing resveratrol , either as the sole active agent or in combination with other active agents , is preferably applied to a wound or incision at any time from prior to formation of a wound or incision up until at most one day after the formation of a wound or incision ; more preferably prior to formation of a wound or incision , up until at most 1 hour after the formation of a wound or incision ; and most preferably prior to formation of a wound or incision , up until at most 10 minutes after the formation of a wound or incision . preferably , only a single application of a composition containing resveratrol is used . for example , a composition containing resveratrol may be applied topically to an incision site , or injected below an incision site , then the skin may be cut , optionally followed by closing the incision ; for example the deep structures which have been cut under the skin may be tied down using vicryl ™ ( polyglactin 910 ) sutures , and then skin sutured or sealed using dermabond advanced ™ topical skin adhesive or new - skin ® liquid bandage . alternatively , a composition containing resveratrol may be applied to the incision or wound after it is formed , followed by closing the wound or incision as described above . preferably , resveratrol is present in a composition at a concentration of at least 0 . 01 micromoles / liter , more preferably at a concentration of at least 0 . 10 micromoles / liter , and most preferably at a concentration of at least 0 . 50 micromoles / liter . preferably , resveratrol is present in the composition at a concentration of at most 100 micromoles / liter , more preferably at most 40 micromoles / liter . examples include 0 . 75 , 0 . 80 , 0 . 90 , 1 . 0 , 1 . 25 , 1 . 5 , 1 . 6 , 1 . 7 , 1 . 8 , 1 . 9 , 2 . 0 , 2 . 1 , 2 . 19 , 2 . 2 , 2 . 3 , 2 . 4 , 2 . 5 , 2 . 6 , 2 . 7 , 2 . 8 , 2 . 9 , 3 . 0 , 3 . 25 , 3 . 5 , 3 . 75 , 4 . 0 , 4 . 25 , 4 . 5 , 4 . 75 , 5 . 0 , 5 . 5 , 6 . 0 , 6 . 5 , 7 . 0 , 7 . 5 , 8 . 0 , 9 . 0 , 10 . 0 , 15 . 0 , 20 . 0 , 25 . 0 , 30 . 0 and 35 . 0 micromoles / liter . concentrations of resveratrol above 100 micromoles / liter appear to be cytotoxic to keratinocytes . in some forms , such as gels and pastes , the delivery medium limits contact with the surrounding tissue , the surrounding tissue rapidly degrades the resveratrol , and the tissue itself will absorb the resveratrol , resulting in a much lower effective concentration of resveratrol . in those cases , the concentration of resveratrol may optionally be increased 10 fold . in those cases , preferably resveratrol is present in a composition at a concentration of at least 0 . 1 micromoles / liter , more preferably at a concentration of at least 1 . 0 micromoles / liter , and most preferably at a concentration of at least 5 . 0 micromoles / liter . preferably , resveratrol is present in those compositions at a concentration of at most 1000 micromoles / liter , more preferably at most 400 micromoles / liter . examples include 7 . 5 , 8 . 0 , 9 . 0 , 10 , 12 . 5 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 21 . 9 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 32 . 5 , 35 , 37 . 5 , 40 , 42 . 5 , 45 , 47 . 5 , 50 , 55 , 60 , 65 , 70 , 75 , 80 , 90 , 100 , 150 , 200 , 250 , 300 and 350 micromoles / liter . resveratrol has a very low solubility in water , however only that portion which is dissolved in water will exert its effects . furthermore , if the resveratrol is applied dissolved in a hydrophobic medium , it may slowly diffuse into the surrounding aqueous medium , and undesirably extend the effective application time . therefore , it is preferable that the resveratrol be applied as a solution in an aqueous medium . for ease of application in a clinical setting , preferably the aqueous medium is a gel , paste , foam , suspension or thickened solution . examples include aqueous compositions containing hydroxypropyl methylcellulose , high molecular weight hyaluronic acid , polyethylene glycol , agar , dextrin , pectin , trehalose , xanthan gum , polyoxyethylene alkyl ethers , chitosan , guar gum and sodium alginate . other vehicles , adjuvants and excipients , which are hydrophilic or have hydrophilic moieties , and are compatible which application into wounds , may also be used . other pharmaceutically acceptable adjuvant , excipients and vehicles may also be included . premeasured amounts of the compositions containing resveratrol may also be used . these are referred to as unit dosage forms , since each premeasured amount is intended to be used on a single patient for one or more application , all used at the same time . examples include prefilled syringes , pouches , packets and tubes . another example would be a tube or dispenser which may be used to form foam of its contents just prior to application , for example by shaking or using a foaming agent . a self - foaming tablet , which forms foam when placed into water , could also be used . the volume of material present in these unit dosage forms may be at least 0 . 1 to 100 ml , or 1 to 50 ml . including 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 20 , 25 , 30 , 35 , 40 and 45 ml . other active agents may be included , such as other activators of sirt1 ; hdac2 ( a class i histone deacetylase ) inhibitors , such as trichostatin a ; agents which stimulate the production of certain growth factors such as egf , fgf - 10 and igf - 1 ; luteolin ; tretinoin ( all - trans retinoic acid ); and high molecular weight hyaluronic acid . although it is not known exactly how resveratrol reduces scarring , resveratrol does up - regulate and increase the expression of a variety of agents which are involved in wound healing . one possible explanation is that resveratrol causes the over - expression of mmp - 9 , interleukin - 8 ( il - 8 ) and sirt1 , and increases expression of egfr on the keratinocyte membrane and nucleus . sirt1 may then promote differentiation , motility and proliferation of keratinocytes , and deacetylation and inactivation of p53 protein thus inhibiting p53 - dependent cell death from apoptosis in response to stress in human tenocytes ( fibroblast - like tendon cells ). sirt1 may induce nitric oxide ( no ) production , which inhibits class i hdac 2 from blocking growth factors , including epithelial growth factor , keratinocyte growth factor 2 , fibroblast growth factor 10 ( fgf - 10 ), and insulin - like growth factor 1 ( igf - 1 ). sirt1 may also decrease inflammation and apoptosis through a variety of mechanisms . il - 8 has a direct and profound stimulatory effect on the migration of keratinocytes , which is likely due via the plc - gamma pathway , and furthermore il - 8 may recruit neutrophils . as noted above , mmp - 9 degrades the type iv collagen of the basement membrane . egfr may cause keratinocyte and fibroblast migration and may protect and repair tissue through nuclear dna repair . resveratrol may also inhibit nf - kb dependent proinflammatory and matrix degrading gene products induced by il - 1β and nicotinamide . in vivo application of various compositions containing resveratrol in a rat model in this example , 15 sprague dawley rats , 6 - 8 weeks old , will be placed randomly into 5 different groups , study groups 1 - 5 , resulting in 3 animals per study group . an incision , 2 cm in length , will be made on both the right and left shoulder of each rat : the left side will be an untreated control , while the right side will be treated with the compositions 1 - 5 , with the study group number corresponding to the composition number . the compositions 1 - 5 are : ( 1 ) 0 . 5 g resveratrol in 1 . 0 cc aqueous hydroxypropyl methyl cellulose gel ( resveratrol concentration = 2 . 19 micromoles / liter ); ( 2 ) 0 . 5 g resveratrol in 1 . 0 cc aqueous high molecular weight hyaluronic acid gel ( resveratrol concentration = 2 . 19 micromoles / liter ); ( 3 ) 0 . 5 g resveratrol and 0 . 5 g tretinoin in 1 . 0 cc aqueous hydroxypropyl methyl cellulose gel ( resveratrol concentration = 2 . 19 micromoles / liter ); ( 4 ) 0 . 5 g resveratrol and 0 . 5 g luteolin in 1 . 0 cc aqueous hydroxypropyl methyl cellulose gel ( resveratrol concentration = 2 . 19 micromoles / liter ); and ( 5 ) resveratrol powder . after each incision is made , the resveratrol containing composition will be applied to the right incision just prior to closure using interrupted 5 - 0 nylon sutures . the left incision will also be closed using interrupted 5 - 0 nylon sutures . each incision will be photographed and measurements will be taken , each day for 7 days . on the 4 th day , serum blood samples will be taken for systemic absorption assay . on the 7 th day , a punch biopsy will be taken from each test and control incision . since each skin flap of the incisions is very close together , when the composition containing resveratrol is applied soon after the incision is made , the incision on the right shoulder heals before fibroplasia begins , so no scar is formed . this is in contrast to the otherwise identical incision on the left side , where no resveratrol is applied , which displays a typical scar . ehrlich h , krummel t : regulation of wound healing from a connective tissue perspective . wound repair & amp ; 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