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Publication numberUS3689667 A
Publication typeGrant
Publication dateSep 5, 1972
Filing dateJun 24, 1970
Priority dateJun 24, 1970
Publication numberUS 3689667 A, US 3689667A, US-A-3689667, US3689667 A, US3689667A
InventorsKwan-Hua Lee
Original AssigneeUniv California
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
C22 acid and its salts to promote wound healing
US 3689667 A
A C22 homolog of retinoic acid and its salts have been found effective in promoting would healing. The acid or the salt is applied to the wound as a solution, ointment or powder.
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Description  (OCR text may contain errors)

United States Patent Lee 1 Sept. 5, 1972 54] C22 ACID AND ITS SALTS TO [56] References Cited PROMOTE WOUND HEALING UNITED STATES PATENTS [72] Invent San 3,026,249 3/1962 Ames ..424/312 3,089,823 5/1963 Czamecki ..424/312 [73] Assignee: The Regents of the University of 3,143,564 8/1964 Matsui et al. ..260/413 California Primary Examiner-Lewis Gotts [22] Flled' June 1970 Assistant Examiner-Ethel G. Love [21] Appl. No.: 49,505 Att0mey--Eckhoff and l-loppe [51] Int. Cl. ..C08h 17/36 A C homolog of retino c acid and its salts have been 58 Field of Search ..260/413; 424/344, 318 found effective in promoting would g- The acid or the salt is applied to the wound as a solution, ointment or powder.

'2 Claims, No

C22 ACE AND HTS SALTS TO PROMOTE WOUND WALKING SUMMARY OF THE INVENTION Inflammation and mucopolysaccharide synthesis are the two important features in the early stage of wound healing. The term wound as used in this application means any topical lesion such as a surgical incision, accidental wound or ulcer. Aspirin inhibits both features. The healing inhibitory action of aspirin and other inflammatory agents has been demonstrated. Vitamin A increases mucopolysaccharide synthesis and it also causes inflammation. The ability of vitamin A alone to promote healing and its efiectiveness in reversing the healing retardation action of aspirin is known. Retinoic acid (the acid form of vitamin A) and its salts also have been found active compounds in promoting healing. Topical application of retinoic acid or its salts reverses the healing retardation action caused by oral administration of sodium salicylate, prednisone and other inflammatory agents and topical application of salicylic acid or hydrocortisone. Topical application of retinoic acid and its salts promotes skin wound healing in rats and human beings.

it has now been found that 2,6,6,-Trimethyl-1-( lcarboxy-3 ,7 '-dirnethyl-deca-1',3 ,5 ','7',9' ,-pentaenyl) cyclohexJ-ene or C Polyene Acid and its salts is even more effective than retinoic acid for this purpose. Further the C24 homolog has been tested and found less effective than the C22 acid of the present invention. The acid of the present invention is sometimes referred to as C22 acid for convenience.

Clinically, hydrocortisone, prednisone and salicylic acid are very commonly used. Hydrocortisone and salicylic acid preparations for topic uses are quite popular. Whitfield Ointment, USP, contains 3% salicylic acid. Prednisone is a potent synthetic analogue of cortisone which is only used orally. It has been used in a large variety of diseases and it is not uncommonly used on surgical patients to reduce edema or inflammation. Corticosteroids are used in organ-transplant surgery to suppress immunological response. Sodium salicylate has been employed in the symptomatic therapy of acute rheumatic fever for many decades. Oftentimes it is still the drug of choice in many incidences. However the salicylates,- hydrocortisone, prednisone, indomethacin, mefenamic acid, retard healing. The retardation action of these drugs can be reversed by applying C22 acid or its salts on the wound. These findings illustrate the principle that one can use a second drug (C22 acid) to modify the untoward effect (wound healing retardation) of a useful drug (anti-inflammatory agents).

1 C22 acid or its salts alone promotes healing. It is very practical to dust this compound on any surgical wound or to apply it as a solution or in an ointment.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The local application of C22 acid and its salts has been found to promote wound healing. This is true both of animals which have not been otherwise treated and also true of animals which have been treated with antiinflammatory agents such as a salicylate, hydrocortisone, prednisone, indomethacin, mefenamic acid and the like. These compounds normally retard healing and C22 acid and its salts has been found to reverse this action.

The C22 acid, namely 2,6,6-trimethyl-l-(10'-carboxy-3',7'-dimethyldeca-l ',3,5',7',9',-pentaenyl)- cyclohex-l-ene acid is a novel compound and can be made as follows:

Sodium hydride (57% in mineral oil) was washed with anhydrous ether. To a suspension of this NaH in anhydrous ether, triethylphosphonoacetate was added with stirring. To the clear solution, retinal was added at 0 C over 15 min. The reaction mixture was kept at 0 C for 30 minutes, and then at 35 C for an additional 30 minutes. Saturated aqueous sodium chloride was added to the mixture and cooled to 0 C. Extraction with petroleum ether (30-60), drying and removal of solvent gave a dark red oil.

Because of the suspected lability of this ester, it was immediately hydrolyzed in alcoholic potash under reflux for 3 hrs. After diluting with water, the nonacidic impurities were extracted as before. The aqueous layer is extracted with ether after acidifying with dilute HCl. After drying and removing solvent, C22 acid was isolated. Recrystallization from EtOH/water three times gave pure trans acid.

mp 181-2 C A max 376 mu (e 46,400);vmax 1,680 cm" (carbonyl) 269 mu (e =1 1,700) 6(CDCl stance a concentration of about 1% has been found' suitable although larger or smaller concentrations may be used. Below about 6%, the efiectiveness falls off and increasing the concentration from 1 to 2% increases the effectiveness only slightly. Therefore a concentration of about 1% whether in an ointment, oil solution or powder is about optimum. I

Suitable oil carriers include physiologically acceptable oils in which the acid is soluble such as isopropyl myristate, corn oil, cotton seed oil and the like. Powder can be prepared utilizing the C22 acid crystals by grinding the crystals with a suitable inert carrier such as talc. C22 acid or its salts can be combined with any of the usual ointment bases used in pharmacy. One suitable base is known as NIB (non-ionic base) developed by the University of California School of Pharmacy having the following approximate composition:

Cetyl alcohol 6% Stearyl alcohol 6 White petrolatum 14 Liquid petrolaturn 20 Methyl paraben 0.15 Propyl paraben 0.06 Polysorbate 80 1.5 Polyoxyl 40 steal-ate 5 Propylene glycol 2 Purified water q s In testing the compound of the present invention and comparing it with its homologs, male rats weighing 230 to 240 grams were anesthetized with ethyl ether and the hair on the back was shaved off. An incision 6 cm in length was made through the skin and cutaneous- In the above synthesis, equal mole quantities of muscle at a distance of about 1.5 cm from the midline on each side. No ligatures were used and bleeding usually ceased after a few minutes. The incisions were closed with continuous through and through sutures with stitches 0.5 cm apart. The wounds were left undressed; NIB preparations were applied, with gentle rubbing, directly on the sutured wound right after wounding. The application was repeated, once a day, on the first and second days after wounding. For the control, only NIB was applied. On the seventh day after wounding, the tensile strength of the wound was measured with a tensiometer by cutting the sutures witha pair of scissors and measuring the tension necessary to pull the wound open. The tensile strength required for opening the wound was measured in grams. In this series of tests, one group of animals was treated with plain NIB base while other'g'rou'ps were treated with various acids in NIB base. The following results were obtained:

EFFECT OF TOPICALAPPLICATION OF RETINOIC ACID HOMOLOGS ON TENSILE STRENGTH OF HEALING WOUND Compound applied Tensile strength Group No. of animals VII 8 All of the acids had the formula 2,6,6,-trimethyl-1- X-cyclohex-l-ene, wherein X is a side chain'of conjugated double bonds. The C20 acid is, of course,

retinoic acid and C22 is the acid of the present.

invention. Au ,7 V g v In another series of tests, granulation was measured by the cotton pellet method.

1 This method involves subcutaneous implantation of cotton-pellets and measuring the size of the. granuloma induced after a few days. Anti-inflammatory agents reduce the size or weight of granuloma as compared with that of the control. Those compound derivatives which promote healing increase the size or weight of the granuloma.

Growth of granulation tissue into cotton-pellets was induced by subcutaneous implantation at two symmetrical dorsolateral sites of Sprague-Dawley male rats weighing 120 1 g under ether anesthesia.

The cotton-pellet implanted on the right side con tains the compound under test and the cotton-pellet implanted on the left side serves as the control. The

compound was introduced to the pellet as its ether solution. The ether was completely evaporated before implantation. On the seventh day after implantation the animals were killed with ether and the body weights were taken. The granulomas were carefully removed and weighed rapidly on a torsion balance. After drying in an oven at 65 C for 48 hours the dried slices were weighed again.

EFFECT OF RETINOIC ACID HOMOLOGS ON .COTT NPEL T NDU E GR U M In addition to the C22 acid itself the salts of the acid were found to be effective. The salts of any physiologically acceptable metal can be employed.

In the following example 2 mg of the sodium salt of the C22 acid was employed. The cotton pellet method described in detail above was used and the following results obtained:

Wet Dry Exp. Control Ratio Exp. Control Ratio 332.1 207.3 1.7 40.0 22.7 1.8

I claim:

1. A wound healing composition comprising an effective amount of a compound selected from 2,6,6,- trimethyll 10'-carboxy-3 7-dimethyldeca-l 3 5,7', 9',-pentaenyl)-cyclohex-l-ene acid and its salts in a physiologically acceptable topical carrier selected from the group consisting of an oil, an ointment or a powder.

2. A method of healing a wound comprising applying to said wound site a composition of claim 1 containing about 1% of the acid or its salt.

Patent Citations
Cited PatentFiling datePublication dateApplicantTitle
US3026249 *Jun 30, 1960Mar 20, 1962Eastman Kodak CoPreparation of stable aqueous isomeric vitamin a compositions
US3089823 *Sep 5, 1961May 14, 1963Eastman Kodak CoAqueous vitamin a oil emulsion
US3143564 *Jan 15, 1962Aug 4, 1964Sumitomo Chemical CoMethod for producing 2-transvitamin a acid
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US3882244 *Mar 21, 1973May 6, 1975Univ CaliforniaMethod of treating acne with a c{hd 20 {b acid
US3934028 *Apr 22, 1974Jan 20, 1976The Regents Of The University Of CaliforniaAcne and psoriasis treatment with retinoic acid analogs
US3966967 *Oct 29, 1974Jun 29, 1976The Regents Of The University Of CaliforniaCompositions and methods of treating psoriasis with vinyligs of desmethyl retinoic acid
US4021573 *Nov 5, 1975May 3, 1977The Regents Of The University Of CaliforniaPsoriasis treatment with retinoic acid analogs
US4048204 *Sep 10, 1976Sep 13, 1977The Regents Of The University Of CaliforniaC20 and C22 acids to promote wound healing
US4203969 *Apr 28, 1978May 20, 1980Drythanol LimitedDithranol compositions for topical applications
US4551480 *Mar 2, 1984Nov 5, 1985Stiefel Laboratories, Inc.Compositions for the treatment of psoriasis
US5243094 *Oct 15, 1990Sep 7, 1993MedaforDerivatives of long chain fatty alcohols, their uses, particularly as cytotrophic and cytoprotective molecules, and pharmaceutical compositions containing them
US5447959 *Mar 5, 1993Sep 5, 1995MedaforMethod of using derivatives of long chain fatty alcohols to treat neuronal degradation
US6063817 *Feb 19, 1998May 16, 2000Bristol-Myers Squibb CompanyUse of substituted (5,6) dihydronaphthalenyl compounds having retinoid-like activity to prevent or reduce ischemic injury
USRE41134Jun 7, 1999Feb 16, 2010Alyzan, Inc.Slow release vehicles for minimizing skin irritancy of topical compositions
WO1991005754A2 *Oct 15, 1990May 2, 1991MedaforDerivatives of long-chain fatty alcohols and their applications, in particular as cytotrophic and cytoprotective molecules, and pharmaceutical compositions containing same
WO1991005754A3 *Oct 15, 1990Nov 28, 1991MedaforDerivatives of long-chain fatty alcohols and their applications, in particular as cytotrophic and cytoprotective molecules, and pharmaceutical compositions containing same
U.S. Classification514/560, 554/221, 554/224, 514/859
International ClassificationA61K31/07, A61K
Cooperative ClassificationC07C2101/16, Y10S514/859, C07C403/20
European ClassificationC07C403/20