TOPICAL TRANSDERMAL TREATMENTS

Abstract: Jojoba alcohol, an oily liquid at moderate ambient temperatures, is readily absorbed by human skin where it relieves irritation and inhibits the formation of lesions caused by viruses. The inhibitory action is applicable to enveloped viruses which express as sores at dermal surfaces in human. When applied topically to an incipient herpes episode, it will quickly penetrate the epidermis to the subdermal cells and suppress viral replication which leads to inflammation and the formation of blisters on the face, genital and other skin and mucosal areas. Compositions of low molecular weight organic acids in jojoba alcohol enhance antiviral activity. Jojoba alcohol is a transdermal delivery system for these virucidal acids and other pharmacologically active agents. Topically applied jojoba alcohol is non-toxic to small animals and humans. Jojoba alcohol prepared here by chemical hydrogenolysis of jojoba oil is a mixture principally of mono unsaturated alcohols with 14 to 24 linear carbons in the chain.

Description: TOPICAL TRANSDERMAL TREATMENTS Field of Invention This invention relates to methods for the preparation of jojoba alcohol, a mixture of principally long chain mono unsaturated alcohols , and the use of this oily liquid and its compositions for the topical treatment of subdermal infections such as herpes simplex virus, and the transdermal delivery of pharmacological agents for the treatment of various disease, conditions. Background of the Invention A large percentage of the world population are infected with herpes viruses. Three of the most common herpes viruses are herpes simplex virus-1 (HSV-1) which is the cause of facial and ocular sores, herpes simplex virus-2 (HSV-2) which has a predilection for genital areas, and herpes simplex virus-3 (HSV-3), also named herpes zoster and varicella zoster, which causes chicken pox and later shingles. Herpes simplex virus-8 is associated with the skin cancer Kaposi sarcoma. These herpes episodes are each susceptable to topical treatments because the viruses replicate in subdermal cells during a recurrence, and before an eruption into a lesion. Inhibition of viral entry into a host cell is a treatment method that is being used even for HIV infected individuals, and is used here vs herpes. Once an individual is infected, herpes viruses become latent principally in nerve cells, and can reactivate to cause recurrences of the original symptoms. When a herpes virus infected individual undergoes stress from exhaustion, strong sunlight, wind, certain foods and medications, menses or microbial infection, the virus migrates to cells under the epidermis where it begins to replicate. For HSV-1 and HSV-2 the initial itchiness, tingling or pain is referred to as the prodromal stage signaling that the virus is active under the skin. Prodromal can occur from an hour to several days before an outbreak of lesions. At the erythema or inflammation stage, the immune system has begun to fight the virus. After this irritating redness stage, vesicles form and eventually erupt into lesions on the skin and mucosal surfaces. HSV-1 and HSV-2 are morphologically indistinguisable, the main difference being where the sores appear on the skin, and there is some interchange in recurrence sites between these two viruses. Herpes migration to the brain or spinal cord leads to encephalitis and meningitis, which are life-threatening conditions. There are several treatment options for herpes infections but no cures. Several of the nucleoside analog drugs can be effective if taken prophylactically on a daily basis. They are less effective if administered at the time of the recurrence, either orally or topically. The nucleoside drugs inhibit viral replication by penetrating into the cell and interfering with nucleic acid production. They are not virucidal, and depend on a functional immune system to deactivate any virus present. A number of commercial "cold sore" preparations are available which treat symptoms, but are generally ineffective in preventing the formation of lesions. They contain principally anesthetic, antibacterial, emolient and wound healing compounds which can reduce pain, prevent microbial infection and help dry up the blister. New antiherpesvirus agents, their targets and therapeutic potential have been reviewed (Alrabiah and Sacks, Drugs, 52: 17-32, 1996), as have topical treatments of herpes simplex virus infections (Hamuy and Berman, Europ. J. Dermatol., 8:310- 319, 1998; Evans and Tyring, Dermatol. Clinic, 16: 409-419, 1998; Syed et al., Clin. Drug Invest.. 16: 187-191, 1998). Alcohols with chain lengths of 16 to 20 carbon atoms and 1 to 4 double bonds inhibited herpes simplex and another lipid enveloped viral bacteriophage in cell cultures (Sands et al., Antimicrob. Agents Chemother., 15: 67-73, 1979). These unsaturated alcohols were more potent in vitro than saturated alcohols with shorter chain lengths (Snipes et al., Antimicrob. Agents Chemother., 11: 98-104, 1977). A patent (Rivici et al., U.S. 4,513,008, 1985) describes the inhibition of enveloped viruses such as herpes with linear polyunsaturated acids, aldehydes or primary alcohols with chain lengths of 20 to 24 carbons and 5 to 7 double bonds. These reports were followed by the investigations and development of n-docosanol as a topical treatment for herpes infections. n-Docosanol, also named 1-docosanol and behenyl alcohol, is a straight chain 22 carbon saturated alcohol, which occurs in the bark, flowers and fruit of the tree Pygeum africanum. n-Docosanol is reported to have broad spectrum in vitro activity against lipid enveloped viruses such as herpes (Katz et al., Proc. Nat. Acad. Sci., 88:10825-10829, 1991; Katz et al., Ann. N.Y.Acad. Sci., 724: 472-488, 1994; Pope et al., J. Lipid Res., 37: 2167-2178, 1996; Pope et al, Antiviral Res., 40: 85-94, 1998), and also the human inmmunodeficiency virus HIV (Marcelletti et al., AIDS Research and Human Retroviruses, 12: 71-74, 1996). These studies demonstrated that the antiviral activity of n-docosanol includes inhibition of the process of viral entry into the cell, while being mediated by intracellular metabolic biotransformation of the drug. A series of patents on the composition of mixtures of n-docosanol in formulations that render it useful for topical application supports these published reports (Katz, U.S. 4,874,794, 1989; Katz, U.S. 5,071,879, 1991; Katz, U.S. 5,166,219, 1992; Katz, U.S. 5,194,451, 1993; Katz, U.S. 5,534,554, 1996). n-Docsanol is not virucidal deactivating viruses directly, but it interferes with viral replication, and depends on a functional immune system to destroy residual viruses. n-Docosanol is a crystalline waxy solid insoluble in water which needs to be formulated with a non-ionic surfactant and carrier to facilitate dermal penetration and interaction at the target cell level. This limitation was also noted where several other long chain compounds with 18 plus linear carbons including amides, alkanes, acids and alcohols needed to be formulated with a surfactant and carrier to facilitate penetration of the epidermis (Katz et al., U.S. 5,534,554, 1996; Katz et al., PCT WO98/11887, 1998). The latter 2 patents claim a composition of n-docosanol or other long chain compounds with a surfactant and a pharmaceutically acceptable diluent or carrier as the active viral replication inhibitor, rather than the pure individual compounds. The long chain alcohols and other compounds are all solids at normal ambient temperatures, and would not be expected to penetrate skin layers alone without a carrier. In a study using 10% n- docosanol suspended in an aqueous system containing a non-ionic surfactant and a carrier, mean healing time of lesions in humans infected with herpes labialis (HSV-1) was shortened (Habbema et al., Acta Derm. Venereol., 76: 479-481, 1996). A 12% n-docosanol cream was tested as a possible transmision prophylactic of simian immunodefficiency virus (SIV) in rhesus macque monkeys (Miller et al., Antiviral Res., 26: A277, 1995). Intravaginal application before exposure prevented transmission in five of the six animals tested. n-Docosanol and other saturated alcohols with chain lengths of 20 to 26 carbons reportedly promote comeal healing due to eye injury (Muller, U.S.5,214,071, 1993; Muller, U.S. 5,296,514, 1994). Jojoba oil is a mixture of esters composed principally of both long chain mono unsaturated alcohols and carboxylic acids (Wisniak, The Chemistry and Technology of Jojoba Oil, publ. by American Oil Chemists Society, Champaign, Illinois, 272 pp, 1987). This oil is obtained from the seeds of the desert shrub Simmonsia chinensis. Jojoba oil has been available commercially for more than twenty years, and several million pounds are used in cosmetic formulations annually. A significant characteristic of jojoba oil is its ability to be absorbed quickly by the skin. This ready absorption has been related to the single carbon-carbon double bond occurring in the middle area of both the alcohol and carboxylic acid parts of the mono ester molecules. Extensive testing and use of jojoba oil has established that it is completely non-toxic when applied to human skin, or administered orally to mice, rats, marmots and rabbits (Taguchi and Kunimoto, Cosmetics and Toiletries, 92: 53-61, 1977; Clark and Yermanos, Biochem. Biophys. Res. Commun., 102: 1409, 1981; Hamm, J. Food Sci., 49: 417-428, 1984; Verschuren and Nugteren, Food Chem. Toxicol., 27: 45-48, 1989). Humans who have ingested jojoba seeds, which are 50% oil, have not been harmed, although some nausea occurred when as much as 200 grams were eaten. In mice, jojoba oil has functioned as an intestinal lubricant (Verbiscar et al., J.Agric. Food Chem., 28: 571-578, 1980). It is estimated that about 20% of jojoba oil is split by hydrolytic enzymes in the gastrointestinal system, thus producing jojoba alcohol in situ. After dermal absorption, jojoba oil would be at least partially metabolized to jojoba alcohol. Jojoba oil is a generally recognized as safe product for topical uses throughout the world. Jojoba alcohol has been prepared from jojoba oil by hydrogenolysis with sodium and alcohol (Molaison et al, J. Amer. Oil Chem. Soc, 36: 379-382, 1959). In this hydrogenolysis reaction, the carboxylic acid part of the ester is converted to its corresponding ester, in comparison with chemical hydrolysis where the fatty acids remain intact and must be separated from the alcohols in the mixture. Hydrogenolysis doubles the amount of jojoba alcohol that can be obtained from jojoba oil. One jojoba alcohol product prepared by hydrogenolysis resulted in a mixture of 6% octadec-9-enol, 62% eiocos-11-enol, 28% docos-13-enol and 4% tetracos-15-enol (Taguchi, Proc. Sixth Int. Conf. Jojoba and Its Uses, eds. Wisniak and Zabicki, Ben-Gurian Univ. Negev, Beer-Shiva, Israel, p 371-391, 1984). The actual alcohol composition will vary according to the source of jojoba oil used in the hydrogenolysis. The relative amounts of individual alcohol components in jojoba alcohol depends on the ester composition of jojoba oil , a product obtained from seeds harvested in the Southwestern United States, Mexico, Israel and South America. Pure long straight chain mono unsaturated alcohols are sometimes liquid or low melting solids, but when in a mixture as in jojoba alcohol exist as a colorles odorless oil at normal ambient temperatures. A characteristic of jojoba alcohol is that it is readily absorbed by human skin, much like the parent jojoba oil. Jojoba alcohol does not require a carrier or surfactant to facilitate transdermal penetration. Jojoba alcohol is reported in one patent on lipstick components along with a large number and variety of carboxylic acids, esters and alcohols with diverse structures and functions (Sato, Lipocolor Composition, U.S. 5,700,453, 1997). In the latter case, the patent technology sought lipocolor properties which would make the composition feel less dry rather than to improve skin penetration. Summary of the Invention Jojoba alcohol is an oily liquid that is readily absorbed by human skin, leaving no residue nor odor. When applied to an incipient herpes simplex virus recurrence, it quickly penetrates the epidermal layer to the subdermal cells where viral replication leading to symptomatic disease would otherwise occur. Jojoba alcohol appears to function in the same manner that n-docosanol functions, that is by inhibiting lipid enveloped viruses from migrating into and within cells. Irritation is relieved and viral replication is delayed, while the host immune system is alerted to destroy the free virus units. When treated early in the prodrome or even the erythema inflammation stages, herpes blisters do not form or at least are inhibited in persons with functional immune systems. This inhibitory action is applicable to enveloped viruses which express as lesions at epidermal surfaces. Herpes simplex viruses which cause recurrent facial sores (HSV-1) and genital sores (HSV-2), shingles (HSV-3) and Kaposi sarcoma (HSV-8) are treatment targets. Detailed Description Of The Invention In tests with mice and guinea pigs it was established that jojoba alcohol is not a virucide nor a microbiocide which destroy viruses directly. Jojoba alcohol is a virustatic which delays viral replication by inhibiting cellular penetration. The nucleoside analog drugs such as acyclovir and penciclovir which are used for oral and topical treatments of viral infections, are also virustatics acting by interferring with nucleic acid production inside the infected cell. For virustatics, it is necessary for a functional immune system to respond and destroy the virus in order to be most effective. Accordingly, it is important to treat herpes recurrences as soon as possible after the virus becomes active, in order to minimize the viral load to be eliminated by the immune system. Jojoba alcohol is most effective in the prodrome stage, just as the skin is becomming irritated and inflammed, when the immune system begins its response to the localized infection. Early applications every several hours works best, eliminating itchiness and other irritations caused by lysis of infected cells. Jojoba alcohol spread on an irritated area of the skin penetrates quickly and is active without the need for a carrier. In contrast, crystalline long chain alcohols such as n-docosanol require a carrier to be active. Compared to small alcohol molecules such as ethanol and isopropyl alcohol, which evaporate or are carried away into the circulation, jojoba alcohol will remain under the general area of skin application for an hour or more. Its insolubility in water and the absence of a surfactant limit its absorption into the circulation and removal from the active subdermal site. In a preferred embodiment, vitamin E (tocopherol) is added to jojoba alcohol to improve stability against oxidation of the double bonds. Vitamin E is the natural antioxident which occurs in jojoba seeds and in the pressed or extracted jojoba oils. In a further embodiment, salicylic acid is added as an antiviral, antiseptic and keratolytic agent. This broadens the efficacy of jojoba alcohol and improves its healing power. Other low molecular weight organic acids such as lactic acid, glycolic acid, pyruvic acid, benzoic acid and acetylsalicylic acid also enhance antiviral efficacy (Poli et al, Food Chem., 4:251-258, 1979; Brown-Skrobot et al., U.S. 4,975,217, 1990; Primache et al., Microbiologica, 21: 397-401, 1998) when in jojoba alcohol. Additional food grade low molecular weight di- and tri-carboxylic organic acids which have shown in vitro activity against herpes and other viruses include malic acid, fumaric acid, succinic acid tartaric acid and citric acid. However, these di- and tri-carboxylic acids are poorly soluble in jojoba alcohol directly, and must be formulated in lower alcohols such as ethanol and 5 isopropyl alcohol for application as lotions. Jojoba alcohol dissolves readily in the lower alcohols as the virustatic part of the composition, while the organic acids act as virucides directly deactivating viruses. In the reported sodium hydrogenolysis, a coreagent alcohol and the jojoba oil ester are added to 10 liquid sodium in boiling toluene. The system generates nacent hydrogen which reduces the ester groups to alcohol groups without reducing the carbon-carbon double bonds. In our hands, this process yielded a 73% yield of pure distilled jojoba alcohol. However, workup and purification of the final product was difficult due to the presence of carboxylic acid by-products resulting from partial hydrolysis of the ester rather rather than hydrogenolysis. The sodium salts of these 15 long chain fatty acids act as surfactants and cannot be water- washed out of the mixture. In addition, while this reaction can be done readily in small quantities, large scale production with liquid sodium presents difficulties. To circumvent these problems, we invented a new chemical hydrogenolysis of the ester group of jojoba oil to the alcohols using a commercial reagent named sodium bis-(2-methoxyethoxy)aluminum hydride (Bazant et al., Tetrahedron Letters, 29; 3303- 20 3306, 1968). With this reagent, a 90.5 % yield of jojoba alcohol was obtained which is identical to the liquid sodium hydrogenolysis product, but with no workup problems or danger due to the reactants. This jojoba alcohol freezing point was about 13 degrees centigrade, and remains an oil at normal ambient temperatures. Major alcohol components of jojoba alcohol are octadec-9-enol, eicos-11-enol, docos-13-enol and tetracos-15-enol. The actual amount of any individual alcohol 25 in a jojoba alcohol preparation will vary according to the source of jojoba oil used in the hydrogenolysis. Other alcohols, ranging in chain length from 14-24 carbon atoms, are also present as minor components totalling about 3% (Wisniak, Chemistry and Technology of Jojoba Oil, publ. American Oil Chemists Society, Champaign, Illinois, 272 pp, 1987). The significant structural factors in the jojoba alcohol compounds is that they are highly lipophylic with a 30 hydrophylic hydroxyl end group, and a carbon carbon double bond in the inner chain which facilitates transdermal penetration. This process is also applicable to sperm whale oil, producing a similar mixture of long chain monounsaturated alcohols. The generic structure of the major components of this jojoba alcohol mixture and examples of 35 individual mono unsaturated alcohols composing jojoba alcohol follows, where the double bond can exist in cis and trans forms and m and n can vary from 5 to 13 carbons. CH3(CH2)mCH=CH(CH2)nCH2OH m n Hexadec-7-enol 7 5 40 Octadec-7-enol 9 5 Octadec-9-enol 7 7 Eicos-11-enol 7 9 Docos-13-enol 7 11 Tetracos-15-enol 7 13 Mouse and Guinea Pig Studies The HSV-2 infected mouse system used here was designed to discover products which have potential to be used in a single dose prophylactic mode against infection. This is principally the domain of virucides, or microbiocides. Viracol is a virustatic and was only expected to delay infection in the mice, which it did as in Example 3. The guinea pig system of Example 4 extends antiinfection tests to first episodes, which are far more severe than recurrences. A principal reason for this is that the newly infected host's immune defense system is not yet programmed to fight this particular virus. Jojoba alcohol merely delays viral entry into the cell where the virus must penetrate in order to replicate. This delay mechanism relies upon an effective immune system to destroy the virus. Jojoba alcohol can only be used to inhibit recurrences, and must be applied several times every few hours after the first feeling of irritation signalling an incipient recurrence. Treatment of an infected guinea pig every twelve hours as in Example 4 is inadequate for a virustatic which delays viral replication. The application protocol was too infrequent in an animal with a high dose of inoculum, and an immune defense system not yet alerted to the virus. Tests in humans against recurrences of herpes episodes are the best way to evaluate efficacy. Human Studies Preliminary tests of jojoba alcohol against herpes labialis (HSV-1) in human subjects were done with pure distilled product with no additives. In one test a 65 year old female subject who normally experiences about two cold sores per year was exposed to strong sunlight for an extended period of time. One day after this exposure the subject began to experience itching and mild inflammation in her upper lip and nasal (perioral) area. One drop of jojoba alcohol was applied and spread around the irritated area, and this was repeated four hours later. Early symptoms disappeared quickly and no lesions formed. This result was typical of several preliminary tests of jojoba alcohol versus herpes simplex virus- 1 episodes in human subjects. Example 5 describes the protocol used to test jojoba alcohol preparations versus HSV-1 induced facial sores and HSV-2 induced genital sores. Results are in Table 1 and Table 2. In these Tables, jojoba alcohol is formulated with 0.5 - 1 % tocopherol as an antioxidant, and named Viracol. The composition Viracol Plus contains 2% salicylic acid. In Table 1, 15 subjects reported a total of 30 recurrences. In 14 (47%) of these episodes there were no sores at all. Another 8 episodes resulted in mild lesions. Several of the moderate to severe lesion recurrences were treated only after blister formation had already started. Several subjects with severe episodes experienced improved results using Viracol Plus. At least one subject (102) experiences all of the symptoms of a cold sore recurrence at one time, with no warning period, but even he was successful in reducing blister formation. One female subject (132), diagnosed with Crohn's disease, has never been without a cold sore and chronic fatique for more than one year due to a depressed immune system. After several trials with Viracol she was switched to Viracol Plus with improved results. A male subject (107) who also experienced frequent cold sores was also more successful with Viracol Plus. In the Viracol Plus treatment, jojoba alcohol acts as a virustatic, delaying viral entry into the cell, while acting as a transdermal delivery system for the solid salicylic acid which is virucidal. Table 1 Human Testing Of Viracol Versus Herpes Labialis (HSV-1) Stage Appl Lesion Results Subject Gender Age Start Doses Days None Mild Mod. Severe 102 M 36 pro 9 1.5 * 102 pro 3 1 * 104 M 68 ery 8 3 * 104 ery 3 1 * 104 pro 3/d 4 * 107 M 40 pro 10/d 7 * 107 pro 10/d 5 * 107+ pap 10/d 2 * 115 F 50 pro 3 1 * 115 pro 2 1 * 115 pro 4 1 * 132 a F 50 pap 3/d 6 * 132 pap 10/d 5 * 132 ery 10/d 7 * 132+ ery 4/d 4 * 132+ ery 8 2.5 * 133 M 52 pap 15 5 * 138 F 32 ery 3 1 * 140+ F 45 ery 70 17 * 140+ pro 6 2 * 140+ ery 10 3 * 141 b F - pro 1 * 142 F 19 pro 6 1 * 145 F 33 pap - 8 * 151 F 67 ery 3 1 * 151 ery 5 1.5 * 153 M 49 ery 5 7 * 153 ery 4 1 * 174+ b F - pro 6 2 * 180+ F 45 pap 4 * Subjects F = 10, M = = 5 14 8 5 3 Total reports = 30 + = Viracol Plus pro = prodrome; ery = erythema; pap = papule a) Subject never without an outbreak of HSV-1 or HSV-2 in past year b) Also experiences genital HSV lesions Table 2 Human Testing Of Viracol Versus Herpes Genitalis (HSV-2) Stag e Appl. Lesion results Subject Gender Age Start Doses Days None Mild Mod. Severe 109 M 55 ery 3 4 * 111 M 33 pro 10 3 * 111 pro 4 2 * 116 M 48 pro 3 - * 124 F 65 pro 12 4 * 124 pap 12 6 * 125 F 51 ery 4 2 * 127 M 50 ery 2 2 * 130 M 52 pro 5 2 * 134 F 27 pro 10 - * 134 ery 5 3 * 136 M 49 pro 2 4 * 137 F 26 pro 3 2 * 137 pro 2 1 * 139 F 36 pap 4/d 8 * 139 ery 4/d 6 * 141 b F - pro 1 11 * 143 M 40 ery 4 4 * 143 pro 12 - * 148 M 44 pap 10 13 * 148+ ery 10 4 * 148+ pro 4 3 * 148+ a pap 3 * 165 F 36 pro 5 * 165 ery 5 * 173+ F 26 pro 6 2 * 173+ pro 9 3 * 173+ pro 3 2 * 174+ b F 59 pap 16 8 * 174+ ery 3/d 5 * 174+ pro 3/d 6 * Subjects F = 9, M = 8 15 9 Total reports = 31 + = Viracol Plus pro = prodrome; ery = erythema; pap = papule a) Viracol depleted before the episode ended; b) Also experiences facial HSV lesions In Table 2, 17 subjects reported a total of 31 genital herpes recurrences. In 15 (48%) of these episodes, there was complete inhibition of lesion formation. Another 9 episodes resulted in mild lesions. Of the 7 episodes where moderate to severe lesions formed, treatment was initiated in 5 episodes at the papule or blister stage. One of these ( 141 ) treated her recurrence only once due to employment conditions. A female subject (174) who experienced both HSV-1 and HSV-2 recurrences had greater success with Viracol Plus. A twelve year old girl experienced pain which after two days led to a few blisters at her waist. Having had chicken pox as an infant, she was diagnosed as having a shingles episode induced by herpes simplex virus-3, also named herpes zoster and varicella zoster. Starting on the third day after initiation of pain, she was treated with Viracol six times per day and with oral famciclovir three times per day. The episode was terminated in seven days total. There was no pain and no additional blister formation after treatment was started with with Viracol. Shingles episodes can be severe and last for several weeks to a month or more. Jojoba alcohol formulations can be used to treat both men and women with equal success against incipient dermal sores caused by herpes viruses. Results are best when treatment is started as early as possible at the prodrome (itchy) or erythema (redness) stages. The treatments were well tolerated with no adverse effects. Viracol Plus containing salicylic acid improves overall antiviral activity and healing of any blisters that may form due to inadequate application of the jojoba alcohol product, or due to a depressed immune system. In this formulation, jojoba alcohol facilitates the transdermal penetration of salicylic acid, a crystalline solid, to the viral replication site. Jojoba alcohol is a mixture of principally mono unsaturated linear alcohols with 16 to 24 carbon atoms in the chain. A mixture of these alcohols is readily prepared by hydrogenolysis of jojoba oil, which is an ester. Mixtures of mono unsaturated linear alcohols can also be prepared from other sources, such as by the hydrogenolysis or hydrolysis of sperm whale oil. In addition, a mixture of the individual alcohol components can be prepared by combining each alcohol in any specific amount. The more alcohols in the mixture, the more likely will the mixture be liquid at ambient temperatures. A formulated mixture of individual alcohols will act like jojoba alcohol, inhibiting viral entry into host cells, and thereby inhibiting inflammation and lesion formation. Jojoba alcohol can actually be comprised of any number of individual long chain mono unsaturated alcohol, depending on the source of jojoba oil from which it is derived. Jojoba alcohol represents mixtures of these alcohols which will remain liquified at ambient temperatures. While the description above contains many specifics, these should not be construed as limitations of the scope of the invention, but rather examples of preferred embodiments. Many more variations are possible for the use of jojoba alcohol and other mixtures of long chain mono unsaturated alcohols as transdermal delivery agents. The enhanced activity of salicylic acid dissolved in jojoba alcohol is an example of this transdermal delivery function. Other applications are numerous with several of these noted below, where jojoba alcohol represents any mixture of long chain mono unsaturated alcohols. Example 1 Jojoba Alcohol by Sodium and Alcohol Hydrogenolysis The ester group of jojoba oil was reduced to jojoba alcohol by the sodium and alcohol procedure reported previously (Molaison et al., J. Amer. Oil Chem. Soc, 36: 379-382,1959) with minor variations. A suspension of 20.2 grams (0.88 moles) of sodium in 100 ml of dry toluene was stirred well and brought to reflux, whereupon the sodium liquified. A solution of 120 grams (0.2 moles) of purified jojoba oil and 36.5 grams (0.48 moles) of 2-methoxyethanol in 100 ml of dry toluene was added slowly with vigorous stirring under reflux. The reaction solution became clear yellow with a small amount of suspended solids. After additional stirring and refluxing, the solution was allowed to cool as a waxy solid formed. Water, 100 ml, was added slowly with stirring as some foaming occurred. The emulsified toluene phase was separated from the emulsified aqueous phase, then washed with 100 ml of saline. The toluene was removed by distillation and hexane was added to the residue. A white waxy solid, 14 grams, was collected and identified by an irfrared spectrum as the sodium salt of some of the carboxylic acid portion of the jojoba oil. Vacuum distillation of the hexane soluble fraction yielded 88.2 grams (73%) of a clear colorless oil. An infrared spectrum was consistant with the known structure. The residue in the distillation pot contained unreacted jojoba oil and more hydrolytic carboxylic acid, as determined by an LR spectrum. Example 2 Jojoba Alcohol by Sodium Bis(2-methoxyethoxy)aiuminumhydride Hydrogenolysis A 70 ml (0.245 moles) portion of a 3.5 M soln. of sodium bis(2-methoxyethoxy) aluminumhydride reagent (Bazant et al., Tetrahedron Letters, 29: 3303-3306, 1968) was charged into a reaction flask with 30 ml of dry toluene. A solution of 120 grams (0.2 moles) of jojoba oil in 120 ml of toluene was dried over molecular sieves. This solution was added dropwise over 30 minutes to the well stirred reducing reagent as frothing occurred. After the addition, the reaction solution was warmed for an hour and a sample was taken. An infrared spectrum showed the absence of ester carbonyl absorption indicating that the hydrogenolysis was complete. After a total of two hours warming, 60 ml of water was added dropwise causing an initial frothing, then the formation of a gelatinous precipitate. The supernatant toluene solution was decanted and the precipitate was washed well with hexane. The combined toluene-hexane extract was dried over calcium sulfate. The clear, colorless, oily jojoba alcohol distilled at 188-218°/5mm, and weighed 108.6 grams (90.5% ). It solidified in the refrigerator at about 13°C. An infrared spectrum of this product was identical with the sodium reduction product, and was consistent with its structure as follows for wavelength cm ~ l, group, type; 3340, OH, strong broad stretch; 3000, CH3, sharp weak stretch; 2920, CH2, strong sharp stretch; 2850, CH, medium sharp stretch; 1650, C=C, weak broad stretch; 1455, CH2, strong deformation; 1375, C-CH3, weak deformation; 1050, C-O, strong stretch; 715, (CH2)n, strong skelatal.

Claims: CLAIMS What is claimed is: 1. A method for the hydrogenolysis of a mixture of long chain esters comprising mono unsaturated alcohols and mono unsaturated carboxylic acid parts, with an effective amount of a metal hydride reducing agent. 2. A method of claim 1 wherein the metal hydride is sodium bis(2-methoxyethoxy)aluminum hydride. 3. A method of claim 1 wherein the metal hydride concentration ranges from 1 to 3 moles per mole of ester. 0 4. A method of claim 1 wherein the product of the process is a mixture of principally mono unsaturated alcohols containing 14 to 24 carbon atoms, as represented by the formula below where m and n are 5 to 13 and the carbon-carbon double bonds are cis or trans. CH3(CH )mCH=CH(CH2) n CH2θH 5 5. A method of claim 4 wherein the product is jojoba alcohol produced from jojoba oil. 6. A method of claim 4 wherein the product is sperm alcohol produced from sperm whale oil. 7. A method for inhibiting replication of enveloped viruses which express as irritations and lesions at dermal surfaces by treating the infected areas of the skin topically with a liquid comprising a mixture of principally mono unsaturated alcohols containing 14 to 24 carbon 0 atoms, as represented by the formula below where m and n are 5 to 13 and the carbon - carbon double bonds are cis or trans. CH3(CH2)mCH=CH(CH2)nCH2OH 8. A method of claim 7 wherein the virus is herpes simplex virus- 1 , also named herpes 5 labialis, which causes facial irritations and sores. 9. A method of claim 7 wherein the virus is herpes simplex virus-2, also named herpes genitalis, which causes genital and anal area irritations and sores. 10. A method of claim 7 wherein the virus is herpes simplex virus-3, also named herpes zoster and varicella zoster, which causes chicken pox and shingles. v 11. A method of claim 7 wherein the virus is herpes simplex virus-8, which causes the skin cancer named Kaposi sarcoma. 12. A method of claim 7 further containing an antioxidant at 0.05 to 5 wtVvol.%. 73. A method of claim 12 wherein the antioxidant is tocopherol. 5 14. A method of claim 7 further containing a low molecular weight organic acid at 0.05 to 5 wt/vol.%. 15. A method of claim 14 wherein the low molecular weight organic acid is salicylic acid. 16. A method of claim 7 wherein the long chain mono unsaturated alcohol mixture contains both an antioxident and a low molecular weight organic acid. 0 17. A method of claim 7 further including a lower molecular weight alcohol to dissolve the components for use as a lotion. 18. A method of claim 17 wherein the alcohols are ethyl alcohol or isopropyl alcohol. 19. A method for transdermal delivery of a pharmaceutically active agent to a subject, comprising: a) formulating said agent in a mixture of a mixture of principally mono unsaturated alcohols containing 14 to 24 carbon atoms, as represented by the formula below where m and n are 5 to 13 and the carbon-carbon double bonds are cis or trans, and CH3(CH2) m CH=CH(CH 2 )nCH20H b) applying such formulation topically to dermal areas of said subject. 20. A method of claim 19 wherein the mono unsaturated alcohol is jojoba alcohol. 21. A method of claim 19 for transdermal delivery of pharmacologically active agent to a subject, comprising: a) formulating such agent in a lower molecular weight alcohol to dissolve the components for use as a lotion, and b) applying such formulation topically to dermal areas of said subject. 22. A method of claim 21 wherein the alcohols are ethyl alcohol or isopropyl alcohol.

Inventors: VERBISCAR ANTHONY J, VERBISCAR, ANTHONY, J.
Applicants: VERBISCAR ANTHONY J, VERBISCAR, ANTHONY, J.
Application year: 1999
Main classification: A61F31
IPC codes: A01N25, A01N31, A01N65, A61F13, A61F15, A61K31, A61K35, A61K36, A61P17, A61P31, C07C27, C07C29, C07C33