Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2001-02-21
2004-03-09
Meller, Michael (Department: 1654)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C514S724000, C514S783000, C424S524000
Reexamination Certificate
active
06703052
ABSTRACT:
FIELD OF INVENTION
This invention relates to methods for the preparation of mixtures of long chain monounsaturated alcohols, such as jojoba alcohol. This oily liquid and its compositions are used for the topical treatment of subdermal infections such as herpes virus infections, and the transdermal delivery of pharmacological agents for the treatment of various disorders.
BACKGROUND OF 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 or varicella zoster, which causes chicken pox and later shingles. Once an individual is infected, herpes viruses become latent principally in nerve cells, and can reactivate to cause recurrences of the original symptoms. Herpes migration to the brain or spinal cord leads to encephalitis and meningitis, which are life-threatening conditions. Human herpes virus-8 (HHV-8) is associated with the skin cancer
Kaposi sarcoma
. These herpes episodes are each susceptible to topical treatments because the viruses replicate in subdermal cells during a recurrence, and before an eruption into a lesion. 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. New anti herpes virus 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. Pat. No. 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 or 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 fusion with or 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. Pat. No. 4,874,794, 1989; Katz, U.S. Pat. No. 5,071,879, 1991; Katz, U.S. Pat. No. 5,166,219, 1992; Katz, U.S. Pat. No. 5,194,451, 1993; Katz, U.S. Pat. No. 5,534,554, 1996). n-Docosanol is not virucidal but is virustatic, interfereing with viral replication, and dependent on a functional immune system to destroy viruses. n-Docosanol is a crystalline waxy solid insoluble in water which needs to be formulated with a surfactant and carrier to facilitate dermal penetration and interaction at the target cell level, This limitation was also noted where several other virustatic 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. Pat. No. 5,534,554, 1996; Katz et al., PCT WO098/11887, 1998). The latter two reports 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 preparation of n-docosanol is not reported in these patents. The long chain alcohols and other compounds are generally waxy solids, 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 corneal healing due to eye injury (Muller, U.S. Pat. No. 5,214,071, 1993; Muller, U.S. Pat. No. 5,296,514, 1994).
Jojoba oil has been available commercially for more than twenty years, and several million pounds are used in cosmetic formulations annually. 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, Ill., 272 pp, 1987). A significant characteristic of jojoba oil is its ability to be absorbed quickly by the skin. Extensive testing and use of jojoba oil has established that it is completely non-toxic when applied to human sin, 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 esterases 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 for cosmetic uses (Final Report on the Safety Assessment of Jojoba Oil and Jojoba Wax, J. Amer. Coll. Toxicol., 11(1): 57-74, 1992).
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 reaction, the carboxylic acid part of the ester is converted to its corresponding alcohol, 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 h
Meller Michael
Reiter Stephen E.
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