Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Reexamination Certificate
2002-08-08
2004-03-23
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
C424S059000, C424S449000, C424S045000, C514S654000, C514S886000, C514S887000, C514S870000, C514S871000
Reexamination Certificate
active
06709664
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for treating wounds, burns, or dermatological damage by administering topical compositions containing selegiline and/or desmethylselegiline.
BACKGROUND OF THE INVENTION
A. Free Radicals
Free radicals are molecules with one or more unpaired electrons in their outer orbitals. The presence of these electrons together with the tendency of molecules to seek the lowest stable energy state causes free radicals to be highly reactive and generally short lived. Among the free radicals commonly found in vivo are oxygen, the superoxide anion and the hydroxyl radical. These are typically referred to as “oxidants” and are often the result of cascades in which electrons are passed from molecule to molecule.
B. Injuries and Free Radical Damage
Injuries such as wounds and burns generate free radicals that have both local and systemic effects. Locally, free radicals have been implicated in both tissue ischemia (Granger, et al., Gastroenterology 81:22-29 (1981); Parks, et al., Gastroenterology 82:9-15 (1982)) and reperfusion injuries (Schiller, et al., Critical Care Med. 21:S92-S100 (1993)). Systemically, burns often cause dysfunction of the heart, lungs and liver. Researchers have found that burn healing is improved when lipid peroxidation (typically caused by the action of free radicals) is reduced (LaLonde, et al., J. Burns Care & Rehabilitation 17:379-383 (1996)).
C. Photodamage
Exposure of skin to electromagnetic radiation in the ultraviolet and visible portions of the spectrum and ionizing radiation may result in damage to both the proteins and the DNA in skin cells. Such “photodamage” has been correlated with the induction of non-melanoma skin cancer, immune function suppression and photoaging.
Exposure of skin to ultraviolet and ionizing radiation and the concomitant pathobiologies have been linked to the generation of oxidants as well as to a reduction in anti-oxidant levels and activity (Stewart, et al., J. Inv. Dermatol. 106:1086-1089 (1996); Darr, et al., Brit. J. Dermatol. 127:247-253 (1992)). Specifically, research has shown that there is a reduction in epidermal superoxide dysmutase activity and in the levels of vitamin C and vitamin E after exposure to UVB radiation. Elimination of oxidants (e.g., by application of exogenous anti-oxidants) or prevention of oxidant production (e.g., by reduction of exposure to ionizing radiation) can alleviate or prevent dermatological damage. The adverse effects of ionizing radiation include edema, vasodilation, lymphocytic and neutrophilic infiltration in the dermis, dyskeratotic keratinocytes and spongiosis of the epidermis.
D. Use of Anti-Oxidants to Detoxify Free Radicals
A number of different strategies have been used in attempting to prevent or reduce free radical damage. Endogenous anti-oxidants, e.g., superoxide dysmutase, catalase or glutathione peroxidase, may be used to protect cell membranes and agents such as ascorbic acid and glutathione may be used to protect cytosols. Other anti-oxidants, such as alpha-tocopherol and tretinoin, have also been used to ameliorate the effect of free radicals.
Administration of superoxide dysmutase, post-ischemia prevents the increased capillary permeability which accompanies reperfusion injuries (Granger, et al., Gastroenterology 81:22-29 (1981)) and the ablation of free radical generation prior to, and at the time of, reperfusion may prevent or lessen the severity of multiple system organ failure syndrome (Schiller, et al., Critical Care Med. 21:S92-S100 (1993)). Stewart, et al. have shown that UVB-induced DNA damage in human keratinocytes is attenuated by supplementing culture medium surrounding the cells with anti-oxidants such as vitamin C, selenite, or a water-soluble vitamin E analog (J. Inv. Dermatol. 106:1086-1089 (1996)).
E. Selegiline and Desmethylselegiline
Monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) are enzymes found in both in the central nervous system and in peripheral tissues. MAO-A and MAO-B catalyze the oxidative deamination of primary amines, including neuroactive and vasoactive amines, resulting in the formation of toxic free radical species and free radical-generating cascades. Selegiline is a potent and selective inhibitor of monoamine oxidase B and has been reported to have an action in protecting or rescuing neurons of the central nervous system (Knoll, Mount Sinai J. Med. 55:67-74 (1988)). Although the exact mechanism by which selegiline causes its effects is not known, there is evidence suggesting that it may provide neuroprotection or neuronal rescue by reducing oxidative damage caused by monoamine oxidase and/or other oxidants (Jenner, et al., Neurology 47:S162-S170 (1996)). In this regard, selegiline has been shown to increase the activity of the endogenous anti-oxidants superoxide dysmutase, catalase and glutathione peroxidase (Id.).
Desmethylselegiline, one of the metabolites of selegiline, exhibits reduced MAO-B inhibitory activity in comparison to selegiline and its activity with respect to the inhibition of MAO-A is decreased to an even greater extent. Thus, it is expected that desmethylselegiline should produce selegiline-like neuroprotective effects with a decreased risk of side effects associated with MAO-A inhibition.
Although selegiline has been used to treat Parkinson's disease, its use as a treatment for injuries, such as burns and wounds, and for alleviating dermatological damage, such as photodamage, has not been known heretofore. The present invention is directed to methods which rely upon the administration of selegiline or desmethylselegiline to speed the healing and reduce the complications associated with these conditions.
SUMMARY OF THE INVENTION
The present invention is based upon the discovery that compositions comprising selegiline and/or desmethylselegiline can be used in the treatment of wounds, burns and photodamaged skin. In the case of burns and wounds, compositions should be administered for a duration sufficient to promote epithelization. In the case of photodamaged skin, the composition should be administered for a duration sufficient to promote healing, as evidenced by a reduction in one or more of the symptoms associated with photodamaged skin. These symptoms include edema, vasodilation, lymphocytic and neutrophilic infiltration in the dermis, dyskeratotic keratinocytes and spongiosis of the epidermis.
Although the invention encompasses administration by any route, delivery by means of a topical composition containing between 1×10−11 moles/liter and 1×10−3 moles/liter of selegiline and/or desmethylselegiline is preferred. Topical compositions may be delivered by means of a spray, patch, salve, cream, lotion or gel. As used herein, the term “desmethylselegiline” refers to either the R(−) enantiomeric form of the drug, the S(+) enantiomeric form of the drug, or a racemic mixture of the two. In carrying out the present methods, the R(−) enantiomer may be used in the substantial absence of the S(+) enantiomer or vice versa. An enantiomer is substantially absent if it constitutes less than 10% of the combined desmethylselegiline enantiomers. Compositions may contain water, suspending agents, thickeners, humectants, preservatives, emollients, emulsifiers and film formers. They may be applied either directly to the skin of a patient or they may be applied as part of a patch.
Although not preferred, non-topical routes of administration are compatible with the present invention and may be used. The dosage of selegiline or desmethylselegiline when used non-orally should be at least 0.015 mg per kg body weight, calculated on the basis of the free secondary amine, with progressively higher doses being employed depending upon the route of administration and the subsequent response to therapy. Typically, the daily non-oral dose will be about 0.10 mg/kg and may extend to about 1.0 mg/kg (all such doses again being calculated on the basis of the free secondary amine).
DETAILED DESCRIPTION OF THE INVENTION
In the following des
Channavajjala Lakshmi
Page Thurman K.
Somerset Pharmaceuticals, Inc.
Vinson & Elkins L.L.P.
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