Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Heavy metal or compound thereof
Reexamination Certificate
1999-06-14
2003-05-06
Dees, Jose G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Heavy metal or compound thereof
C424S405000, C424S406000, C424S409000, C424S641000, C424SDIG006, C514S494000, C514S561000, C514S772000, C514S784000, C514S788000, C514S836000, C514S922000, C514S974000
Reexamination Certificate
active
06558710
ABSTRACT:
FIELD OF INVENTION
The present invention relates to zinc-containing compositions and methods for topical use of such compositions to treat cutaneous wounds, irritations, lesions, abrasions or the like. More particularly, the invention relates to zinc-containing compositions containing an amino acid to minimize external irritation from the zinc when applied to the skin without diminishing the amount of free zinc available for absorption.
BACKGROUND OF THE INVENTION
The value of zinc in tissue growth and repair is well documented. Zinc is essential for the function of at least 70 enzymes and is involved in a variety of metabolic processes. Zinc is a limiting factor in the formation of RNA and DNA. Zinc is also a limiting factor in zinc-dependent enzymes such as RNA and DNA polymerases, deoxythymidine kinase, and reverse transcriptase, which are responsible for the regulation of RNA and DNA metabolism. Diminished zinc availability slows protein synthesis, thereby slowing the replication of cells and inhibiting tissue repair. Approximately half of the total body zinc content of 2-3 gm (based on an average 70 kg adult) is found in ossified tissues and is, therefore, not readily available for metabolic processes. Although the skin boasts a higher zinc concentration than most tissues (10 micrograms/g of tissue), this is quickly depleted during the regeneration process. It has been shown experimentally that the activity of deoxythymidine kinase in rapidly regenerating connective tissue decreases as early as six days after animals are placed on a zinc-deficient diet, demonstrating that an external supply of zinc for use in tissue repair is essential. In fact, zinc supplementation has been shown to markedly improve wound healing in zinc-deficient individuals, while topical zinc improves wound healing in zinc-deficient and in normal individuals.
Zinc salts are known to inhibit bacterial and viral growth. Ophthalmic preparations of zinc sulfate to treat herpetic keratitis have been recommended since 1943. Oral preparations of zinc citrate used to treat gingivitis and periodontitis have been shown to reduce plaque formation and inhibit bacterial growth. Oral preparations of several zinc salts have been shown to reduce the symptoms and duration of the common cold caused by rhinovirus, but they are unpalatable and cause mouth irritation and nausea. Until the development of a palatable and less irritating zinc salt-with-amino-acid formulation, patients often refused to continue treatment with the oral preparations containing zinc salts.
Successful topical treatment of skin infections and lesions with zinc salts is well documented. Topical zinc pyrithione is an effective anti-fungal, effective in treating
Malassezia furfur
, the causative agent in several skin disorders including pityriasis versicolor. Topical zinc pyrithione has also been used to treat psoriasis and dandruff by inhibiting the over-proliferation of cells characterized by these conditions. Application of a zinc chloride solution before and after UV exposure in hairless mice reduced the number of sunburn cells in the epidermis and was reported in 1976 as a successful topical treatment of basal cell carcinoma in a human patient. Erythromycinzinc lotion is sebosuppressive and potentially beneficial to the acneic patient.
Herpes of the lips occurs in 50% of the population, while genital herpes is now one of the most common venereal diseases. Zinc salts irreversibly inhibit herpes virus replication in vitro and are effective in treating herpes infections in vivo. Zinc ions irreversibly inhibit herpes simplex virus (HSV) glycoprotein functions by accumulating in the sulfhydryl groups of glycoprotein B in the viral membrane, blocking synthesis of DNA. In the closely related rhinovirus, it is theorized that free zinc ions also sequester in the membrane, inhibiting viral binding with ICAM receptor sites in mucous membranes. Other closely related viruses may similarly be affected by zinc ions. U.S. Pat. No. 5,545,673 cites in vitro evidence that HIV infectivity was reduced or completely eliminated when concentrated viral stocks were incubated with 1-1.5% zinc acetate for 2 hours. HSV has significant homology to varicella-zoster virus. Eruptions of herpes zoster are thought to be more frequent in the elderly not because of immune dysfunction, but because of slowed mobilization of the immune system. It follows that prompt treatment with a zinc salt would be extremely beneficial as it would markedly decrease viral load and painful lesions independent of immune system activation.
Zinc salt solutions applied to herpetic lesions decrease viral load and markedly improve healing rates, relieving the symptoms of herpes as healing occurs. Long-term topical application of zinc salt solutions appears to greatly reduce or eliminate recurrences of genital herpetic lesions as well as prevent post-herpetic erythema multiform. It has been postulated that the delivery of a high concentration (compared to natural tissue and body fluid levels of ionic zinc) of the virucidal agent to the infection site may prevent retrograde spread of virus along involved ganglia.
Zinc oxide has been shown in numerous studies to accelerate the healing of both chronic and acute wounds. This effect may be in part due to stimulation of epidermal basal cells, noted in mice, and in part due to increased insulin-like growth factor-1 and mRNA (messenger RNA), noted in granulation tissue of full-thickness wounds in domestic pigs. Zinc paste bandages containing inorganic zinc compounds, e.g., zinc sulfate and zinc oxide, have long been a standard treatment of venous stasis ulcers. Zinc chloride paste has been shown effective in debridement and formation of granulation tissue on chronic leg ulcers. Zinc oxide has been shown to promote cleansing and re-epithelialization of leg ulcers and to reduce infections and deterioration of ulcers.
Unfortunately, topical application of some zinc solutions can cause painful or irritating side effects if not used in very low concentrations. Zinc sulfate solutions of 0.2-1% can cause severe irritation, unpleasant dryness and stimulate the emetic reflex when applied circumorally.
Reports of dermal irritancy in animal dermal abrasion models examining wound healing show the following: 1% aqueous zinc chloride is severely irritant; 20% aqueous zinc acetate is slightly less irritant; 20% suspension zinc oxide, 1% aqueous zinc sulfate, and 20% suspension zinc pyrithione, are not overtly irritant. The less irritant zinc salts, such as zinc oxide (which is only slightly soluble in water), were only marginally effective in stimulating epidermal healing in comparison to the more irritating and more water-soluble zinc salts.
Further, it is interesting to note that in other studies the zinc solutions, particularly of zinc sulfate, do not maintain constant local concentration levels when applied to the skin as does zinc oxide. The zinc in these studies is not slowly solubilized to provide a constant level for absorption, being already in frank solution. This indicates that a zinc preparation that provides a higher concentration of solubilized zinc in a minimally irritating formulation allowing controlled absorption would be of great clinical value.
Compositions for treating various skin irritations are also known including zinc and another material or materials. Such are described, for example, in the following U.S. Patents:
U.S. Pat. No. 4,937,234 describes a pharmaceutically acceptable composition providing minerals(s) (e.g. Zn) in a bioavailable form by the inclusion of certain amino acids (see col. 2, lines 56-59), with the molar amount of an acidic mineral salt (e.g., zinc gluconate) to an amino acid (e.g., lysine) being from about 0.05M:1.0M to about 1.0M:0.05M and neutralized to a pH of 6-8. Zinc oxide is mentioned only as not being water insoluble. In Example 13, zinc oxide is solubilized in water by the addition of ascorbic-acid. Various skin irritations can be healed.
U.S. Pat. No. 4,711,780 describes a composition to treat surface epithelium to promo
Breiner & Breiner L.L.C.
Choi Frank
Dees Jos,e G.
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