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WO1995026194A1 - Complexes allantoine-metaux pour la peau et les cheveux - Google Patents

Complexes allantoine-metaux pour la peau et les cheveux Download PDF

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Publication number
WO1995026194A1
WO1995026194A1 PCT/US1995/003849 US9503849W WO9526194A1 WO 1995026194 A1 WO1995026194 A1 WO 1995026194A1 US 9503849 W US9503849 W US 9503849W WO 9526194 A1 WO9526194 A1 WO 9526194A1
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WO
WIPO (PCT)
Prior art keywords
allantoin
ionic metal
skin
copper
composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1995/003849
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English (en)
Inventor
Loren R. Pickart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Skin Biology Inc
Original Assignee
Skin Biology Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Skin Biology Inc filed Critical Skin Biology Inc
Priority to AU21989/95A priority Critical patent/AU2198995A/en
Publication of WO1995026194A1 publication Critical patent/WO1995026194A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A61K8/4906—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom
    • A61K8/4913—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with one nitrogen as the only hetero atom having five membered rings, e.g. pyrrolidone carboxylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q7/00—Preparations for affecting hair growth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
    • A61K2800/58—Metal complex; Coordination compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/74—Biological properties of particular ingredients
    • A61K2800/75—Anti-irritant

Definitions

  • Allantoin a metabolic product of uric acid, is extensively used as a component of skin and hair products.
  • the compound which is generally well tolerated by the skin, is anecdotally reported to possess soothing properties on the skin and is often included in preparations designed to aid skin healing.
  • allantoin include a preparation for the treatment of bedsores and skin sores as reported in JP 4208219, for burned skin as reported in JP 55104205, to improve skin elasticity as reported in JP 5310548, and as a skin soothing agent in a moisturizing cream, as reported in US 4,863,725.
  • Scientific evidence for direct skin or hair stimulating properties of allantoin is sparse, however. Klouchek-Popova et al., Acta Phvsiol. Pharmacol. Bulg..
  • complexes possess anti-inflammatory activity, while others possess both anti-inflammatory activity and healing actions. Yet other complexes reportedly possess hair growth stimulating actions in addition to anti-inflammatory and/or healing activities, as described in, for example, Applicant's U.S. Patent No. 5,382,431, which is incorporated in its entirety by reference herein.
  • EP 66,283 discloses "eustatic" compositions which contain a non-toxic metal ion (including copper) and a glycosamino-glycan of hyaluronic acid or chondroitin sulfate useful as a cicatrizant (wound healing by closure) .
  • UK Patent Application GB 2 044 265 describes metal complexes (including copper) of adenosine triphosphate as aiding the recovery of bone tissue in cases of fractures as well as in osteoporosis and bone cysts.
  • Konishi (US Pat. No. 4,461,724) reports the tetrapeptide Gly-Ser-His-Lys and peptides of related structures possess anti-inflammatory and healing actions when complexed with metals such as ionic copper and zinc.
  • Yu (U.S. Patent 4,053,630) discloses the use of cysteic acid and its derivatives cysteine sulfinic acid or homocysteic acid, chelated to metal ions such as ferric, cupric, zinc or aluminum, to form compositions that alleviated symptoms of diseases characterized by defects of keratinization and achieved a remission of ichthyosis, dandruff and acne. Bertelli (U.S.
  • Patent 4,156,737 suggests that copper complexes of p-aminomethyl-benzene-sulfonamide possess healing and protective effects on skin burns.
  • Van Scott U.S. Patent 4,283,386 teaches that metallic (copper, zinc, or aluminum) salt forms of cysteic acid, cysteine sulfinic acid and homocysteic acid have therapeutic actions that produce remissions of dry and broken skin, keratoses, warts and palmar and plantar hyperkeratosis.
  • Yamashiki Japan Pat. 70018997
  • Morelle U.K. Pat. GB 2097256, DE Pat. 32212448
  • amino acid derivatives N- butyryl amino acids
  • 4,503,047 disclose a composition containing primarily one or more sulfur-containing amino acid(s) and copper(II) ions plus smaller amounts of allyl isothiocyanate and rhodanide ions to produce hair growth stimulating actions.
  • Pickart e.g., WO 91/07431, 88/08695 and EP 288,278, found a number of metal complexes of derivatives of Gly-L-His-L-Lys to increase hair follicle size and the rate of hair growth.
  • copper(II)-Gly-L-His-L- Lys supports cellular viability and possesses anti- inflammatory and healing actions, yet close synthetic aroylhydrazone analogs of its copper-binding region are extremely toxic to cells and tissues.
  • Another problem with the therapeutic use of copper complexes concerns the binding affinity of copper ion to the complexing molecule. While a defined copper complex can be synthesized, its therapeutic use places it in the physiological milieu of the tissues where a plethora of literally hundreds of compounds compete for binding to the copper ion, which can form electrostatic bonds to as many as six separate molecules. If the copper is removed from the complex and becomes loosely-bound, then tissue irritation occurs (see Raju et al., J. Natl. Cancer Inst. 69:1183-1188 (1982)) .
  • metal complexes are formulated into carrier creams or ointments.
  • Various chemicals are added to the formulations to increase adherence to skin and wound surfaces and to enhance the penetration of the complexes into the target tissue.
  • the expected therapeutic benefits may be nullified or significantly attenuated.
  • detergents such as sodium dodecyl sulfate are used to help blend oil and water phases of the emulsions and stabilize the formulations.
  • such detergents are themselves tissue irritants that can delay healing.
  • antimicrobial chemicals must be added during manufacture to inhibit the growth of microorganisms and the transmission of viruses.
  • antimicrobial agents may also inhibit the viability and function of a host's cells such as macrophages and fibroblasts that are involved in the maintenance and repair of skin and other tissue, and thus these agents may retard the healing response.
  • compositions useful in tissue protection, tissue healing, and/or stimulation of hair growth which compositions could be conveniently produced and at low cost.
  • the compositions could be sterilized without loss of bioactivity and could be formulated for topical application without the use of detergents or other potentially irritating compounds.
  • the compositions should be prepared from materials that are generally recognized as safe by regulatory agencies and thus could be used with minimal safety concerns and regulatory barriers. Quite surprisingly, the present invention fulfills these and other related needs.
  • the present invention is based on the discovery of methods to markedly increase the skin active properties of allantoin by complexing it with ionic metals such as copper or tin.
  • the present invention provides allantoin-metal compositions and methods for accelerating the healing of topical wounds and skin irritation, for protecting skin from damaging effects of oxidation, and for increasing the size of hair follicles and the rate of hair growth in warm-blooded animals.
  • the compositions useful in these methods, including pharmaceutical compositions are prepared from complexes of allantoin and an ionic metal such as copper, indium, zinc, tin, etc.
  • the invention provides methods for preparing the pharmaceutical compositions useful in accelerating the healing of topical wounds or increasing hair follicle size and hair growth in a warm-blooded animal.
  • Allantoin is combined with an aqueous solution of an ionic metal salt, then adjusted to a useful acidity range for skin products.
  • the resulting aqueous mixture is composed of complexes of allantoin and the metal ions.
  • the amount of water in the mixture is adjusted to produce a paste-like mixture.
  • the mixture may be used directly or combined with a pharmaceutically acceptable carrier to form a cream, lotion, etc. in a concentration of from about 5% to about 50% allantoin-ionic metal complex or more.
  • the preparation may be sterilized or pasteurized, as desired, without destroying the healing or hair-growth stimulating activity of the allantoin- ionic metal complex.
  • the invention provides methods for enhancing the recovery of skin of a warm-blooded animal from wounds, such as surgical incisions, burns, inflammation or minor irritation due to oxidative damage, etc.
  • the methods comprise administering to the skin wound or irritation a therapeutically or, in some cases a prophylactically effective amount of a composition which comprises the allantoin-ionic metal complex.
  • compositions and methods for increasing hair follicle size and the rate of hair growth in warm-blooded animals comprise administering to the skin in the area in which hair growth is desired an amount of allantoin-ionic metal complex sufficient to increase hair follicle size and the rate of hair growth in the animal.
  • the composition will be administered topically as a cream, and will be applied on a daily basis until hair growth is observed and for a time thereafter sufficient to maintain the desired amount of hair growth.
  • compositions and methods are provided by the present invention for topical skin treatments to protect damaged skin and thereby allow natural healing processes to proceed, to enhance tissue regenerative processes in the skin of warm blooded animals, and to stimulate hair growth in warm blooded animals.
  • the compositions are formed by complexing allantoin with ionic metals such as copper, zinc, tin or the like. Methods are provided for improving the recovery of wounds and surgical incisions, and stimulating hair growth in warm ⁇ blooded mammals.
  • allantoin is commonly meant glyoxylic diureide or glyoxyuric acid diuride, which is produced by the oxidation of uric acid and is widely available in nature. Allantoin can be prepared synthetically, as described in, e.g., U.S. Patent No. 2,158,098, incorporated herein by reference, or can be obtained from a variety of commercial suppliers.
  • the allantoin is complexed via admixture or other suitable procedure with one or more ionic metals, such as copper, indium, tin, zinc, or the salts thereof, such as sulfate, acetate, phosphate, chloride, citrate, succinate, oxalate, cinnamate, tartrate, fumarate, maleate, glutarate, etc.
  • ionic metals such as copper, indium, tin, zinc, or the salts thereof, such as sulfate, acetate, phosphate, chloride, citrate, succinate, oxalate, cinnamate, tartrate, fumarate, maleate, glutarate, etc.
  • allantoin at a concentration of about 5 to 50% (weight/volume) , is mixed with a aqueous solution of the metal salt (copper(II) chloride, tin(II) chloride, tin(IV) chloride, indium(III) chloride, or zinc(II) chloride) at a salt concentration of about 10 to 50% (w/v) , more preferably about 20% (w/v) .
  • the metal salt copper(II) chloride, tin(II) chloride, tin(IV) chloride, indium(III) chloride, or zinc(II) chloride
  • the allantoin-ionic metal complexes of the invention may be administered for a variety of therapeutic, prophylactic or cosmetic uses to humans or in veterinary applications to other warm-blooded animals.
  • veterinary animals particularly well suited for treatment with the present compositions are species of equine, bovine, porcine, ovine, caprine, canine, avian, feline, etc.
  • compositions and pharmaceutical preparations thereof are intended for local, topical, oral or parenteral
  • compositions are administered locally, e.g., topically, as a paste, cream, salve or ointment.
  • the allantoin-ionic metal compositions will typically be sterilized or pasteurized and incorporated into pharmaceutical or veterinary formulations.
  • Compositions which comprise the allantoin-ionic metal complexes can be sterilized by conventional, well known sterilization techniques, e.g., boiling or pasteurization, without substantially adversely affecting the biological activity of the allantoin-ionic metal complexes.
  • the compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions and as necessary to prepare compositions for convenient administration, such an pH adjusting and buffering agents, and delivery vehicles.
  • Actual methods for preparing pharmaceutically administrable compounds will be known or apparent to those skilled in the art and are described in detail in, for example, Remington's Pharmaceutical Science. Mack Publishing Co., Easton, PA pp. 428-429 (1975) , which is incorporated herein by reference, infra.
  • compositions may converted to solid, semi-solid, or liquid dosage forms, such, for example, as powders, granules, crystals, liquids, suspensions, liposomes, pastes, cremes, salves, etc., and may be in unit-dosage forms suitable for administration of relatively precise dosages.
  • the compositions may include a conventional pharmaceutical carrier or excipient and, in addition, may include other medicinal agents, growth factors, wound sealants, carriers, etc., as further described below.
  • the allantoin-ionic metal complexes can be provided separately or may be compounded with conventional nontoxic carriers such as, for example, aloe vera gel, squalane, glycerol sterate, polyethylene glycol, cetyl alcohol, stearic acid, and propylene glycol, among others.
  • nontoxic carriers such as, for example, aloe vera gel, squalane, glycerol sterate, polyethylene glycol, cetyl alcohol, stearic acid, and propylene glycol, among others.
  • Such compositions may contain about 5-100% active ingredient, more preferably about 20- 40%.
  • the concentration of the allantoin-ionic metal complexes in these formulations can vary widely, and will be selected primarily by intended use, viscosities, etc., in accordance with the particular mode of administration selected.
  • composition or formulation to be administered will, in any event, contain a quantity of the allantoin-ionic metal complexes sufficient to achieve the desired therapeutic or prophylactic effect in the subject being treated.
  • tissue healing compositions of the invention are administered to a warm-blooded animal, such as humans, already suffering from a wound, oxidative skin damage, inflammatory skin lesions, other the like as described above, in an amount sufficient to allow the healing process to proceed more quickly than if the host were not treated.
  • a warm-blooded animal such as humans
  • the compositions of the invention are administered in an amount sufficient to increase hair follicle size and the rate of hair growth.
  • Amounts adequate to accomplish these effects are defined as a "therapeutically effective doses.” Amounts effective for this use will depend on the severity of the wound, sore, etc, in the case of wound healing, and the extent of decreased follicle size in the case of impaired hair growth has, and the general state of health of the patient being treated, but generally range from about 1 mg to about 25 mg per day of allantoin-ionic metal complex per day per square centimeter of wound site, with dosages of from about 5 mg to about 10 mg per day per square centimeter of wound site being more commonly used. Maintenance dosages over a prolonged period of time may be adjusted as necessary. For veterinary uses higher levels may be administered as necessary. Determining actual amounts of the allantoin-ionic metal complexes necessary to treat a particular wound or condition as described above will be through standard empirical methods well known in the art.
  • compositions containing the allantoin-ionic metal complexes are administered to a host susceptible to or otherwise at risk of skin lesions or similar damage, to enhance the host's own wound healing or anti- oxidative capabilities.
  • a host susceptible to or otherwise at risk of skin lesions or similar damage to enhance the host's own wound healing or anti- oxidative capabilities.
  • Such an amount is defined to be a "prophylactically effective dose.”
  • the precise amounts again depend on the host's condition and general state of health, but generally range from about 0.1 mg to about 10 mg per day per square centimeter of skin, more commonly from about 1 mg to about 3 mg per cm 2 of skin per day.
  • Single or multiple administrations of the compositions can be carried out.
  • the allantoin-ionic metal complexes of the invention may be administered in relatively large amounts without serious side effects, although indiscriminate use may produce discoloration of the skin.
  • the dose may be adjusted accordingly to lower maintenance levels.
  • compositions of the invention may be administered alone or as adjunct therapy or prophylaxis.
  • the allantoin-ionic metal compositions can be used in combination with other factors found to improve other aspects of healing. In this manner, a synergistic effect may be attained that yields a clinical efficacy greater than that realized with any single factor.
  • compositions described herein stimulate a spectrum of healing processes, clinical wounds may differ considerably in their properties and healing patterns, leading one to utilize a combination of a composition described herein and a growth factor or a preparation such as described in commonly owned copending U.S. Patent 5,382,431 and patent applications USSN 08/219,047 and 08/219,681, each of which is incorporated herein by reference in its entirety.
  • nerve regeneration is defective in many burns and thus one can add a specific nerve growth factor to supplement the composition to enhance nerve regrowth into the burn area.
  • factors with other reported healing properties include epidermal growth factor, fibroblast growth factor, nerve growth factor, transforming growth factors, angiogenic growth factors, heparin, fibronectin, fibrin, platelet-derived growth factor, enzymatic superoxide dismutase, extracts of blood or factors from the blood, and other similar factors.
  • the following examples are offered by way of illustration, not by way of limitation.
  • the allantoin was mixed with sufficient room temperature water (about 23°C) to form a thick paste.
  • allantoin (1 gram) was mixed with 2 milliliters of water.
  • the paste was then mixed with a aqueous solution of cupric chloride hydrate or tin (II) chloride, at a concentration of about 20% (w/v) .
  • the volume of metal salt solution added was that amount needed to obtain a final metal concentration in the paste of 0.3 to 1.2% (weight/weight).
  • the addition of the metal salt reduced the pH of the paste to about 3.0.
  • the pH of the paste was then raised to 6.5 by careful addition of 1 N sodium hydroxide. This pH is useful for skin preparations but other pH levels near neutrality or in the slightly acidic range are also efficacious.
  • the paste can be applied directly to the skin or is formulated into skin creams and lotions at concentrations of usually 5 to 20% (w/w) although higher concentration are also effective.
  • the allantoin-copper complexes are used to treat damaged or irritated skin. Damaged or irritated skin healed faster after treatment with such a composition. As described further below, the allantoin-copper and allantoin-tin were used to promote hair growth and the enlargement of hair follicles. In hair growth models in mice, application of these complexes to the skin produced a marked stimulation of hair growth after 15 to 20 days.
  • Table 1 Effect of allantoin-copper complex on incision length.
  • Pasteurization consists of heating a solution to 160°F for 30 minutes which process kills all but the hardiest microorganisms.
  • allantoin was complexed with copper chloride by the methods described above in Example I.
  • the resultant paste was thoroughly mixed, then heated to 160°F for 30 minutes. After cooling to room temperature, the pastes were applied to surgical incision wounds in mice in the manner described in Example II.
  • Healing activity was similar to that observed with unpasteurized active composition, as shown in Table 2. There were six mice in each group.
  • allantoin was complexed with copper chloride by the procedure described above in Example I. The mixture was thoroughly mixed, then heated in a boiling water bath for 10 minutes. After cooling to room temperature, the active composition was applied to surgical wounds in mice in the manner described in Example II. The healing activity observed with the sterilized allantoin-copper complexes was similar to results obtained with unsterilized active compositions, as shown in Table 4. Each group had six mice.
  • This Example describes the use of compositions containing allantoin-copper and allantoin-tin complexes to stimulate the growth of hair follicles in warm blooded animals.
  • the model used in this test was a mouse model that has been found to successfully predict the therapeutic response in humans (see, e.g., U.S. Pat. No. 5,118,665, which is incorporated herein by reference) .
  • Hair growth in mammals proceeds through actively growing stages (anagen) followed by dormant stages (telogen) .
  • the test method generally involves applying the hair-growth stimulant to the skin of mice in telogen phase.
  • Female, Swiss-Webster mice begin a telogen phase at about 45 days of age that lasts until about 90 days of age. After application of the active substance, enhanced hair growth is noted within 14 days. For this test, mice 50 days of age were used.
  • Allantoin complexes containing copper(II) and tin(II) were tested.
  • the allantoin-metal pastes were mixed with saline (25% allantoin complex and 75% physiological saline by weight). Mice were shaved, then 0.05 ml of the mixture was infiltrated immediately below the skin by injection. Control mice were injected with an equal volume of saline or with allantoin not complexed with the metal. Each group contained 10 mice. After 20 days, the groups were compared. The percentage of mice with hair growth at the injection site and the relative strength of the hair growth response (on a scale of 1 to 5 where 1 is barely noticeable growth and 5 is very strong hair growth) were determined. The results, shown in Table 5, indicate that all complexes stimulated hair growth.
  • the subject invention provides compositions of allantoin-ionic metal complexes for topical skin, wound and surgical treatments to protect damaged skin and facilitate natural healing processes, to enhance tissue regenerative processes in the epidermis, and to stimulate hair growth in warm blooded animals.
  • the invention also provides economical methods for preparing and formulating the compositions for topical administration.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Birds (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention a pour objet des procédés et des compositions destinés à protéger les peaux irritées ou abîmées contre de nouvelles dégradations biochimiques et oxydatives. Ces procédés et compositions permettent de favoriser les processus de guérison naturelle, d'accélérer la guérison des brûlures et des plaies chirurgicales, d'accroître la taille des follicules pileux et d'accélérer la pousse des cheveux. Ces compositions comprennent des complexes d'allantoïne et de métaux ioniques tels que les sels cuivriques et les sels stanneux.
PCT/US1995/003849 1994-03-28 1995-03-27 Complexes allantoine-metaux pour la peau et les cheveux Ceased WO1995026194A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU21989/95A AU2198995A (en) 1994-03-28 1995-03-27 Allantoin-metal complexes for skin and hair

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21839294A 1994-03-28 1994-03-28
US08/218,392 1994-03-28

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WO1995026194A1 true WO1995026194A1 (fr) 1995-10-05

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164367A (en) * 1990-03-26 1992-11-17 Procyte Corporation Method of using copper(ii) containing compounds to accelerate wound healing

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5164367A (en) * 1990-03-26 1992-11-17 Procyte Corporation Method of using copper(ii) containing compounds to accelerate wound healing

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