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WO1996010474A1 - Cartouches de rasoir comprenant des compositions de cicatrisation de blessures - Google Patents

Cartouches de rasoir comprenant des compositions de cicatrisation de blessures Download PDF

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Publication number
WO1996010474A1
WO1996010474A1 PCT/US1995/008433 US9508433W WO9610474A1 WO 1996010474 A1 WO1996010474 A1 WO 1996010474A1 US 9508433 W US9508433 W US 9508433W WO 9610474 A1 WO9610474 A1 WO 9610474A1
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WO
WIPO (PCT)
Prior art keywords
wound healing
vitamin
acid
fatty acids
healing composition
Prior art date
Application number
PCT/US1995/008433
Other languages
English (en)
Inventor
Alain Martin
William Elbert Vreeland
Anthony R. Booth
Original Assignee
Warner-Lambert Company
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 Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to JP51171896A priority Critical patent/JP3940166B2/ja
Priority to AU29607/95A priority patent/AU2960795A/en
Priority to DE69524963T priority patent/DE69524963T2/de
Priority to EP95925499A priority patent/EP0783398B1/fr
Publication of WO1996010474A1 publication Critical patent/WO1996010474A1/fr

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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
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/361—Carboxylic acids having more than seven carbon atoms in an unbroken chain; Salts or anhydrides thereof
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A61K31/355—Tocopherols, e.g. vitamin E
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • 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
    • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
    • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
    • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q9/00—Preparations for removing hair or for aiding hair removal
    • A61Q9/02—Shaving preparations
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B26—HAND CUTTING TOOLS; CUTTING; SEVERING
    • B26B—HAND-HELD CUTTING TOOLS NOT OTHERWISE PROVIDED FOR
    • B26B21/00—Razors of the open or knife type; Safety razors or other shaving implements of the planing type; Hair-trimming devices involving a razor-blade; Equipment therefor
    • B26B21/40—Details or accessories
    • B26B21/44—Means integral with, or attached to, the razor for storing shaving-cream, styptic, or the like
    • B26B21/443—Lubricating strips attached to the razor head
    • 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
    • A61K2800/52—Stabilizers
    • A61K2800/522—Antioxidants; Radical scavengers

Definitions

  • This invention pertains to therapeutic wound healing compositions and/or their metabolites useful for preventing and reducing injury to mammalian cells affixed to razor cartridges to form therapeutic razor cartridges comprising wound healing compositions. This invention also pertains to methods for preparing and using the razor cartridges comprising the wound healing compositions.
  • a preferred embodiment of the therapeutic wound healing composition of this invention comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the wound healing composition comprises an antioxidant.
  • Wounds are internal or external bodily injuries or lesions caused by physical means, such as mechanical, chemical viral, bacterial, or thermal means, which disrupt the normal continuity of structures.
  • Such bodily injuries include contusions, wounds in which the skin is unbroken, incisions, wounds in which the skin is broken by a cutting instrument, and lacerations, wounds in which the skin is broken by a dull or blunt instrument.
  • Wounds may be caused by accidents or by surgical procedures. Patients who suffer major wounds could benefit from an
  • Wound healing consists of a series of processes whereby injured tissue is repaired, specialized tissue is regenerated, and new tissue is reorganized. Wound healing consists of three major phases: a) an inflammation phase (0-3 days), b) a cellular proliferation phase (3-12 days), and (c) a remodeling phase (3 days-6 months).
  • platelet aggregation and clotting form a matrix which traps plasma proteins and blood cells to induce the influx of various types of cells.
  • cellular proliferation phase new connective or granulation tissue and blood vessels are formed.
  • remodeling phase granulation tissue is replaced by a network of collagen and elastin fibers leading to the formation of scar tissue.
  • a wound healing step is desirable to resuscitate the injured cells and produce new cells to replace the dead cells.
  • the healing process requires the reversal of cytotoxicity, the suppression of inflammation, and the stimulation of cellular viability and proliferation. Wounds require low levels of oxygen in the initial stages of healing to suppress oxidative damage and higher levels of oxygen in the later stages of healing to promote collagen formation by fibroblasts.
  • Mammalian cells are continuously exposed to activated oxygen species such as superoxide (On-), hydrogen peroxide (H2O2), hydroxyl radical (OH ), and singlet oxygen ( O2).
  • activated oxygen species such as superoxide (On-), hydrogen peroxide (H2O2), hydroxyl radical (OH ), and singlet oxygen ( O2).
  • these reactive oxygen intermediates are generated by cells in response to aerobic metabolism, catabolism of drugs and other xenobiotics, ultraviolet and x-ray radiation, and the respiratory burst of phagocytic cells (such as white blood cells) to kill invading bacteria such as those introduced through wounds.
  • Hydrogen peroxide for example, is produced during respiration of most living organisms especially by stressed and injured cells.
  • lipid peroxidation which involves the oxidative degradation of unsaturated lipids.
  • Lipid peroxidation is highly detrimental to membrane structure and function and can cause numerous cytopathological effects.
  • Cells defend against lipid peroxidation by producing radical scavengers such as superoxide dismutase, catalase, and peroxidase. Injured cells have a decreased ability to produce radical scavengers.
  • Excess hydrogen peroxide can react with DNA to cause backbone breakage, produce mutations, and alter and liberate bases.
  • Hydrogen peroxide can also react with pyrimidines to open the 5, 6-double bond, which reaction inhibits the ability of pyrimidines to hydrogen bond to complementary bases, Hallaender et al (1971).
  • oxidative biochemical injury can result in the loss of cellular membrane integrity, reduced enzyme activity, changes in transport kinetics, changes in membrane lipid content, and leakage of potassium ions, amino acids, and other cellular material.
  • Antioxidants have been shown to inhibit damage associated with active oxygen species. For example, pyruvate and other //? ⁇ -ketoacids have been reported to react rapidly and stoichiometrically with hydrogen peroxide to protect cells from cytolytic effects, O'Donnell-Tormey et al, J. Exp. Med., 165, pp. 500-514 (1987).
  • United States Patents Nos. 3,920,835, 3,984,556, and 3,988,470 all issued to Van Scott et al, disclose methods for treating acne, dandruff, and palmar keratosis, respectively, which consist of applying to the affected area a topical composition comprising from about 1 % to about 20% of a lower aliphatic compound containing from two to six carbon atoms selected from the group consisting of Alpha- hydroxyacids, ⁇ //? ⁇ -ketoacids and esters thereof, and 3-hydroxybutryic acid in a pharmaceutically acceptable carrier.
  • the aliphatic compounds include pyruvic acid and lactic acid.
  • United States Patents Nos. 4,105,783 and 4,197,316 both issued to Yu et al, disclose a method and composition, respectively, for treating dry skin which consists of applying to the affected area a topical composition comprising from about 1% to about 20% ⁇ of a compound selected from the group consisting of amides and ammonium salts of ⁇ //) ⁇ -hydroxyacids, j ⁇ -hydroxyacids, and ⁇ //j ⁇ -ketoacids in a pharmaceutically acceptable carrier.
  • the compounds include the amides and ammonium salts of pyruvic acid and lactic acid.
  • United States Patent No. 4,234,599 issued to Van Scott et al, discloses a method for treating actinic and nonactinic skin keratoses which consists of applying to the affected area a topical composition comprising an effective amount of a compound selected from the group consisting of ⁇ //j ⁇ -hydroxyacids, ⁇ -hydroxyacids, and p ⁇ -ketoacids in a pharmaceutically acceptable carrier.
  • the acidic compounds include pyruvic acid and lactic acid.
  • United States Patent No. 4,294,852 issued to Wildnauer et al, discloses a composition for treating skin which comprises the Alpha-hydroxyacids, Miydroxyacids, and ⁇ /pA ⁇ -ketoacids disclosed above by Van Scott et al. in combination with Co-Co aliphatic alcohols.
  • Sodium pyruvate has been reported to reduce the number of erosions, ulcers, and hemorrhages on the gastric mucosa in guinea pigs and rats caused by acetylsalicylic acid.
  • the analgesic and antipyretic properties of acetylsalicylic acid were not impaired by sodium pyruvate, Puschmann, Arzneistoffforschung, 33, pp. 410-415 and 415-416 (1983).
  • Pyruvate has been reported to produce a relative stabilization of left ventricular pressure and work parameter and to reduce the size of infarctions. Pyruvate improves resumption of spontaneous beating of the heart and restoration of normal rates and pressure development, Bunger et al, J. Mol. Cell. Cardiol., 18, pp. 423-438 (1986), Mochizuki et al, J. Physiol. (Paris), 76, pp. 805-812 (1980), Regitz et al, Cardiovasc. Res., 15, pp. 652-658 (1981), Giannelli et al, Ann. Thorac. Surg., 21, pp. 386-396 (1976).
  • Sodium pyruvate has been reported to act as an antagonist to cyanide intoxication (presumably through the formation of a cyanohydrin) and to protect against the lethal effects of sodium sulfide and to retard the onset and development of functional, morphological, and biochemical measures of acrylamide neuropathy of axons, Schwartz et /., Toxicol. Appl. Pharmacol., 50, pp. 437-442 (1979), Sabri et al, Brain Res., 483, pp. 1-11 (1989).
  • United States Patents Nos. 4,158,057, 4,351,835, 4,415,576, and 4,645,764, all issued to Stanko disclose methods for preventing the accumulation of fat in the liver of a mammal due to the ingestion of alcohol, for controlling weight in a marnmal, for inhibiting body fat while increasing protein concentration in a mammal, and for controlling the deposition of body fat in a living being, respectively.
  • the methods comprise administering to the mammal a therapeutic mixture of pyruvate and dihydroxyacetone, and optionally riboflavin.
  • 4,548,937 discloses a method for controlling the weight gain of a mammal which comprises administering to the mammal a therapeutically effective amount of pyruvate, and optionally riboflavin.
  • United States Patent No. 4,812,479, issued to Stanko discloses a method for controlling the weight gain of a mammal which comprises administering to the mammal a therapeutically effective amount of dihydroxyacetone, and optionally riboflavin and pyruvate.
  • Rats fed a calcium-oxalate lithogenic diet including sodium pyruvate were reported to develop fewer urinary calculi (stones) than control rats not given sodium pyruvate, Ogawa et al, Hinyokika Kiyo, 32, pp. 1341-1347 (1986).
  • United States Patent No. 4,521,375 discloses a method for sterilizing surfaces which come into contact with living tissue. The method comprises sterilizing the surface with aqueous hydrogen peroxide and then neutralizing the surface with pyruvic acid.
  • United States Patent No. 4,416,982 issued to Tauda et al, discloses a method for decomposing hydrogen peroxide by reacting the hydrogen peroxide with a phenol or aniline derivative in the presence of peroxidase.
  • United States Patent No. 4,696,917 issued to Lindstrom et al, discloses an eye irrigation solution which comprises Eagle's Minimum Essential Medium with Earle's salts, chondroitin sulfate, a buffer solution, 2-mercaptoethanol, and a pyruvate.
  • the irrigation solution may optionally contain ascorbic acid and ⁇ / j p ⁇ -tocopherol.
  • an irrigation solution which comprises a balanced salt solution, chondroitin sulfate, a buffer solution, 2- mercaptoethanol, sodium bicarbonate or dextrose, a pyruvate, a sodium phosphate buffer system, and cystine.
  • the irrigation solution may optionally contain ascorbic acid and g ⁇ mm ⁇ -tocopherol.
  • United States Patent No. 4,847,069 discloses a photoprotective composition comprising (a) a sorbohydroxamic acid, (b) an anti- inflammatory agent selected from steroidal anti-inflammatory agents and a natural anti- inflammatory agent, and (c) a topical carrier. Fatty acids may be present as an emollient.
  • United States Patent No. 4,847,071 issued to Bissett et al, discloses a photoprotective composition comprising (a) a tocopherol or tocopherol ester radical scavenger, (b) an anti-inflammatory agent selected from steroidal anti-inflammatory agents and a natural anti-inflammatory agent, and (c) a topical carrier.
  • United States Patent No. 4,847,072, issued to Bissett et al discloses a topical composition comprising not more than 25% tocopherol sorbate in a topical carrier.
  • United States Patent No. 4,533,637 discloses a culture medium which comprises a carbon source, a nucleic acid source precursor, amino acids, vitamins, minerals, a lipophilic nutrient, and serum albumin, and cyclodextrins.
  • the lipophilic substances include unsaturated fatty acids and lipophilic vitamins such as Vitamin A, D, and E. Ascorbic acid may also be present.
  • United Kingdom patent application no. 2,196,348A, to Kovar et al discloses a synthetic culture medium which comprises inorganic salts, monosaccharides, amino acids, vitamins, buffering agents, and optionally sodium pyruvate adding magnesium hydroxide or magnesium oxide to the emulsion.
  • the oil phase may include chicken fat.
  • United States Patent No. 4,284,630 issued to Yu et al, discloses a method for stabilizing a water-in-oil emulsion which comprises adding magnesium hydroxide or magnesium oxide to the emulsion.
  • the oil phase may include chicken fat.
  • Preparation H has been reported to increase the rate of wound healing in artificially created rectal ulcers.
  • the active ingredients in Preparation H are skin respiratory factor and shark liver oil, Subramanyam et al, Digestive Diseases and Sciences, 29, pp. 829-832 (1984).
  • European patent application no. 0410696A1 discloses a mucoadhesive delivery system comprising a treating agent and a polyacrylic acid cross- linked with from about 1% to about 20% by weight of a polyhydroxy compound such as a sugar, cyclitol, or lower polyhydric alcohol.
  • Razor Cartridges disclose a mucoadhesive delivery system comprising a treating agent and a polyacrylic acid cross- linked with from about 1% to about 20% by weight of a polyhydroxy compound such as a sugar, cyclitol, or lower polyhydric alcohol.
  • Conventional wet shaving systems contain a reusable razor main frame with a handle which receives disposable blade cartridges. Spent cartridges are removed from the main frame and replaced by fresh units.
  • United States Patent No. 4,170,821 discloses a disposable razor cartridge comprising a blade seat, a razor blade, a cap, and an integral solid water-soluble shaving aid.
  • the shaving aid is permanently and immovably affixed to the cartridge.
  • Applicants have discovered that affixing the therapeutic wound healing composition of this invention to a razor cartridge results in a therapeutic razor cartridge which can reduce the duration and severity of shaving cuts and nicks.
  • the therapeutic razor cartridge comprises:
  • pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • an antioxidant an antioxidant
  • fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic razor cartridge comprises:
  • This invention also pertains to methods for making and using the razor cartridges comprising therapeutic wound healing compositions.
  • This invention further pertains to razor cartridges comprising therapeutic wound healing compositions that are combined with medicaments useful for treating wounds to form razor cartridges comprising augmented wound healing compositions.
  • Figure 1 depicts in bar graph format the viability of U937 monocytic cells following exposure of the cells to various antioxidants (Examples 1-5).
  • Figure 2 depicts in bar graph format the viability of U937 monocytic cells following exposure of the cells to various combinations of antioxidants (Examples 6- 13).
  • FIG 3 depicts in bar graph format the levels of hydrogen peroxide produced by U937 monocytic cells following exposure of the cells to various antioxidants (Examples 14-18).
  • Figure 4 depicts in bar graph format the levels of hydrogen peroxide produced by U937 monocytic cells following exposure of the cells to various combinations of antioxidants (Examples 19-26).
  • Figure 5 depicts in bar graph format the levels of hydrogen peroxide produced by U937 monocytic cells following exposure of the cells to various combinations of antioxidants with and without a mixture of saturated and unsaturated fatty acids
  • Figure 6 depicts in bar graph format the levels of hydrogen peroxide produced by epidermal keratinocytes following exposure of the cells to various antioxidants with and without a mixture of saturated and unsaturated fatty acids (Examples 33-42).
  • Figure 7 depicts in bar graph format the levels of hydrogen peroxide produced by epidermal keratinocytes following exposure of d e cells to various combinations of antioxidants with and without a mixture of saturated and unsaturated fatty acids (Examples 43-52).
  • Figure 8 depicts in bar graph format a summary analysis of the levels of hydrogen peroxide produced by epidermal keratinocytes following exposure of the cells to the individual components of the wound healing composition, to various combinations of the wound healing composition, and to the wound healing composition.
  • Figure 9 is a photograph of wounded mice after 4 days of treatment with:
  • Preparation H (Example A); a petrolatum base formulation containing live yeast cell derivative, shark oil, and a mixture of sodium pyruvate, vitamin E, and chicken fat
  • Example B a petrolatum base formulation containing live yeast cell derivative and shark oil (Example C); and no composition (Example E, control).
  • Figure 10 is a photograph of a wounded mouse after 4 days of treatment witii a petrolatum base formulation only (Example D).
  • FIG 11 is a view of a razor cartridge incorporating an embodiment of the present invention. For clarity, double cross-hatching has been used to depict portions of the razor cartridge which contain an integral wound healing composition delivery system affixed to the cartridge.
  • This invention pertains to therapeutic wound healing compositions and/or their metabolites for preventing and reducing injury to mammalian cells affixed to razor cartridges to form therapeutic razor cartridges with wound healing compositions.
  • the wound healing composition delivery system is preferably in the form of a solid strip of a water-soluble encapsulating agent comprising the wound healing composition premixed with a polymeric delivery system.
  • Wound healing compositions can increase the resuscitation rate of injured mammalian cells and the proliferation rate of new mammalian cells to replace dead cells.
  • binding a wound healing composition to a razor cartridge results in a therapeutic razor cartridge which can reduce the duration and severity of shaving cuts and nicks.
  • Applicant has discovered therapeutic wound healing compositions for preventing and reducing injury to mammalian cells and increasing the resuscitation rate of injured mammalian cells.
  • Cells treated with the therapeutic wound healing compositions of this invention show decreased levels of hydrogen peroxide production, increased resistance to cytotoxic agents, increased rates of proliferation, and increased viability.
  • Cellular cultures containing the therapeutic wound healing compositions showed enhanced differentiation and proliferation over control cultures and rapidly formed attachments or tight junctions between the cells to form an epidermal sheet.
  • Wounded mammals treated with the therapeutic wound healing compositions show significantly improved wound closing and healing over untreated mammals and mammals treated with conventional healing compositions.
  • the wound healing compositions may be used alone or in combination with other medicaments.
  • the therapeutic wound healing compositions or their metabolites of this invention are Embodiment One.
  • the therapeutic wound healing composition comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition comprises (a) an antioxidant and (b) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition comprises (a) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition comprises an antioxidant.
  • the therapeutic wound healing compositions of this invention may be further combined with one or more additional medicaments for treating wounds to form razor cartridges comprising augmented wound healing compositions.
  • an injured cell means a cell that has any activity disrupted for any reason.
  • an injured cell may be a cell that has injured membranes or damaged DNA, RNA, and ribosomes, for example, a cell which has (a) injured membranes so that transport through the membranes is diminished resulting in an increase in toxins and normal cellular wastes inside the cell and a decrease in nutrients and other components necessary for cellular repair inside the cell, (b) an increase in concentration of oxygen radicals inside the cell because of the decreased ability of the cell to produce antioxidants and enzymes, or (c) damaged DNA, RNA, and ribosomes which must be repaired or replaced before normal cellular functions can be resumed.
  • resuscitation of injured mammalian cells means the reversal of cytotoxicity, the stabilization of the cellular membrane, an increase in the proliferation rate of the cell, and/or the normalization of cellular functions such as the secretion of growth factors, hormones, and the like.
  • cytotoxicity as used herein means a condition caused by a cytotoxic agent that injures the cell. Injured cells do not proliferate because injured cells expend all energy on cellular repair. Aiding cellular repair promotes cellular proliferation.
  • prodrug refers to compounds which undergo biotransformation prior to exhibiting their pharmacological effects.
  • drug latentiation is the chemical modification of a biologically active compound to form a new compound which upon in vivo enzymatic attack will liberate the parent compound.
  • the chemical alterations of the parent compound are such that the change in physicochemical properties will affect the absorption, distribution and enzymatic metabolism.
  • the definition of drug latentiation has also been extended to include nonenzymatic regeneration of the parent compound.
  • prodrugs latentiated drugs, and bioreversible derivatives are used interchangeably.
  • latentiation implies a time lag element or time component involved in regenerating the bioactive parent molecule in vivo.
  • prodrug is general in that it includes latentiated drug derivatives as well as those substances which are converted after administration to the actual substance which combines with receptors.
  • prodrug is a generic term for agents which undergo biotransformation prior to exhibiting their pharmacological actions.
  • the term "prodrug” also includes compounds which may not necessarily undergo biotransformation to the administered drug but may undergo biotransformation to the active agent which exhibits the desired pharmacological effect.
  • metabolic refers to any substance produced by metabolism or by a metabolic process.
  • Metabolism refers to the various chemical reactions involved in the transformation of molecules or chemical compounds occurring in tissue and the cells therein.
  • the cells which may be treated with the therapeutic wound healing compositions in the present invention are mammalian cells. Although applicant will describe the present therapeutic wound healing compositions as useful for treating mammalian epidermal keratinocytes and mammalian monocytes, applicant contemplates that the therapeutic wound healing compositions may be used to protect or resuscitate all mammalian cells. Keratinocytes are representative of normal mammalian cells and are the fastest proliferating cells in the body. The correlation between the reaction of keratinocytes to injury and therapy and that of mammalian cells in general is very high. Monocytes are representative of specialized mammalian cells such as the white blood cells in the immune system and the organ cells in liver, kidney, heart, and brain.
  • the mammalian cells may be treated in vivo and in vitro.
  • Epidermal keratinocytes are the specialized epithelial cells of the epidermis which synthesize keratin, a scleroprotein which is the principal constituent of epidermis, hair, nails, horny tissue, and the organic matrix of the enamel of teeth.
  • Mammalian epidermal keratinocytes constitute about 95% of the epidermal cells and together with melanocytes form the binary system of the epidermis. In its various successive stages, epidermal keratinocytes are also known as basal cells, prickle cells, and granular cells.
  • Monocytes are mononuclear phagocytic leukocytes which undergo respiratory bursting and are involved in reactive oxygen mediated damage within the epidermis.
  • Leukocytes are white blood cells or corpuscles which may be classified into two main groups: granular leukocytes (granulocytes) which are leukocytes with abundant granules in the cytoplasm and nongranular leukocytes (nongranulocytes) which are leukocytes without specific granules in the cytoplasm and which include the lymphocytes and monocytes.
  • Phagocyte cells are cells which ingest microorganisms or other cells and foreign particles.
  • Monocytes are also known as large mononuclear leukocytes, and hyaline or transitional leukocytes.
  • Epidermal keratinocytic cells and monocytic cells have multiple oxygen generating mechanisms and the degree to which each type of mechanism functions differs in each type of cell.
  • monocytes for example, the respiratory bursting process is more pronounced than in epidermal keratinocytes.
  • the components in the therapeutic wound healing compositions of the present invention may vary depending upon the types of cells involved in the condition being treated.
  • the therapeutic wound healing composition for treating mammalian cells preferably epidermal keratinocytes, comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition for treating mammalian cells comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition for treating mammalian cells comprises (a) an antioxidant and (b) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the therapeutic wound healing composition for treating mammalian cells preferably monocytes, comprises (a) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • Pyruvic acid (2-oxopropanoic acid, ⁇ -ketopropionic acid, CH3COCOOH) or pyruvate is a fundamental intermediate in protein and carbohydrate metabolism and in the citric acid cycle.
  • the citric acid cycle (tricarboxylic acid cycle, Kreb's cycle) is the major reaction sequence which executes the reduction of oxygen to generate adenosine triphosphate (ATP) by oxidizing organic compounds in respiring tissues to provide electrons to the transport system.
  • Acetyl coenzyme A (“active acetyl”) is oxidized in this process and is thereafter utilized in a variety of biological processes and is a precursor in the biosynthesis of many fatty acids and sterols.
  • acetyl coenzyme A The two major sources of acetyl coenzyme A are derived from the metabolism of glucose and fatty acids. Glycolysis consists of a series of transformations wherein each glucose molecule is transformed in the cellular cytoplasm into two molecules of pyruvic acid. Pyruvic acid may then enter the mitochondria where it is oxidized by coenzyme A in the presence of enzymes and cofactors to acetyl coenzyme A. Acetyl coenzyme A can then enter the citric acid cycle. In muscle, pyruvic acid (derived from glycogen) can be reduced to lactic acid during anerobic metabolism which can occur during exercise. Lactic acid is reoxidized and partially retransformed to glycogen during rest. Pyruvate can also act as an antioxidant to neutralize oxygen radicals in the cell and can be used in the multifunction oxidase system to reverse cytotoxicity.
  • the pyruvate in the present invention may be selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, prodrugs of pyruvic acid, and mixtures thereof.
  • the pharmaceutically acceptable salts of pyruvic acid may be alkali salts and alkaline earth salts.
  • the pyruvate is selected from the group consisting of pyruvic acid, lithium pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, methyl pyruvate, Alpha-ketoglutaric acid, and mixtures thereof.
  • the pyruvate is selected from the group of salts consisting of sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and the like, and mixtures thereof. Most preferably, the pyruvate is sodium pyruvate.
  • the amount of pyruvate present in the therapeutic wound healing compositions of the present invention is a therapeutically effective amount.
  • a therapeutically effective amount of pyruvate is that amount of pyruvate necessary for the inventive composition to prevent and reduce injury to mammalian cells or increase the resuscitation rate of injured mammalian cells.
  • the exact amount of pyruvate is a matter of preference subject to such factors as the type of condition being treated as well as the other ingredients in the composition.
  • pyruvate is present in the therapeutic wound healing composition in an amount from about 10% to about 50%, preferably from about 20% to about 45%, and more preferably from about 25% to about 40%, by weight of the therapeutic wound healing composition.
  • CH3CHOHCOOH or lactate occurs in small quantities in the blood and muscle fluid of mammals. Lactic acid concentration increases in muscle and blood after vigorous activity. Lactate is a component in the cellular feedback mechanism and inhibits the natural respiratory bursting process of cells thereby suppressing the production of oxygen radicals.
  • the lactate in the present invention may be selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, prodrugs of lactic acid, and mixtures thereof.
  • the pharmaceutically acceptable salts of lactic acid may be alkali salts and alkaline earth salts.
  • the lactate is selected from the group consisting of lactic acid, lithium lactate, sodium lactate, potassium lactate, magnesium lactate, calcium lactate, zinc lactate, manganese lactate, and the like, and mixtures thereof. More preferably, the lactate is selected from the group consisting of lactic acid, sodium lactate, potassium lactate, magnesium lactate, calcium lactate, zinc lactate, manganese lactate, and mixtures thereof. Most preferably, the lactate is lactic acid.
  • the amount of lactate present in the therapeutic wound healing compositions of the present invention is a therapeutically effective amount.
  • a therapeutically effective amount of lactate is that amount of lactate necessary for the inventive composition to prevent and reduce injury to mammalian cells or increase the resuscitation rate of injured mammalian cells.
  • a therapeutically effective amount of lactate is that amount necessary to suppress the respiratory bursting process of white blood cells to protect and resuscitate the mammalian cells.
  • a therapeutically effective amount of lactate in an ingestible composition is from about 5 to about 10 times the amount of lactate normally found in serum. The exact amount of lactate is a matter of preference subject to such factors as the type of condition being treated as well as the other ingredients in the composition.
  • lactate is present in the therapeutic wound healing composition in an amount from about 10% to about 50%, preferably from about 20% to about 45%, and more preferably from about 25% to about 40%, by weight of the therapeutic wound healing composition.
  • Antioxidants are substances which inhibit oxidation or suppress reactions promoted by oxygen or peroxides. Antioxidants, especially lipid-soluble antioxidants, can be absorbed into the cellular membrane to neutralize oxygen radicals and thereby protect the membrane.
  • the antioxidants useful in the present invention may be selected from the group consisting of all forms of Vitamin A (retinol), all forms of
  • Vitamin2 (3, 4-didehydroretinol), all forms of carotene such as ⁇ /jp ⁇ -carotene, ⁇ - carotene (beta, j ⁇ -carotene), g ⁇ mm ⁇ -carotene, rfe/f ⁇ -carotene, all forms of Vitamin C (D-ascorbic acid, L-ascorbic acid), all forms of tocopherol such as Vitamin E (Alpha- tocopherol, 3,4-dihydro-2,5,7,8-tetramethyl-2-(4,8,12-trimethyltri-decyl)-2H-l- benzopyran-6-ol), ⁇ -tocopherol, g ⁇ mm ⁇ -tocopherol, rfeto-tocopherol, tocoquinone, tocotrienol, and Vitamin E esters which readily undergo hydrolysis to Vitamin E such as Vitamin E acetate and Vitamin E succinate, and pharmaceutically acceptable Vitamin E salts such as Vitamin E phosphate,
  • the antioxidant is selected from the group of lipid-soluble antioxidants consisting of Vitamin A, j ⁇ -carotene, Vitamin E, Vitamin E acetate, and mixtures thereof. More preferably, the antioxidant is Vitamin E or Vitamin E acetate. Most preferably, the antioxidant is Vitamin E acetate.
  • the amount of antioxidant present in the therapeutic wound healing compositions of the present invention is a therapeutically effective amount.
  • a therapeutically effective amount of antioxidant is that amount of antioxidant necessary for the inventive composition to prevent and reduce injury to mammalian cells or increase the resuscitation rate of injured mammalian cells.
  • the exact amount of antioxidant is a matter of preference subject to such factors as the type of condition being treated as well as the other ingredients in the composition.
  • the antioxidant is present in the therapeutic wound healing composition in an amount from about 0.1% to about 40%, preferably from about 0.2% to about 30%, and more preferably from about 0.5% to about 20%, by weight of the therapeutic wound healing composition.
  • the mixture of saturated and unsaturated fatty acids in the present invention are those fatty acids required for the repair of mammalian cellular membranes and the production of new cells.
  • Fatty acids are carboxylic acid compounds found in animal and vegetable fat and oil.
  • Fatty acids are classified as lipids and are composed of chains of alkyl groups containing from 4 to 22 carbon atoms and 0-3 double bonds and characterized by a terrninal carboxyl group, -COOH.
  • Fatty acids may be saturated or unsaturated and may be solid, semisolid, or liquid.
  • the most common saturated fatty acids are butyric acid (C 4 ), lauric acid (C j2 ). palmitic acid (C j g), and stearic acid (C j g).
  • Unsaturated fatty acids are usually derived from vegetables and consist of alkyl chains containing from 16 to 22 carbon atoms and 0-3 double bonds with the characteristic terminal carboxyl group.
  • the most common unsaturated fatty acids are oleic acid, linoleic acid, and linolenic acid (all Ci o acids).
  • the mixture of saturated and unsaturated fatty acids required for the repair of mammalian cellular membranes in the present invention may be derived from animal and vegetable fats and waxes, prodrugs of saturated and unsaturated fatty acids useful in the present invention, and mixtures thereof.
  • the fatty acids in the therapeutic wound healing composition may be in the form of mono-, di-, or trigylcerides, or free fatty acids, or mixtures thereof, which are readily available for the repair of injured cells.
  • Cells produce the chemical components and the energy required for cellular viability and store excess energy in the form of fat. Fat is adipose tissue stored between organs of the body to furnish a reserve supply of energy.
  • the preferred animal fats and waxes have a fatty acid composition similar to that of human fat and the fat contained in human breast milk.
  • the preferred animal fats and waxes may be selected from the group consisting of human fat, chicken fat, cow fat (defined herein as a bovine domestic animal regardless of sex or age), sheep fat, horse fat, pig fat, and whale fat.
  • the more prefened animal fats and waxes may be selected from the group consisting of human fat and chicken fat. The most prefened animal fat is human fat.
  • oils especially sunflower oil
  • marine oils especially shark liver oil
  • synthetic waxes and oils which have a fatty acid composition similar to that of animal fats and waxes, and preferably to that of human fats and waxes, may also be employed.
  • the mixture of saturated and unsaturated fatty acids has a composition similar to that of human fat and comprises the following fatty acids: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid.
  • butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid are present in the mixture in about the following percentages by weight, respectively (carbon chain number and number of unsaturations are shown parenthetically, respectively): 0.2%-0.4% (C 4 ), 0.1% (C 6 ), 0.3%-0.8% (C g ), 2.2%-3.5%
  • the mixture of saturated and unsaturated fatty acids is typically chicken fat comprising the following fatty acids: lauric acid, myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, margaroleic acid, stearic, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid.
  • lauric acid, myristic acid, myristoleic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, margaroleic acid, stearic, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid are present in the mixture in about the following percentages by weight, respectively: 0.1% (C 12 ), 0.8% (C 14 ), 0.2% (C 14: ] ), 0.1% (C 15 ), 25.3% (C, 6 ), 7.2% (C 16: 1 ), 0.1% (C 17 ), 0.1% (C 17 . ⁇ ), 6.5% (C l g ), 37.7% (C l g: 1 ), 20.6% (C, g:2 ), 0.8% (C l g:3 ), 0.2% (C 2 Q). and 0.3% (C 2() . ⁇ )> all percentages +/- 10%.
  • the mixture of saturated and unsaturated fatty acids comprises lecithin.
  • Lecithin phosphatidylcholine
  • Lecithin is a phosphatide found in all living organisms (plants and animals) and is a significant constituent of nervous tissue and brain substance.
  • Lecithin is a mixture of the diglycerides of stearic, palmitic, and oleic acids, linked to the choline ester of phosphoric acid.
  • the product of commerce is predominantly soybean lecithin obtained as a by-product in the manufacturing of soybean oil.
  • Soybean lecithin contains palmitic acid 11.7%, stearic 4.0%, palmitoleic 8.6%, oleic 9.8%, linoleic 55.0%, linolenic 4.0%, C 2 Q to C 2 acids (includes arachidonic) 5.5%.
  • Lecithin may be represented by the formula:
  • R is selected from the group consisting of stearic, palmitic, and oleic acid.
  • fatty acids and percentages thereof present in the fatty acid mixture are given as an example.
  • the exact type of fatty acid present in the fatty acid mixture and the exact amount of fatty acid employed in the fatty acid mixture may be varied in order to obtain the result desired in the final product and such variations are now within the capabilities of those skilled in the art without die need for undue experimentation.
  • the amount of fatty acids present in the therapeutic wound healing compositions of the present invention is a therapeutically effective amount.
  • a therapeutically effective amount of fatty acids is that amount of fatty acids necessary for the inventive composition to prevent and reduce injury to mammalian cells or increase the resuscitation rate of injured rijarranalian cells.
  • the exact amount of fatty acids employed is subject to such factors as the type and distribution of fatty acids employed in the mixture, the type of condition being treated, and the other ingredients in the composition.
  • the fatty acids are present in the therapeutic wound healing composition in an amount from about 10% to about 50%, preferably from about 20% to about 45%, and more preferably from about 25% to about 40%, by weight of the therapeutic wound healing composition.
  • the therapeutic wound healing compositions of Embodiment One (I.A-E) for treating mammalian cells may be selected from the group consisting of:
  • LA (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • LB (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof;
  • the wound healing compositions of Embodiment One (I) for treating mammalian cells may be selected from the group consisting of:
  • LA (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) an antioxidant; and
  • LB (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof;
  • the wound healing compositions of Embodiment One (I) for treating mammalian cells may be selected from the group consisting of: (I. A) (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • the wound healing compositions of Embodiment One (I) for treating mammalian cells may be selected from the group consisting of:
  • LA (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • LB (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof;
  • the wound healing compositions of Embodiment One (I) for treating ⁇ iammalian cells preferably epidermal keratinocytes, comprise:
  • fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • the wound healing compositions of Embodiment One (I) for treating mammalian cells preferably monocytes, comprise:
  • lactate selected from d e group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof;
  • pyruvate can be transported inside a cell where it can act as an antioxidant to neutralize oxygen radicals in the cell.
  • Pyruvate can also be used inside the cell in the citric acid cycle to provide energy to increase cellular viability, and as a precursor in die synthesis of important biomolecules to promote cellular proliferation.
  • pyruvate can be used in the multifunction oxidase system to reverse cytotoxicity.
  • Antioxidants, especially lipid-soluble antioxidants can be absorbed into die cell membrane to neutralize oxygen radicals and thereby protect the membrane.
  • the saturated and unsaturated fatty acids in the present invention are those fatty acids required for the resuscitation of mammalian cells and are readily available for the repair of injured cells and die proliferation of new cells.
  • Cells injured by oxygen radicals need to produce unsaturated fatty acids to repair cellular membranes.
  • die production of unsaturated fatty acids by cells requires oxygen.
  • the injured cell needs high levels of oxygen to produce unsaturated fatty acids and at the same time needs to reduce d e level of oxygen within the cell to reduce oxidative injury.
  • die need of the cell for unsaturated fatty acids is reduced and the need for high oxygen levels is also reduced.
  • the combination of pyruvate inside the cell and an antioxidant in die cellular membrane functions in an unexpected synergistic manner to reduce hydrogen peroxide production in the cell to levels lower than can be achieved by use of eidier type of component alone.
  • the presence of mixtures of saturated and unsaturated fatty acids in d e therapeutic wound healing composition significantly enhances die ability of pyruvate and the antioxidant to inhibit reactive oxygen production.
  • unsaturated fatty acids By stabilizing the cellular membrane, unsaturated fatty acids also improve membrane function and enhance pyruvate transport into the cell.
  • the three components in d e dierapeutic wound healing composition of the first aspect of Embodiment One (LA) function together in an unexpected synergistic manner to prevent and reduce injury to mammalian cells and increase the resuscitation rate of injured mammalian cells.
  • lactate is employed instead of an antioxidant. Antioxidants react witii, and neutralize, oxygen radicals after the radicals are already formed. Lactate, on die other hand, is a component in the cellular feedback mechanism and inhibits die respiratory bursting process to suppress die production of active oxygen species.
  • the combination of pyruvate to neutralize active oxygen species and lactate to suppress the respiratory bursting process functions in a synergistic manner to reduce hydrogen peroxide production in the cell to levels lower tiian can be achieved by use of either type of component alone.
  • the presence of mixtures of saturated and unsaturated fatty acids in the therapeutic wound healing composition significantly enhances die ability of pyruvate and lactate to inhibit reactive oxygen production.
  • die tiiree components in the dierapeutic wound healing composition in the second aspect of Embodiment One (LB) function together in a synergistic manner to protect and resuscitate mammalian cells.
  • the presence of mixtures of saturated and unsaturated fatty acids in d e therapeutic wound healing composition in this embodiment significantly enhances the ability of the antioxidant to inhibit reactive oxygen production.
  • the combination of an antioxidant to neutralize active oxygen species and fatty acids to rebuild cellular membranes and reduce the need of die cell for oxygen functions in a synergistic manner to reduce hydrogen peroxide production in the cell to levels lower than can be achieved by eidier type of component alone.
  • the components in the therapeutic wound healing composition in the third aspect of Embodiment One (LC) function together in a synergistic manner to protect and resuscitate mammalian cells.
  • lactate is employed because die respiratory bursting process is more pronounced in monocytes than in epidermal keratinocytes.
  • the combination of lactate to suppress die respiratory bursting process and an antioxidant to neutralize active oxygen species functions in a synergistic manner to reduce hydrogen peroxide production in the cell to levels lower tiian can be achieved by eidier component alone.
  • the presence of mixtures of saturated and unsaturated fatty acids in the therapeutic wound healing composition in this embodiment significantly enhances the ability of lactate and the antioxidant to inhibit reactive oxygen production.
  • die therapeutic wound healing composition in the fourth aspect of Embodiment One function together in an unexpected synergistic manner to protect and resuscitate mammalian cells.
  • die combination of ingredients set out in the above embodiments functions together in an enhanced manner to prevent and reduce injury to mammalian cells and increase the resuscitation rate of injured mammalian cells.
  • the dierapeutic effect of die combination of the components in each of the above embodiments is markedly greater than that expected by die mere addition of the individual therapeutic components.
  • applicant's therapeutic wound healing compositions for treating mammalian cells have the ability to decrease intracellular levels of hydrogen peroxide production, increase cellular resistance to cytotoxic agents, increase rates of cellular proliferation, and increase cellular viability.
  • a therapeutic wound healing composition is made by forming an admixture of the components of the composition.
  • a therapeutic wound healing composition is made by forming an admixture of (a) pyruvate selected from d e group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • a dierapeutic wound healing composition is made by forming an admixture of (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures tiiereof, (b) lactate selected from d e group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • a therapeutic wound healing composition is made by forming an admixture of (a) an antioxidant and (b) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • a dierapeutic wound healing composition is made by forming an admixture of (a) lactate selected from die group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for d e repair of cellular membranes and resuscitation of mammalian cells.
  • a d erapeutic-wound healing composition is made using an antioxidant.
  • die admixture may be formed in a solvent such as water, and a surfactant may be added if required. If necessary, the pH of die solvent is adjusted to a range from about 3.5 to about 8.0, and preferably from about 4.5 to about 7.5, and more preferably about 6.0 to about 7.4. The admixture is tiien sterile filtered.
  • Otiier ingredients may also be incorporated into die therapeutic wound healing composition as dictated by the nature of the desired composition as well known by ti ose having ordinary skill in die art.
  • the ultimate therapeutic wound healing compositions are readily prepared using methods generally known in the pharmaceutical arts.
  • the invention is directed to a method for preparing a dierapeutic wound healing composition (LA) for preventing and reducing injury to mammalian cells, and increasing the resuscitation rate of injured mammalian cells, which comprises d e steps of admixing the following ingredients:
  • pyruvate selected from d e group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • the present invention extends to metiiods for employing die dierapeutic wound healing compositions of Embodiment One (I) in vivo and in vitro.
  • a therapeutic wound healing composition is employed by contacting die dierapeutic composition with mammalian cells.
  • the invention is directed to a metiiod for preventing and reducing injury to mammalian cells, and increasing the resuscitation rate of injured mammalian cells, which comprises the steps of (A) providing a dierapeutic wound healing composition which comprises (a) pyruvate selected from die group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures tiiereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are tiiose fatty acids required for die resuscitation of injured mammalian cells, and (B) contacting d e therapeutic wound healing composition with the mammalian cells.
  • a dierapeutic wound healing composition which comprises (a) pyruvate selected from die group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures tiiereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated
  • the invention is directed to a method for preventing and reducing injury to mammalian cells, and increasing die resuscitation rate of injured mammalian cells, which comprises the steps of (A) providing a dierapeutic wound healing composition which comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof, and (c) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are those fatty acids required for die resuscitation of injured mammalian cells, and (B) contacting die therapeutic wound healing composition with the mammalian cells.
  • a dierapeutic wound healing composition which comprises (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof, (b) lactate selected from the group consisting of lactic acid
  • the invention is directed to a method for preventing and reducing injury to mammalian cells, and increasing die resuscitation rate of injured mammalian cells, which comprises die steps of (A) providing a dierapeutic wound healing composition which comprises (a) an antioxidant, and (b) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are tiiose fatty acids required for the resuscitation of injured mammalian cells, and (B) contacting the dierapeutic wound healing composition with the mammalian cells.
  • a dierapeutic wound healing composition which comprises (a) an antioxidant, and (b) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are tiiose fatty acids required for the resuscitation of injured mammalian cells
  • B contacting the dierapeutic wound healing composition with the mammalian cells.
  • the invention is directed to a metiiod for preventing and reducing injury to mammalian cells, and increasing the resuscitation rate of injured rriammalian cells, which comprises the steps of (A) providing a therapeutic wound healing composition which comprises (a) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein d e fatty acids are those fatty acids required for the resuscitation of injured mammalian cells, and (B) contacting the therapeutic wound healing composition with die mammalian cells.
  • a therapeutic wound healing composition which comprises (a) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids wherein d e fatty acids are those fatty acids required for the
  • the invention is directed to a method for preventing and reducing injury to mammalian cells, and increasing d e resuscitation rate of injured mammalian cells, which comprises die steps of (A) providing a tiierapeutic-wound healing composition comprising an antioxidant and (B) contacting the dierapeutic wound healing composition witii mammalian cells.
  • the invention is directed to a method for healing a wound in a mammal which comprises die steps of: (A) providing a dierapeutic wound healing composition (LA) which comprises:
  • pyruvate selected from die group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • the types of wounds which may be healed using die wound healing compositions of Embodiment One (I.A-E) of d e present invention are tiiose which result from an injury which causes epidermal damage such as incisions, wounds in which die skin is broken by a cutting instrument, and lacerations, wounds in which d e skin is broken by a dull or blunt instrument.
  • the dierapeutic compositions may also be used to treat various dermatological disorders such as hyperkeratosis, photo-aging, bu s, donor site wounds from skin transplants, ulcers (cutaneous, decubitus, venous stasis, and diabetic), psoriasis, skin rashes, and sunburn photoreactive processes.
  • the topical dierapeutic compositions may also be used orally in the form of a moutii wash or spray to protect and accelerate die healing of injured oral tissue such as mouth sores and bums.
  • the topical therapeutic compositions may further be used in ophd almological preparations to treat wounds such as those which result from corneal ulcers, radialkeratotomy, corneal transplants, epikeratophakia and otiier surgically induced wounds in die eye.
  • the topical dierapeutic compositions may in addition be used in anorectal creams and suppositories to treat such conditions as pruritus and, proctitis, anal fissures, and hemo ⁇ hoids.
  • die dierapeutic compositions are used to treat wounds such as incisions and lacerations.
  • the wound healing compositions of Embodiment One (I.A-E) of the present invention may be utilized in topical products, ingestible products, and tissue culture medium to protect mammalian cells and increase die resuscitation rate of injured mammalian cells.
  • die dierapeutic wound healing compositions may be used in topical skin care products to protect and increase die resuscitation rate of skin tissue such as in d e treatment of various dermatological disorders such as hyperkeratosis, photo-aging, and sunburn photoreactive processes.
  • Injury to skin can occur for a variety of reasons. Damage often occurs to individuals who wash their hands often, to individuals who are exposed to stressful environmental conditions
  • wound healing compositions of d e present invention to a lotion provides a source of antioxidants to the skin which would protect die skin from the harmful effects of UV light, chemicals, and severe drying.
  • the wound healing compositions can be used for the following indications: a) Moisturizing and protecting; b) Healing dry cracked skin; c) Treating irritated skin such as diaper rash; d) Healing severe dry skin due to other diseases (venous dermatitis); e) Treating psoriasis and otiier hyperproliferative diseases; f) Protecting skin from UV light damage (antioxidant skin replacement); g) Treating seborrheic conditions; and h) Treating shaving wounds in an after shave lotion.
  • the topical therapeutic wound healing compositions may also be used orally in die form of a moutii wash or spray to protect and accelerate the healing of injured oral tissue such as mouth sores and bums.
  • the topical therapeutic wound healing compositions may further be used in ophdialmological preparations such as eye care products to neutralize hydrogen peroxide used in d e cleaning of contact lenses.
  • the topical dierapeutic wound healing compositions may in addition be used in anorectal creams and suppositories to treat such conditions as pruritus ani, proctitis, anal fissures, and hemorrhoids. Initially as white blood cells enter a wound site, d e cells release oxygen radicals, depleting die antioxidants at the wound site, thus impairing the healing process.
  • wound healing compositions of the present invention into a wound healing formulation would facilitate healing by providing the site with usable antioxidants, and a source of fatty acids needed for membrane repair.
  • the wound healing compositions can be used for die following indications: a) Healing of cuts and scrapes; b) Burns (heals bums witii less scaring and scabbing); c) Decubitus ulcers; d)
  • the therapeutic wound healing compositions may also be used in ingestible products to protect and increase die resuscitation rate of erosions, stomach ulcers, and hemorrhages in die gastric mucosa.
  • Otiier ingestible therapeutic products include: stroke medications; autoimmune disease medications; arthritis medications; ulcer medications; cancer medications (cytotoxic agents); heart medication to improve regional ventricular function and restore normal heart rate and pressure functions; lung medication to repair injured tissue; liver medication to suppress lipogenesis of alcoholic origin and prevent hepatic steatosis; kidney medication to suppress urinary calculi (kidney stones); detoxification medication to antagonize heavy metal poisoning, cyanide poisoning, sodium sulfide poisoning, other types of poisoning.
  • the dierapeutic wound healing compositions may be used in ingestible products to treat inflammatory diseases such as hepatitis, gastritis, colitis, esophagitis, arthritis, and pancreatitis.
  • the therapeutic wound healing compositions of the present invention may also be used in tissue culture media and organ transplant media to prevent and reduce injury to mammalian cells and increase die resuscitation rate of injured mammalian cells.
  • Tissue cultures and transplant organs encounter reactive oxygen species generated in die culture media by die injured cells.
  • Organs particularly susceptible to oxidative damage during transport and transplantation due to reperfusion injury following ischemia are corneas, livers, hearts, and kidneys.
  • the dierapeutic wound healing compositions may be useful to abrogate reperfusion injury to such transplant organs.
  • die invention is directed to a metiiod for preserving mammalian cells in a culture medium which comprises the steps of:
  • LA (a) pyruvate selected from die group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • (LB) (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof; and (c) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells;
  • LC (a) an antioxidant; and (b) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof;
  • inventive dierapeutic wound healing compositions of Embodiment One may be stored for future use or may be formulated in effective amounts with pharmaceutically acceptable carriers to prepare a wide variety of pharmaceutical compositions.
  • pharmaceutically acceptable carriers are pharmaceutical appliances, topical vehicles (non-oral and oral), and ingestible vehicles.
  • Non-oral topical compositions employ non-oral topical vehicles, such as creams, gels formulations, foams, ointments and sprays, salves, and films, which are intended to be applied to the skin or body cavity and are not intended to be taken by mouth.
  • Oral topical compositions employ oral vehicles, such as mouthwashes, rinses, oral sprays, suspensions, and dental gels, which are intended to be taken by moutii but are not intended to be ingested.
  • Ingestible compositions employ ingestible or partly ingestible vehicles such as confectionery bulking agents which include hard and soft confectionery such as lozenges, tablets, toffees, nougats, suspensions, chewy candies, and chewing gums.
  • the therapeutic wound healing composition is incorporated into a pharmaceutical appliance which may be in the form of sutures, staples, gauze, bandages, bum dressings, artificial skins, liposome or micell formulations, microcapsules, aqueous vehicles for soaking gauze dressings, and die like, and mixtures thereof.
  • a pharmaceutical appliance which may be in the form of sutures, staples, gauze, bandages, bum dressings, artificial skins, liposome or micell formulations, microcapsules, aqueous vehicles for soaking gauze dressings, and die like, and mixtures thereof.
  • a variety of traditional ingredients may optionally be included in the pharmaceutical composition in effective amounts such as buffers, preservatives, tonicity adjusting agents, antioxidants, polymers for adjusting viscosity or for use as extenders, and excipients, and the like.
  • Such traditional ingredients include acetate and borate buffers; thimerosal, sorbic acid, methyl and propyl paraben and chlorobutanol preservatives; sodium chloride and sugars to adjust the tonicity; and excipients such as mannitol, lactose and sucrose.
  • Other conventional pharmaceutical additives known to those having ordinary skill in the pharmaceutical arts may also be used in the pharmaceutical composition.
  • die therapeutic wound healing compositions of the present invention may be employed in the pharmaceutical appliance. These amounts are readily determined by those skilled in die art without the need for undue experimentation. The exact amount of the therapeutic wound healing composition employed is subject to such factors as the type and concentration of the therapeutic wound healing composition and the type of pharmaceutical appliance employed. Thus, the amount of therapeutic wound healing composition may be varied in order to obtain d e result desired in the final product and such variations are within the capabilities of those skilled in the art without the need for undue experimentation.
  • die pharmaceutical composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 5%, by weight of the pharmaceutical composition.
  • the pharmaceutical composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 3%, by weight of the pharmaceutical composition. In a most preferred embodiment, the pharmaceutical composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 1%, by weight of the pharmaceutical composition.
  • a pharmaceutical composition is made by contacting a therapeutically effective amount of a therapeutic wound healing composition with a pharmaceutical appliance and the other ingredients of the final desired pharmaceutical composition.
  • the therapeutic wound healing composition may be in a solvent and may be absorbed onto a pharmaceutical appliance.
  • Otiier ingredients will usually be incorporated into the composition as dictated by the nature of the desired composition as well known by those having ordinary skill in the art.
  • the ultimate pharmaceutical compositions are readily prepared using methods generally known in the pharmaceutical arts.
  • the therapeutic wound healing composition is incorporated into a non-oral topical vehicle which may be in die form of a cream, gel, foam, ointment, spray, and the like.
  • Typical non-toxic non-oral topical vehicles known in the pharmaceutical arts may be used in the present invention.
  • the preferred non- oral topical vehicles are water and pharmaceutically acceptable water-miscible organic solvents such as ethyl alcohol, isopropyl alcohol, propylene glycol, glycerin, and die like, and mixtures of these solvents. Water-alcohol mixtures are particularly preferred and are generally employed in a weight ratio from about 1 :1 to about 20:1, preferably from about 3:1 to about 20:1, and most preferably from about 3:1 to about 10:1, respectively.
  • the non-oral topical therapeutic wound healing compositions may also contain conventional additives employed in those products.
  • Conventional additives include humectants, emollients, lubricants, stabilizers, dyes, and perfumes, providing the additives do not interfere with the therapeutic properties of the therapeutic wound healing composition.
  • Suitable humectants useful in die non-oral topical therapeutic wound healing compositions include glycerin, propylene glycol, polyethylene glycol, sorbitan, fructose, and die like, and mixtures tiiereof. Humectants, when employed, may be present in amounts from about 10% to about 20%, by weight of the topical therapeutic wound healing composition.
  • the coloring agents (colors, colorants) useful in the non-oral topical therapeutic wound healing composition are used in amounts effective to produce die desired color.
  • coloring agents include pigments which may be incorporated in amounts up to about 6% by weight of the non-oral topical dierapeutic wound healing composition.
  • a preferred pigment, titanium dioxide may be incorporated in amounts up to about 2%, and preferably less than about 1 %, by weight of the non-oral topical therapeutic wound healing composition.
  • the coloring agents may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These coloring agents are known as F.D.& C. dyes and lakes.
  • the materials acceptable for the foregoing uses are preferably water-soluble.
  • Illustrative nonlimiting examples include the indigoid dye known as F.D.& C. Blue No.2, which is the disodium salt of 5,5-indigotindisulfonic acid.
  • the dye known as F.D.& C. Green No.l comprises a triphenylmetiiane dye and is the monosodium salt of 4-[4-(N-eti ⁇ yl-p.-sulfoniumbenzylarnino) diphenylmethylene]-[l-(N-ethyl-N-p-sulfoniumbenzyl)-delta-2,5-cyclohexadieneimine].
  • therapeutically effective amounts of the therapeutic wound healing compositions of d e present invention may be admixed with a non-oral topical vehicle to form a topical therapeutic wound healing composition.
  • a non-oral topical therapeutic wound healing composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 10% and a non-oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the non-oral topical therapeutic wound healing composition.
  • the non-oral topical therapeutic wound healing compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 5%, and in a most preferred embodiment, die non-oral topical dierapeutic wound healing compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 2%, and a non-oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the non-oral topical therapeutic wound healing composition.
  • the present invention extends to metiiods for preparing the non-oral topical therapeutic wound healing compositions.
  • the non-oral topical therapeutic wound healing composition is prepared by admixing a therapeutically effective amount of the therapeutic wound healing composition of the present invention and a non-oral topical vehicle.
  • the final compositions are readily prepared using standard methods and apparatus generally known by those skilled in die pharmaceutical arts.
  • the apparatus useful in accordance with die present invention comprises mixing apparatus well known in the pharmaceutical arts, and therefore the selection of the specific apparatus will be apparent to the artisan.
  • die therapeutic wound healing composition is incorporated into an oral topical vehicle which may be in the form of a mouthwash, rinse, oral spray, suspension, dental gel, and die like.
  • Typical non-toxic oral vehicles known in the pharmaceutical arts may be used in the present invention.
  • the preferred oral vehicles are water, ethanol, and water-etiianol mixtures.
  • the water-ethanol mixtures are generally employed in a weight ratio from about 1:1 to about 20:1, preferably from about 3:1 to about 20:1, and most preferably from about 3:1 to about 10:1, respectively.
  • the pH value of the oral vehicle is generally from about 4 to about 7, and preferably from about 5 to about 6.5.
  • An oral topical vehicle having a pH value below about 4 is generally irritating to the oral cavity and an oral vehicle having a pH value greater than about 7 generally results in an unpleasant mouth feel.
  • the oral topical therapeutic wound healing compositions may also contain conventional additives normally employed in tiiose products.
  • Conventional additives include a fluorine providing compound, a sweetening agent, a flavoring agent, a coloring agent, a humectant, a buffer, and an emulsifier, providing the additives do not interfere with the therapeutic properties of the therapeutic wound healing composition.
  • the coloring agents and humectants, and the amounts of these additives to be employed, set out above as useful in the non-oral topical therapeutic wound healing composition may be used in the oral topical dierapeutic wound healing composition.
  • Fluorine providing compounds may be fully or slightly water soluble and are characterized by their ability to release fluoride ions or fluoride containing ions in water and by their lack of reaction with other components in the composition.
  • Typical fluorine providing compounds are inorganic fluoride salts such as water-soluble alkali metal, alkaline earth metal, and heavy metal salts, for example, sodium fluoride, potassium fluoride, ammonium fluoride, cuprous fluoride, zinc fluoride, stannic fluoride, stannous fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, sodium monofluorophosphate, aluminum mono- and di-fluorophosphates and fluorinated sodium calcium pyrophosphate.
  • Alkali metal fluorides, tin fluoride and monofluorophosphates such as sodium and stannous fluoride, sodium monofluorophosphate and mixtures thereof, are preferred.
  • the amount of fluorine providing compound present in the present oral topical therapeutic wound healing composition is dependent upon the type of fluorine providing compound employed, the solubility of the fluorine compound, and the nature of the final oral therapeutic wound healing composition.
  • the amount of fluorine providing compound used must be a nontoxic amount. In general, the fluorine providing compound when used will be present in an amount up to about 1%, preferably from about 0.001% to about 0.1%, and most preferably from about 0.001% to about 0.05%, by weight of the oral topical therapeutic wound healing composition.
  • sweetening agents those sweeteners well known in die art, including both natural and artificial sweeteners, may be employed.
  • the sweetening agent used may be selected from a wide range of materials including water- soluble sweetening agents, water-soluble artificial sweetening agents, water-soluble sweetening agents derived from naturally occurring water-soluble sweetening agents, dipeptide based sweetening agents, and protein based sweetening agents, including mixtures thereof.
  • sweetening agents include: (a) water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, com syrup solids, dihydrochalcones, monellin, steviosides, and glycyrrhizin, and mixtures thereof;
  • water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch
  • water-soluble artificial sweeteners such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3 ,4-dihydro-6-methyl- 1 ,2,3-oxathiazine-4-one-2,2-dioxide, the potassium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4-one-2,2 -dioxide (Acesulfame-K), the free acid form of saccharin, and die like;
  • soluble saccharin salts i.e., sodium or calcium saccharin salts, cyclamate salts
  • the sodium, ammonium or calcium salt of 3 ,4-dihydro-6-methyl- 1 ,2,3-oxathiazine-4-one-2,2-dioxide the potassium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4
  • dipeptide based sweeteners such as L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (Aspartame) and materials described in United States Patent No. 3,492,131, L-Alpha-aspartyl-N-(2,2,4,4- tetramethyl-3-thietanyl)-D-alanin-amide hydrate (Alitame), methyl esters of L-aspartyl- L-phenylglycerineandL-aspartyl-L-2,5-dihydrophenyl-glycine, L-aspartyl-2,5-dihydro- L-phenylalanine; L-aspartyl-L-(l-cyclohexen)-alanine, and d e like;
  • L-aspartic acid derived sweeteners such as L-aspartyl-L-phenylalanine methyl ester (Aspartame) and materials described
  • water-soluble sweeteners derived from naturally occurring water- soluble sweeteners such as chlorinated derivatives of ordinary sugar (sucrose), e.g., chlorodeoxysugar derivatives such as derivatives of chlorodeoxysucrose or chlorodeoxygalactosucrose, known, for example, under the product designation of Sucralose;
  • chlorodeoxysucrose and chlorodeoxygalacto-sucrose derivatives include but are not limited to: l-chloro-l'-deoxysucrose; 4-chloro-4-deoxy-Alpha-D- galacto-pyranosyl-Alpha-D-fructofuranoside, or 4-chloro-4-deoxygalactosucrose; 4- chloro-4-deoxy-Alpha-D-galacto-pyranosyl- 1 -chloro- 1 -deoxy- ⁇ -D-fructo-furanoside, or 4, 1' -dichloro
  • an effective amount of sweetening agent is utilized to provide the level of sweetness desired in the particular oral topical therapeutic wound healing composition, and tiiis amount will vary with the sweetener selected and the final oral therapeutic product desired.
  • the amount of sweetener normally present is in the range from about 0.0025% to about 90%, by weight of the oral topical therapeutic wound healing composition, depending upon die sweetener used. The exact range of amounts for each type of sweetener is well known in the art and is not the subject of die present invention.
  • flavoring agents include those flavors known to the skilled artisan, such as natural and artificial flavors.
  • suitable flavoring agents include mints, such as peppermint, citrus flavors such as orange and lemon, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed, and the like.
  • the amount of flavoring agent employed in the oral topical dierapeutic wound healing composition is normally a matter of preference subject to such factors as the type of final oral therapeutic wound healing composition, the individual flavor employed, and the strength of flavor desired. Thus, the amount of flavoring may be varied in order to obtain d e result desired in the final product and such variations are within the capabilities of those skilled in die art without the need for undue experimentation.
  • the flavoring agents, when used, are generally utilized in amounts that may, for example, range in amounts from about 0.05% to about 6%, by weight of the oral topical therapeutic wound healing composition.
  • Suitable buffer solutions useful in the non-oral topical therapeutic wound healing compositions include citric acid-sodium citrate solution, phosphoric acid- sodium phosphate solution, and acetic acid-sodium acetate solution in amounts up to about 1%, and preferably from about 0.05% to about 0.5% by weight of the oral topical therapeutic wound healing composition.
  • therapeutically effective amounts of the therapeutic wound healing compositions of die present invention may be admixed with an oral topical vehicle to form a topical therapeutic wound healing composition. These amounts are readily determined by those skilled in the art without the need for undue experimentation.
  • the oral topical therapeutic wound healing compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 10% and a oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the oral topical therapeutic wound healing composition.
  • die oral topical therapeutic wound healing compositions will comprise the dierapeutic wound healing composition in an amount from about 0.1% to about 5%, and in a most preferred embodiment, the oral topical therapeutic wound healing compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 2%, and a oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the oral topical therapeutic wound healing composition.
  • the present invention extends to metiiods for preparing the oral topical therapeutic wound healing compositions.
  • die oral topical therapeutic wound healing composition is prepared by admixing a therapeutically effective amount of die therapeutic wound healing composition of die present invention and an oral topical vehicle.
  • the final compositions are readily prepared using standard metiiods and apparatus generally known by those skilled in the pharmaceutical arts.
  • the apparatus useful in accordance with die present invention comprises mixing apparatus well known in the pharmaceutical arts, and therefore the selection of the specific apparatus will be apparent to the artisan.
  • an oral topical therapeutic wound healing composition is made by first dissolving coloring agents, sweetening agents, and similar additives in water.
  • the therapeutic wound healing composition is then admixed with the aqueous solution.
  • sufficient water or ethanol, or mixtures of water and edianol, are added to the solution with mixing until die final solution volume is reached.
  • the therapeutic wound healing composition is added to the solution as the final ingredient.
  • the final oral topical dierapeutic wound healing compositions are readily prepared using metiiods generally known in the pharmaceutical arts.
  • the oral therapeutic wound healing composition may also be in the form of dental gel.
  • gel means a solid or semisolid colloid which contains considerable quantities of water.
  • the colloid particles in a gel are linked togedier in a coherent meshwork which immobilizes the water contained inside die meshwork.
  • the dental gel compositions of the present invention may contain the conventional additives set out above for oral topical therapeutic wound healing compositions such as mouthwashes, rinses, oral sprays, and suspensions and, in addition, may contain additional additives such as a polishing agent, a desensitizing agent, and die like, providing the additional additives do not interfere with the therapeutic properties of the therapeutic wound healing composition.
  • the oral vehicle In a dental gel composition, the oral vehicle generally comprises water, typically in an amount from about 10% to about 90%, by weight of die dental gel composition.
  • Polyethylene glycol, propylene glycol, glycerin, and mixtures thereof may also be present in the vehicle as humectants or binders in amounts from about 18% to about 30%, by weight of die dental gel composition.
  • Particularly preferred oral vehicles comprise mixtures of water with polyethylene glycol or water with glycerin and polypropylene glycol.
  • the dental gels of the present invention include a gelling agent (thickening agent) such as a natural or synthetic gum or gelatin.
  • Gelling agents such as hydroxyethyl cellulose, methyl cellulose, glycerin, carboxypolymethylene, and gelatin and the like, and mixtures thereof may be used.
  • the preferred gelling agent is hydroxyethyl cellulose.
  • Gelling agents may be used in amounts from about 0.5% to about 5%, and preferably from about 0.5% to about 2%, by weight of the dental gel composition.
  • the dental gel compositions of die present invention may also include a polishing agent.
  • a polishing agent of colloidal silica and/or alkali metal aluminosilicate complexes is preferred since these materials have refractive indices close to the refractive indices of the gelling systems commonly used in dental gels.
  • a polishing agent of calcium carbonate or calcium dihydrate may be used. These polishing agents may be used in amounts up to about 75%, and preferably in amounts up to about 50%, by weight of the dental gel composition.
  • the dental gel may also contain a desensitizing agent such as a combination of citric acid and sodium citrate.
  • a desensitizing agent such as a combination of citric acid and sodium citrate.
  • Citric acid may be used in an amount from about 0.1% to about 3%, and preferably from about 0.2% to about 1%, by weight
  • sodium citrate may be used in an amount from about 0.3% to about 9%, and preferably from about 0.6% to about 3%, by weight of the dental gel composition.
  • therapeutically effective amounts of the therapeutic wound healing compositions of the present invention may be admixed into the dental gel compositions. These amounts are readily determined by tiiose skilled in the art without the need for undue experimentation.
  • the dental gel compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 10% and an oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the dental gel composition.
  • the dental gel compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 5%, and in a most preferred embodiment, the dental gel compositions will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 2%, and an oral topical vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight of the dental gel composition.
  • the present invention extends to methods for preparing the therapeutic dental gel compositions. In such a method, die dental gel composition is prepared by admixing a therapeutically effective amount of the therapeutic wound healing composition of the present invention and an oral topical vehicle. The final compositions are readily prepared using methods generally known by those skilled in the dental and pharmaceutical arts.
  • the apparatus useful in accordance witii the present invention comprises mixing apparatus well known in the pharmaceutical arts, and therefore the selection of the specific apparatus will be apparent to the artisan.
  • a therapeutic dental gel composition is made by first dispersing a gelling agent in a humectant or water, or a mixture of both, then admixing to the dispersion an aqueous solution of the water-soluble additives such as the fluorine providing compound, sweeteners and the like, then adding the polishing agent, and lastly admixing the flavoring agent and the therapeutic wound healing composition.
  • the final gel mixture is then tubed or otherwise packaged.
  • the liquids and solids in a gel product are proportioned to form a creamy or gelled mass which is extrudable from a pressurized container or from a collapsible tube.
  • the final therapeutic wound healing compositions are readily prepared using methods generally known in the pharmaceutical arts.
  • die therapeutic wound healing composition is incorporated into an ingestible vehicle.
  • the ingestible vehicle may be a confectionery bulking agent in the form of lozenges, tablets, toffees, nougats, suspensions, chewy candies, chewing gums, and the like.
  • the pharmaceutically acceptable carriers may be prepared from a wide range of materials including, but not limited to, diluents, binders and adhesives, lubricants, disintegrants, coloring agents, bulking agents, flavoring agents, sweetening agents and miscellaneous materials such as buffers and adsorbents diat may be needed in order to prepare a particular therapeutic confection.
  • confectionery formulations are historically well known and has changed little through the years. Confectionery items have been classified as either "hard” confectionery or "soft” confectionery.
  • the therapeutic wound healing compositions of the present invention can be incorporated into confectionery compositions by admixing the inventive composition into conventional hard and soft confections.
  • confectionery material means a product containing a bulking agent selected from a wide variety of materials such as sugar, com syrup, and in d e case of sugarless bulking agents, sugar alcohols such as sorbitol and mannitol and mixtures tiiereof Confectionery material may include such exemplary substances as lozenges, tablets, toffee, nougat, suspensions, chewy candy, chewing gum and the like.
  • the bulking agent is present in a quantity sufficient to bring the total amount of composition to 100%. In general, the bulking agent will be present in amounts up to about 99.98%, preferably in amounts up to about 99.9%, and more preferably in amounts up to about 99%, by weight of the ingestible therapeutic wound healing composition.
  • Lozenges are flavored medicated dosage forms intended to be sucked and held in the mouth. Lozenges may be in the form of various shapes such as flat, circular, octagonal and biconvex forms.
  • the lozenge bases are generally in two forms: hard boiled candy lozenges and compressed tablet lozenges.
  • Hard boiled candy lozenges may be processed and formulated by conventional means.
  • a hard boiled candy lozenge has a base composed of a mixture of sugar and other carbohydrate bulking agents kept in an amorphous or glassy condition.
  • This amorphous or glassy form is considered a solid syrup of sugars generally having from about 0.5% to about 1.5% moisture.
  • Such materials normally contain up to about 92% co syrup, up to about 55% sugar and from about 0.1% to about 5% water, by weight of the final composition.
  • the syrup component is generally prepared from co syrups high in fructose, but may include other materials. Further ingredients such as flavoring agents, sweetening agents, acidulants, coloring agents and the like may also be added.
  • Boiled candy lozenges may also be prepared from non-fermentable sugars such as sorbitol, mannitol, and hydrogenated com syrup.
  • Typical hydrogenated co syrups are Lycasin, a commercially available product manufactured by Roquette Corporation, and Hystar, a commercially available product manufactured by Lonza, Inc.
  • the candy lozenges may contain up to about 95% sorbitol, a mixture of sorbitol and mannitol in a ratio from about 9.5:0.5 up to about 7.5:2.5, and hydrogenated co syrup up to about 55%, by weight of the solid syrup component.
  • Boiled candy lozenges may be routinely prepared by conventional methods such as tiiose involving fire cookers, vacuum cookers, and scraped-surface cookers also referred to as high speed atmospheric cookers.
  • Fire cookers involve die traditional med od of making a boiled candy lozenge base.
  • die desired quantity of carbohydrate bulking agent is dissolved in water by heating the agent in a kettle until the bulking agent dissolves. Additional bulking agent may then be added and cooking continued until a final temperature of 145°C. to 156°C. is achieved.
  • the batch is then cooled and worked as a plastic-like mass to incorporate additives such as flavors, colorants and the like.
  • a high-speed atmospheric cooker uses a heat-exchanger surface which involves spreading a film of candy on a heat exchange surface, the candy is heated to 165°C. to 170°C. in a few minutes. The candy is then rapidly cooled to 100°C. to 120°C. and worked as a plastic-like mass enabling incorporation of the additives, such as flavors, colorants and the like.
  • the carbohydrate bulking agent is boiled to 125°C. to
  • the mass When cooking is complete, the mass is a semi-solid and has a plastic-like consistency.
  • flavors, colorants, and other additives are admixed in the mass by routine mechanical mixing operations.
  • the optimum mixing required to uniformly mix the flavoring agents, coloring agents and other additives during conventional manufacturing of boiled candy lozenges is determined by the time needed to obtain a uniform distribution of die materials. Normally, mixing times of from 4 to 10 minutes have been found to be acceptable.
  • the boiled candy lozenge Once the boiled candy lozenge has been properly tempered, it may be cut into workable portions or formed into desired shapes. A variety of forming techniques may be utilized depending upon the shape and size of die final product desired. A general discussion of the composition and preparation of hard confections may be found in H.A. Lieberman, Pharmaceutical Dosage Forms: Tablets, Volume I (1980), Marcel
  • the apparatus useful in accordance witii the present invention comprises cooking and mixing apparatus well known in the confectionery manufacturing arts, and therefore the selection of the specific apparatus will be apparent to the artisan.
  • compressed tablet confections contain particulate materials and are formed into structures under pressure.
  • These confections generally contain sugars in amounts up to about 95%, by weight of the composition, and typical tablet excipients such as binders and lubricants as well as flavoring agents, coloring agents and the like.
  • the lozenges of the present invention may be made of soft confectionery materials such as those contained in nougat.
  • the preparation of soft confections, such as nougat involves conventional methods, such as the combination of two primary components, namely (1) a high boiling syrup such as a co syrup, hydrogenated starch hydrolysate or die like, and (2) a relatively light textured frappe, generally prepared from egg albumin, gelatin, vegetable proteins, such as soy derived compounds, sugarless milk derived compounds such as milk proteins, and mixtures thereof.
  • the frappe is generally relatively light, and may, for example, range in density from about 0.5 to about 0.7 grams/cc.
  • the high boiling syrup, or "bob syrup” of the soft confectionery is relatively viscous and has a higher density than die frappe component, and frequently contains a substantial amount of carbohydrate bulking agent such as a hydrogenated starch hydrolysate.
  • carbohydrate bulking agent such as a hydrogenated starch hydrolysate.
  • the final nougat composition is prepared by d e addition of the "bob syrup” to the frappe under agitation, to form die basic nougat mixture.
  • the procedure for preparing the soft confectionery involves known procedures.
  • the frappe component is prepared first and thereafter die syrup component is slowly added under agitation at a temperature of at least about 65°C, and preferably at least about 100°C.
  • the mixture of components is continued to be mixed to form a uniform mixture, after which the mixture is cooled to a temperature below 80°C, at which point, the flavoring agent may be added.
  • the mixture is further mixed for an additional period until it is ready to be removed and formed into suitable confectionery shapes.
  • the ingestible therapeutic wound healing compositions may also be in the form of a pharmaceutical suspension.
  • Pharmaceutical suspensions of this invention may be prepared by conventional methods long established in the art of pharmaceutical compounding. Suspensions may contain adjunct materials employed in formulating the suspensions of the art.
  • the suspensions of the present invention can comprise:
  • preservatives such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), benzoic acid, ascorbic acid, methyl paraben, propyl paraben, tocopherols, and d e like, and mixtures thereof.
  • Preservatives are generally present in amounts up to about 1%, and preferably from about 0.05% to about 0.5%, by weight of the suspension;
  • buffers such as citric acid-sodium citrate, phosphoric acid-sodium phosphate, and acetic acid-sodium acetate in amounts up to about 1%, and preferably from about 0.05% to about 0.5%, by weight of the suspension;
  • suspending agents or thickeners such as cellulosics like methylcellulose, carrageenans like alginic acid and its derivatives, xanthan gums, gelatin, acacias, and microcrystalline cellulose in amounts up to about 20%, and preferably from about 1% to about 15%, by weight of the suspension;
  • antifoaming agents such as dimethyl polysiloxane in amounts up to about 0.2%, and preferably from about 0.01% to about 0.1%, by weight of the suspension;
  • sweetening agents such as those sweeteners well known in the art, including both natural and artificial sweeteners.
  • Sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, com syrup solids, dihydrochalcones, monellin, steviosides, glycy ⁇ hizin, and sugar alcohols such as sorbitol, mannitol, maltitol, hydrogenated starch hydrolysates and mixtures thereof may be utilized in amounts up to about 60%, and preferably from about 20% to about 50%, by weight of the suspension.
  • Water-soluble artificial sweeteners such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-methyl-l,2,3- oxathiazine-4-one-2,2-dioxide, the potassium salt of 3,4-dihydro-6-methyl-l,2,3- oxathiazine-4-one-2,2 -dioxide (Acesulfame-K), the free acid form of saccharin, and die like may be utilized in amounts from about 0.001% to about 5%, by weight of the suspension;
  • flavoring agents such as those flavors well known to the skilled artisan, such as natural and artificial flavors and mints, such as peppermint, menthol, citrus flavors such as orange and lemon, artificial vanilla, cinnamon, various fruit flavors, both individual and mixed and the like may be utilized in amounts from about 0.5% to about 5%, by weight of the suspension;
  • coloring agents such as pigments which may be incorporated in amounts up to about 6%, by weight of the suspension.
  • a preferred pigment, titanium dioxide may be incorporated in amounts up to about 2%, and preferably less than about 1%, by weight of the suspension.
  • the coloring agents may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as F.D.& C. dyes and lakes.
  • the materials acceptable for the foregoing uses are preferably water-soluble.
  • Such dyes are generally present in amounts up to about 0.25%, and preferably from about 0.05% to about 0.2%, by weight of the suspension;
  • decolorizing agents such as sodium metabisulfite, ascorbic acid and the like may be incorporated into die suspension to prevent color changes due to aging.
  • decolorizing agents may be used in amounts up to about 0.25%, and preferably from about 0.05% to about 0.2%, by weight of the suspension;
  • solubilizers such as alcohol, propylene glycol, polyethylene glycol, and the like may be used to solubilize the flavoring agents.
  • solubilizing agents may be used in amounts up to about 10%, and preferably from about 2% to about 5%, by weight of the suspension.
  • the pharmaceutical suspensions of the present invention may be prepared as follows:
  • (A) admix the thickener with water heated from about 40°C. to about 95°C, preferably from about 40°C. to about 70°C, to form a dispersion if the thickener is not water soluble or a solution if the thickener is water soluble;
  • step (E) admix the optional adjunct materials such as coloring agents, flavoring agents, decolorants, solubilizers, antifoaming agents, buffers and additional water with the mixture of step (D) to form the suspension.
  • the ingestible therapeutic wound healing compositions of this invention may also be in chewable form. To achieve acceptable stability and quality as well as good taste and mouth feel in a chewable formulation several considerations are important. These considerations include die amount of active substance per tablet, die flavoring agent employed, die degree of compressibility of the tablet and the organoleptic properties of the composition.
  • Chewable therapeutic candy is prepared by procedures similar to those used to make soft confectionery.
  • a boiled sugar-com syrup blend is formed to which is added a frappe mixture.
  • the boiled sugar-com syrup blend may be prepared from sugar and com syrup blended in parts by weight ratio of about 90:10 to about 10:90.
  • the sugar-com syrup blend is heated to temperatures above about 120°C. to remove water and to form a molten mass.
  • the frappe is generally prepared from gelatin, egg albumin, milk proteins such as casein, and vegetable proteins such as soy protein, and the like, which is added to a gelatin solution and rapidly mixed at ambient temperature to form an aerated sponge like mass.
  • the frappe is then added to the molten candy mass and mixed until homogeneous at temperatures between about 65°C. and about 120°C.
  • the ingestible therapeutic wound healing composition of the instant invention can then be added to the homogeneous mixture as the temperature is lowered to about 65°C.-95°C. whereupon additional ingredients can then be added such as flavoring agents and coloring agents.
  • additional ingredients can then be added such as flavoring agents and coloring agents.
  • the formulation is further cooled and formed into pieces of desired dimensions.
  • therapeutically effective amounts of the therapeutic wound healing compositions of the present invention may be admixed into die hard and soft confectionery products. These amounts are readily determined by those skilled in the art without the need for undue experimentation.
  • the ingestible therapeutic wound healing composition will comprise the dierapeutic wound healing composition in an amount from about 0.1% to about 10% and an ingestible vehicle, that is a pharmaceutically acceptable carrier, in a quantity sufficient to bring the total amount of composition to 100%, by weight the ingestible therapeutic wound healing composition.
  • the ingestible composition will comprise the dierapeutic wound healing composition in an amount from about 0.1% to about 5%, and in a most prefened embodiment, the ingestible composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 2%, and an ingestible vehicle in a quantity sufficient to bring the total amount of composition to 100%, by weight the ingestible therapeutic wound healing composition.
  • the present invention extends to methods of making the ingestible therapeutic wound healing compositions.
  • an ingestible therapeutic wound healing composition is prepared by admixing a tiierapeutically effective amount of the therapeutic wound healing composition witii a pharmaceutically-acceptable carrier.
  • the apparatus useful in accordance with the present invention comprises mixing and heating apparatus well known in the confectionery arts, and therefore the selection of the specific apparatus will be apparent to the artisan.
  • the final ingestible therapeutic wound healing compositions are readily prepared using methods generally known in d e confectionery arts.
  • the therapeutic wound healing compositions may also be incorporated into chewing gums.
  • the chewing gum composition contains a gum base, a bulking agent, the inventive therapeutic wound healing composition, and various additives.
  • the gum base employed will vary greatly depending upon various factors such as the type of base desired, the consistency of gum desired and the otiier components used in the composition to make the final chewing gum product.
  • the gum base may be any water-insoluble gum base known in die art, and includes those gum bases utilized for chewing gums and bubble gums.
  • suitable polymers in gum bases include both natural and synthetic elastomers and rubbers.
  • tiiose polymers which are suitable as gum bases include, without limitation, substances of vegetable origin such as chicle, crown gum, nispero, rosadinha, jelutong, perillo, niger gutta, tunu, balata, gutta-percha, lechi-capsi, sorva, gutta kay, mixtures thereof and die like.
  • Synthetic elastomers such as butadiene-styrene copolymers, polyisobutylene, isobutylene-isoprene copolymers, polyethylene, mixtures thereof and die like are particularly useful.
  • the gum base may include a non-toxic vinyl polymer, such as polyvinyl acetate and its partial hydrolysate, polyvinyl alcohol, and mixtures tiiereof.
  • a non-toxic vinyl polymer such as polyvinyl acetate and its partial hydrolysate, polyvinyl alcohol, and mixtures tiiereof.
  • die molecular weight of the vinyl polymer may range from about 2,000 up to and including about 94,000.
  • the amount of gum base employed will vary greatly depending upon various factors such as the type of base used, die consistency of die gum desired and die other components used in the composition to make the final chewing gum product.
  • the gum base will be present in amounts from about 5% to about 94%, by weight of the final chewing gum composition, and preferably in amounts from about
  • the gum base composition may contain conventional elastomer solvents to aid in softening die elastomer base component.
  • elastomer solvents may comprise terpinene resins such as polymers of Alpha-pinene or ⁇ -pinene, methyl, glycerol or pentaerythritol esters of rosins or modified rosins and gums, such as hydrogenated, dimerized or polymerized rosins or mixtures thereof.
  • elastomer solvents suitable for use herein include the pentaerythritol ester of partially hydrogenated wood or gum rosin, the pentaerythritol ester of wood or gum rosin, the glycerol ester of wood rosin, the glycerol ester of partially dimerized wood or gum rosin, the glycerol ester of polymerized wood or gum rosin, the glycerol ester of tall oil rosin, the glycerol ester of wood or gum rosin and the partially hydrogenated wood or gum rosin and the partially hydrogenated methyl ester of wood or rosin, mixtures thereof, and die like.
  • the elastomer solvent may be employed in amounts from about 5% to about 75%, by weight of the gum base, and preferably from about 45% to about 70%, by weight of the gum base.
  • a variety of traditional ingredients may be included in the gum base in effective amounts such as plasticizers or softeners such as lanolin, palmitic acid, oleic acid, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glyceryl lecithin, glyceryl monostearate, propylene glycol monostearate, acetylated monoglyceride, glycerine, mixtures thereof, and the like may also be incorporated into the gum base to obtain a variety of desirable textures and consistency properties.
  • plasticizers or softeners such as lanolin, palmitic acid, oleic acid, stearic acid, sodium stearate, potassium stearate, glyceryl triacetate, glyceryl lecithin, glyceryl monostearate, propylene glycol monostearate, acetylated monoglyceride, glycerine, mixtures thereof, and the like may also
  • Waxes for example, natural and synd etic waxes, hydrogenated vegetable oils, petroleum waxes such as polyurethane waxes, polyethylene waxes, paraffin waxes, microcrystalline waxes, fatty waxes, sorbitan monostearate, tallow, propylene glycol, mixtures thereof, and the like may also be incorporated into the gum base to obtain a variety of desirable textures and consistency properties.
  • These traditional additional materials are generally employed in amounts up to about 30%, by weight of the gum base, and preferably in amounts from about 3% to about 20%, by weight of the gum base.
  • the gum base may include effective amounts of mineral adjuvants such as calcium carbonate, magnesium carbonate, alumina, aluminum hydroxide, aluminum silicate, talc, tricalcium phosphate, dicalcium phosphate and the like as well as mixtures thereof. These mineral adjuvants may serve as fillers and textural agents.
  • mineral adjuvants such as calcium carbonate, magnesium carbonate, alumina, aluminum hydroxide, aluminum silicate, talc, tricalcium phosphate, dicalcium phosphate and the like as well as mixtures thereof. These mineral adjuvants may serve as fillers and textural agents.
  • fillers or adjuvants may be used in the gum base in various amounts.
  • the amount of filler when used will be present in an amount up to about 60%, by weight of the chewing gum base.
  • the chewing gum base may additionally include the conventional additives of coloring agents, antioxidants, preservatives and the like.
  • coloring agents for example, titanium dioxide and other dyes suitable for food, drug and cosmetic applications, known as F.D. & C. dyes, may be utilized.
  • An antioxidant such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propyl gallate, and mixtures thereof, may also be included.
  • BHT butylated hydroxytoluene
  • BHA butylated hydroxyanisole
  • propyl gallate propyl gallate
  • Other conventional chewing gum additives known to one having ordinary skill in die chewing gum art may also be used in die chewing gum base.
  • the gum composition may include effective amounts of conventional additives selected from the group consisting of sweetening agents (sweeteners), plasticizers, softeners, emulsifiers, waxes, fillers, bulking agents, mineral adjuvants, flavoring agents (flavors, flavorings), coloring agents (colorants, colorings), antioxidants, acidulants, thickeners, mixtures thereof and the like.
  • sweeteners e.g., sorbitol or other sugar alcohol or mixtures thereof
  • the sugar sweetener can also function as a bulking agent.
  • the plasticizers, softeners, mineral adjuvants, colorants, waxes and antioxidants discussed above as being suitable for use in the gum base may also be used in the gum composition.
  • examples of other conventional additives which may be used include emulsifiers, such as lecitiiin and glyceryl monostearate, thickeners, used alone or in combination with other softeners, such as methyl cellulose, alginates, carrageenan, xanthan gum, gelatin, carob, tragacanth, locust bean, and carboxy metiiyl cellulose, acidulants such as malic acid, adipic acid, citric acid, tartaric acid, fumaric acid, and mixtures tiiereof, and fillers, such as those discussed above under the category of mineral adjuvants.
  • the fillers when used may be utilized in an amount up to about 60%, by weight of die gum composition.
  • Bulking agents (carriers, extenders) suitable for use in chewing gums include sweetening agents selected from the group consisting of monosaccharides, disaccharides, poly-saccharides, sugar alcohols, and mixtures thereof; polydextrose; maltodextrins; minerals, such as calcium carbonate, talc, titanium dioxide, dicalcium phosphate, and the like. Bulking agents may be used in amounts up to about 90%, by weight of the final gum composition, with amounts from about 40% to about 70%, by weight of the gum composition being preferred , with from about 50% to about 65%, by weight, being more preferred and from about 55% to about 60%, by weight of the chewing gum composition, being most preferred.
  • the sweetening agent used may be selected from a wide range of materials including water-soluble sweeteners, water-soluble artificial sweeteners, water-soluble sweeteners derived from naturally occurring water-soluble sweeteners, dipeptide based sweeteners, and protein based sweeteners, including mixtures thereof.
  • sweeteners include: (a) water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribulose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltose, invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, com syrup solids, dihydrochalcones, monellin, steviosides, glycyrrhizin, and sugar alcohols such as sorbitol, mannitol, maltitol, hydrogenated starch hydrolysates and mixtures thereof;
  • water-soluble sweetening agents such as monosaccharides, disaccharides and polysaccharides such as xylose, ribulose, glucose (dextrose), mannose, galactose, fructose (levulose), sucrose (sugar), maltos
  • water-soluble artificial sweeteners such as soluble saccharin salts, i.e., sodium or calcium saccharin salts, cyclamate salts, the sodium, ammonium or calcium salt of 3,4-dihydro-6-med ⁇ yl-l ,2,3-oxathiazine-4-one-2,2-dioxide, thepotassium salt of 3,4-dihydro-6-methyl-l,2,3-oxathiazine-4-one-2,2-dioxide (Acesulfame-K), the free acid form of saccharin, and the like;
  • soluble saccharin salts i.e., sodium or calcium saccharin salts, cyclamate salts
  • sodium, ammonium or calcium salt of 3,4-dihydro-6-med ⁇ yl-l ,2,3-oxathiazine-4-one-2,2-dioxide thepotassium salt of 3,4-dihydro-6-methyl-l,2,3-oxathia
  • dipeptide based sweeteners such as L-aspartic acid derived sweeteners, such as L-aspartyl-L-phenylalanine methyl ester (Aspartame) and materials described in United States Patent No. 3,492,131, L-Alpha-aspartyl-N-(2,2,4,4- tetramethyl-3-thietanyl)-D-alanin-amide hydrate (Alitame), methyl esters of L-aspartyl-
  • water-soluble sweeteners derived from naturally occurring water- soluble sweeteners such as chlorinated derivatives of ordinary sugar (sucrose), known, for example, under the product designation of Sucralose;
  • e protein based sweeteners such as thaumaoccous danielli (Thaumatin I and JT).
  • an effective amount of sweetener is utilized to provide the level of bulk and/or sweetness desired, and this amount will vary with the sweetener selected.
  • This amount of sweetener will normally be present in amounts from about 0.0025% to about 90%, by weight of the gum composition, depending upon the sweetener used.
  • the exact range of amounts for each type of sweetener is well known in the art and is not the subject of the present invention.
  • the amount of sweetener ordinarily necessary to achieve the desired level of sweetness is independent from the flavor level achieved from flavor oils.
  • Preferred sugar based-sweeteners are sugar (sucrose), co syrup and mixtures thereof.
  • Preferred sugarless sweeteners are die sugar alcohols, artificial sweeteners, dipeptide based sweeteners and mixtures thereof.
  • sugar alcohols are used in the sugarless compositions because these sweeteners can be used in amounts which are sufficient to provide bulk as well as the desired level of sweetness.
  • Preferred sugar alcohols are selected from the group consisting of sorbitol, xylitol, maltitol, mannitol, and mixtures thereof. More preferably, sorbitol or a mixture of sorbitol and mannitol is utilized. The gamma form of sorbitol is preferred.
  • An artificial sweetener or dipeptide based sweetener is preferably added to the gum compositions which contain sugar alcohols.
  • the coloring agents useful in the gum compositions are used in amounts effective to produce the desired color. These coloring agents include pigments which may be incorporated in amounts up to about 6% by weight of the gum composition. A preferred pigment, titanium dioxide, may be incorporated in amounts up to about 2%, and preferably less than about 1% by weight of the composition.
  • the colorants may also include natural food colors and dyes suitable for food, drug and cosmetic applications. These colorants are known as F.D.& C. dyes and lakes.
  • the materials acceptable for the foregoing uses are preferably water-soluble. Illustrative nonlimiting examples include the indigoid dye known as F.D.& C. Blue No.2, which is the disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dye known as F.D.& C.
  • Green No.l comprises a triphenylmethane dye and is the monosodium salt of 4-[4-(N- ethyl-p-sulfoniumbenzylamino)iiphenylmethylene]-[l-(N-ethyl-N-p-sulfoniumbenzyl)- delta-2,5-cyclohexadieneimine].
  • a full recitation of all F.D.& C. colorants and their corresponding chemical structures may be found in the Kirk-Othmer Encyclopedia of Chemical Technology. 3rd Edition, in volume 5 at pages 857-884, which text is incorporated herein by reference.
  • Suitable oils and fats usable in gum compositions include partially hydrogenated vegetable or animal fats, such as coconut oil, palm kernel oil, beef tallow, lard, and the like. These ingredients when used are generally present in amounts up to about 7%, by weight, and preferably up to about 3.5%, by weight of the gum composition.
  • therapeutically effective amounts of the therapeutic wound healing compositions of the present invention may be admixed into a chewing gum. These amounts are readily determined by those skilled in the art without the need for undue experimentation.
  • the final chewing gum composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 10% and a chewing gum composition in a quantity sufficient to bring the total amount of composition to 100%, by weight of the chewing gum composition.
  • the final chewing gum composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 5%, and in a most preferred embodiment, the final chewing gum composition will comprise the therapeutic wound healing composition in an amount from about 0.1% to about 2%, and a chewing gum composition in a quantity sufficient to bring the total amount of composition to 100%, by weight of the chewing gum composition.
  • the present invention extends to methods of making the therapeutic chewing gum compositions.
  • the therapeutic wound healing compositions may be incorporated into an otiierwise conventional chewing gum composition using standard techniques and equipment known to those skilled in the art.
  • the apparatus useful in accordance witii the present invention comprises mixing and heating apparatus well known in the chewing gum manufacturing arts, and therefore the selection of the specific apparatus will be apparent to the artisan.
  • a gum base is heated to a temperature sufficiently high enough to soften the base widiout adversely effecting the physical and chemical make up of the base.
  • the optimum temperatures utilized may vary depending upon the composition of the gum base used, but such temperatures are readily determined by those skilled in the art widiout undue experimentation.
  • the gum base is conventionally melted at temperatures that range from about 60°C. to about 120°C. for a period of time sufficient to render the base molten.
  • d e gum base may be heated under these conditions for a period of about tiiirty minutes just prior to being admixed incrementally with the remaining ingredients of the base such as die plasticizer, fillers, the bulking agent and/or sweeteners, the softener and coloring agents to plasticize the blend as well as to modulate the hardness, viscoelasticity and formability of the base.
  • the chewing gum base is then blended witii the therapeutic wound healing composition of the present invention which may have been previously blended with other traditional ingredients. Mixing is continued until a uniform mixture of gum composition is obtained. Thereafter the gum composition mixture may be formed into desirable chewing gum shapes.
  • the invention is directed to a dierapeutic pharmaceutical composition for preventing and reducing injury to mammalian cells, and increasing die resuscitation rate of injured mammalian cells, which comprises:
  • Embodiment One selected from the group consisting of:
  • LA (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures tiiereof;
  • fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells;
  • LB pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof; and (c) a mixture of saturated and unsaturated fatty acids wherein the fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells;
  • LC (a) an antioxidant; and (b) a mixture of saturated and unsaturated fatty acids wherein die fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells;
  • lactate selected from die group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof;
  • the pharmaceutically acceptable carrier may be selected from the group consisting of pharmaceutical appliances, topical vehicles, and ingestible vehicle.
  • the invention is directed to a method for preparing a therapeutic pharmaceutical composition for preventing and reducing injury to mammalian cells, and increasing the resuscitation rate of injured rriammalian cells, which comprises the steps of :
  • Embodiment One (I.A-E) selected from the group consisting of: (LA) (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • LB (a) pyruvate selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof; and
  • lactate selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures tiiereof;
  • step (C) admixing the therapeutic wound healing composition from step (A) and the pharmaceutically acceptable carrier from step (B) to form a therapeutic pharmaceutical composition.
  • Marnmalian epidermal keratinocytes and monocytes were employed to examine the ability of various antioxidants to reduce levels of hydrogen peroxide in these cells. Hydrogen peroxide was measured after the cells were exposed to ultraviolet light in die wavelength range from 290 to 320 nm (UV-B) or to the inflammatory compound 12-0- tetradecanoyl-phorbol-13-acetate (TPA). Sodium pyruvate was tested at various concentrations to determine die effect of concentrations of this antioxidant on the hydrogen peroxide production by epidermal cells and monocytes.
  • UV-B ultraviolet light in die wavelength range from 290 to 320 nm
  • TPA 12-0- tetradecanoyl-phorbol-13-acetate
  • Sodium pyruvate was tested at various concentrations to determine die effect of concentrations of this antioxidant on the hydrogen peroxide production by epidermal cells and monocytes.
  • Mammalian epidermal keratinocytes were isolated by trypsinization of epithelial sheets and grown in modified basal MCDB 153 medium supplemented witii epidermal growth factor, bovine pituitary extract, and hydrocortisone. Cells were maintained in a humidified incubator with 5% carbon dioxide at 37°C.
  • Keratinocytes were seeded in 60 mm culture dishes at a cell density of 3 x 10 cells per dish and the cultures were exposed to 1 M.E.D. dose of ultraviolet-B light (100 mJ/cm ) or treated witii lOO ng/ml of TPA.
  • U937 monocytic cells are a cultured cell line grown in RPMI media with 10% fetal calf serum. Cells were maintained in a 60 mm culture dish at 5% carbon dioxide at 37°C. at a seeding density not exceeding 1 x 10 cells per dish.
  • Sodium pyruvate, lactic acid, ascorbic acid, and Vitamin E were dissolved in distilled water, with sufficient surfactant.
  • the concentrations of the sodium pyruvate solutions prepared were 1 mM, 10 mM, 50 mM, 100 mM, and 200 mM.
  • the concentrations of the lactic acid solutions prepared were 1.0%, 0.1%, and 0.05%.
  • the concentrations of the ascorbic acid solutions prepared were 1.0%, 0.1%, 0.05%, and 0.025%.
  • the concentrations of the Vitamin E solutions prepared were 1 U, 10 U, 50 U, and 100 U.
  • the test solutions were adjusted to a pH value of 7.4 witii 1.ON sodium hydroxide solution and tiien sterile filtered.
  • test solution or combination of test solutions was added to the cells immediately prior to exposure of the cells to ultraviolet light-B or TPA [lOOng/ml].
  • Stock solutions were prepared so that the vehicle did not constitute more than 1 % of the total volume of d e culture media.
  • Intracellular hydrogen peroxide production by ⁇ iammalian epidermal keratinocytes and U937 monocytes was measured using dichlorofluorescein diacetate (DCFH-DA, Molecular Probes, Eugene, Ore.).
  • DCFH-DA is a non-polar non- fluorescent compound that readily diffuses into cells where it is hydrolyzed to the polar non-fluorescent derivative DCFH which then becomes trapped within die cells.
  • DCFH-DA is a non-polar non- fluorescent compound that readily diffuses into cells where it is hydrolyzed to the polar non-fluorescent derivative DCFH which then becomes trapped within die cells.
  • DCFH is oxidized to the highly fluorescent compound DCF.
  • cellular fluorescence intensity is directly proportional to the level of intracellular hydrogen peroxide produced. Cellular fluorescence intensity can be monitored by fluorimetry and by flow cytometry.
  • the viability of the U937 monocytic cells after exposure of the cells to various antioxidants for 24 hours was measured.
  • the viability of the cells was determined by exposing the cells to die dye propidium iodide. Permeable cell membranes which absorbed the dye were not considered viable.
  • the viability of the cells was represented as die percentage of cells that excluded propidium iodide.
  • Figure 1 depicts in bar graph format the viability of U937 monocytic cells after exposure of the cells to no antioxidant (Example 1, control), to sodium pymvate (Example 2), to ascorbic acid (Example 3), to lactic acid (Example 4), and to Vitamin E (Example 5).
  • Figure 2 depicts in bar graph format the viability of U937 monocytic cells after exposure of the cells to various combinations of antioxidants. Specifically, die viability of U937 monocytic cells was measured after exposure to no antioxidant (Example 6, control), to ascorbic acid and lactic acid (Example 7), to ascorbic acid and Vitamin E (Example 8), to sodium pyruvate and ascorbic acid (Example 9), to sodium pyruvate and lactic acid (Example 10), to sodium pyruvate and Vitamin E (Example 11), to lactic acid and Vitamin E (Example 12), and to sodium pyruvate, ascorbic acid, and lactic acid (Example 13).
  • Figure 1 shows that ascorbic acid is cytotoxic to monocytes at concentrations as low as 0.25%.
  • Figure 2 shows that the cytotoxicity of ascorbic acid was reversed by the addition of 10 mM of sodium pyruvate.
  • Figures 1 and 2 show that the viability rate of 15% to 20% of the cells when treated with ascorbic acid was increased to 95% to 98% upon addition of sodium pyruvate. Lactic acid and Vitamin E did not reverse the cytotoxicity of ascorbic acid.
  • Sodium pyruvate was then tested at various concentrations to determine d e effect of concentrations of tiiis antioxidant on the hydrogen peroxide production by epidermal cells and monocytes.
  • Mammalian epidermal keratinocytes and monocytes were exposed to (a) 1 M.E.D. dose of ultraviolet light-B and (b) 100 ng/ml of 12-0- tetradecanoylphorbol- 13 -acetate (TPA) in the presence of sodium pyravate at die following concentrations: 200 mM, 100 mM, 50 mM, 10 mM, 1 mM.
  • the optimum concentration of sodium pyruvate to reduce die hydrogen peroxide production by epidermal cells and monocytes was found to be 10 mM. Concentrations of sodium pyruvate of 50 mM and above were cytotoxic to botii epidermal keratinocytes and monocytes.
  • Magnesium pyravate, calcium pyruvate, zinc pyruvate, ascorbic acid, lactic acid, and Vitamin E, and combinations of sodium pyravate with ascorbic acid, lactic acid, and Vitamin E were then tested to determine the effect of these salts and combinations of antioxidants on die hydrogen peroxide production by epidermal cells and monocytes.
  • the following test solutions were prepared.
  • the optimum concentration of lactic acid to reduce the hydrogen peroxide production by epidermal cells and monocytes was found to be 0.05%.
  • the optimum concentration of ascorbic acid was found to be 0.025%.
  • the higher concentrations of both of these compounds were found to be cytotoxic to both types of cells.
  • the optimum concentration of Vitamin E was found to be 50 U.
  • Figure 3 depicts in bar graph format the levels of hydrogen peroxide produced by U937 monocytic cells after exposure of the cells to no antioxidant (Example 14, control), to sodium pyruvate (Example 15), to ascorbic acid (Example 16), to lactic acid (Example 17), and to Vitamin E (Example 18).
  • Sodium pyravate and Vitamin E significantly reduced the hydrogen peroxide production by monocytes.
  • Figure 4 depicts in bar graph format the levels of hydrogen peroxide produced by U937 monocytic cells after exposure of the cells to various combinations of antioxidants. Specifically, the levels of hydrogen peroxide produced by U937 monocytic cells were measured after exposure to no antioxidant (Example 19, control), to ascorbic acid and lactic acid (Example 20), to ascorbic acid and Vitamin E (Example 21), to sodium pyravate and ascorbic acid (Example 22), to sodium pyravate and lactic acid (Example 23), to sodium pyruvate and Vitamin E (Example 24), to lactic acid and Vitamin E (Example 25), and to sodium pyruvate, ascorbic acid, and lactic acid (Example 26). The combination of lactic acid (0.05%) and Vitamin E (50 U) significantly reduced the hydrogen peroxide production by monocytes.
  • epidermal keratinocytes The morphological alterations in epidermal keratinocytes were observed in control cultures and in cultures exposed to ultraviolet-B.
  • Cells in the layer closest to the dermis are basal keratinocytes. These cells proliferate and migrate into the spinous and granular layers of the epidermis where the cells begin to differentiate.
  • the differentiation pattern results in cells enucleating and forming comified envelopes at the uppermost portion of the epidermis, the statum comeum.
  • the differentiation of keratinocytes is controlled by the levels of calcium, magnesium, and other elements in die medium. Cells in culture systems promoting differentiation appear as an epidermal sheet forming attachments or tight junctions with each other. Keratinocytes that become nonadherent or float in the media were considered responding to a cytotoxic event.
  • Ascorbic Acid Cells were floating in a cytotoxic response to ascorbic acid.
  • Lactic Acid Cells appeared dramatically altered as an epidermal sheet and as flat granular cells.
  • Lactic Acid 0.05% Lactic Acid and 10 mM Sodium Pyravate: Cells formed an epidermal sheet but appeared smaller than the cell in the lactic acid culture. 50 U Vitamin E: Cells appeared the same as the cells in die control culture.
  • Vitamin E 50 U Vitamin E and 10 mM Sodium Pyruvate: Cells increased in number and changed in appearance resembling the cells in die sodium pyravate culture.
  • Ascorbic Acid Cells were nonadherent and floating in a cytotoxic response to ascorbic acid greater tiian the cytotoxic response of the corresponding cells without ultraviolet-B light exposure.
  • Lactic Acid Cells formed an epidermal sheet and were more granular than cells in the control culture without ultraviolet-B light exposure.
  • Vitamin E Cell growth was inhibited but cells appeared similar to cells in the control culture without ultraviolet-B light exposure.
  • Vitamin E and 10 mM Sodium Pyravate Cells appeared similar to cells in the control culture and proliferated to a greater extent tiian cells in the control cultures without ultraviolet-B light exposure.
  • Vitamin E at 50 U and 100 U.
  • Mammalian epidermal keratinocytes and U937 monocytic cells and the test solutions of sodium pyravate, lactic acid, ascorbic acid, and Vitamin E were prepared as describe above for Examples 1-26. Intracellular hydrogen peroxide production by the mammalian epidermal keratinocytes and U937 monocytes was also measured as described above.
  • a mixture of fatty acids derived from chicken fat was prepared for addition to die cultured cells by mixing 0.1% of the chicken fat with the culture media. At die temperature of the culture media, 37°C, the chicken fat was miscible. This chicken fat mixture was added to cultures of cells prior to exposure of the cells to ultraviolet-B light or TPA treatment.
  • mammalian epidermal keratinocytes and monocytes were exposed to (a) 1 M.E.D. dose of ultraviolet light-B and (b) 100 ng/ml of 12-0-tetradecanoylphorbol-13-acetate in the presence of various antioxidants and combinations of antioxidants with and without a mixture of saturated and unsaturated fatty acids [0.1%, 0.5%, and 1.0% chicken fat].
  • Figure 5 depicts in bar graph format the levels of hydrogen peroxide produced by U937 monocytic cells after exposure of the cells to various combinations of antioxidants with and widiout a mixture of saturated and unsaturated fatty acids. Specifically, die levels of hydrogen peroxide produced by U937 monocytic cells were measured after exposure to lactic acid and Vitamin E without fatty acids (Example 27) and with fatty acids (Example 28), to ascorbic acid and lactic acid widiout fatty acids (Example 29) and witii fatty acids (Example 30), and to ascorbic acid and Vitamin E widiout fatty acids (Example 31) and with fatty acids (Example 32).
  • Figure 6 depicts in bar graph format the levels of hydrogen peroxide produced by epidermal keratinocytes after exposure of the cells to various antioxidants with and without a mixture of saturated and unsaturated fatty acids.
  • the levels of hydrogen peroxide produced by epidermal keratinocytes were measured after exposure to no antioxidant without fatty acids (Example 33, control) and with fatty acids (Example 34), to sodium pyravate without fatty acids (Example 35) and with fatty acids (Example 36), to ascorbic acid without fatty acids (Example 37) and with fatty acids (Example 38), to lactic acid without fatty acids (Example 39) and with fatty acids
  • Example 40 Example 40
  • Example 41 Example 41
  • Example 42 Example 42
  • the ability of sodium pyravate and Vitamin E to reduce the hydrogen peroxide production by epidermal keratinocytes was increased in the presence of fatty acids.
  • the most effective combinations to reduce the hydrogen peroxide production of epidermal keratinocytes were sodium pyravate in combination with a mixture saturated and unsaturated fatty acids and Vitamin E in combination with a mixture of saturated and unsaturated fatty acids.
  • Figure 7 depicts in bar graph format the levels of hydrogen peroxide produced by epidermal keratinocytes after exposure of the cells to various combinations of antioxidants with and without a mixture of saturated and unsaturated fatty acids.
  • the levels of hydrogen peroxide produced by epidermal keratinocytes were measured after exposure to no antioxidant without fatty acids (Example 43, control) and with fatty acids (Example 44), to sodium pyravate and ascorbic acid widiout fatty acids (Example 45) and with fatty acids (Example 46), to sodium pyravate and lactic acid without fatty acids (Example 47) and with fatty acids (Example 48), to sodium pyravate and Vitamin E without fatty acids (Example 49) and with fatty acids (Example 50), and to ascorbic acid and Vitamin E without fatty acids (Example 51) and with fatty acids (Example 52).
  • Human epidermal keratinocytes were isolated by trypsinization of epithelial sheets and grown in modified base MCDB 153 medium supplemented with epidermal growth factor and bovine pituitary extract. Cells were seeded in culture dishes at a density of 3 x 10 ⁇ /dish. Prior to exposure to UV B light (lOOmJ/cm 2 ) or treatment with lOOng/ml TPA, the cultures were treated with the appropriate concentration of wound healing components.
  • Intracellular production of hydrogen peroxide was measured using DCFH-DA, a nonpolar compound that readiiy diffuses into cells, hydrolyzad to a nonpolar derivative. In the presence of intracellular hydrogen peroxide, DCFH is oxidized to a highly fluorescent compound DCF. Thus, cellular fluorescence intensity is directly proportional to levels of hydrogen peroxide produced and can be monitored by flow cytometry. Hydrogen peroxide is cytotoxic, therefore lower levels of hydrogen peroxide production is desirable for cellular viability.
  • Column 3 shows the production of H2O2 after treatment with wound healing components.
  • Column 4 shows the difference in production of H2O2 from control after the treatment.
  • the wound healing compositions of Examples A-D were prepared having the compositions set out in Table A.
  • Wound healing composition A was commercially available Preparation H .
  • Wound healing composition B was a petrolatum base formulation containing live yeast cell derivative, shark oil, and a mixture of sodium pyravate, vitamin E, and chicken fat.
  • Wound healing composition C was a petrolatum base formulation containing live yeast cell derivative and shark oil.
  • Wound healing composition D was a petrolatum base formulation only.
  • the animals were sacrificed on day 3 and day 7 using cervical dislocation.
  • the dorsal skin including the incision was dissected without the subcutaneous tissue.
  • the skin was placed in neutral buffered formalin and subsequently sectioned and stained with hematoxylin and eosin.
  • the wounds were examined microscopically and representative tissue sections were photographed.
  • Photographs of the wounded mice on day 4 are set out in Figures 9 and 10.
  • Figures 9 and 10 show that Formulation B, which was a petrolatum base formulation containing live yeast cell derivative, shark oil, and a mixture of sodium pyruvate, vitamin E, and chicken fat, was a significantly better wound healing agent than the otiier formulations.
  • Formulation D which was a white petrolatum formulation only, was judged to be significantly more effective to promote healing than either Formulation C, which was a petrolatum base formulation containing shark liver oil and live yeast cell derivative, or Formulation A, which was Preparation H .
  • the superior ability of Formulation D over Formulation C to improve healing may result from a delay in the healing process caused when the live yeast cell derivative is depleted and the cells shift to an alternative nutrient source.
  • the presence of the mixture of sodium pyravate, vitamin E, and chicken fat in Formulation B apparently offsets the depletion of the live yeast cell derivative.
  • Formulation C which was a petrolatum base formulation containing live yeast cell derivative and shark oil, was judged comparable to the control (untreated wound) in speed of wound closure and extent of healing.
  • Formulation A which was Preparation H , appeared to be the least effective healing formulation by both subjective grading of wound healing and by objective examination of tissue sections.
  • the superior ability of Formulation D and Formulation C over Formulation A to improve healing may be due to their ability to act as an occlusive wound dressing that prevents transepidermal water loss and thus promotes healing and wound closure.
  • the poor ability of Formulation A to improve healing may be due to the potential cytotoxicity of phenylmercuric nitrate present in Preparation H as a preservative.
  • wound healing compositions of the present invention which comprise a mixture of sodium pyravate, vitamin E, and chicken fat increase the proliferation and resuscitation rate of rnammalian cells.
  • the wound healing compositions mediate low levels of oxygen in the initial stages of healing to suppress oxidative damage and higher levels of oxygen in the later stages of healing to promote collagen formation.
  • the disposable razor cartridge comprises: (a) a blade seat; (b) at least one razor blade; and (c) a cap.
  • the wound healing composition delivery system may comprise the wound healing compositions of Embodiment One
  • the wound healing composition (LA) in the delivery system comprises (a) pyravate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids.
  • the integral wound healing composition delivery system is preferably in the form of a solid strip of a water-soluble encapsulating agent comprising the wound healing composition premixed with a polymeric delivery system.
  • Wound healing compositions can increase the resuscitation rate of injured mammalian cells and the proliferation rate of new mammalian cells to replace dead cells.
  • Applicants have found that binding a wound healing composition to a razor cartridge results in a therapeutic razor cartridge which can reduce the duration and severity of shaving cuts and nicks.
  • the invention is directed to a disposable razor cartidge comprising:
  • a cap a cap
  • a wound-healing composition delivery system affixed to die cartridge, wherein the wound healing composition in the delivery system comrpises: (a) pyravate selected from the group consisting of pyravic acid, pharmaceutically acceptable salts of pyravic acid, and mixtures thereof;
  • the combination of the razor cartridge and the wound healing compositions of the present invention provides a therapeutic razor cartridge useful for reducing the duration of shaving cuts and increasing the resuscitation rate of injured mammalian cells.
  • the tissue damage associated with many shaving cuts and nicks is believed to be caused by the production of cellular produced active oxygen species.
  • Combination of the therapeutic razor cartridge and the wound healing compositions may suppress such reactive oxygen-linked tissue injury.
  • razor cartridge 10 is typical of the type of shaving device to which the present invention is applicable in affording a wound healing composition delivery system which may be applied directly to the skin continuously with each stroke of die razor during the act of wet shaving.
  • Razor cartridge 10 comprises a blade seat 12 having formed thereon a guard bar 14 for smoothening the skin adjacent to the cutting edge 16 of a razor blade 18 during shaving.
  • Blade seat 12 further includes a channel 20 which may be used to load cartridge 10 upon a conventional reusable razor main frame (not shown) in the customary manner of sliding a receiving portion of the main frame into channel 20 or sliding channel 20 over the receiving portion of the razor main frame. Completing the main supporting stracture of razor cartridge 10 and holding blade 18 in place against seat 12 is cap 22.
  • cartridge 10 has been illustrated as being of the single-blade type, it should be understood that this stracture is shown for purposes of illustration only and that the invention to be described in detail herein is applicable not only to single-blade cartridges but equally as well to multiple-blade shaving cartridges.
  • the basic components of cartridge 10 are fused, cemented, or otherwise bonded together and are commonly referred to in the trade as bonded razor blade cartridges.
  • a strip 24 formed of an integral wound healing composition delivery system is cemented to cap 22 preferably within a recess 26 provided therefor.
  • Strip 24 is disposed in juxtaposition with edge 16 of blade 18 and extended from a point adjacent one end of the blade to a point similarly adjacent to the opposite end of the blade.
  • Strip 24 may be a continuous solid strip or a discontinuous strip comprising dots, or the like.
  • the razor cartridge may also contain one or more a shaving aids such as:
  • a lubricating agent for reducing the frictional forces between the razor and the skin e.g., a microencapsulated silicone oil.
  • An agent which reduces the drag between the razor parts and the shaver's face e.g., a polyethylene oxide in die range of molecular weights between 100,000 and 6,000,000; a non-ionic polyacrylamide; and/or a natural polysaccharide derived from plant materials such as guar gum.
  • An agent which modifies die chemical stracture of the hair to allow the razor blade to pass through the whiskers easily e.g., a depilatory agent.
  • a cleaning agent which allows the whisker and skin debris to be washed more easily from the razor parts during shaving e.g., a silicon polyethylene oxide block copolymer and detergent such as sodium lauryl sulfate.
  • E A medicinal agent for killing bacteria or repairing skin damage and abrasions.
  • F A cosmetic agent for softening, smoothing, conditioning, or improving the skin.
  • the disposable razor cartridge comprises a wound healing composition delivery system affixed to the cartridge.
  • the wound healing composition delivery system is preferably in the form of a solid strip of a water-soluble encapsulating agent. Encapsulating agents may be used to controllably release a large variety of agents including various oils.
  • Encapsulating agents are disclosed in more detail in "Microencapsulation", pages 420-437 in "The Theory & Practice of Industrial Pharmacy", Second Edition, 1970, 1976, published by Lea & Febiger, a publication by Union Carbide Corporation of May 1977, entitled “Polyox , Water Soluble Resins: Forming Association Compounds” (the use of polyethylene oxide for microencapsulating water-immiscible oils at page 11 and the use of gelatin and polyethylene oxide to form soluble films for microencapsulation applications at page 17), and a publication by Union Carbide Corporation of May 1972, entitled “Polyox , Water Soluble Resins: Thermoplastic Processing: Calendaring, Extrusion, and Injection Molding”, (discloses a basic process for injection molding items using polyethylene oxide and the formation of calendared films and sheets of polyediylene), which disclosures are incorporated herein by reference.
  • the water-soluble encapsulating agent is polyethylene oxide.
  • the amount of wound healing composition used in die water-soluble encapsulating agent of the present invention may vary depending upon the therapeutic dosage recommended or permitted. In general, the amount of wound healing composition present is the ordinary dosage required to obtain the desired result. In a prefened embodiment, the wound healing composition is present in the water-soluble encapsulating agent in an amount from about 0.01% to about 30%, preferably from about 0.1% to about 15%, and more preferably from about 1% to about 10%, by weight. As set out above, the wound healing composition may also be first premixed with a polymeric delivery system. Polymeric delivery systems can be used to control the delivery of liquids. Polymeric delivery systems are capable of adsorbing high levels of lipophilic materials and thereafter controllably releasing die materials. Suitable polymeric delivery system include porous polymeric beads such as a cross- linked polymethacrylate copolymer.
  • die cross-linked polymethacrylate copolymer is POLYTRAP 6603 Polymer Powder, available from Dow Coming Corporation.
  • POLYTRAP 6603 is a highly cross-linked polymethacrylate copolymer (acrylates copolymer) with high and selective oil adsorption capacity and hydrophobic surface properties.
  • POLYTRAP 6603 Polymer Powder is capable of quickly adsorbing high levels of lipophilic materials while maintaining free-flowing powder characteristics. The adso ⁇ tion of these lipophilic materials is a physical phenomenon controlled by the surface tension of the fluids on die polymer powder surface and filling of die interstitial voids by capillary action.
  • This adso ⁇ tion characteristic can be used to control the delivery of a fluid (converting liquids to solids) or to adsorb a liquid from a surface.
  • Lipophilic materials are delivered by mechanical disruption of the agglomerate or vapor pressure differentials between the inside of the matrix and the outer environment surrounding the polymer. When rubbed on the skin, the lipophilic materials come into direct contact with die skin and meter out as the lipophilic materials is removed from the surface of the particle.
  • the cross-linked polymethacrylate copolymer is MICROSPONGE SKIN OIL ADSORBER 5640 POWDER, available from Dow
  • MICROSPONGE SKIN OIL ADSORBER 5640 is a highly cross-linked polymethacrylate copolymer (acrylates copolymer) with selective oil and water adsorption capacity hydrophilic/hydrophobic surface properties. MICROSPONGE SKIN OIL ADSORBER 5640 is capable of adsorbing high levels of lipophilic materials.
  • the amount of wound healing composition used in the polymeric delivery system of the present invention may vary depending upon the therapeutic dosage recommended or permitted. In general, the amount of wound healing composition present is the ordinary dosage required to obtain die desired result. In a preferred embodiment, the wound healing composition is present in the polymeric delivery system in an amount from about 20% to about 80%, preferably from about 40% to about 70%, and more preferably from about 50% to about 65%, by weight.
  • the wound healing composition delivery system may be microencapsulated and mixed with a cement or binder and adhered to an appropriate surface of razor cartridge 10.
  • the wound healing composition delivery system may be attached to an outer surface of a razor cartridge, recessed therein as in cartridge 10, formed as an integral part of one or more of the basic cartridge components (e.g., the guard bar or a spacer between blades in a twin-blade cartridge) and/or impregnated or dispersed in the material from which one or more of the blade supporting cartridge components are molded or otherwise formed.
  • the wound healing composition delivery system is an integral system permanently and substantially immovably affixed to the cartridge.
  • the wound healing composition delivery system becomes immediately and repeatedly applied to die skin witii each stroke of the razor.
  • its intended function is performed continuously throughout the shaving act as opposed to the requirement of pre-shave or after-shave treatment.
  • the wound healing composition of this invention comprises an antioxidant (E).
  • the invention is directed to a disposable razor cartridge comprising: (A) a blade seat;
  • the antioxidant in the wound healing composition on the razor cartridge may be selected from the group consisting of all forms of Vitamin A including retinol and 3,4-didehydoretinol, all forms of carotene including Alpha- carotene, j3-carotene, g ⁇ -carotene, and cfe/ta-carotene, all forms of Vitamin C including D-ascorbic acid and L-ascorbic acid, all forms of Vitamin E including Alpha- tocopherol.yS-tocopherol, g ⁇ mm ⁇ -tocopherol, ⁇ te/r ⁇ -tocopherol, tocoquinone, tocotrienol, Vitamin E esters which readily undergo hydrolysis to Vitamin E including Vitamin E acetate and Vitamin E succinate, and pharmaceutically acceptable Vitamin E salts such as Vitamin E phosphate, prodrugs of Vitamin A, carotene, Vitamin C, and Vitamin E, pharmaceutically acceptable salts of Vitamin A, carotene, Vitamin C, and Vitamin
  • the present invention extends to methods for making the therapeutic razor cartridges comprising the wound healing compositions (I.A-E + R).
  • a therapeutic razor cartridge is made by forming an admixture of the wound healing components of the composition of Embodiment One (I.A-E) and affixing the composition to the cartridge.
  • LA + R a therapeutic razor cartridge is made by affixing to the cartridge an admixture of a wound healing composition comprising (a) a pyravate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids.
  • a therapeutic razor cartridge is made by affixing to the cartridge an admixture of a wound healing composition comprising (a) a pyravate, (b) a lactate, and (c) a mixture of saturated and unsaturated fatty acids.
  • a therapeutic razor cartridge is made by affixing to the cartridge an admixture of a wound healing composition comprising (a) an antioxidant, and (b) a mixture of saturated and unsaturated fatty acids.
  • a therapeutic razor cartridge is made by affixing to the cartridge an admixture of a wound healing composition comprising (a) a lactate, (b) an antioxidant, and (c) a mixture of saturated and unsaturated fatty acids.
  • a therapeutic razor cartridge is made by affixing to the cartridge a wound healing composition comprising an antioxidant.
  • the invention is directed to a method for preparing a disposable razor cartridge which comprises providing a cartridge comprising:
  • A a blade seat;
  • B at least one razor blade;
  • die wound healing composition (LA) in the delivery system comprises:
  • pyravate selected from the group consisting of pyravic acid, pharmaceutically acceptable salts of pyravic acid, and mixtures thereof;
  • fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells.
  • Embodiment Two (LA-E + R)
  • the present invention extends to methods for employing the therapeutic razor cartridges comprising wound healing compositions.
  • a razor cartridge is employed by contacting the cartridge with skin during the process of shaving.
  • the invention is directed to a method for employing a disposable razor cartridge which comprises providing a cartridge comprising:
  • a wound healing composition delivery system affixed to the cartridge, wherein die wound healing composition (LA) in the delivery system comprises:
  • pyruvate selected from die group consisting of pyravic acid, pharmaceutically acceptable salts of pyravic acid, and mixtures thereof;
  • fatty acids are those fatty acids required for the repair of cellular membranes and resuscitation of mammalian cells; and contacting the cartridge with skin during die process of shaving.
  • Embodiment Two (LA-E + R + M)
  • the therapeutic razor cartridges comprising wound healing compositions (LA-E + R) of the present invention may be combined with medicaments useful for treating wounds (M) to form razor cartridges comprising augmented wound healing compositions (LA-E + R + M).
  • the combination of the razor cartridges comprising a wound healing composition of the present invention and the medicament useful for treating wounds provides an augmented razor cartridge comprising a wound healing composition having an enhanced ability to increase the proliferation and resuscitation rate of mammalian cells.
  • the therapeutic compositions of the present invention may be used in combination with medicaments useful for treating wounds such as immunostimulating agents (Betafectin ), antiviral agents, antikeratolytic agents, anti- inflammatory agents, antifungal agents, tretinoin, sunscreen agents, dermatological agents, topical antihistamine agents, antibacterial agents, bioadhesive agents, respiratory bursting inhibitors (lactic acid, adenosine), inhibitors of prostaglandin synthesis (ibuprofen, aspirin, indometiiacin, meclofenomic acid, retinoic acid, padimate O, meclomen, oxybenzone), steroidal anti-inflammatory agents (corticosteroids including syndietic analogs), antimicrobial agents (neosporin ointment, silvadine), antiseptic agents, anesthetic agents (pramoxine hydrochloride, lidocaine, benzocaine), cell nutrient media, bum relief medications, sun bum
  • the medicament useful for treating wounds is selected from the group consisting of immunostimulating agents, antiviral agents, antikeratolytic agents, anti-inflammatory agents, antifungal agents, tretinoin, sunscreen agents, dermatological agents, topical antihistamine agents, antibacterial agents, bioadhesive agents, respiratory bursting inhibitors, inhibitors of prostaglandin synthesis, antimicrobial agents, cell nutrient media, scar reducing agents, and mixtures thereof.
  • the medicament useful for treating wounds is selected from the group consisting of immunostimulating agents, antiviral agents, antikeratolytic agents, anti- inflammatory agents, antifungal agents, acne treating agents, sunscreen agents, dermatological agents, antihistamine agents, antibacterial agents, bioadhesive agents, and mixtures thereof.
  • the invention is directed to a razor cartridge comprising an augmented wound healing composition (LA + R + M) which comprises a disposable razor cartridge comprising: (A) a blade seat;
  • pyravate selected from the group consisting of pyravic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof;
  • an antioxidant an antioxidant
  • the present invention extends to methods for making the razor cartridges comprising an augmented wound healing composition.
  • the razor cartridges comprising an augmented wound healing composition are made by affixing to the razor cartridge a wound healing composition and a medicament useful for treating wounds to prepare the augmented razor cartridges.
  • the present invention extends to methods for employing the therapeutic razor cartridges comprising augmented wound healing compositions.
  • a razor cartridge is employed by contacting the augmented cartridge with skin during the process of shaving.
  • the invention is directed to a method for employing a disposable razor cartridge comprising an augmented wound healing composition which comprises providing a cartridge comprising:
  • A a blade seat;
  • B at least one razor blade;
  • a wound healing composition delivery system affixed to the cartridge, wherein the wound healing composition (LA) in the delivery system comprises: (a) pyravate selected from the group consisting of pyravic acid, pharmaceutically acceptable salts of pyravic acid, and mixtures thereof;
  • the types of wounds which may be healed using the razor cartridges comprising wound healing compositions and the augmented razor cartridges comprising wound healing compositions of the present invention are wounds such as nicks and cuts.
  • the therapeutic cartridges may be used to protect and accelerate the healing of injured tissue.
  • This study demonstrates a method for preparing an integral wound healing composition delivery system. Specifically, this study demonstrates a method for inco ⁇ orating a wound healing composition into a water-soluble encapsulating agent, wherein the wound healing composition is premixed with a polymeric delivery system.
  • Vitamin E Alpha-Tocopherol acetate
  • a typical formulation could contain:
  • This study demonstrates a method for preparing an integral wound healing composition delivery system. Specifically, this study demonstrates a method for inco ⁇ orating a wound healing composition into a water-soluble encapsulating agent, wherein the wound healing composition is premixed with a polymeric delivery system.
  • Vitamin E Alpha-Tocopherol acetate
  • sunflower oil 6 grams of sunflower oil
  • Vitamin E/sunflower oil mixture 6 grams of Polytrap 6603 while the Polytrap 6603 is being stirred. When addition is complete, continue to mix for 10 minutes to insure good distribution.
  • step 3 Continue stirring the mixture in step 2 (above) and add 6 grams of sodium pyravate to the mixture.
  • Vitamin E and sunflower oil are now contained in the Polytrap 6603 which has been coated with sodium pyravate.
  • This mixture can then be added to a Polyox lubricating strip formulation in the same manner described above.

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Abstract

Cette invention concerne des compositions thérapeutiques de cicatrisation de blessures utiles pour la prévention et la guérison de blessures infligées à des cellules mammaliennes, ces compositions étant incorporées dans des cartouches de rasoir afin de former des cartouches de rasoir thérapeutiques contenant les compositions de cicatrisation. Dans un mode de réalisation de l'invention, la composition thérapeutique de cicatrisation comprend (a) un pyruvate, (b) un anti-oxydant, et (c) un mélange d'acides gras insaturés. Cette invention concerne également des procédés de fabrication et d'utilisation de cartouches de rasoir comprenant des compositions thérapeutiques de cicatrisation.
PCT/US1995/008433 1994-09-30 1995-07-07 Cartouches de rasoir comprenant des compositions de cicatrisation de blessures WO1996010474A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP51171896A JP3940166B2 (ja) 1994-09-30 1995-07-07 創傷を治癒する組成物を含むレザーカートリッジ
AU29607/95A AU2960795A (en) 1994-09-30 1995-07-07 Razor cartridges comprising wound healing compositions
DE69524963T DE69524963T2 (de) 1994-09-30 1995-07-07 Rasierklingeneinheit mit wundenheilmittel
EP95925499A EP0783398B1 (fr) 1994-09-30 1995-07-07 Cartouches de rasoir comprenant des compositions de cicatrisation de blessures

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US31573494A 1994-09-30 1994-09-30
US44698995A 1995-05-22 1995-05-22
US08/446,989 1995-05-22
US08/315,734 1995-05-22

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0854019A1 (fr) * 1997-01-17 1998-07-22 Warner-Lambert Company Barre de confort pour rasoir avec additif d'acide d'alphahydroxy
US6018476A (en) * 1996-09-16 2000-01-25 Altera Corporation Nonvolatile configuration cells and cell arrays
JP2003012525A (ja) * 2001-07-02 2003-01-15 Hoshizaki Electric Co Ltd 生体の損傷部位用の洗浄水およびその製造装置

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090223057A1 (en) * 2008-03-07 2009-09-10 Eveready Battery Company, Inc. Shaving aid material

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2009017A (en) * 1977-12-02 1979-06-13 Warner Lambert Co Razor cartridges
EP0348627A1 (fr) * 1988-05-02 1990-01-03 Permatik Celik Ve Plastik Sanayi A.S. Unité de rasage avec moyens de lubrification incorporés
WO1992015292A1 (fr) * 1991-03-01 1992-09-17 Warner-Lambert Company Compositions therapeutiques de protection et de regeneration cellulaire chez les mammiferes et procedes de preparation et d'utilisation
WO1993010776A1 (fr) * 1991-11-26 1993-06-10 Warner-Lambert Company Compositions pour la cicatrisation de lesions, contenant un pyruvate, un antioxydant et un melange d'acides gras

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2009017A (en) * 1977-12-02 1979-06-13 Warner Lambert Co Razor cartridges
EP0348627A1 (fr) * 1988-05-02 1990-01-03 Permatik Celik Ve Plastik Sanayi A.S. Unité de rasage avec moyens de lubrification incorporés
WO1992015292A1 (fr) * 1991-03-01 1992-09-17 Warner-Lambert Company Compositions therapeutiques de protection et de regeneration cellulaire chez les mammiferes et procedes de preparation et d'utilisation
WO1993010776A1 (fr) * 1991-11-26 1993-06-10 Warner-Lambert Company Compositions pour la cicatrisation de lesions, contenant un pyruvate, un antioxydant et un melange d'acides gras

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6018476A (en) * 1996-09-16 2000-01-25 Altera Corporation Nonvolatile configuration cells and cell arrays
EP0854019A1 (fr) * 1997-01-17 1998-07-22 Warner-Lambert Company Barre de confort pour rasoir avec additif d'acide d'alphahydroxy
AU746841B2 (en) * 1997-01-17 2002-05-02 Warner-Lambert Company Razor comfort strip with alpha-hydroxy acid additive
JP2003012525A (ja) * 2001-07-02 2003-01-15 Hoshizaki Electric Co Ltd 生体の損傷部位用の洗浄水およびその製造装置

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AU2960795A (en) 1996-04-26
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