JP3506701B2 - Wound healing composition, its preparation and use - Google Patents

Description

BACKGROUND OF THE INVENTION The present application is directed to application 663,500, filed March 1, 1991.
It is a continuation of part of the issue.

1. Field of the Invention The present invention relates to wound healing compositions for use in therapeutics useful in increasing the proliferation rate and resuscitation rate of mammalian cells. More specifically, the wound healing composition comprises
It contains (a) pyruvates, (b) antioxidants (antioxidants), and (c) a mixture of saturated and unsaturated fatty acids. The invention also relates to a method of preparing a wound healing composition and its use, as well as a topically applied pharmaceutical product in which the therapeutic composition is used.

2. Background Description Wounds are physical injuries caused by physical means that disrupt the normal continuity of structures such as the body. Such bodily injuries include bruise (bruise, contusion), i.e. unbroken skin, cuts, i.e. wounds that the skin tears with a cutting device, and lacerations, i.e. devices with a blunt skin or There are scratches that are broken by the blunt weapon. Wounds are caused by accidents or disasters or by surgery. Patients with major wounds may benefit from enhanced wound healing methods.

Wound healing consists of a series of processes in which damaged tissue is repaired, specialized tissue is regenerated, and new tissue is reorganized inside the scar. Wound healing consists of three main phases: a) stage of inflammation (0-3 days), b) stage of cell proliferation (3-12 days), c) stage of tissue reorganization (3-6 days).
Months).

During the inflammation stage, platelet aggregation and clot formation capture plasma proteins and blood cells, forming a matrix that induces the influx of various types of cells. During the proliferative stage of cells, new connective tissue or granulation tissue (granulation tissue) is formed and blood vessels are formed. In tissue reorganization, granulocytes are replaced by collagen (collagen) networks and elastin (fibrous connective tissue composed of elastic hard proteins) fibers leading to the formation of scar tissue.

When cells are damaged or die as a result of injury, the wound healing stage is desirable to resuscitate the damaged cells and produce new cells in place of the dead cells.
The process of wound healing requires reversal of cytotoxicity, suppression of inflammation, and stimulation of cell viability and cell proliferation. Wounds require low levels of oxygen to suppress oxidative damage in the first stages of wound healing, and higher levels of oxygen to promote fibroblast collagen formation in later stages of wound healing. .

Cells oppressed injured mammalian superoxide (superoxide) (O ₂ ^-), hydrogen peroxide (H ₂ O _2), hydroxyl radical (OH ·) and singlet oxygen ⁽¹ O _2), such as Exposed to activated oxygen species. In vivo, these reactive oxygen intermediates introduce aerobic metabolism, catabolism between drugs and other xenobiotics, UV and X-ray irradiation, and external introduction such as through wounds. Respiratory burst of phagocytic cells (such as white blood cells) to kill invading bacteria (respiratory burst, rapid respiration of granulocytes) occurs in response. For example, hydrogen peroxide is produced during the respiration of most living microorganisms, especially by pressured and damaged cells.

These reactive oxygen species can damage cells.
An important example of such damage is lipid peroxidation, which involves the oxidative breakdown of unsaturated lipids. Lipid peroxidation is extremely detrimental to membrane structure and function and can cause a number of cytopathological effects. Cells counteract peroxidation of lipids and oxidize substrates by using superoxide dismutase (dismutation enzyme), catalase (hydrogen peroxide degrading enzyme), and peroxidase (hydrogen peroxide as electron acceptor). Self-defense by producing radical scavengers (free radical scavengers) such as Damaged cells have a reduced ability to produce radical scavengers. Excess hydrogen peroxide reacts with DNA (deoxyribonucleic acid), destroys the backbone of the molecule, causes mutations, changes the base sequence,
Release the base. Hydrogen peroxide also reacts with pyrimidines to open double bonds at positions 5 and 6, which interferes with the ability of pyrimidines to hydrogen bond with complementary bases (Hallae
Nder et al. (1971)). Such oxidative biochemical damage results in loss of cell membrane integrity (or integrity), diminishes enzyme activity, and alters transport kinetics (transport kinetics across biological membranes). Change the lipid content of the membrane, resulting in leakage of potassium ions, amino acids and other cellular substances.

Antioxidants have been shown to suppress reactive oxygen species-related damage. For example, pyruvates and other α-keto acids are reported to react rapidly and stoichiometrically (stoichiometrically) with hydrogen peroxide, protecting cells from the effects of cytolysis. Has been done (O'Donnell-Tormey
Other papers, J. Exp. Med., 165, 500-514).

U.S. Pat.Nos. 3,920,835, 3,984,556, 3,988,47
Issue 0 (all issued to Van Scott et al.) Treats symptoms of comedones (acne), (head) dandruff, and palmar keratoderma (warts, octopuses), respectively. Disclosed are methods, which are carbon atoms selected from the group consisting of α-hydroxy acid, α-keto acid and its ester, and 3-hydroxybutyric acid supported on a pharmaceutically acceptable carrier. Approximately 1 to 2 to 6 lower aliphatic compounds
% To about 20% of a topical composition applied to the affected area. Aliphatic compounds include pyruvic acid and lactic acid.

U.S. Pat. Disclosed is a method for treating dry dermatosis, which comprises applying to the symptomatic area a topical composition comprising from about 1% to about 20% of a compound selected from the group consisting of: The compounds include amides and ammonium salts of pyruvic acid and lactic acid.

U.S. Pat. No. 4,234,599 issued to Van Scott et al.
No. is α supported on a pharmaceutically acceptable carrier.
-A photoactinic act comprising applying a topical composition comprising an effective amount of a compound selected from the group consisting of hydroxy acids, β-hydroxy acids, and α-keto acids to the affected skin area. Disclosed is a method of treating non-photoactinic skin keratoderma. Acidic compounds include pyruvic acid and lactic acid.

U.S. Pat.No. 4,294,852 to Wildnauer et al.
Disclosed is a composition for the treatment of skin comprising the combination of α-hydroxy acids, β-hydroxy acids, and α-keto acids disclosed above by Van Scott et al. With a C ₃ -C ₈ aliphatic alcohol. There is.

U.S. Pat.No. 4,663,166 issued to Veech
A mixture of L-lactic acid and pyruvic acid in a ratio of 20: 1 to 1: 1 or D in a ratio of 6: 1 to 0.5: 1, respectively.
An electrolyte solution consisting of a mixture of hydroxybutyric acids and acetoacetic acids.

Sodium pyruvate has been reported to reduce the number of erosions, ulcers, and bleeding on the guinea pig and rat gastric mucosa caused by acetyl salicylate. The analgesic and antipyretic effects of acetyl salicylate were not impaired by sodium pyruvate (Puschmann, Arzneimit
telfors-chung, 33, pages 410-415 and 415-416 (1983
Year))).

Pyruvates are transiently unconscious myocardium (myocardial infarction), a relatively long-term ventricular dysfunction following a brief coronary occlusion that does not cause irreversible damage.
Has been reported to exert a positive inotropic effect (an effect that changes muscle contraction force) (Mentzer et al., Ann. Surg., 209).
Vol. 629-633 (1989)).

Pyruvates have been reported to create relative stabilization of left ventricular pressure and operating factors (work parameters), reducing the magnitude of rule violations. Pyruvate improves the spontaneous resumption of heartbeat and recovery of normal heart rate and pressure development (Bunger et al., J. Mol. Cell. Cardiol, Vol. 18, 423.
Pp. 438 (1986). Mochizuki et al., J. Physiol. (Pari
s), 76, 805-812 (1980). Regitz et al., Cardiovas
c. Res., 15: 652-658 (1981), Giannelli et al., Ann.
Thorac. Surg., 21: 386-396 (1976)).

Sodium pyruvate acts as an antagonist (or blocker) of cyanide poisoning (possibly through the formation of cyanohydrin), protects humans from the lethal effects of sodium sulfide, and induces neuropathy due to acrylamide in neuronal axons. It delays the onset and progression of attacks by functional, morphological, and biochemical means. Schwartz et al., Toxicol.Appl.Pharmacol., 50, 437
~ 442 (1979); Sabri et al., Brain Res., 483, 1-11.
See page (1989).

A cure for advanced L1210 leukemia chemotherapy that restores abnormally deformed red blood cells to normal using sodium pyruvate has been reported. The deformed erythrocytes hindered full drug delivery to the tumor cells. Cohen, Cancer Chemother.Pha
rmacol., 5: 175-179 (1981).

Primary cultures of heterotopic tracheal explants exposed to 7,12-dimethylbenzanthraquinone in vivo were performed on interleukin-2-stimulated peripheral blood lymphocytes, plasma cells and fused hybrid tumor cells, Pig embrio. And human blastocysts were successfully maintained in enriched medium supplemented with sodium pyruvate along with cultures of human blastocysts. Shacter, J. Immunol. Methods, 99, 259-270 (19
87); Marchok et al., Cancer Res., 37, 1811-1821 (19
77); Davis, J. Reprod. Fertil. Suppl., 33, 115-124 (1985), Okamoto et al., Brain and Nerve, 38, 593-598 (1
986); Cohen et al., J. In Vitro Fert. Embryo Transfer, 2
Volume, pages 59-64.

U.S. Pat.Nos. 4,158,057, 4,351,835, 4,645,76
No. 4 (all issued to Stanko) is a method to prevent the accumulation of fat in the liver of mammals by the ingestion of alcohol, and to increase body protein levels in mammals to suppress body fat. Each discloses a method for controlling body weight and a method for suppressing body fat deposition in a human body. The method consists of administering to the mammal a therapeutic mixture of pyruvates and dihydroxyacetone, optionally riboflavin. US Pat. No. 4,548,937 issued to Stanko discloses a method of inhibiting weight gain in a mammal which comprises administering to the mammal a therapeutically effective amount of pyruvates, optionally riboflavin. Similarly, US Patent No. issued to Stanko
4,812,479 discloses a method of inhibiting weight gain in a mammal comprising administering to the mammal a therapeutically effective amount of dihydroxyacetone, optionally with riboflavin and pyruvates.

It was reported that rats fed a calcium oxalate stone-forming diet containing sodium pyruvate formed less urinary stones than control rats not fed sodium pyruvate. Ogawa et al., Hinyokika Kivo, 32
Vol., 1341-1347 (1986).

U.S. Pat. No. 4,521,375 issued to Houlsby discloses a method of disinfecting surfaces in contact with living tissue. This method consists of sterilizing the surface with an aqueous solution of hydrogen peroxide and then neutralizing the surface with pyruvic acid.

US Pat. No. 4,416,982 issued to Tauda et al. Discloses a method of reacting hydrogen peroxide with a derivative of phenol or aniline in the presence of peroxidase to decompose hydrogen peroxide.

United States Patent No. 4,696,917 issued to Lindstrom et al.
Issue is Earle's salts, chondroitin sulfate, buffer solution,
Disclosed is an irrigation solution for eye drop consisting of 2-mercaptoethanol and Eagle's minimum essential medium with pyruvates. The irrigation solution for eye drops can optionally include ascorbic acid and α-tocopherol. Lindst
U.S. Pat. No. 4,725,586 issued to Rom et al. discloses an irrigation solution consisting of balanced salt solution, 2-mercaptoethanol, sodium bicarbonate or dextrose, pyruvates, sodium phosphate buffer system, and cystine. The irrigation solution may optionally include ascorbic acid and γ
-Comprising tocopherols.

U.S. Pat. No. 3,887,702 issued to Baldwin discloses a composition for treating fingernails and toenails consisting essentially of soybean oil or sunflower oil in combination with Vitamin E.

U.S. Pat. No. 4,847,069 issued to Bissett et al. Discloses an anti-inflammatory agent selected from (a) sorbohydroxamic acid, (b) steroid anti-inflammatory agents and natural anti-inflammatory agents,
And (c) a photoprotective composition comprising a topical carrier. Fatty acids can also be present as emollients. US Pat. No. 4,8 issued to Bissett et al.
No. 47,071 is a photoprotective agent consisting of (a) a free radical scavenger of tocopherol or tocopherol ester, (b) an anti-inflammatory agent selected from steroid anti-inflammatory agents and natural anti-inflammatory agents, and (c) a topical carrier. A composition is disclosed. U.S. Pat. No. 4,847,072 issued to Bissett et al.
The publication discloses topical compositions containing up to 25% tocopherol sorbate in a topical carrier.

U.S. Pat.No. 4,533,637 issued to Yamane et al. Discloses carbon sources, nucleic acid source precursors, amino acids, vitamins,
A medium (culture medium) composed of minerals, lipophilic nutrients, and serum albumin and cyclodextrin is disclosed. Lipophilic substances include unsaturated fatty acids and lipophilic vitamins such as vitamins A, D and E. Ascorbic acid may be present.

United Kingdom patent application no. A medium is disclosed. The oil phase contains chicken fat.

Preparation-H ™ is reported to increase the wound healing rate of artificially created rectal ulcers. The active ingredients of Preparation-H are skin respiratory factors and shark liver oil. Subramanyam et al., Digestive Diseases and
Sciences, 29, 829-832 (1984).

It has been reported that the addition of sodium pyruvate to bacterial and yeast systems hinders the production of hydrogen peroxide, enhances bacterial growth and protects the system from the toxicity of reactive oxygen intermediates. Unsaturated and saturated fatty acids contained in chicken fat enhanced the repair of biological membranes and reduced cytotoxicity. The antioxidants glutathione and thioglycolate reduced the damage induced by oxygen radical species. See Martin, Ph.D. PhD dissertation (1987-89).

U.S. Pat. No. 4,615,697 issued to Robinson, consists of a bioadhesive and a therapeutic agent consisting of a water-swellable but water-insoluble fibrous cross-linked carboxy-functional polymer. Disclosed are therapeutic compositions with controlled release rates.

European patent application No. 04106 issued to Kellaway et al.
96AI is about 1% to about 20% by weight of a polyhydroxy compound such as sugar, cyclitol, or a lower polyhydric alcohol.
A mucoadhesive release system comprising a cross-linked polyacrylic acid and a therapeutic agent is disclosed.

Although the therapeutic compositions described above are reported to inhibit the production of reactive oxygen intermediates, none of the above compositions are completely satisfactory wound healing compositions. Any one of the compositions to reduce the production of hydrogen peroxide at the cellular level, increase the resistance of cells to cytotoxic agents, increase the growth rate of cells and protect and restore mammalian cells. Nothing increases cell viability. The present invention provides improved therapeutic wound healing compositions without the detrimental properties of previously known compositions.

SUMMARY OF THE INVENTION The present invention relates to wound healing compositions for use in therapy.
The composition comprises (a) pyruvic acid, a pharmaceutically (pharmaceutically) acceptable pyruvic acid salt, and a pyruvic acid selected from the group consisting of a mixture thereof, (b) an antioxidant, and (c). A mixture of saturated and unsaturated fatty acids, provided that the fatty acids are those required for mammalian cell membrane repair and cell resuscitation. The therapeutic composition is used as a wide range of products from topically applied medicines to orally ingestible medicines. The present invention also relates to a method for preparing a therapeutic agent composition and a method for using the same, and a pharmaceutical for topical application (or application) in which the therapeutic agent composition is used.

DETAILED DESCRIPTION OF THE INVENTION The Applicant has found that wound healing compositions as therapeutic agents to increase the resuscitation rate of injured mammalian cells and increase the proliferation rate of new mammalian cells to replace dead cells. I found a thing. Cells treated with the therapeutic composition of the present invention,
It shows reduced levels of hydrogen peroxide production, increased resistance to cytotoxic agents, increased growth rate, and increased likelihood of survival. Wounded mammals treated with the therapeutic agent composition exhibit significantly improved wound closure and wound healing than untreated mammals and mammals treated with conventional conventional wound healing compositions.

The term "damaged cell" as used herein refers to
(A) Damage to biological membranes (cell membranes) reduces transport through the membranes, resulting in increased intracellular toxins and normal cell metabolites, and nutrients required for intracellular cell repair. And other components are deficient, and (b) the ability of the cells to produce antioxidants and enzymes is reduced, so that the concentration of oxygen radicals in the cells is increased, and (c) or normal cell functions are restored. There are damaged DNAs, RNAs and ribosomes that have to be repaired and replaced before being repaired; The term "resuscitation" of injured mammalian cells refers to the reversal of cytotoxicity, stabilization of cell membranes, increased cell proliferation rate, and / or cell secretion of growth factors, hormones, etc. It means normalization of function. As used here, “cytotoxicit”
The term "y)" means a condition caused by a cytotoxic agent that damages cells. Injured cells cannot afford to grow because the injured cells spend all their energy in repairing the cells. Helps repair cells and promotes cell growth.

The epidermal keratinocytes and mononuclear cells have multiple layers of oxygen evolution and each type of mechanism has a different degree within each type of cell. For example, in mononuclear cells, the process of respiratory burst is more pronounced than in epidermal keratinocytes. Thus, the components in the therapeutic composition of the present invention will vary depending on the cell type involved in the condition being treated.

In a first embodiment, a therapeutic wound healing composition for treating mammalian cells, preferably epidermal keratinocytes, comprises (a) pyruvates, (b) antioxidants, and (c) It consists of a mixture of saturated and unsaturated fatty acids.

Without wishing to be bound by any theory, the applicant believes that pyruvate (or pyruvate) is transported inside the cell where it neutralizes intracellular oxygen radicals. . Pyruvates are also used intracellularly in the citric acid cycle, which provides energy to the cells to increase their viability, and are used in the synthesis of important biomolecules to promote cell proliferation. Used as a precursor material. Moreover, pyruvates can be used in a multifunctional oxidase system to reverse cytotoxicity. Antioxidants, especially lipid-soluble antioxidants, are absorbed into the cell membrane and neutralize oxygen radicals, thereby protecting the membrane. The combination of pyruvates inside the cell and antioxidants in the cell membrane works synergistically, with low levels of intracellular hydrogen peroxide production that cannot be achieved using either component alone. Decrease to.

The saturated fatty acid and unsaturated fatty acid in the present invention are fatty acids required for repair of cell membrane and recovery (or resuscitation) of mammalian cells. Thus, the fatty acids in the therapeutic composition, which may be in the form of mono- or di-, and / or tri-glycerides or free fatty acids, can be used to repair damaged cells and dead cells. Are immediately available for the production of new cells to replace Cells damaged by oxygen radicals are required to produce unsaturated fatty acids in order to repair the cell membrane. However, oxygen is required for the production of unsaturated fatty acids by cells. Thus, injured cells require a high concentration of oxygen to produce unsaturated fatty acids, while at the same time reducing intracellular oxygen levels to reduce oxidative damage. Supplying the cells with unsaturated fatty acids for repair of the cells reduces the need for the cells to produce unsaturated fatty acids, as well as the need for high oxygen concentrations. The presence of a mixture of saturated and unsaturated fatty acids in the therapeutic composition significantly enhances the ability of pyruvates and antioxidants to inhibit reactive oxygen production. By stabilizing the cell membrane, unsaturated fatty acids also improve membrane function and facilitate the transport of pyruvates into the cell. By improving cell viability,
Unsaturated fatty acids also improve the cell membrane repair rate (repair rate) of cells. Thus, the three components in the therapeutic composition work together synergistically to increase the rate of recovery of wounded mammalian cells and the rate of new cell production.

In a second embodiment, a therapeutic composition for treating mammalian cells, preferably epidermal keratinocytes, comprises (a)
It is composed of pyruvic acids, (b) lactic acids, and (c) a mixture of saturated and unsaturated fatty acids. In this embodiment, lactic acids are used instead of antioxidants. Antioxidants neutralize oxygen radicals after the radicals have already been formed. On the other hand, lactic acids are one of the components in the cellular feedback mechanism, and suppress the respiratory bursting reaction in order to suppress the production of reactive oxygen species. The combination of pyruvic acids to neutralize reactive oxygen species and lactic acids to suppress the process of respiratory bursting function synergistically to make intracellular hydrogen peroxide acidic either one component alone. Reduced below what can be achieved when used. The presence of a mixture of saturated and unsaturated fatty acids in the therapeutic composition significantly enhances the ability of pyruvates and lactic acids to suppress the production of reactive oxygen species. Thus, the three components in the therapeutic composition in this embodiment together act synergistically to increase the rate of proliferation and recovery (revival) of mammalian cells.

In a third embodiment, a therapeutic wound healing composition for treating mammalian cells, preferably epidermal keratinocytes, comprises (a) an antioxidant, (b) saturated and unsaturated fatty acids. Composed of a mixture. The presence of a mixture of saturated and unsaturated fatty acids in the therapeutic composition significantly enhances the antioxidant's ability to suppress the production of reactive active oxygen as in this embodiment. The combination of antioxidants that neutralize reactive oxygen species and fatty acids that rebuild cell membranes requires the cellular oxygen function to reduce intracellular hydrogen peroxide production, using either component alone. It will decrease synergistically below the level that can be achieved. Thus, in this embodiment, the components of the therapeutic composition work together to synergistically increase the growth and recovery rates of mammalian cells.

In a fourth embodiment, a therapeutic wound healing composition for treating mammalian cells, preferably mononuclear cells, comprises:
It comprises (a) lactic acids, (b) antioxidants, and (c) saturated and unsaturated fatty acids. In this embodiment, lactic acids are used because respiratory bursting in mononuclear cells is more prominent than in epidermal keratinocytes. The combination of lactic acids to suppress the process of respiratory bursting and antioxidants to neutralize reactive oxygen species act synergistically to produce intracellular hydrogen peroxide, either component Reduced below levels achievable when used alone.
The presence of a mixture of saturated and unsaturated fatty acids in the therapeutic wound healing composition in this embodiment significantly impairs the ability of lactic acids and antioxidants to inhibit the production of reactive oxygen species. Raise to. Thus, the three components in the therapeutic composition in this embodiment together act synergistically to increase the rate of proliferation and recovery (revival) of mammalian cells.

Thus, the combination of components in the above embodiments work together to enhance the growth and recovery rates of mammalian cells. The therapeutic effect of the combination of ingredients in each of the above embodiments is significantly greater than that expected by adding more individual therapeutic agent ingredients. As such, Applicants' wound healing composition reduces the acid level of hydrogen peroxide within the cell, increases the resistance of the cell to cytotoxic components, increases the rate of cell growth, and improves cell viability. To increase.

The cells treated with the therapeutic composition of the present invention are mammalian cells. Applicants will describe the therapeutic compositions of this invention as being useful in treating mammalian epidermal keratinocytes and mammalian mononuclear cells,
Applicants believe that all mammalian cells protected or resuscitated by the therapeutic composition of the present invention can be used within the present invention. Keratin cells are a typical example of normal mammalian cells and are the fastest growing cells in the body. The interrelationship between the response of keratinocytes to injury and treatment and the response of mammalian cells in general is very high. Mononuclear cells are representative of white blood cells in the immune system and specialized mammalian cells such as liver, kidney, heart, and brain organ cells. Mammalian cells can be processed in vivo or in vitro.

Epidermal keratinocytes are specialized epithelial cells of the epidermis that synthesize keratin, a hard protein that is a major constituent of the organic matrix of the epidermis, hair, nails, keratinous tissue, and tooth enamel. Mammalian epidermal keratinocytes make up about 95% of epidermal cells and, together with melanocytes, form the epidermal binary system. In its various successive stages,
Keratinocytes of the epidermis are also known as basal cells, trichome cells, and granule cells.

Mononuclear cells are mononuclear phagocyte leukocytes that undergo respiratory bursting and are involved in reactive oxygen-mediated cell damage inside the epidermis. White blood cells are white blood cells
Small bodies, which are two main groups: white blood cells with abundant granules in the cytoplasm and non-granular cells containing lymphocytes and mononuclear cells with no special granules in the cytoplasm. It is a body that is classified as white blood cells (non-granular cells). Phagocytic cells are cells that ingest microbes or other cells and foreign particles. Mononuclear cells are also known as large mononuclear leukocytes and clear or transition leukocytes.

Pyruvate (2-oxopropanoic acid, α-ketopropanoic acid, CH ₃ COCOOH) or pyruvate (at physiological pH) is involved in the (new) metabolism of proteins and carbohydrates,
And it is a basic intermediate in the citric acid cycle. The citric acid cycle (tricarboxylic acid cycle (circuit), also called Krebs cycle) is
It is the main reaction sequence that oxidizes organic compounds in respiring tissues to generate adenosine triphosphate (ATP), which reduces oxygen to transfer electrons to the transport system. Acetyl coenzyme A (“active acetyl”) is oxidized in this process and subsequently utilized in various biological processes,
It then becomes a precursor in the biosynthesis of many fatty acids and sterols. The two main sources of acetyl coenzyme A (source) are derived from glucose and fatty acid metabolism. Glycolysis consists of a series of molecular translocations in which each glucose molecule is transformed in the cytoplasm to two molecules of pyruvate. Pyruvate then enters mitochondria (the glomerulus) where it is oxidized by coenzyme A in the presence of the enzyme and the cofactor for acetylcoenzyme A. Acetyl coenzyme A then enters the citric acid cycle.

In muscle, pyruvate (derived from glycogen) is reduced to lactate while working the muscle. Lactic acid is reoxidized and partially reconverted to glycogen during muscle quiescence. Pyruvates can also act as antioxidants to neutralize intracellular oxygen radicals and are also used in multifunctional oxidase systems to reverse cytotoxicity.

In the present invention, the pyruvic acids are selected from the group consisting of pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof. In general, the pharmaceutically acceptable salts of pyruvic acid are alkali metal salts and alkaline earth metal salts. Preferably, the pyruvic acids are pyruvic acid,
It is selected from the group consisting of sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and mixtures thereof. More preferably, the pyruvates are selected from the group of salts consisting of sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and mixtures thereof. Most preferably, the pyruvates are sodium pyruvate.

The amount of pyruvates present in the therapeutic composition of the present invention is a therapeutically effective amount. A therapeutically effective amount of pyruvates is the amount of pyruvates needed to increase the proliferation and resuscitation rate of mammalian cells. The exact amount of pyruvates is a matter of preference that depends on factors such as the wound condition to be treated, as well as other ingredients included in the composition. In a preferred embodiment, the pyruvic acids are present in the therapeutic composition in an amount of about 10% to about 50%, preferably about 20% to about 45%, by weight of the therapeutic composition.
%, More preferably about 25% to about 40%.

L-lactic acid ((S) -2-hydroxypropanoic acid,
(+) Α-Hydroxypropionic acid, CH ₃ CHOHCOOH) or lactate is contained in small amounts in mammalian blood and muscle fluid. Lactic acid levels increase in muscle and blood after strenuous activity. Lactates are components in the cellular feedback mechanism that inhibit the cell's natural respiratory bursting process, thereby inhibiting the production of oxygen radicals.

The lactate used in the present invention is selected from the group consisting of lactic acid, pharmaceutically acceptable salts of lactic acid, and mixtures thereof. Generally, the pharmaceutically acceptable salts of lactic acid are alkali metal salts and alkaline earth metal salts. Preferably the lactic acid is selected from the group consisting of lactic acid, sodium lactate, potassium lactate, magnesium lactate, calcium lactate, zinc lactate, manganese lactate, and mixtures thereof. More preferably, the lactic acid is selected from sodium lactate, potassium lactate, magnesium lactate, calcium lactate, zinc lactate, manganese lactate, and mixtures thereof. Most preferably, the lactic acid is lactic acid.

The amount of lactic acid present in the therapeutic composition of the present invention is
It is a pharmaceutically effective amount. A pharmaceutically effective amount of lactic acid is an amount required to increase the growth rate and recovery rate of mammalian cells. In the case of the composition, the amount of pharmaceutically effective lactates protects mammalian cells,
The amount required to suppress respiratory bursting of white blood cells in order to restore the cells. Generally, the amount of pharmaceutically active lactic acid in the composition is from about 5 to about 10 times the amount of lactic acid normally found in serum. The exact amount of lactic acid is a matter of priority (or preference) which will depend on factors such as the condition of the wound to be treated as well as other ingredients included in the composition. In a preferred embodiment, the amount of lactic acids present in the therapeutic composition is from about 10% to about 50%, preferably from about 20% to about 45%, more preferably, by weight of the therapeutic composition. It is about 25% to about 40%.

Antioxidants are substances that prevent oxidation or suppress reactions promoted by oxygen or peroxide. Antioxidants,
Especially lipid-soluble antioxidants neutralize oxygen radicals,
It is thereby absorbed into the cell membrane to protect it. Antioxidants useful in the present invention include vitamin A (retinol), vitamin A ₂ (3,4-didehydroretinol),
α-carotene (same as carotene), β-carotene (β,
β-carotene), γ-carotene, all types of carotene such as γ-carotene, vitamin C (alcorbic acid, L-ascorbic acid), vitamin E (α-tocopherol, 3,
4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-
Trimethyltridecyl) -2H-1-benzopyran-6-
All tocopherols, such as β-tocopherol, γ-tocopherol, δ-tocopherol, and mixtures thereof. Preferably the antioxidant is selected from the group of lipid soluble antioxidants composed of vitamin A, β-carotene, vitamin E, and mixtures thereof. More preferably, the antioxidant is vitamin E.

The amount of antioxidant present in the therapeutic composition of the present invention is a therapeutically effective amount. A therapeutically effective amount of an antioxidant is an amount of antioxidant needed to increase the rate of proliferation and resuscitation (or recovery) of mammalian cells. The exact amount of antioxidant will be a matter of preference depending on factors such as the condition of the wound to be treated, as well as other ingredients included in the composition. In a preferred embodiment, the amount of antioxidant present in the therapeutic agent composition is from about 10% to about 50%, preferably about 20% to about 45%, more preferably about 20% by weight of the therapeutic agent composition. 25% to about 40%.

The mixture of saturated fatty acid and unsaturated fatty acid in the present invention,
Fatty acids as required for repair of mammalian cell membranes and production of new cells. Thus, fatty acids are easily incorporated into cells and are readily available for repair of damaged cells and growth of new cells. By supplying cells with the unsaturated fatty acids needed for cell repair, the cellular need for unsaturated fatty acids is reduced, as is the need for high oxygen levels. Thus, the presence of a mixture of saturated and unsaturated fatty acids in the therapeutic composition significantly enhances the ability of pyruvates, lactic acids and antioxidants to suppress the production of reactive oxygen. .

Fatty acids are carboxylic acid compounds found in animal and vegetable fats. Fatty acids are classified as lipids and are composed of a chain of alkyl groups containing 4 to 22 carbon atoms and 0 to 3 double bonds, a carboxyl group at the end, -CO
It is characterized by having OH. Fatty acids can be saturated or unsaturated and can be solid, semi-solid, or liquid. The most common saturated fatty acids are butyric acid (C _4), lauric acid (C _12), palmitic acid (C _16), and stearic acid (C _18). Unsaturated fatty acids are usually derived from plants,
It is characterized by having an alkyl chain containing 16 to 22 carbon atoms and 0 to 3 double bonds and having a carboxyl group at the end of the molecule. The most common unsaturated fatty acids are oleic acid, linoleic acid, and linolenic acid (all C ₁₈ acids).

In general, the mixture of saturated and unsaturated fatty acids required in the present invention for repairing mammalian cell membranes is derived from animal fats and waxes. Cells produce the chemical components and energy needed for cell survival and store excess energy in the form of fat. Fat is adipose tissue stored between the organs of the body to provide a reserve supply of energy. Preferred animal fats and waxes have a fatty acid composition similar to that contained in human fat and human breast milk. The preferred animal fats and waxes are human fat, chicken fat,
It is selected from the group consisting of beef fat (cattle here refers to bovine livestock regardless of sex or age), sheep fat, horse fat, pig fat, and whale fat. More preferred animal fats and waxes are human fats and chicken fats. The most preferred animal fat is human fat. Other fat and wax mixtures, such as vegetable waxes, marine animal fats (especially shark liver oils), and animal fats and waxes, especially synthetic waxes with a fatty acid composition similar to human fats and waxes. Oil is also used. Mixtures of saturated and unsaturated fatty acids can likewise be derived from animal and vegetable fats and waxes, and mixtures thereof.

In a preferred embodiment, the mixture of saturated and unsaturated fatty acids has a composition similar to human fat and consists of the following fatty acids: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristolic acid. , Palmitic acid, palmitolic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid. Preferably, butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, myristolic acid, palmitic acid, palmitolic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid are mixture, respectively Re husband midsole present in a weight percentage of the _{following: 0.2~0.4% (C 4),} 0.1%
_{(C 6), 0.3~0.8% (} C 8), 2.2~3.5% (C 10), 0.9~
_{5.5% (C 12), 2.8~8.5} % (C 14), 0.1~0.6% (C 14 ~
C ₁ ), 23.2 to 24.6% (C ₁₆ ), 1.8 to 3.0% (C _{16 to} C ₁ ),
_{6.9~9.9% (C 18), 36.0~36.5} % (C 18 ~C 1), 20~2
_{0.6% (C 18 ~C 2)} , 7.5~7.8% (C 18 ~C 3), 1.1~4.9
_{% (C 20), 3.3~6.4%} (C 20 ~C 1).

In another preferred embodiment, the mixture of saturated and unsaturated fatty acids is chicken fat consisting of the following fatty acids:
Lauric acid, myristic acid, myristolic acid, pentadecanoic acid, palmitic acid, palmitolic acid, margaric acid, margallol acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid. Preferably, lauric acid, myristic acid, myristolic acid, pentadecanoic acid, palmitic acid, palmitoleic acid, margaric acid, margaric acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadoleic acid are fatty acids. They are present in the mixture in the following weight percentages: 0.1% (C ₁₂ ), 0.8% (C
₁₄ ), 0.2% (C _{14 to} C ₁ ), 0.2% (C _{14 to} C ₁ ), 0.1% (C
_{15), 25.3% (C 16} ), 7.2% (C 16 ~C 1), 0.1%
(C ₁₇ ), 0.1% (C _{17 to} C ₁ ), 6.5% (C ₁₈ ), 37.7% (C
_{18 ~C 1), 20.6% (} C 18 ~C 2), 0.8% (C 18 ~C 3), 0.2
% (C _20), and _{0.2% (C 20 ~C 1)} . The accuracy of all percentages is ± 10%.

The above fatty acids and their percentages present in the fatty acid mixture are given as an example only.
The exact type of fatty acid present in the fatty acid mixture and the exact amount of fatty acid used in the fatty acid mixture will vary to obtain the desired result in the final product, but such changes are Those skilled in the art can easily do so within the capabilities of their people without the need for undue experimentation.

The amount of fatty acids present in the therapeutic composition of the present invention is a therapeutically effective amount. The therapeutically effective amount of fatty acids is the amount of fatty acids required to increase the rate of cell membrane repair and cell resuscitation in mammals. The exact amount of fatty acid used will vary depending on such factors as the type and distribution of fatty acid used in the mixture, the condition of the wound to be treated, and other ingredients included in the composition. In a preferred embodiment, the amount of fatty acids present in the therapeutic composition is from about 10% to about 10% thereof, based on the weight of the therapeutic composition.
50%, preferably about 20% to about 45%, more preferably
It is about 25% to about 40%.

According to the invention, a therapeutic wound healing composition for treating mammalian cells is: (1) (a) Pyruvate, a pharmaceutically acceptable salt of pyruvate, and mixtures thereof. Pyruvates selected from: (b) antioxidants; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are required for repair of mammalian cell membranes and resuscitation of mammalian cells. (2) (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a pyruvic acid selected from the group consisting of a mixture thereof; (b) lactic acid, a pharmaceutically acceptable salt of lactic acid. And (c) a mixture of saturated fatty acids and unsaturated fatty acids, provided that the fatty acids are for repair of mammalian cell membranes and resuscitation of mammalian cells. A fatty acid as required; (3) (a) an antioxidant; and (b) a mixture of saturated and unsaturated fatty acids, provided that the fatty acid repairs mammalian cell membranes and resuscitates mammalian cells. (4) (a) lactic acid, a pharmaceutically acceptable salt of lactic acid,
And lactic acids selected from the group consisting of a mixture thereof; (b) an antioxidant; and (c) a mixture of a saturated fatty acid and an unsaturated fatty acid, provided that the fatty acid is used for repair of mammalian cell membranes and mammalian cells. It is a fatty acid required for resuscitation; it is selected from the group consisting of the above (1) to (4).

In a preferred embodiment, the wound healing composition for treating mammalian cells, preferably epidermal keratinocytes, comprises: (1) (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and mixtures thereof. Pyruvates selected from the group consisting of: (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are necessary for repair of mammalian cell membranes and resuscitation of mammalian cells. (2) (a) Pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a pyruvic acid selected from a mixture thereof; (b) Lactic acid, a pharmaceutically acceptable salt of lactic acid, and Lactic acids selected from the group consisting of the mixture; and (c) a mixture of saturated fatty acids and unsaturated fatty acids, provided that the fatty acids are mammalian cell membrane repair and mammalian cells (3) (a) an antioxidant; and (b) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are mammalian cell membrane repairs and mammals. Is a fatty acid required for the resuscitation of cells of the above; selected from the group consisting of the above (1) to (3).

In a more preferred embodiment, the wound healing composition for treating mammalian cells, preferably epidermal keratinocytes, comprises: (1) (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and mixtures thereof. Pyruvates selected from the group consisting of: (b) an antioxidant; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are for repair of mammalian cell membranes and resuscitation of mammalian cells. A fatty acid as required; and (2) (a) pyruvic acid, a pyruvic acid selected from the group consisting of pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) lactic acid, as a drug. Lactic acids selected from the group consisting of acceptable lactic acid salts, and mixtures thereof; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are mammalian cells. Selected from the group consisting of above (1) to (2); repair of mammalian cells is a fatty acid such as required for the resuscitation of.

In a most preferred embodiment, a wound healing composition for treating mammalian cells, preferably epidermal keratinocytes, is composed of: (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and mixtures thereof. Pyruvates selected from the group; (b) antioxidants; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are required for repair of mammalian cell membranes and resuscitation of mammalian cells. Is a fatty acid such as

In another preferred embodiment, the wound healing composition for treating mammalian cells, preferably mononuclear cells, comprises: (a) lactic acid, a pharmaceutically acceptable salt of lactic acid, and mixtures thereof. Selected lactic acids; (b) antioxidants; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are required for repair of mammalian cell membranes and resuscitation of mammalian cells. Is a fatty acid.

The present invention further extends to methods of making wound healing compositions as therapeutic agents. Generally, the therapeutic composition is made by admixing the components of the composition. In one embodiment, the therapeutic composition is made by forming an admixture of (a) pyruvic acids, (b) antioxidants, and (c) a mixture of saturated and unsaturated fatty acids. . In a second embodiment, the therapeutic composition is made by forming a mixture of (a) pyruvic acids, (b) lactate, and (c) a mixture of saturated and unsaturated fatty acids. In a third embodiment, the therapeutic composition is made by forming a mixture of (a) an antioxidant and (b) a mixture of saturated and unsaturated fatty acids. In a fourth embodiment, the therapeutic composition comprises (a) lactic acids, (b) antioxidants,
And (c) formed by forming a mixture of a mixture of saturated and unsaturated fatty acids.

In some applications, the admixture is formed in a solvent such as water. If necessary, the pH of the solvent is about 3.5 to about 8.0, preferably about 4.5 to about 7.5, more preferably about
Adjusted from 6.0 to about 7.4. The admixture is then sterile filtered. As is well known to those of ordinary skill in the art, other ingredients may be incorporated into the therapeutic composition in the proportions dictated by the desired composition properties. The final therapeutic composition can be readily prepared using methods generally known in the art of pharmacy.

The present invention further extends to the use of wound healing compositions as therapeutic agents. Generally, the therapeutic composition is used by contacting the therapeutic composition with the wound. In a particular embodiment, the present invention is directed to a method of healing a mammalian wound comprising the steps of: (A) (a) Pyruvate, a pharmaceutically acceptable salt of pyruvate, and mixtures thereof. Pyruvates selected from the group: (b) antioxidants; and (c) a mixture of saturated and unsaturated fatty acids, where the fatty acids are for repair of mammalian cell membranes and resuscitation of mammalian cells. A fatty acid as required for the method of claim 1. A wound healing composition comprising a therapeutic agent comprising: (B) contacting the wound healing composition with the wound;

In the first embodiment, the therapeutic composition is used alone (by itself) to increase the growth rate and resuscitation rate of mammalian cells. In a second embodiment, the therapeutic composition treats wounds to form a more effective wound healing composition with enhanced ability to further increase mammalian cell proliferation and resuscitation rates. It is used in combination with a useful medicine.

In a first embodiment, the wound healing therapeutic composition is used alone in a topically applied product to increase the proliferation and resuscitation rate of mammalian cells. For example, the therapeutic compositions are utilized in topical skin care products to treat wounds such as incisions and lacerations.

In a second embodiment, the therapeutic wound healing composition of the present invention is combined with other agents useful in the treatment of wounds to form an enhanced wound healing composition. In this embodiment, the combination of the therapeutic composition of the present invention and the agents useful in the treatment of wounds is an effective wound healing composition with enhanced capacity to increase mammalian cell capacity growth and resuscitation rates. Give things. For example, the therapeutic composition of the present invention comprises an anti-inflammatory agent, respiratory burst inhibitor (lactic acid, adenosine), prostaglandin synthesis inhibitor (ibuprofen, aspirin, indomethacin, meclofenome, retinoic acid, padimate O, mechromene, oxybenzone. ), Steroid anti-inflammatory agents (corticosteroids including similar compounds), antibacterial agents, antimicrobial agents (neosporine ointment, silvadine), preservatives, anesthetics (plamoxin hydrochloride, lidocaine, benzocaine), cell nutrient media , In combination with burn relievers, sunscreens, acne preparations, insect stings, wound cleaners, wounds, scar reducers (vitamin E), immunostimulants (betafectin)), and mixtures thereof , It is used to further promote the growth rate and resuscitation rate of mammalian cells. Preferably, the agent useful for treating wounds is selected from the group consisting of respiratory burst inhibitors, prostaglandin synthesis inhibitors, antimicrobial agents, cell nutrient media, scar reducing agents, and mixtures thereof. More preferably, the agent useful in the treatment of wounds is cell nutrient medium.

Cellular nutrient media is a complete diet of nutrients needed to heal wounds. Cellular nutrient media can be obtained from sources such as animals, plants, and yeast. Typical cell nutrient media are live yeast cell derivatives, Eagle's media, and artificial serum. A preferred cellular nutrient medium is a derivative of live yeast cells.
Live yeast cell derivatives provide skin respiration factors that increase the absorption of oxygen in skin tissue and promote collagen production. Living yeast cell derivatives generally contain many amino acids for collagen production, mono- and disaccharides as carbon sources, vitamins, minerals, phosphorus-containing compounds, nucleosides, nucleotides, salts. Generally, amino acids present in living yeast cell derivatives are aspartic acid, glutamic acid, histidine, serine, glycine, alanine, arginine, tyrosine, valine, methionine,
Includes isoleucine, leucine, phenylalanine and lysine. The coenzymes present in living yeast cell derivatives are:
Contains vitamin A, vitamin E, vitamin D ₃ , folic acid, pantothenic acid, niacinamide, vitamin B ₁ , vitamin B ₂ , vitamin B ₆ , and vitamin B ₁₂ . Cofactor-type minerals present in living yeast cell derivatives include calcium, copper, iron, magnesium, zinc, phosphorus. A preferred tissue respiration factor is Biodynes®, TRF (thyrotropin releasing factor), commercially available from Brooks Industries Inc. of South Plainfield, NJ. Generally, the cell nutrient medium comprises about 0.01% to about 5%, preferably about 0.1% to about 1 of the therapeutic agent resuscitation based on the weight of the therapeutic agent resuscitation.
%, More preferably about 0.2% to about 0.4%.

In a particular embodiment, the present invention is directed to an enhanced wound healing composition consisting of: (A) (a) Pyruvate, a pharmaceutically acceptable salt of pyruvate, and mixtures thereof. Pyruvates from the group; (b) antioxidants; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are required for repair of mammalian cell membranes and resuscitation of mammalian cells. Enhanced wound healing composition comprising: (B) a fatty acid; and (B) a medicament useful in treating wounds.

The present invention extends to a method of making a wound healing composition with enhanced efficacy. Generally, a more effective wound healing composition is made by admixing a therapeutic wound healing composition with a medicament useful in the treatment of wounds to prepare a more effective wound healing composition.

Also, the invention extends to methods of using the enhanced efficacy wound healing compositions. Generally, a more effective wound healing composition is used by contacting the composition with the wound. In a particular embodiment, the invention provides a therapeutic wound healing composition comprising the following steps: (A) (a) Pyruvate, a pharmaceutically acceptable salt of pyruvate, and mixtures thereof. Pyruvates selected from the group; (b) antioxidants; and (c) a mixture of saturated and unsaturated fatty acids, provided that the fatty acids are required for repair of mammalian cell membranes and resuscitation of mammalian cells. A wound healing composition comprising the above-mentioned therapeutic agents (a) to (c), (B) a medicinal agent useful for treating a wound, and (C) step. It consists of simultaneously contacting a wound healing composition from (A) and a medicament useful in the treatment of wounds from step (B) with the wound.

The types of wounds to be healed using the wound healing composition of the present invention and the wound healing composition having enhanced effects are caused by an injury that causes damage to the epidermis such as an incision, and the skin is ruptured by a cutting instrument. Wounds and lacerations in which the skin is broken by a blunt blade or blunt instrument. Therapeutic compositions also include hyperkeratosis, photoaging, burns, wounds on the skin donor side due to skin grafts, ulcers (due to pressure sores on the skin, venous circulation disorders, diabetes, etc.), psoriasis, skin rashes. , And also to treat various dermatological conditions such as photoreactive sunburn. Topically applied therapeutic compositions are also in the form of mouthwashes and sprays to protect or accelerate healing of wounded tissues in the mouth such as wounds and inflammation and burns (burns). Can be used in the oral cavity. Topical therapeutic compositions may also be used for ocular ulcers (swelling), radial keratoses, corneal transplants, post-operative corneal keratosis, and other surgically-induced ocular lesions. It can be used in ophthalmic preparations for treating wounds. Topical therapeutic compositions are also used in anal creams and suppositories to treat pruritus, hemorrhoids, split hemorrhoids, and hemorrhoids. In a preferred embodiment, the therapeutic composition is used to treat wounds such as incisions and lacerations.

A method of healing a wound comprises topically administering the composition of the invention directly to the site of the wound in order to increase the rate of wound healing. The composition is kept in contact with the wound for a time sufficient to increase the proliferation and recovery rate of the cells.

Once prepared, the therapeutic wound healing composition of the present invention and the enhanced efficacy wound healing composition may be stored for future use or prepared into a wide variety of pharmaceutical compositions to prepare pharmaceutical compositions. Formulated with an effective amount of a pharmaceutically acceptable carrier and a topical vehicle (non-oral and oral) used in.

Examples of therapeutic devices include sutures, staples, gauze, burn dressings, artificial skin, liposomes or micelle formulations, microcapsules, aqueous vehicles for dipping gauze dressings, and the like. It is a mixture. Non-oral topical compositions use non-oral topical vehicles such as oils, petrolatum bases, emulsions, lotions, creams, gel formulations, foams, ointments, sprays, salves, films. However, these are intended to be applied to the skin or body cavities, not to be placed in the mouth. The topical composition for the oral cavity is
Oral vehicles such as mouth rinses (gargles), rinses, mouth sprays, suspensions, bioadhesives, and dental gels are used, which are intended to be applied to the oral cavity. Do not ingest.

Bioadhesives are substances that adhere to live or just dead mucous membranes or skin tissue. Bioadhesives are generally fibrous, cross-linked materials that are water-swellable, but insoluble in water. Bioadhesives generally consist of mucoadhesives (muco means mucus), such as polyacrylic acid, which are cross-linked by polyhydroxy compounds such as carbohydrates (sugars, cyclitols) to form virtually water-insoluble hydrogels. . Other adhesives include Carboxymethyl Cellulose (CMC) and BF in Cleveland, Ohio.
There are polycarbophils, which are high molecular weight polymers of acrylic acid such as Carbopol ™ sold by Goodrich Company. Bioadhesives are described, for example, in European Patent Application Publication No. 041 by Kellaway et al.
0696A1, and U.S. Pat. No. 4, issued to Robinson,
It is discussed in more detail in 615,697. These patents are incorporated herein by reference.

In one form of the invention, a therapeutic wound healing composition is a suture, staple, gauze, bandage, burn wound bandage, artificial skin, liposome or micelle formulation, microcapsule, gauze bandage. Is incorporated into a medical device in the form of an aqueous vehicle or the like for dipping, and mixtures thereof. Traditionally used traditional pharmaceutical ingredients such as buffers, preservatives, tonicity (muscle and tissue) regulators, antioxidants, viscosity modifiers or as bulking agents (or extenders) An effective amount of a polymer, a bioadhesive, and a (medicinal) excipient or binder, etc., can be optionally included in the medicinal composition. Examples of such traditional specialty ingredients are acetate and borate buffers; thimerosal (serum and antiseptic), sorbic acid, methyl and propyl paraben and chlorobutanol preservatives; body tonicity. Modulating sodium chloride and sugar; carboxymethyl cellulose (CMC), C
Bioadhesive agents such as arbopol and polycarbophil; mannitol, lactose, sucrose (or sucrose, sucrose) and the like.

According to the invention, a therapeutically effective amount of the wound healing composition of the invention is used in a pharmaceutical product. These amounts can be readily determined by one skilled in the art without the need for undue experimentation. The exact amount of therapeutic composition used will depend on the type and concentration of therapeutic composition,
And determined depending on factors such as the type of pharmacy article used. Thus, the amount of therapeutic composition will vary to obtain the desired result in the final product, but such variations are within the ability of one skilled in the art without the need for undue experimentation. It is inside. In a preferred embodiment, the pharmaceutical composition comprises the therapeutic agent composition in an amount ranging from about 0.1% to about 10% thereof, based on the total weight of the pharmaceutical composition. In a more preferred embodiment, the pharmaceutical composition comprises the therapeutic agent composition in an amount ranging from about 0.1% to about 8% by total weight of the pharmaceutical composition. In the most preferred embodiment, the pharmaceutical composition comprises about 0.1% by weight of the pharmaceutical composition.
To about 5% of the therapeutic composition.

The scope of the present invention extends to methods of making pharmaceutical compositions. In general, the pharmaceutical composition is made by contacting a therapeutically effective amount of the wound healing composition with the pharmaceutical product and the other ingredients of the final desired pharmaceutical composition.
The therapeutic composition can be in a solvent or absorbed on a pharmaceutical article.

The other ingredients will normally be incorporated into the wound healing composition in proportions as dictated by the desired composition properties, as is well known to those having ordinary skill in the art. The final pharmaceutical composition is readily prepared using methods commonly known in the art of pharmacy.

In another form of the invention, a therapeutic wound healing composition comprises an oil,
Petrolatum base, emulsion, lotion, cream,
It is incorporated into non-oral topical vehicles in the form of gel formulations, foams, ointments, sprays, salves, films and the like. Non-toxic, non-oral topical vehicles well known in the pharmaceutical arts are used.

Preferred non-oral topical vehicles are occlusive vehicles that minimize the amount of water lost from the wound through the epidermis to the exterior. Minimizing the amount of water lost through the epidermis promotes wound healing and reduces scarring. A preferred non-oral topical vehicle is a petrolatum / mineral oil based product. Shark liver oil and cod liver oil can also be incorporated to act as protective agents to smooth and soften the tissue and minimize the amount of water lost through the epidermis. Vitamin E is also incorporated into the composition to reduce scarring. Other non-oral topical vehicles such as emulsions and hydrogels can also be used, provided that the vehicle minimizes water loss through the epidermis. Other non-oral topical vehicles include water and pharmaceutically acceptable water-miscible organic solvents such as ethyl alcohol, isopropyl alcohol, propylene glycol, glycerin, and the like, and mixtures thereof.

Non-oral therapeutic compositions may also include conventional additives used in such products.
Conventional additives include humectants, emollients, lubricants, stabilizers, dyes, and perfumes, provided such additives do not interfere with the therapeutic properties of the therapeutic composition.

Suitable humectants useful in non-oral topical therapeutic compositions include glycerin, propylene glycol, polyethylene glycol, sorbitan, fructose,
And mixtures thereof. If used, the humectant is present in an amount of about 10% to about 20% by weight of the topical therapeutic composition.

Colorants (dyes, colorants) useful in non-oral therapeutic compositions are used in an amount effective to produce the desired color. These colorants include pigments (pigments, pigments) incorporated up to about 6% of the total weight of the non-oral topical therapeutic composition. A preferred pigment, titanium dioxide, is included in an amount of up to about 2%, preferably up to about 1%, based on the weight of the non-oral topical therapeutic composition. Coloring agents also include natural food pigments and dyes suitable for food, pharmaceutical and cosmetic applications.
These colorants are known as FD & C. dyes and organic pigments. The substances acceptable for the above-mentioned uses are preferably water-soluble. A non-limiting example is FD &C.'s Blue
There is an indigoid dye known as No.2, which is
It is the disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dye known as FD &C.'s Green No. 1 consists of a triphenylmethane dye, which is 4- [4- (N
-Ethyl) -p-sulfoniumbenzylamino) diphenylmethylene]-[1- (N-ethyl-N-p-sulfoniumbenzyl) -δ-2,5-cyclohexadieneimine] monosodium salt. A complete listing of all FD & C. colorants and their corresponding chemical structural formulas is given in Kirk-Ot.
Seen on pages 857-884 of hmer's Encyclopedia of Chemical Technology, 3rd edition, 5th volume. This text is incorporated herein by reference.

According to the present invention, a therapeutically effective amount of the wound healing composition of the present invention is admixed with a non-oral topical vehicle to form a topical therapeutic composition. These amounts are easily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the non-oral topical therapeutic composition comprises from about 0.1% to about 10% thereof, based on the weight of the non-oral therapeutic agent composition, and the non-oral topical vehicle is of the composition. Consists of enough to bring the total to 100%. In a more preferred embodiment, the non-oral topical therapeutic composition comprises from about 0.1% to about 10% thereof, based on the total weight of the non-oral therapeutic composition, and in the most preferred embodiment The non-oral topical therapeutic agent composition comprises from about 0.1% to about 8% thereof, and the non-oral topical vehicle composition comprises 100% of the total composition.

The scope of the present invention is further extended to methods of preparing non-oral topical therapeutic composition. In such a method, a non-oral topical therapeutic composition is prepared by admixing a therapeutically effective amount of the wound healing composition of the invention with a non-oral topical vehicle. The final composition is readily prepared using standard methods and equipment generally known to those of ordinary skill in the pharmaceutical arts. The devices useful in accordance with the present invention comprise mixing devices well known in the art of pharmaceutics, and the choice of a particular device will be obvious to the skilled worker.

In another form of the invention, the wound healing composition is a topical vehicle for the oral cavity, such as a mouthwash (gargle), rinse (mouth rinse), mouth spray, suspension, dental gel, bioadhesive and the like. Is blended with. Typical non-toxic oral vehicles known in the pharmaceutical art are used in the present invention. The preferred oral vehicle is water, ethanol, and a mixture of water-ethanol. The water-ethanol mixture is generally about 1: 1 to about 20: 1, preferably about 3: 1 to about.
Used in a weight ratio of 20: 1, and most preferably about 3: 1 to about 10: 1. Oral vehicles generally have a pH of about 4
To about 7, preferably about 5 to about 6.5. Oral vehicles with pH values below about 4 generally irritate the oral cavity,
Oral vehicles with pH values above about 7 generally give the mouth an unpleasant sensation.

The buccal topical therapeutic composition may also include conventional additives commonly used in such products. Conventional additives include compounds which provide fluorine, sweeteners, flavors, colorants, humectants, buffers and emulsifiers, provided such additives do not interfere with the therapeutic properties of the therapeutic composition. including.

The amounts of colorants and humectants described above useful in non-oral topical therapeutic compositions, and these additives, are also used in oral topical therapeutic compositions.

Fluorine donating compounds are wholly or slightly water-soluble and are characterized by their ability to release fluoride ions or fluoride-containing ions in water and their inability to react with other components in the composition. Typical fluorine donating compounds are inorganic fluoride salts such as water soluble alkali metal salts, alkaline earth metal salts, and heavy metal salts such as sodium fluoride,
Potassium fluoride, ammonium fluoride, cuprous fluoride, zinc fluoride, stannic fluoride, stannous fluoride, barium fluoride, sodium fluorosilicate, ammonium fluorosilicate, sodium fluorozirconate, monofluorophosphoric acid sodium,
Aluminum monofluorophosphate, aluminum difluorophosphate and sodium fluorinated calcium pyrophosphate. Alkali metal fluorides, tin fluoride and monofluorophosphates, such as sodium fluoride and stannous fluoride, sodium monofluorophosphate, and mixtures thereof are preferred.

The amount of fluorine-donor compound in the oral topical therapeutic composition of the present invention depends on the type of fluorine-donating compound used, the solubility of the fluorine compound, and the nature of the final oral therapeutic composition. The amount of fluorine donating compound used should be non-toxic. Fluorine donating compounds, when used in general, are up to about 1%, preferably from about 0.001% to about 0.1%, most preferably from about 0.001% by weight of the topical therapeutic composition for the oral cavity. It will be present in an amount of about 0.05%.

When using sweeteners (sweeteners), sweeteners well known in the art are used, including both natural and artificial sweeteners. The sweetener used is selected from a wide range of substances including water-soluble sweeteners, water-soluble artificial sweeteners. Water-soluble sweeteners are derived from naturally occurring water-soluble sweeteners, dipeptide-based sweeteners, protein-based sweeteners, and mixtures thereof. Representative categories and examples include, but are not limited to, specific sweeteners: (a) Water-soluble sweeteners such as monosaccharides, disaccharides and polysaccharides, such as xylose, ribose, glucose (dextrose), mannose, Galactose, fructose (Lebrose), sucrose (sucrose), maltose,
Invert sugar (a mixture of fructose and glucose derived from sucrose), partially hydrolyzed starch, corn syrup solids, dihydrochalcone, monerin, stevioside, glycyridine, and mixtures thereof; (b) water-soluble artificial sweeteners. , For example, soluble saccharin salts, ie sodium or calcium salts of saccharinic acid, cyclamate, 3,4-dihydro-6-methyl-
1,2,3-oxathiazin-4-one-2,2-dioxide sodium salt, ammonium salt or calcium salt, 3,4
-Dihydro-6-methyl-1,2,3-oxathiazine-4
-On-2,2-dioxide potassium salt (acesulfame K), the free acid form of saccharin, etc .; (c) dipeptide-based sweeteners, such as the sweeteners of L-aspartic acid derivatives, eg, Methyl ester of L-aspartyl-L-phenylalanine (aspartame) and materials as described in US Pat. No. 3,492,131. L-α-aspartyl-N- (2,2,4,4-tetramethyl-3-thietanyl) -D-alanine-amide hydrate (Alitame), L-aspartyl-L-2,5-dihydrophenyl- Glycine, L-aspartyl-2,5-dihydro-L-phenylalanine, L-aspartyl-L
-(1-Cyclohexene) -alanine and the like; (d) Water-soluble sweeteners derived from naturally occurring water-soluble sweeteners such as chlorinated derivatives of common sugar (sucrose), for example, chlorodeoxysucrose or chlorodeoxy. A chlorodeoxy sugar derivative such as a derivative of galactosucrose (eg known by the Sucralose product number);
And (e) thaumaccous daniell
i) Protein-based sweeteners such as (Taumatins I and II).

There is.

Generally, an effective amount of a sweetener is utilized to provide the level of sweetness desired in a particular oral topical therapeutic composition, which amount depends on the type of sweetener selected and the final sweetener. It will vary depending on the desired oral therapeutic product. Generally, the amount of sweetener will range from about 0.0025% to about 90% by weight of the oral topical therapeutic composition, depending on the type of sweetener used.
Is in the range. The exact amount of each type of sweetener is well known in the art and is not the subject of this invention.

Flavoring agents used (flavors and seasonings) include those well known to the skilled artisan, such as natural and artificial flavoring agents. Suitable flavoring agents include peppermint and other peppermint (light load), orange and lemon-like citrus flavors,
There are artificial vanilla, cinnamon (cinnamon, cinnamon), various fruit flavors (single or mixed), etc.

The amount of the topical therapeutic composition for the oral cavity is usually a matter of preference, which varies depending on factors such as the type of final oral therapeutic agent composition, the type of flavoring agent used, the desired flavor intensity and the like. is there. Thus, the amount of flavoring agent will vary to obtain the desired result in the final product, but such variation will be within the ability of a person of ordinary skill in the art to determine without undue experimentation. It is inside. When used, the amount of flavoring agent is in the range of about 0.05% to about 6% by weight of the oral topical therapeutic composition.

Suitable buffer solutions useful in buccal topical therapeutic compositions include citric acid-sodium citrate solutions, phosphoric acid-sodium phosphate solutions, acetic acid-sodium acetate solutions, which are topical therapeutics for the oral cavity. It is used in an amount of up to about 1% by weight of the pharmaceutical composition, preferably about 0.05% to about 0.5%.

According to the present invention, a therapeutically effective amount of the wound healing composition of the present invention is admixed with a topical vehicle for the oral cavity to form a topical therapeutic composition. These amounts can be readily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the oral topical therapeutic composition comprises an amount of about 0.1% to about 10% of the therapeutic agent composition, based on the weight of the oral topical therapeutic composition, and 100% total. Consisting of an amount of topical vehicle for the oral cavity such that In a more preferred embodiment, the oral therapeutic composition comprises from about 0.1% to about 10%, and in the most preferred embodiment, from about 0.1% to about 8%, by weight of the oral topical therapeutic composition. 100% of the therapeutic composition and the whole composition
Consisting of a topical vehicle for the oral cavity in an amount such that

The scope of the present invention extends to a method of preparing a topical therapeutic composition for the oral cavity. In such methods, a buccal topical therapeutic composition is prepared by admixing a therapeutically effective amount of a therapeutic composition of the present invention with a buccal topical vehicle. The final composition is readily prepared using standard methods and equipment generally known to those skilled in the art of pharmacy. The devices useful in accordance with the present invention comprise mixing devices well known in the art of pharmaceutics, and the choice of a particular device will be obvious to the skilled worker.

In a preferred embodiment, the oral topical therapeutic composition is made by first dissolving the colorant, sweetener, and similar additives in water. The therapeutic composition is then mixed with the aqueous solution. Sufficient water or a mixture of water and ethanol is added to the solution with stirring until the final solution volume is reached. In a more preferred embodiment, the therapeutic composition is added to the solution as the final ingredient. The final oral topical therapeutic composition is readily prepared using methods well known in the art of pharmaceutics.

The oral therapeutic composition may also be in the form of a dental gel. The term "gel" as used herein means a solid or semi-solid colloid containing a substantial amount of water. The colloidal particles in the gel state are bound in a coherent mesh that passivates the water contained within the coherent (coherent) mesh.

The dental gel composition of the present invention is a conventional additive as described above for the topical therapeutic composition for the oral cavity, for example, mouthwash (gargle), rinse (rinse solution), mouthwash. Sprays and suspensions may also be included, further provided that the additional additives do not interfere with the therapeutic properties of the therapeutic composition.
An abrasive polishing agent, a desensitizing agent (or desensitizing agent) and the like can also be included.

In dental gel compositions, the oral vehicle is generally water, the amount of which is from about 10% to about 90% thereof, based on the weight of the dental gel composition. Polyethylene glycol, polypropylene glycol, glycerin, and mixtures thereof also serve as wetting agents or binders (binders, binders) from about 18% to about 18% by total weight of the dental gel composition.
It can also be present in the vehicle at a rate of 30%. A particularly preferred oral vehicle consists of a mixture of water and polyethylene glycol or water, glycerin and polypropylene glycol.

The dental gel of the present invention comprises a gelling agent (thickener) such as a naturally occurring or synthetic gum or gelatin. Gelling agents such as hydroxyethyl cellulose, methyl cellulose, glycerin, carboxypolymethylene, gelatin and the like, and mixtures thereof are used. Carboxymethyl cellulose (CMC), Carbopol ™, and polycarbophil are also used. The preferred gelling agent is hydroxyethyl cellulose. The gelling agent is about 0.5% to about 5% of the weight of the dental gel composition,
Preferably, it is used in an amount of about 0.5% to about 2%.

The dental gel composition of the present invention may also include a polish. Among the transparent gels, colloidal silica and / or alkali metal aluminosilicate complexes are preferred. Because these materials have an index of refraction close to that of gelling systems commonly used in dental gels. In non-transparent gels, calcium carbonate or calcium dihydrate is used. These polishes are used in amounts of up to about 75%, preferably up to about 50%, based on the weight of the dental gel composition.

Dental gels may also include desensitizing agents such as a combination of citric acid and sodium citrate.
Citric acid, based on the weight of the dental gel composition,
From about 0.1% to about 3%, preferably from about 0.2% to about 1
% Sodium citrate is used in an amount of about 0.3% to about 9%, preferably about 0.6% to about 3%.

According to the present invention, a therapeutically effective amount of the wound healing composition of the present invention is incorporated into the dental gel composition. These amounts are easily determined by those skilled in the art without the need for undue experimentation. In a preferred embodiment, the dental gel composition comprises the therapeutic agent composition in an amount of about 0.1% to about 10% and an oral topical vehicle in an amount to provide 100% of the total composition. In a more preferred embodiment, the dental gel composition comprises the therapeutic agent composition in an amount of about 0.1% to about 5% thereof, based on the weight of the dental gel composition, and in the most preferred embodiment, the dental composition. A gel composition for use comprises from about 0.1% to about 2% of the therapeutic composition and 100% total topical vehicle for the oral cavity.

The scope of the present invention extends to a method of preparing a dental gel composition of a therapeutic agent. In such methods, a dental gel composition is prepared by admixing a therapeutically effective amount of a therapeutic agent composition of the present invention with a topical vehicle for the oral cavity. The final composition is readily prepared using methods generally known to those skilled in the dentistry and pharmaceutical arts.
The devices useful in accordance with the present invention comprise mixing devices well known to the pharmaceutical art, and thus the choice of a particular device will be obvious to the skilled artisan.

In a preferred embodiment, a therapeutic dental gel composition comprises first dissolving a gelling agent in a wetting agent or water, or a mixture of both, and then dispersing an aqueous solution of a fluorine donating compound, a sweetener, etc. It is prepared by admixing with the liquor, then adding the polish and finally admixing the flavoring agent and the therapeutic agent composition.
The final gel mixture is then packaged in tubes or otherwise packaged. The liquid and solids in the gel product are compounded in such proportions as to form a creamy or gelled mass that can be extruded from a pressurized container or collapsible tube (a finger collapsible tube). The final therapeutic composition is readily prepared using methods generally known in the pharmaceutical arts.

In a particular embodiment, the present invention is directed to a pharmaceutical composition for wound healing comprising a therapeutically effective amount of a wound healing composition comprising a pharmaceutically acceptable carrier and the following components: (a) Pyruvine An acid, a pharmaceutically acceptable salt of pyruvic acid, and a pyruvic acid selected from the group consisting of a mixture thereof; (b) an antioxidant; and (c) a mixture of a saturated fatty acid and an unsaturated fatty acid, provided that the fatty acid is A fatty acid as required for repair of mammalian cell membrane and resuscitation of mammalian cells; A pharmaceutical composition for wound healing comprising the above components (a) to (c).

Pharmaceutically acceptable carriers can be selected from the group consisting of pharmaceutical products and topical vehicles. Preferably, the topical vehicle is an absorbable / adsorbable vehicle.

In another particular embodiment, the invention is directed to a method of preparing a pharmaceutical composition for increasing the growth rate and resuscitation rate of mammalian cells. It comprises the following steps: (A) (a) pyruvic acid, a pyruvic acid selected from the group consisting of pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) antioxidants; and (c) ) A mixture of saturated fatty acids and unsaturated fatty acids, provided that the fatty acids in this case are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; Providing a therapeutically effective amount of a wound healing composition comprising (c); (B) providing a pharmaceutically acceptable carrier; and (C) a wound healing composition from step (A) in step (B). A) and a pharmaceutically acceptable carrier from A) to form a pharmaceutical composition.

Throughout this application, various publications (patents,
I've been quoting books). The disclosures of these publications are hereby incorporated herein by reference for a more complete explanation of the inventive technology.

The present invention will be more specifically described by the following examples, but these examples are not intended to limit the effective scope of the claims. All parts used in the examples, throughout the specification and the claims
s) and percentages are by weight unless otherwise stated.

Examples 1-5 These examples compare the wound healing ability of the therapeutic wound healing compositions of the present invention to conventional conventional wound healing compositions.

The wound healing compositions of Examples AD were prepared to have the compositions shown in Table 1.

Wound healing composition A is commercially available as Preparation H. Wound healing composition B is a formulation and formulation based on live yeast cells, shark oil, and petrolatum containing a mixture of sodium pyruvate, vitamin E, and chicken fat. Wound healing composition C is a petrolatum-based formulation / compound containing a cell derivative of live yeast and shark oil. Wound healing composition D is a petrolatum-based only formulation. Wound healing studies were performed using hairless mice (SKR-1, Charles River) 6-8 weeks old. One group of mice, which received no treatment as a control group, was called Example E. There were 6 mice in each group for evaluation 3 and 7 days after treatment. The total number of animals used in the study was 60.
Mice were anesthetized with ether, and a longitudinal incision with a depth of 3 cm was made in the midline using a surgical No. 10 scalpel. The wounds of the incision were closed with steel clips at 1 cm intervals. Formulations AD above were applied to wounds in a randomized, blinded study, 2 hours after the day of injury and reapplied at 24 hour intervals for 7 days of the study. Wounds were inspected daily and a 6-point scale of 0-5 was provided for wound closure each day of the study. A rating of 5 indicates that the wound was best healed.

Mice were sacrificed using cervical dislocation on days 3 and 7 (neck twist was killed). The skin on the back, including the incision, was dissected, leaving subcutaneous tissue, and examined closely. The skin was placed in a neutral buffer solution, after which microscopic sectioned tissue was excised and stained with hematoxylin and eosin.
The wounds were examined microscopically and representative tissue sections were photographed.

On each day of the experiment, the score and rank order of wound closure and healing rate were recorded. The results were as follows.

B (5) >> D (4) >> C (2) >> / = E, Control (2)> A (1) Cell derivative of live yeast, shark oil according to injured mouse on day 4 , And sodium pyruvate, vitamin E,
Formula B, a petrolatum-based formulation containing a mixture of chicken fat, was a significantly better wound healing agent than the other formulations. These results show that, in addition to the subjective ranking of wound closure and healing rate (daily 1 to 7 days of the experiment), the extent of infiltration of inflamed cells into the wound and the edge of the wound. It is also supported by an objective history test to measure the extent of regeneration of the epithelial cells of the epithelium. The final result was that mice treated with Formulation B had less scar tissue at day 7.

Formulation D, which is a white petrolatum formulation only, is better than either Formula C, which is based on petrolatum containing shark liver oil and a derivative of live enzyme cells, or Formulation H, Formulation A. Was also determined to be significantly effective in promoting healing. Formulation D had a better ability to improve wound healing than Formulation C when derivation of live yeast cell derivatives caused the cells to shift to another nutrient source. It is likely due to the time delay of the healing process. The presence of a mixture of sodium pyruvate, vitamin E, and chicken fat in Formulation B had a clear effect of compensating for the depletion of the live yeast cell derivative. Because of that.

Formula C, a petrolatum-based formulation containing a derivative of live yeast cells and shark oil, is approximately equivalent to control (untreated wound) in wound closure rate and degree of healing. Was determined. Prepar
Formulation A, an ation H, appeared to be the least effective wound healing composition, both from a subjective rating of wound healing and an objective examination of tissues. Formulas D and C outperformed Formula A better in healing, perhaps due to the occlusive wound bandage preventing water loss through the epidermis,
It may be because it promoted healing of wound and closure of wound. The poor ability of Formulation A to improve healing was probably due to the potential cytotoxicity of phenylmercuric nitrate present in Preparation H as a preservative.

These results indicate that the wound healing composition of the present invention consisting of a mixture of sodium pyruvate, vitamin E, and chicken fat increases the proliferation rate and recovery rate (or resuscitation rate) of mammalian cells. Shows. The wound healing composition of the present invention mediates low oxygen levels in the first stage of healing to suppress oxidative damage and high oxygen levels in later stages of healing to promote collagen formation.

Having described the invention, it will be apparent that the same invention can be varied in many ways. Such changes should not be considered as departing from the spirit and scope of the invention, and all such modifications should be included within the scope of the following [Claims]. Is intended.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61K 31/375 A61K 31/375 A61P 17/00 A61P 17/00 (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/19 A61K 31/015 A61K 31/07 A61K 31/20 A61K 31/355 A61K 31/375 A61P 17/00 CA (STN) REGISTRY (STN) MEDLINE (STN) BIOSIS (STN) EMBASE (STN)

Claims (23)

(57) [Claims] 1. A pyruvic acid selected from the group consisting of (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a mixture thereof; (b) an antioxidant; A mixture of saturated fatty acids, provided that the fatty acids are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; therapeutic wounds comprising (a)-(c) above. Healing composition. 2. The composition according to claim 1, wherein the mammalian cells are epidermal keratinocytes. 3. The pyruvates are selected from the group consisting of pyruvate, sodium pyruvate, potassium pyruvate, magnesium pyruvate, calcium pyruvate, zinc pyruvate, manganese pyruvate, and mixtures thereof. The composition according to item 1. 4. The composition according to claim 3, wherein the pyruvic acid is sodium pyruvate. 5. The antioxidant is retinol, 3,4-didehydroretinol, α-carotene, β-carotene, γ-carotene, δ-carotene, ascorbic acid, α-tocopherol, β-tocopherol, γ-tocopherol. , Δ−
The composition of claim 1 selected from the group consisting of tocopherols and mixtures thereof. 6. The composition according to claim 5, wherein the antioxidant is α-tocopherol. 7. The composition according to claim 1, wherein the mixture of saturated fatty acids and unsaturated fatty acids includes animal fats, vegetable fats and waxes. 8. A mixture of saturated and unsaturated fatty acids including human fat, chicken fat, beef fat, sheep fat, horse fat, pork fat and whale fat. 7. The composition according to item 7. 9. A mixture of saturated fatty acids and unsaturated fatty acids, wherein lauric acid, myristic acid, myristolic acid, pentadecanoic acid, palmitic acid, palmitolic acid, margaric acid,
The composition of claim 8 including margallol acid, stearic acid, oleic acid, linoleic acid, linolenic acid, arachidic acid, and gadrenic acid. 10. The composition according to claim 1, wherein the pyruvic acid is present in the therapeutic agent composition in an amount of 10% to 50% thereof, based on the weight of the therapeutic agent composition. 11. The composition of claim 1 wherein the antioxidant is present in the therapeutic agent composition in an amount of 10% to 50% thereof, based on the weight of the therapeutic agent composition. 12. The composition of claim 1 wherein the mixture of saturated fatty acids and unsaturated fatty acids is present in the therapeutic agent composition in an amount of 10% to 50% thereof, based on the weight of the therapeutic agent composition. object. 13. The following components: (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a pyruvic acid selected from the group consisting of a mixture thereof; (b) an antioxidant; and (c). A mixture of saturated and unsaturated fatty acids, provided that the fatty acids are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; A method of preparing the composition. 14. A pyruvic acid selected from the group consisting of (A) (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a mixture thereof; (b) an antioxidant; and (c) a saturation. Mixtures of fatty acids and unsaturated fatty acids, provided that the fatty acids are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; Treatment comprising (a)-(c) above A wound healing composition comprising a drug; (B) a medicament useful for treating a wound; and a wound healing composition having an enhanced effect, which comprises the above (A) and (B). 15. A medicine useful for treating wounds is an anti-inflammatory agent, respiratory burst inhibitor, inhibitor of prostaglandin synthesis, antibacterial agent, antimicrobial agent (antibiotic), antiseptic agent, anesthetic agent, Cell nutrient media, burn preventives, sunscreens, acne relief preparations, insect bite and sting wound medicines, wound cleansers, wound dressings, scar reducers, immunity The wound healing composition with enhanced effect according to claim 14, which is selected from the group consisting of a stimulant and a mixture thereof. 16. A pyruvic acid selected from the group consisting of (A) (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a mixture thereof; (b) an antioxidant; and (c) a saturation. Mixtures of fatty acids and unsaturated fatty acids, provided that the fatty acids are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; Treatment comprising (a)-(c) above A wound healing composition for use in: (B) providing a medicament useful in treating wounds; and (C) a wound healing composition from step (A) useful in treating wounds from step (B) A method for preparing a wound healing composition having an enhanced effect, which comprises the steps (A) to (C) described above. 17. A pyruvic acid selected from the group consisting of (a) pyruvic acid, a pharmaceutically acceptable salt of pyruvic acid, and a mixture thereof; (b) an antioxidant; Mixtures of saturated fatty acids, provided that the fatty acids are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; Wound healing composition comprising (a)-(c) above A medicinal composition for wound healing, comprising a therapeutically effective amount of: and a pharmaceutically acceptable carrier. 18. A pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable carrier is a pharmaceutical product. 19. The pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable carrier is a bioadhesive. 20. The pharmaceutical composition according to claim 17, wherein the pharmaceutically acceptable carrier is a vehicle for topical application. 21. The pharmaceutical composition according to claim 20, wherein the vehicle for topical application is an absorptive or adsorptive vehicle. 22. The pharmaceutical composition according to claim 17, wherein the wound healing composition is present in the pharmaceutical composition in an amount of 0.1% to 10% thereof, based on the weight of the pharmaceutical composition. 23. Pyruvates selected from the group consisting of (A) (a) pyruvic acid, pharmaceutically acceptable salts of pyruvic acid, and mixtures thereof; (b) antioxidant; and (c) saturated. Mixtures of fatty acids and unsaturated fatty acids, provided that the fatty acids are those required for repair of mammalian cell membranes and resuscitation of mammalian cells; wounds comprising (a)-(c) above Providing a therapeutically effective amount of the healing composition; (B) providing a pharmaceutically acceptable carrier; and (C) the wound healing composition from step (A) and the medicament from step (B). An acceptable carrier is mixed to form a pharmaceutical composition; A method for preparing a pharmaceutical composition for wound healing, comprising the steps (A) to (C) above.