JP2005518381A - Treatment of peripheral nerve and vascular disease - Google Patents

Abstract

【Task】
A composition and method for treating peripheral nerve / vascular disease are disclosed. The method comprises the step of administering a composition comprising a therapeutically effective amount of a flavonoid having an antioxidant effect, and optionally an acceptable carrier. This composition or mixture of ingredients provides significant and effective healing with respect to peripheral nerve / vascular disease. In addition, this composition, when used in accordance with the methods of the present invention, does not exhibit serious side effects like many prior art compositions that have been proposed to treat such diseases.

Description

  The present invention relates to compositions and methods for the treatment of diseases of peripheral nerves and peripheral blood vessels. According to the method of the present invention, flavonoids are administered to patients suffering from peripheral nerve or peripheral vascular disease.

  The terms “peripheral nerve disease” and “small fiber neuropathy” are used interchangeably herein and refer to functional or pathological changes in the peripheral nerve system, small diameter, unmyelinated nerve fibers. Used for the purpose of indicating a series of states to be characterized. For the purposes of this application, diabetic neuropathy is not included in peripheral small fiber neuropathy.

  Peripheral or small fiber neuropathy is caused by any of the approximately 100 identified factors that cause nerve damage. The cause is metabolic, such as hypertriglyceridemia or pellagra. Toxic substance exposure is also a small fiber neuropathy, for example, they are alcoholic, excessive vitamin 136, exposure to toxic metals such as thallium or exposure to certain chemotherapeutic agents (eg vinca alkaloids). Is caused by. It is known that certain congenital conditions, including amyloidosis, (tangier) α-lipoproteinemia and (fabry) agalactosidase, cause small fiber neuropathy. Small fiber neurological diseases include infections such as leprosy, AIDS, herpes simplex, herpes zoster (herpes zoster), cell spreading virus, hepatitis B and C, Lyme disease, autoimmune disease, Fabry disease, diphtheria, Caused by diseases such as vasculitis and porphyria. In nearly 15% of cases, the cause of small fiber neuropathy cannot be determined. In that case, the cause of the neurological disorder is unknown.

  Patients suffering from peripheral nerve disease have pain in their limbs. Pain can initially be perceived as a tingling sensation in the finger or toe. Reduced sensitivity to heat or cold is also generally an early sign. However, screening often shows that the patient's reflexes, forces, sensory levels, and electrophysiology are normal. This has historically complicated the diagnosis of peripheral neuropathy, or has led to undiagnosed diagnosis, especially in early neurological disorders. Recent techniques, however, have improved the probability of detecting peripheral neurological diseases, such as skin biopsy and measurement of the density of different nerve fiber types in the epidermis.

  Fibrils or peripheral nerve diseases tend to progress by spreading upward, and patients develop severe pain and / or a burning sensation that is severe enough to be debilitating. Other signs of these neurological disorders are cold hands or feet, convulsions, muscle weakness and / or atrophy, eventual loss of pressure, pain and / or temperature perception, neuropathic ulcers, lack of sweating, dryness Includes eye, dry mouth, impotence, and foot restless syndrome.

  In some cases, treatment of the underlying cause can also reverse or reduce small fiber neuropathy. When the underlying cause cannot be identified, while incapable of treatment, however, therapy consists of reducing symptoms of neuropathy, which is typically known to reduce pain from neuropathy and related conditions. By prescribing the drugs that are being used. These medications include tricyclic antidepressants, anticonvulsants, opioid medications, local anesthetics applied to painful areas. Suffered patients also experience physical and occupational therapy to improve motility and function.

  Often, the symptoms of peripheral nerve disease are not different because of their underlying causes. For example, neuropathies caused by exposure to chemotherapeutic agents show the same symptoms as those neuropathies caused by Lyme disease. As a further example, diabetic neuropathy is a fairly common long-term complication of diabetes mellitus that shares many of the symptoms of peripheral neuropathy. However, the cause of diabetic neuropathy is thought to be a chronic excess of the glucose metabolite sorbitol throughout the body. Furthermore, treatment of the underlying cause of diabetic neuropathy, i.e. improving glycemic control, often prevents the symptoms from getting worse. It is known that diabetic neuropathy can also be reversed if good glycemic control is achieved while the condition is in its early stages.

Peripheral neuropathy, including diabetic neuropathy, also weakens circulation in the affected area. Impaired circulation can adversely affect the appearance of the skin. Negative effects on the appearance of the skin caused by radiation injury include, for example, redness, discoloration, and dryness of the skin.

  A “peripheral vascular disease” is a disease of the blood vessels outside the heart that leads to blood vessel restriction or blockage. Atherosclerosis is an example of peripheral vascular disease when it affects the limb rather than the coronary artery. Peripheral vascular disease is also a long-term complication of other diseases such as lectin stimulation, Raynaud's phenomenon, hypertension or Burger's disease (Thromboangitis obliterans).

  Early symptoms of peripheral vascular disease, including pain, include pain from exercise that is healed by rest. These diseases, however, are progressive and patients may also become numbness, muscle weakness or pain, loss of hair on the affected limbs, cyanosis, pulse of affected limbs will be weakened or lost Experience gait abnormalities, pain at rest, skin ulcers, and consequent gangrene. Impaired circulation caused by peripheral vascular disease can also adversely affect the appearance of the skin. Negative effects on the appearance of the skin caused by radiation injury include, for example, redness, discoloration, and dryness of the skin.

  In general, agents that promote or induce angiogenesis, or agents that clear at least partially blocked or restricted vessels, or other means, i.e., by causing cell adhesion, Agents that facilitate circulation are effective in treating peripheral vascular disease.

  Reduced microcirculation is also a long-term complication of diabetes. In general, therapies that are effective for peripheral vascular disease are also effective in combating the reduced microcirculatory system caused by diabetes.

  There remains a need for the treatment of small fiber neurological diseases that are clinically effective when the cause underlying neuropathy is unknown. There also remains a need for effective treatments for small fiber neurological diseases that do not have the disadvantages of causing severe side effects.

  In addition, there remains a need for clinically effective treatments for peripheral vascular disease.

  Accordingly, it is an object of embodiments of the present invention to provide a method that is effective for the treatment of small fiber neuropathy and peripheral vascular disease.

  Another object of certain embodiments of the invention is to provide a method for peripheral vascular disease by treating a small fiber neurological disease or formulating a composition that does not cause severe patient side effects.

  Another object of certain embodiments of the present invention is to provide a composition for the treatment of peripheral nerve disease or peripheral vascular disease.

  These and other objects of the invention will become apparent from the following summary of the invention and the detailed description of the invention.

  The present invention provides a method of treating peripheral neurovascular diseases by administering a composition comprising a therapeutically effective amount of a flavonoid having antioxidant properties and a selectively acceptable carrier.

  In another embodiment, the present invention relates to a composition for treating peripheral neurovascular diseases. The composition comprises a therapeutically effective amount of a mixture of flavonoids having antioxidant properties, a therapeutically effective amount of a non-flavonoid antioxidant compound, and optionally an acceptable carrier.

  The compositions and methods of the present invention provide a pronounced and effective relief of the symptoms of peripheral neurovascular disease, and in some cases provide partial recovery of lost microcirculatory system or nerve function. Surprisingly, the effectiveness of the present invention does not depend on the underlying cause of peripheral nerve / vascular disease. In addition, the compositions used in the methods of the present invention do not cause severe side effects when administered in therapeutically effective amounts to treat peripheral neurovascular disease.

  The topical compositions and methods of the present invention also treat the adverse appearance of the skin (skin) caused by peripheral nerve disease and / or peripheral vascular disease. These aesthetic benefits are obtained in patients with this type of upset. For example, adverse effects on skin appearance include redness, discoloration, and dryness. This type of aesthetic effect relates to the skin appearance of people using the compositions and methods, but this effect is intended to be included within the meaning of “treatment of disease”. is there. Thus, the present invention treats or cosmetically improves the appearance of a person with peripheral vascular / neurological disorders, for example, reducing or preventing skin redness, skin discoloration, etc. Reduce or prevent, beautify skin, improve skin appearance, promote skin attractiveness, cleanse skin, dead or damaged skin or skin cells It is done by removing and moisturizing the skin.

  The oral compositions and methods of the present invention also provide nutritional and / or dietary benefits. These nutritional or dietary aesthetic benefits are obtained in patients with peripheral nerve disease and / or peripheral vascular disease. Such nutritional or dietary effects are also intended to be included within the meaning of “treating a disease”.

  Thus, the present invention provides dietary or nutritional benefits in supporting and / or maintaining the health of nerves, blood vessels and muscles, maintaining sensory integrity, i.e., thermal and cold sensations, and Support the maintenance of skin health.

  The term “derivative”, as used herein, exhibits a common activity (eg, an antioxidant) and includes at least one important common structural element and the compound from which it is derived, Means structurally similar compounds in which the structural elements provide a common activity.

  As used herein, the expression “therapeutically effective amount” refers to a non-toxic amount of a compound that is sufficient to provide the desired therapy to prevent small fiber neuropathy or peripheral vascular disease. Point to. The amount of treatment can, for example, reduce pain, reversing sensory fiber loss or two-head / neck-adherent twins, promote angiogenesis, or increase microcirculation Can increase sensory perception. The exact amount required will vary depending on the patient's species, aging and general condition, the nature of the complications, the particular combination of compounds, the mode of management, etc. The term “as a treatment” is intended to include not only medical effects, but also beneficial aesthetic effects and improved nutritional effects.

  The composition used in the method of the present invention comprises at least one flavonoid. Flavonoids are small organic compounds having a phenyl benzopyrone structure. They are found in the leaves, fruits, seeds, bases or flowers of all vascular plants. Citrus fruits are a significant source of over 4000 flavonoids that have been identified as originating from plant sources. On average, the western food we eat daily contains about 1 gram of mixed flavonoids.

  Examples of flavonoids include flavones, flavanols, anthocyanidins, proanthocyanidins, procyanidic oligomers, biflavans, polyphenols, lutinosides, hydroxyethyl lutinosides and hydridoline. leucoanthocyanins), but is not limited thereto.

  Suitable flavonoids for use in the present invention include those that do not induce significant adverse side effects when administered to mammals in a therapeutically effective amount, which is different from other components of the compositions used in the present invention. It does not react and does not cause a substantial loss in the activity of one or more compounds of the composition. Suitable flavonoids are those obtained from nature. However, derivatives of this type of compound may also be suitable for the present invention. When used in therapeutically effective amounts, suitable flavonoids can be administered to humans without significant adverse side effects.

  The choice of flavonoid (s) contained in the composition is determined by factors such as toxicity, bioavailability, solubility or partitionability. For the purposes of the present invention, examples of suitable flavonoids include, but are not limited to: (−)-epigallocatechin; (−)-epigallocatechin-potassium salt; , 2,3,6-tetra-o-galol-β-d-glucose (1,2,3,6-tetra-o-gallyol-d-glucos); 3,3 ′, 4-tri-o-methyl -Potassium salt; 2'-o-acetylacetoside; 6,3 ', 4'-trihydroxy-5,7,8-trimethoxyflavone (6,3', 4 ' -Trihydroxy-5,7,8-trimethylflavone); 6-hydroxy-luteoline; 6-hydroxykaempferol-3,6-dimethyl ether (6-hydroxykaempferol-3,6-dimethylether); 7-o-acetyl-8-epi-loganoic acid (7-o-acetyl-8-epi-lognicacid); acecetin; acetoside; acetyl Trisulfate quercetin; amentoflavone; apigenin; apiin; astragalin; avilarin; axilaline; xylarin; axilaline; Brevifolin; carboxylic acid (carb) caryophyllene; catechins; chrysin; chrysin-5,7-dihydroxyflavone; chrysoeriol (chryseolyol); Chrysosplenoside-a; chrysosplenoside-d; chsosplenoside-d; cosmosin; δ-cadinene; δ-cadinene; curcumin; cyanidin; (Dihydroquercetin); dimethylmussaenoside (dimethylm) disaminside; diosmin; diosmetin; dosmetin; ebinein; epicatechin; epiflavin carboxybile flavinyl carboline Flavocantibide; Flavosativaside; Galangin; Genistine; Ginkgoflavone glycosides; n); gosipetin-8-glucoside; hematoxin; hesperidin; hispiduloside; hyperinid; indoleid; Isoliquiritigenin; isoliquiritin; isoquercitrin; dionoside; juglanin; kaempferol 3-r-no-de -3-Neohesperidoside ( kaempferol-3-neohesperidoside; coraviron; lycraside; linariin; linalin; loniserin; luteolin-te-lu-te-lu Luteolin-7-glucoronide; macrocarpal-a; macrocarpal-b; macrocarpal-d; macrocarpal-g; (Maniflavone); morin; methylscutellare Monohydroxyethyl rutoside (monoHER), dihydroxyethyl rutoside (diHER), trihydroxyethyl rutoside (triHER), tetrahydroxyethyl rutoside (tetraHER), myricetin; naringenin; Naringin; Nelumoside; Nepetin; Nepetrin; Nerolidol; Oligomeric proanthocyanidins; Pectrina Pelegonaridin; pelargonidin; phloretin; phloridin; quercetagein; quercetin; quercimertrin; quercitritine; quercitryl-2 "acetate; reinoutrin; rhamnetin; rhofolin; rutin; scutellarein; sidiritofilin; siritoflavinine; Listin (silichristine); silymarin (solimarin); sophoricoside (sorbarin); spiroeoside (spireoside); tacforin (trifoline); Acceptable salts; solvates; derivatives thereof.

  Suitable flavonoids are also those that have strong antioxidant properties. Examples of preferred flavonoids include, but are not limited to, (−)-epigallocatechin-3-potassium salt; catechins; rutin; quercetin; quercitrin , Myricetin, kaempferol; myrcetrin; luteolin; morin; fisetin, silymarin, esperitin, esperidine ), Citrin, gosipetin, chrysin, oligo Rick proanthocyanidins (bialalein), curcumin, gallic acid, epicatechin, dihydroquineline, ginnan flavinoid, ginnan flavinoid silibiin, silidianin silicristine, galangin, monohydroxyethyl rutoside (monoHER), dihydroxyethyl rutoside (diHER), trihydroxyethyl rutoside (triHER), tetrahydroxyethyl rutoside (triHER) tetraH ER); Naringenin; Naringin; Taxofolin, diosmin, phloretin, phlorizin, cyanidin, pelargonidin and pelargonidin Salts that can be made; solvates; derivatives thereof.

  Examples of further preferred flavonoids include, but are not limited to, (−)-epigallocatechin-3-potassium salt; catechins; rutin; quercetin; quercitrin ), Myricetin, kaempferol; myrecetrin. These compounds exhibit good antioxidant properties coupled with relatively low toxicity.

  Advantageously, flavonoids and flavonoid derivatives can provide additional beneficial effects of the compositions of the present invention. For example, quercetin acts as a chelator for transition metals. Flavonoids are also believed to have anti-inflammatory effects and functions to assist cell membrane stabilization, both of which promote the treatment of small fiber neuropathy. Quercetin is also considered to have anti-toxic properties. In addition, some flavonoids and flavonoid derivatives act as radical neutralizers, reduce the concentration of hydroxyl radicals, for example, and thereby enhance the antioxidant effect of the compositions used in the present invention. .

  Suitable non-flavonoid antioxidants for use in the present invention include those that exhibit antioxidant activity without causing any severe adverse side effects when administered in therapeutically effective amounts, and in the present invention It does not react with the other components of the composition used to cause a substantial loss of activity of one or more compounds. Suitable antioxidants include those that occur naturally in the human body and materials obtained from plants or animals, or derivatives of such compounds.

  Ideal non-flavonoid antioxidants are ascovir palmitate, ascorbic acid (vitamin C), vitamin A, vitamin E and pharmaceutically acceptable esters (including but not limited to acetate); α Lipoic acid, in particular DL-α-lipoic acid, coenzyme Q10; glutathione (GSH); galangin, ginkgolides, tocotrienols, carotenoids, cyanidin and curcuminoids, curcuminoids Includes derivatives that exhibit antioxidant activity.

  More preferably, a mixture of two or more antioxidants is used in the composition used in the present invention. One or more derivatives of these compounds that exhibit antioxidant activity when administered in the compositions of the invention can also be employed herein. Antioxidants can also be used in the form of their pharmaceutically acceptable salts. Salts are sometimes preferred, for example to increase solubility or diffusibility or reduce adverse side effects.

  In a preferred embodiment, the antioxidant used in the composition of the invention can consist of one or more antioxidant enzymes. Antioxidant enzymes useful in the present invention are those that can remove radicals, activate radical neutralizers, or prevent radical generation. One or more antioxidant enzymes work in concert with one or more other antioxidants in the composition to remove free radicals more efficiently, thereby preventing skin cell damage To help. In more preferred embodiments, the antioxidant enzyme used in the present invention is one that can be bioabsorbed through the skin. Suitable antioxidant enzymes for use in the present invention include superoxide disproportionating enzyme, catalase, glutathione peroxidase, M reductase, and the like.

  In more preferred embodiments, quercetin and antioxidants are included in the compositions of the present invention. This combination of quercetin and antioxidant results in enhanced antioxidant action. The antioxidant may be a flavonoid or a non-flavonoid.

  Other compounds also provide additional benefits such as absorbability when applied topically, free radical scavenging, transition metal chelation, nitric oxide stabilization, lack of pain and anti-inflammatory activity, etc. Can be included in the composition of the present invention. These properties can have beneficial effects on the pain of other related diseases such as fibromyalgia. Additional substances that can optionally be included in the compositions used in the present invention include inositol and other B-complex vitamins.

Some suitable compositions for use in the present invention also include vitamin D ₃ , vitamin D ₃ analogues, components that are converted or metabolized to vitamin D ₃ in the body, and metabolites of vitamin D ₃ .

Vitamin D _3, also known as cholecalciferol is further in the liver by hydroxylase and oxygen molecules mitochondrial in the presence of NADPH Another vitamin D ₃ intermediate is converted to 25-hydroxycholecalciferol.

If higher activity of vitamin D ₃ is required, 25-hydroxycholecalciferol is new hydrolase is transported to the kidney being synthesized. The enzyme introduces another hydroxyl group on the position 1 carbon, biological active form of calcitriol Vitamin D ₃ is produced.

A typical vitamin D ₃ analog is 1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptin-1-yl) -9, 10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene (1 (S), 3 (R) -dihydroxy-20 (R)-(1-ethyoxy-5-ethyl-5) -Hydroxy-2-heptyn-1-yl) -9,10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene). Typical vitamin _{D 3} metabolites include 1,25-dihydroxyvitamin _{D 3.} Also, pharmaceutically acceptable salts of components that modulate cell differentiation and / or cell proliferation are used. Vitamin D ₃ is used particularly favored by the present invention.

It is desirable to use a dispersing agent in order to facilitate the production of the vitamin D ₃ or related compounds. Suitable dispersants are well known to those skilled in the art. A particularly suitable dispersant for components that regulate cell differentiation and / or cell growth is corn oil. Corn oil also has the advantage of being a natural product. Corn oil is used in an amount sufficient to distribute vitamin D ₃ or related compounds.

  When administered in a therapeutically effective amount, the composition used in the present invention can provide the patient with one or more of the following localized or osmotic beneficial effects: pain, burns Release from stinging, electrical hypersensitivity and / or hyperalgesia; increased microcirculation; nitric oxide stabilization; enhanced healing of skin ulcers and injuries; protein kinase C inhibition; reduced acid stress; anti-inflammatory activity; Blockade of leukotriene formation; stabilization of cell membranes; enhanced synthesis of nerve growth factor.

  The composition according to the invention can provide an additional effect of improving the appearance of the skin. The appearance of the skin is adversely affected by peripheral neuropathy, including diabetic neuropathy and / or peripheral vascular disease, or by other causes unrelated to the peripheral neuropathy and / or peripheral vascular disease being treated. When the composition of the present invention is administered topically in an effective amount, one or more of the following beneficial properties can be realized: reduction or prevention of skin redness, reduction of skin discoloration or Preventing, beautifying the skin, improving the appearance of the skin, enhancing the attractiveness of the skin, cleansing the skin, removing dead or damaged skin or skin cells from the skin, and on the skin Moisturize.

  Without wishing to be held to a particular theory, there are a number of physiological processes that may be affected by effective treatment for small fiber neuropathy. For example, effective treatment can slow or stop peripheral nerve degeneration. Alternatively, effective treatment may induce healing or regeneration of damaged nerves. Effective treatment may also cause generation of new nerve generations and replace damaged nerves.

  Thus, it appears that effective treatment for small fiber neurological diseases can be applied to other diseases or conditions affecting peripheral nerves. The method of regenerating nerves is beneficial for treating any patient suffering from nerve injury, such as a skin transplant patient or a traumatic victim who is nerve-cutting. In fact, many flavonoids are potent aldose reductase inhibitors. Oral administration of an aldose reductase inhibitor has been shown to increase the diameter of the peripheral nerve bundle. Thus, the method of the present invention is expected to extend to nerve generation and regeneration.

Although it is known that the cause underlying diabetic neuropathy is specifically different from other causes of small fiber neuropathy, symptoms and pathology are shared. Therefore, it is expected that effective treatment for small fiber neuropathy will stop, reverse or alleviate certain symptoms of diabetic neuropathy. Also, for the treatment of diabetic neuropathy, the optional ingredient, vitamin D ₃ or a derivative thereof or a metabolite thereof is removed from the composition, and the composition contains other suitable ingredients Given that, it has been found that the composition still provides a beneficial effect.

  Flavonoids activate the microcirculation and can therefore also be used to treat peripheral vascular disease. For example, the flavonoid quercetin generally supports vascular function and is therefore an effective treatment for peripheral vascular disease. The reduced microcirculation is thought to be caused, at least in part, by acid stress resulting from excess free radicals. Quercetin, which is an example of a flavonoid with antioxidant properties and is therefore an effective treatment for this condition. The chelating properties of flavonoids such as quercetin contribute to its effectiveness. The excess of sorbitol in the bloodstream of diabetic patients attracts metal ions, which are sequestered by chelation.

  The composition used in the present invention is preferably prepared with an acceptable carrier. Non-carrier components can be mixed with a carrier material to form a specific dosage form, or customized for a specific therapeutic procedure. Thus, the amount of each component depends on the mode of administration, the activity of the particular compound used, age, weight, public health, sex, patient weight, time of administration, rate of elimination, compound combination or , Among other factors, can vary depending on the sensitivity to the disease, etc.

  The standard reference book on pharmaceutical formulation, Remington's “Pharmaceutical Sciences, 18th edition, published by Mac Pan Publishing Company 1990,” is incorporated herein by this reference.

  It is known that the individual components of the formulated product may interact with each other. For example, these interactions include chemical equilibria and other scientific or physical processes. These interactions change the original individual components of the formulated product over time. This type of change is chemical or physical. For example, the acidic component can also be deprotonated in a formulation that includes the basic component. Alternatively, one or more components solidify or crystallize from the prepared product. Equilibrium and other processes are expected to increase in number and complexity with increasing number of components in the composition. Such equilibration and other processes are harmless or harmful to the activity of the prepared product.

  As used herein, the term “stable” means the property of maintaining at least a portion of the intended activity for a predetermined period of time.

  As used herein, the terms “mixture”, “composition” and “formulation” refer to stable mixtures, compositions and formulations, respectively. Suitable mixtures, compositions and formulations are stable over a period of at least about 3 months.

  In the method of the present invention, the composition may be by several routes, including but not limited to, routes including locally, orally, via an implanted reservoir, or via aspiration. Can be administered.

  In the method of the present invention, the composition is administered orally. The oral composition used in the present invention is administered 1 to 6 times a day or as needed to alleviate the symptoms of pain and other small fiber neuropathy. Preferably, when administered orally, the composition is administered twice to four times daily as needed for pain. Sufficient amounts must be administered to provide one or more of the beneficial effects of the composition described above. The method initially treats acute symptoms, but may continue indefinitely to relieve pain, prevent symptoms from returning, and possibly restore some nerve and / or skin function. Return to.

  The oral compositions and methods of the present invention function as a dietary or nutritional supplement. In accordance with this aspect of the invention, oral compositions and methods can maintain and / or support nerve health, maintain and / or support vascular health and circulation, and muscle health. Maintain and / or support, maintain a sense of sensory integrity, ie heat and coldness, and support the health of the skin.

  The oral composition used in the present invention includes any, including but not limited to, capsules, tablets, lozenges, troches, hard candy, powders, sprays, elixirs, syrups and suspensions or liquids. Orally administered in an acceptable dosage form.

  Suitable acceptable carriers for tablets include, for example, lactose and corn starch. Smoothing agents such as magnesium stearate, sodium lauryl sulfate and talc can be added to the tablets. Tablets may also contain excipients such as sodium citrate, calcium carbonate and calcium phosphate. Disintegrants such as starch, alginic acid and synthetic silicates can be employed. Tablets may also contain binders such as polyvinyl pyrrolidone, gelatin and gum arabic.

  With or without diluent, the composition used in the present invention can be administered in the form of a capsule. Useful diluents for capsules include, but are not limited to, lactose and dried corn starch. In addition, a solid composition similar to the tablet described above can be administered in soft and hard gelatin capsules.

  The compositions used in the present invention can be administered orally as capsule or non-capsule suspensions and they can have, for example, emulsifiers and / or suspensions known to those skilled in the art. it can. Adjunct ingredients such as sweeteners, flavourants, colorants, dyes, diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof may be included in the oral composition.

  The compositions used in the present invention can also be administered by inhalation with a nasal aerosol. Appropriate formulations can be prepared using well known techniques. For this mode of administration, preferred carriers are prepared, for example, with salts and / or other conventional solubilizing or dispersing agents, optionally with one or more preservatives, and bioabsorption enhancers that enhance bioavailability And / or a fluorocarbon.

  In a preferred method of the invention, the composition is applied topically to a region of the skin near the tissue suffering from the small fiber nerve disease to relieve the pain and other symptoms of the small fiber nerve disease. . Such areas generally include the patient's limbs (eg, the fingers, fingers, hands and feet), and neuropathy is often most prevalent in such areas.

  Preferably, a suitable amount of the topical composition of the present invention is 1-6 times a day, as needed. More preferably, the topical composition is applied 2-4 times a day as needed. Also preferably, a sufficient amount of the topical composition is applied to cover the suffering area with a thin layer of the composition, and to the extent that little residue remains on the skin. Is rubbed into the skin. The treatment is effective almost immediately to alleviate acute symptoms, but to relieve pain, prevent the return of symptoms of small fiber nerve disease, and possibly restore some nerve and / or skin function , May continue for a predetermined period or permanently.

  Preferably, the topical formulation of the composition used in the present invention comprises an acceptable topical carrier. Many acceptable topical carriers are known to those of ordinary skill in the art. The compound in the composition can be dissolved, dispersed and suspended in a topical carrier.

  Suitable hydrophilic ointment bases are known to those skilled in the art. For the purposes of the present invention, suitable typical hydrophilic ointment bases are non-U.S. Such as those manufactured by Fougera, a division of Altana, Melville, New York. S. P. A hydrophilic ointment base. Sufficient hydrophilic ointment base is employed to serve as a carrier for the compound of the composition. Generally, the hydrophilic ointment base forms 80% or more of the total composition, and more preferably, 80-90% of the composition is the hydrophilic ointment base. The hydrophilic ointment base functions as a carrier and preferably enhances penetration of the compound into the skin.

  One suitable topical carrier consists of hydroxymethyl fibrin. Other suitable acceptable carriers include non-aqueous solvent based acrylic copolymer solutions. The non-aqueous solvent system preferably comprises polyethylene glycol, such as methoxy polyethylene glycol 550 (MPEG). One suitable MPEG is Sentry Carbowax MPEG550 (Dow, Midland, Michigan) and it is suitable for use in food, pharmaceuticals and cosmetics. The acrylic copolymer is present in a concentration range of preferably 3 to 6% by weight of the solution. Also preferably, the acrylic copolymer has a molecular weight of 20,000 or more. More preferably, the acrylic copolymer has a molecular weight of 100,000 or more to prevent substantial bioabsorption of the acrylic copolymer through the skin by the human body.

  Preferably, the acceptable topical carrier individually provides benefits to the patient. For example, the topical carrier can consist of panthenol or a panthenol derivative. Panthenol or panthenol derivatives that can be used in the present invention include at least D-panthenol, DL-panthenol, and mixtures thereof. This carrier serves as a component that helps to quickly and deeply penetrate non-carrier components with moisturizing properties through the skin to the treatment area. A healing effect can also be added to the damaged epithelium. The predetermined amount of panthenol or panthenol derivative used is from about 0.25 to about 10 percent in the total weight predetermined amount of the topical pharmaceutical composition. More desirable is from about 0.5 to about 5 percent. Most desirable is from about 1 to about 2 percent.

  The topical carriers of the present invention may use other penetrants in addition to or as an alternative to panthenol. Typical penetrants are ethanol, oleic acid, sodium dodecyl sulfate, isopropyl myristate, glyceryl monoolefin, caprylic acid / capric triglyceride, crodarnor GTC / C, glyceryl tricaprylate / Capric acid, Migma 810, Migma 812, MCT oil, Neobee M5, Nesatole, oleum neutral, oleum vegetable tenue, dilute vegetable oil, photomineral oil and stearyl alcohol Contains lanolin mixed with suitable vegetable oil or soft paraffin. These penetrants can have a relaxing effect and can facilitate the absorption of the components of the topical composition of the present invention into the skin.

  The topical carrier comprises a dispersion to disperse at least one hydrophilic ointment, panthenol or panthenol derivative, and, if necessary, one or more insoluble or partially insoluble active ingredients in the carrier. Agents can be included.

  The topical carriers of the present invention may also contain additional ingredients well known to those skilled in the art, such as other carrier materials, other moisturizers, wetting agents, mild, emission blocking compounds, especially UV-blockers, as well as Other materials used may include other materials that do not significantly adversely affect the operation of the topical composition. A preferred additional component for inclusion of the carrier is sodium acidic phosphate ester (moisturizer).

  The topical composition of the present invention is preferably prepared by cold preparation when one or more compounds employed in the topical composition are sensitive to heat. Thus, in some cases, the stability or activity of the composition may be adversely affected as a result of other formulation methods. Preferably, a sufficient amount of the topical carrier is used to provide a substantially uniform cream or ointment. It dissolves, disperses or suspends one or more ingredients prior to formulation to ensure that one or more of the ingredients of the composition are substantially uniformly dispersed. There is a need.

  As noted above, the dosage can vary depending on the method of preparation of the compound. In general, makeup is made up from 0.5 to 90 percent by weight of the total composition to provide the desired daily dose, including the components of the composition, the flavonoids and optional antioxidants. The body weight dose here is based on a 70 kg patient, if not standardized. The appropriate unit dose is determined by dividing the daily unit usage by the number of doses.

  At least one flavonoid of the invention is administered in a safe and effective amount. Preferred topical compositions of the present invention comprise from about 1 to about 150 grams of one or more flavonoids and from about 0.1 to about 50 grams of non-flavonoid antioxidant per pound and topical administration The carrier component is suitable for use as a carrier.

  Preferably, flavonoids are used in an amount of about 2 to about 100 grams per pound of composition. Even further, it is desirable to use an amount of about 10 to about 50 grams per pound of composition. If possible, an amount of about 15 to about 40 grams per pound of composition is optimal.

When vitamin D ₃ , or a derivative or metabolite thereof is used in this composition, the ratio of the amount of compound to the amount of flavonoid employed in the composition of the present invention is about 1 gram of antioxidant. From 200 IU to 3 million IU per gram of flavonoid. More preferably, the composition comprises from 1800 IU to about 1 million IU of nerve growth factor synthesis promoting factor per gram of flavonoid, and even more preferably from about 5000 IU to about 200,000 IU per gram of flavonoid. Including nerve growth factor synthesis promoting factors.

When formulating a composition comprising both vitamin A and vitamin D ₃ is desirably carried out in dispersion of corn oil. Generally, about 500,000 to about 2,000,000 IU of vitamin A and about 50,000 to about 200,000 IU of vitamin D ₃ per cubic centimeter (cc) or milliliter (mL) are corn. Used dispersed in oil. Ideally, corn oil containing about 800,000 to about 1,200,000 IU of vitamin A and about 80,000 to about 120,000 IU of vitamin D ₃ per milliliter is desirable. More ideally, corn oil containing about 1,000,000 vitamin A and about 100,000 IU vitamin D ₃ is desirable for the composition used in the invention.

When administering the vitamin D ₃ or derivative thereof or a composition comprising a metabolite of vitamin D _3,, derivative thereof or metabolites of vitamin D ₃ or vitamin D _3, it is used in a safe and effective predetermined amount. Ideally, the predetermined amount is from about 6 to about 14.3 IU per kg of patient body weight in a single administration. Even more desirable is a predetermined amount of about 8 to about 14.3 IU per kg patient body weight. Even more desirable is to administer a predetermined amount of about 10 to about 13 IU per kg body weight of the patient.

  The flavonoid is used in an amount that provides substantially the same level of activity as a daily dose of 13 to 22 mg / Kg relative to the weight of quercetin. More preferably, the flavonoid is used in an amount that provides substantially the same level of activity as the daily dose of 17.2 to 21.4 mg / Kg relative to the weight of quercetin, and more preferably the weight of quercetin Is used in an amount that substantially provides the same level of activity as a daily dose of 18 to 21 mg / Kg.

  About 11 to about 29 mg / kg body weight / day of ascorbyl palmitate is administered. More preferably, about 14.3 to 28.6 mg / kg body weight / day is administered.

  When vitamin E is administered in the form of mixed tocopherols, the daily dose is preferably about 4 to about 12 per kg. More preferably, the daily dose is about 5.7 to 11.4 IU / kg body weight. More preferably, the daily dose of mixed tocopherol is 6-10 IU / kg body weight. When vitamin E is administered in another form, it is administered in an amount that provides the same effect as the above-mentioned amount of mixed tocopherols.

  The dosage for administering vitamin A is preferably about 170 to about 360 IU per kg body weight per day. Ideally, about 214.3 to about 357.1 IU per kg body weight per day is desirable. Even more ideal is about 220 to about 340 IU per kg body weight per day.

  Preferred topical compositions of the present invention are used as about 2 to about 50 grams of one or more flavonoids and about 1 to about 50 grams of non-flavonoid antioxidant per pound and as a topical agent. A suitable carrier component is included.

  American witch hazel extract is a predetermined amount of about 2.5-40 cc per pound of topical agent, more preferably about 5-30 cc. Most desirable is about 10-20 cc. High moisture glycerin is a predetermined amount of about 2 to 20 cc per pound of topical agent, more preferably about 3.5 to 15 cc. Most preferred is about 5-10 cc. Apricot kernel oil is a predetermined amount of about 0.5-5 cc per pound of topical agent, more preferably about 0.5-4 cc. Most desirable is about 1 to 3 cc. AJIDEW NL-50NaPCA (50% aqueous solution) is a predetermined amount of about 15-45 cc per pound, more preferably about 20-40 cc. Most preferred is about 25-35 cc.

  More preferred topical compositions of the present invention can be prepared using the following ingredients: ARDEW NL-50 NaPCA (50% aqueous solution) about 25 cc to 35 cc of a 50% aqueous solution of a moisturizing agent, About 5 cc to about 10 cc of D- or DL-panthenol, about 10 to about 50 grams of quercetin powder.

  The above amounts are suitable in combination with 1 pound of hydrophilic ointment base. As is known in the art, higher amounts of one or more components (eg, antioxidants) can be employed by reducing the amount of other components of the same type or type of operation that are similar.

  In a preferred embodiment, 10 g / kg body weight quercetin is used. In another preferred embodiment, about 5 g / kg body weight to about 25 g / kg body weight, more preferably about 5 g / kg body weight rutin is added to the composition. In another preferred embodiment, about 5 g / kg body weight to about 25 g / kg body weight, more preferably about 5 g / kg body weight of glutathione is added to the composition.

  In an embodiment of the present invention, the composition is substantially free of a nitric acid derivative having the following chemical formula.

  Wherein X, Y and R are independently of each other, H and branched or unbranched alkyl having 1 to 18 carbon atoms, acids thereof, and physiologically acceptable salts thereof. You can select from a group.

  The following examples are provided to describe the invention in further detail. These are examples describing the preferred embodiments presently contemplated for carrying out the invention, but these are merely examples and are not intended to limit the invention.

  A topical composition prepared with said acceptable carrier comprising a hydrophilic ointment base, sodium acidic phosphate humectant and DL-panthenol, further comprising quercetin and prepared by cold conditioning . The composition of the composition is given in Table 1. The composition can optionally be supplemented with coenzyme Q10 (500 mg) and can optionally include other antioxidants.

  The composition was prepared by first placing the hydrophilic ointment base in a stainless steel bowl and vigorously mixing until the ointment was creamy. Sodium acidic phosphate ester, panthenol, quercetin and other antioxidants, if any, were then added in that order. After each ingredient was added, it was continuously mixed until no traces of dry ingredients were visible and a substantially uniform mixing was obtained. The final color is a stable yellow and the cream has cake frosting hardness. The mixture was stored in a sterile container. For example, all containers and tools that come into contact with the composition during mixing must also be sterilized with zephyran chloride, bleach or betadyne.

  Under the supervision of a physician, the composition can be administered topically to patients diagnosed with small fiber neuropathy. The topical composition is administered, for example, twice a day, twice in the morning and afternoon, or up to six times a day for a few days as needed for wound healing. Treated patients are expected to experience positive results for 1 or 2 days after discontinuing treatment.

  Other combinations of compounds suitable for use in the methods of the invention are described in Examples 2-7. The compound may be mixed with about 1 pound of a hydrophilic ointment base for topical administration.

  A topical composition was prepared using the ingredients listed in Table 2 below.

The composition of Table 2 shows 24 patients who have diabetic neuropathy in at least one leg as a result of having type 1 and type 2 diabetes mellitus in a double blind function verification of placebo control in France. Twelve patients administered topically 3 times a day for 4 weeks received a placebo consisting of the composition of Table 2 above except for ascorbyl palmitate and quercetin dihydrate. Eligible patients include the "A Practical Two-Step Quantitative Clinical and Electrophysiological Digestion of the Michigan Neuropathy Screening Institute (MNSI), Feldman et al." Screened using page.

  Topical ointment 5.3 ml was administered topically three times a day to the affected area. Treatment was assessed using a detailed symptom assessment and a quality of life questionnaire. The test result was positive. The formulation resulted in a significant reduction in diabetic peripheral neuropathy pain and discomfort and an improvement in skin appearance and texture including a reduction in redness. Similar formulations without ascorbyl palmitate also provide relief from the discomfort of diabetic peripheral nerve disease and small fiber peripheral nerve disease, as well as doors that are effective on diabetic and aging skin.

  While the invention has been described and described with reference to specific preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is thus not limited to the specific embodiments described above, but can be modified and changed. The scope of the invention is set forth with particularity in the appended claims.

Claims (44)

  A method for treating a peripheral nerve / vascular disease, comprising a step of administering a composition comprising an effective amount of a flavonoid having an antioxidant action and, optionally, an acceptable carrier.   2. The method according to claim 1, wherein the treatment of the peripheral nerve / vascular disease is to treat the systemic effect of the peripheral nerve / vascular disease.   2. The method according to claim 1, wherein the treatment of peripheral nerve / vascular disease is to treat a local effect of peripheral nerve / vascular disease.   2. The method according to claim 1, wherein the treatment of peripheral nerve / vascular disease includes reduction of bruising, reduction of irritation, normalization of sensation to cold, reduction of convulsions, reduction of muscle weakness, reduction of numbness, hair removal. Selected from the group consisting of: reduced vascularization, increased angiogenesis, remodeling damaged nerves, forming new nerves, and improving peripheral circulation.   The method according to claim 1, wherein the antioxidant flavonoid is (-)-epigallocatechin; (-)-epigallocatechin-potassium salt; 1,2,3,6-tetra- o-galol-β-d-glucose; 3,3 ′, 4-tri-o-methyl-potassium salt; 2′-o-acetylacetoside; 6,3 ′, 4′-trihydroxy-5,7 , 8-trimethoxyflavone; 6-hydroxy-luteoline; 6-hydroxy kaempferol-3,6-dimethyl ether; 7-o-acetyl-8-epi-logonic acid; acacetin; acetoside; acetyl trisulfate quercetin; Amentoflavone; apigenin; apiin; astragalin; abiclarin; axilaline; baicalen; brazirine; brebiforin; carboxylic acid; caryophyllene; catechi Chrysin; chrysin-5,7-dihydroxyflavone; chrysoeriol; chrysoprenol; chrysoprenoside-a; chrysosprenoside-d; cosmosin; delta-cadinene; curcumin; cyanidin; dihydroquercetin; dimethylmussaeno Sid; diaceryl sarcaritin; diosmin; diosmethine; dosmethine; ebine; epicatechin; ethyl brebiforin carboxylate; flavocannibid; flavosativibaside; galanthin; genistin; ginkgoflavone glycoside; ginkgo heteroside; Glucoside; hematoxin; hesperdine; hispiduroside; hyperin; indole; iridine; isoliquiretigenin; isoliquiritin; isoquercitrin; dionoside; jugranine; kaempferol; Nferrol-3-neohesperidoside; corabilon; lycraside; linariin; linalin; lonisine; luteolin; luteolin-7-glucoside; luteolin-7-glucoronide; macrocarpal-a; macrocarpal-b; macrocarpal-d; macrocarpal-g; Morin; methyl scutellarein; monohydroxyethyltoside, dihydroxyethyltoside, trihydroxyethyltoside, tetrahydroxyethyltoside, myricetin; naringenin; naringin; nermoboside; nepetin; nepetrin; nerolidol; Oxyayanine-a; pectrinaligenin; pectrinalin; pelargonidin; phloretin; phlorizin; quercetagetin; quercetin; quercimeltrin; quercitrin; quercitril- "Acetate; Reynothrin; Ramunetin; Reifolin; Rutin; Scutellarein; Sideritoflavone; Silybin; Silydianin; Cyricristine; Silymarin; Sophoricoside; Sorvaline; Spireoside; Tacforin; Trifolin; Vitexin; Selected from the group consisting of salts that can be made.   The method according to claim 1, wherein the antioxidant flavonoid is (−)-epigallocatechin-3-potassium salt; catechins; rutin; quercetin; quercitrin ( quercitrin, myricetin, kaempferol; myrcetrin; luteolin; morin; fisetin, simarin, esperin (h), apigenin, h (Hesperidin), citrin, gosipetin, chrysin, oligo Ricproanthocyanidins, polyphenols; biacalin; curcumin; epicatechin, dihydroquinones, dihydroquinone, hydane, hemi It is selected from the group consisting of siribin, silidianin, silicristine, green tea ingredients and pharmaceutically acceptable salts thereof.   3. The method of claim 1, wherein the antioxidant flavonoids are quercetin; quercitrin, myricetin, rutin, kaempferol; myrecetrin; gallangin (galgin) ), Monohydroxyethyl rutoside (monoHER), dihydroxyethyl rutoside (diHER), trihydroxyethyl rutoside (triHER), tetrahydroxyethyl rutoside (tetraHER); naringenin; naringin; tacforin ( taxofolin, diosmin, phloretin, phloridozine phloridzin), cyanidin (cyanidin), pelargonidin (pelargonidin), is selected from the group consisting of green tea component and pharmaceutically acceptable salts thereof.   3. The method of claim 1, wherein the antioxidant flavonoids are quercetin; quercitrin, myricetin, rutin, kaempferol; myrcetrin, green tea component and Selected from the group consisting of those pharmaceutically acceptable salts.   2. The method according to claim 1, wherein the flavonoid having an antioxidant action has a green tea component.   2. The method of claim 1, wherein the composition is further formulated from a non-flavonoid antioxidant compound.   11. The method of claim 10, wherein said non-flavonoid antioxidant compound is ascovir palmitate, ascorbic acid, vitamin A, vitamin E and pharmaceutically acceptable esters; α-lipoic acid, especially DL-α-lipoic acid, coenzyme Q10; glutathione; selected from the group consisting of polyphenols, green tea ingredients, and pharmaceutically acceptable salts thereof.   11. The method of claim 10, wherein the non-flavonoid antioxidant compound comprises glutathione.   11. The method of claim 10, wherein the non-flavonoid antioxidant compound has a green tea component. The method of any of claims 1 to 13, wherein the composition further vitamin _D 3; 1,25- dihydroxyvitamin _{D 3; 1 (S),} 3 (R) - dihydroxy -20 (R) - ( 1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl) -9,10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene (1 (S) , 3 (R) -dihydroxy-20 (R)-(1-ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl) -9,10-seco-pregna-5 (Z), 7 ( E), 10 (19) -triene; or a pharmaceutically acceptable salt thereof.   14. The method of any of claims 1-13, wherein the acceptable carrier comprises a sufficient amount of D-pantenol and DL-pantenol, and one or more components of the composition are placed in the skin. Promote penetration.   2. The method of claim 1, wherein the administration comprises oral administration.   17. The method of claim 16, wherein the treatment of peripheral nerve and vascular disease is to maintain and / or support nerve health, maintain and / or support vascular health, maintain and / or support circulation, and maintain muscle health. And / or support, having at least one of maintaining sensory integrity.   14. The method of any of claims 1-13, wherein the acceptable carrier is a sufficient amount of at least one non-U. S. P. Having a hydrophilic ointment base to form a substantially topical composition.   14. The method of claim 13, wherein the treatment of peripheral nerve / vascular disease is to reduce or prevent skin redness, to reduce or prevent skin discoloration, to beautify the skin, to improve the appearance of the skin. Selected from the group consisting of: promoting skin attractiveness; cleansing the skin; removing dead or damaged skin or skin cells from the skin; and moisturizing the skin.   14. The method of claim 13, wherein the step of applying is rubbing, pouring, spraying or sprinkling.   19. The method of claim 18, wherein the composition comprises a humectant, DL-panthenol, querceltin and a further antioxidant.   19. The method of claim 18, wherein the composition comprises a hydrophilic ointment base, 2-100 g sodium L-pyrrolidone carboxylic acid per pound of composition, and 1-10 cc DL-panthenol per pound of composition. 10 g to 50 g of quercetin per pound of composition and 18 g to 50 g of compound selected from the group consisting of glutathione and rutin per pound of composition.   A method of treating diabetic neurological disease, comprising administering to a patient having diabetic neurological disease a composition comprising an anti-oxidative and therapeutically effective amount of a flavonoid and an acceptable carrier Having a method. A method of treating diabetic neurological disease, comprising a flavonoid in an amount that has an antioxidant effect and is therapeutically effective for a patient having diabetic neurological disease, and optionally an acceptable carrier But the composition is free of vitamin D ₃ and vitamin D ₃ analogs. 24. The method of claim 23, wherein the flavonoid having an antioxidant action is
Quercetin; quercitrin, myricetin, rutin, kaempferol; myrcetrin; galangin, monohydroxyethyltoside (monoHERER) diHER), trihydroxyethyl rutoside (triHER), tetrahydroxyethyl rutoside (tetraHER); naringenin; naringin; taxufolin, diosmin, phloretin, fluoridin (phloridin) ), Cyanidin, pella Gonijin (pelargonidin), is selected from the group consisting of green tea component and pharmaceutically acceptable salts thereof.   24. The method of claim 23, wherein the antioxidant flavonoids are quercetin; quercitrin, myricetin, rutin, kaempferol; myrcetrin, green tea component and Selected from the group consisting of those pharmaceutically acceptable salts.   24. The method of claim 23, wherein the composition further comprises a non-flavonoid antioxidant.   24. The method of claim 23, wherein said non-flavonoid antioxidant compound is ascovir palmitate, ascorbic acid, vitamin A, vitamin E and pharmaceutically acceptable esters; [alpha] -lipoic acid, particularly DL- [alpha] -lipoic acid, coenzyme Q10: selected from the group consisting of glutathione, and pharmaceutically acceptable salts thereof.   24. The method of claim 23, wherein the acceptable carrier further comprises a humectant and DL-pantenol.   A composition for treating small-fiber neuropathy or peripheral vascular disease, comprising a therapeutically effective amount of flavonoid for treating small-fiber neuropathy or peripheral vascular disease, and small-fiber neuropathy Or a mixture of a therapeutically effective amount of a non-flavonoid antioxidant to treat peripheral vascular disease, wherein the composition is an oral or topical formulation further comprising a penetrant.   31. The composition of claim 30, wherein the antioxidant flavonoid is (-)-epigallocatechin; (-)-epigallocatechin-potassium salt; 1,2,3,6-tetra- o-galol-β-d-glucose (1,2,3,6-tetra-o-gallyol-d-glucos); 3,3 ′, 4-tri-o-methyl-potassium acid salt; 2′-o -Acetyl acetoside (2'-o-acetylacetoside); 6,3 ', 4'-trihydroxy-5,7,8-trimethoxyflavone (6,3', 4'-trihydroxy-5,7,8- 6-hydroxy-luteolin; 6-hydroxy kaempferol-3,6-dimethyl ether (6-hydroxyka) mpferol-3,6-dimethylether); 7-o-acetyl-8-epi-logonic acid (7-o-acetyl-8-epi-lognicacid); acecetin; acetoside; acetyltrisulfate quercetin ( acetyltrisulfatequarcetin; amentoflavone; apigenin; apiin; astragalin; abiclarin; axilarin; axilaline; Carboxylic acid; Cario Catechins; chrysin; chrysin-5,7-dihydroxyflavone; chrysoeriol; chrysosnosol Sid-a (Chrysosplenoside-a); Chrysosprenoside-d (Chrysosplenoside-d); Cosmosinin (δ-Cadinene); Curcumin (Curcumin); Dimethylmussaenoside; dia Diacyrylcimaritin; diosmin; diosmethin; dosmetin; ebinin; epicatechin; Flavosatibaside; galangin; genistin; ginkgoflavone glycosides; ginkgoheterosides; gossipetine; Gossypetin-8-glucoside; hematoxin; hesperidine; hispiduloside; hyperin; idoline; iridine; iridine; iridine; iridine (Isoliquiritin); isoquercitrin; dionoside; juglanin; kaempferol; kaempferol-3-rhamnoside 3-kamperidoside; (Kaempferol-3-n eohesperidoside; colaviron; lycraside; linariin; linarilin; lonericin; luteolin; luteolin-7-glucoside (luteoline); Glucuronide (luteolin-7-glucoronide); macrocarpal-a; macrocarpal-b; macrocarpal-d; macrocarpal-g; macroflavon (maniflavone) Morin; methylscuterarein (methylscute) monohydroxyethylrutoside (monoHER), dihydroxyethylrutoside (diHER), trihydroxyethylrutoside (triHER), tetrahydroxyethylrutoside (tetraHER), myricetin; naringenin; naringin ( nermoboside; nepetin; nepetrin; nerolidol; oligomeric proanthocyanidins; pectolinari ); Pelargonidin; phloretin; phloridin; quercetagein; quercetin; quercimertrin-2; quercitrin-2 quercitrin "acetate"; reinoutrin; rhamnetin; rhoifolin; rutin; scutellarein; sideritoflavone; tiny); silymarin; sophoricoside; sorbarin; spiraeside; taxofolin; trifolin; vitexin and green ingredient; Selected from the group consisting of pharmaceutically acceptable salts.   30. The composition of claim 29, wherein the antioxidant flavonoids are (-)-epigallocatechin-3-potassium salt; catechins; rutin; quercetin; quercitrin. , Myricetin, kaempferol; myrcetrin; luteolin; morin; fisetin, silymarin, esperitin, esperidine ), Citrin, gosipetin, chrysin, oligo Ricproanthocyanidins, polyphenols; biacalin; curcumin; epicatechin, dihydroquinones, dihydroquinone, hydane, hemi It is selected from the group consisting of siribin, silidianin, silicristine, green tea ingredients and pharmaceutically acceptable salts thereof. 30. The composition of claim 29, wherein the flavonoid having an antioxidant action is
Quercetin; quercitrin, myricetin, rutin, kaempferol; myrcetrin; galangin, monohydroxyethyltoside (monoHERER) diHER), trihydroxyethyl rutoside (triHER), tetrahydroxyethyl rutoside (tetraHER); naringenin; naringin; taxufolin, diosmin, phloretin, fluoridin (phloridin) ), Cyanidin, pella Gonijin (pelargonidin), is selected from the group consisting of green tea component and pharmaceutically acceptable salts thereof. 30. The composition of claim 29, wherein the flavonoid having an antioxidant action is
Quercetin; selected from the group consisting of quercitrin, myricetin, rutin, kaempferol; myrcetrin, green tea ingredients and pharmaceutically acceptable salts thereof The   30. The composition of claim 29, wherein the non-flavonoid antioxidant compound is ascovir palmitate, ascorbic acid, vitamin A, vitamin E and pharmaceutically acceptable esters; [alpha] -lipoic acid, particularly DL- [alpha] -lipoic acid, Coenzyme Q10; glutathione; selected from the group consisting of polyphenols, green tea ingredients, and pharmaceutically acceptable salts thereof.   30. The method of claim 29, wherein the non-flavonoid antioxidant compound comprises glutathione.   30. The method of claim 29, wherein the non-flavonoid antioxidant compound has a green tea component. In any of the compositions of claims 29 to 36, wherein the composition further vitamin _D 3; 1,25- dihydroxyvitamin _{D 3; 1 (S),} 3 (R) - dihydroxy -20 (R) - (1-Ethoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl) -9,10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene (1 (S ), 3 (R) -dihydroxy-20 (R)-(1-ethyoxy-5-ethyl-5-hydroxy-2-heptyn-1-yl) -9,10-seco-pregna-5 (Z), 7 (E), 10 (19) -triene; or a pharmaceutically acceptable salt thereof.   37. The composition of any of claims 29-36, wherein the acceptable carrier comprises a sufficient amount of D-pantenol and DL-pantenol, and one or more components of the composition are contained in the skin. Promote penetration.   40. The composition of claim 38, wherein the composition comprises a humectant, DL-panthenol, querceltin and a further antioxidant.   39. The composition of claim 38, wherein the composition comprises a hydrophilic ointment base, 2-100 g sodium L-pyrrolidone carboxylic acid per pound of composition, and 1-10 cc DL-panthenol per pound of composition. And from 10 g to 50 g of quercetin per pound of composition and from 18 g to 50 g per pound of composition selected from the group consisting of glutathione and rutin.   A method for improving the appearance of the skin, comprising at least one flavonoid formulated in an acceptable carrier that is effective in improving the appearance of the skin of mammalian skin suffering from peripheral nerve / vascular disease A method of applying a topical composition.   43. The method of claim 42, wherein the enhancement of skin appearance comprises reducing or preventing skin redness, reducing or preventing skin discoloration, beautifying the skin, improving skin appearance, skin Selected from the group consisting of promoting attractive effects, cleansing the skin, removing dead or damaged skin or skin cells from the skin, and moisturizing the skin.   43. The method of claim 42, wherein the step of applying is rubbing, pouring, spraying, or sprinkling.