US 2002O115618A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2002/0115618 A1 ROSenbloom (43) Pub. Date: Aug. 22, 2002

(54) METHOD AND COMPOSITION FOR THE compounded mixture of a compound that promotes Synthe TOPCAL TREATMENT OF DABETIC sis of nerve growth factor, an aldose reductase inhibitor and NEUROPATHY an antioxidant formulated in a pharmaceutically acceptable carrier. It has been found that this combination of active (76) Inventor: Richard Allen Rosenbloom, Elkins agents provides significant, effective relief of the Symptoms Park, PA (US) of diabetic neuropathy, as well as at least partial recovery of Correspondence Address: lost neurological function in Some cases. In View of the KNOBLE & YOSHIDA consensus in the art that effective combinations of various EIGHT PENN CENTER active agents have not been demonstrated to be effective for SUITE 1350, 1628 JOHN F KENNEDY BLVD the treatment of diabetic neuropathy, the present invention PHILADELPHIA, PA 19103 (US) provides a Surprising and unexpected effect. In addition, the topical compositions of the present invention, when used in (21) Appl. No.: 09/740,811 effective amounts to treat diabetic neuropathy, do not exhibit (22) Filed: Dec. 21, 2000 the Severe Side effects of many prior art compositions proposed for treatment of this ailment, Publication Classification In a Second aspect, a method for the topical administration (51) Int. Cl.' ...... A61K 31/7048; A61K 31/593; of a composition in accordance with the present invention A61K 31/335; A61K 31/365 for the treatment of diabetic neuropathy is disclosed. In the (52) U.S. Cl...... 514/27; 514/168; 514/456; method, an effective amount of the composition of the 514/458; 514/474 invention is topically administered to the areas of the body that have been adversely affected by the diabetic neuropathy (57) ABSTRACT on a regular basis over a period of time Sufficient to provide A method and composition for the treatment of diabetic the beneficial effects of relief from the symptoms and at least neuropathy is disclosed. The composition comprises a cold Some recover of the damaged nerve tissues. US 2002/0115618 A1 Aug. 22, 2002

METHOD AND COMPOSITION FOR THE 0009 Still another approach to the treatment of neuropa TOPCAL TREATMENT OF DABETIC thy is disclosed in U.S. Pat. No. 5,550,249 (Della Ville et NEUROPATHY al.). In this approach, compositions Suitable for treatment of vitamin H deficiencies are administered for the treatment of BACKGROUND OF THE INVENTION neuropathy. This patent relates to biotin Salts with alkano lamines. The compositions may be administered orally, 0001) 1. Field of the Invention parenterally or topically. 0002 The present invention relates to a method and 0010 U.S. Pat. No. 5,665,360 (Mann) relates to the composition for the topical treatment of diabetic neuropathy. treatment of peripheral neuropathies associated with diabe More particularly, the present invention relates to a topical tes mellitus by periodic topical application of a composition composition including a combination of ingredients that containing capsicum oleoresin as the active ingredient. provide a Surprising degree of effective relief from the When applied to the Skin of the affected area, pain and Symptoms of diabetic neuropathy and to a method for burning associated with the neuropathy are said to be administering the topical composition to treat diabetic neu reduced. However, capsicum oleoresin has been shown to ropathy. kill nerve endings in Some cases and thus this composition 0003 2. Description of the Prior Art Suffers from this disadvantage. 0004 Diabetes mellitus is a common disease that is 0.011 U.S. Pat. No. 5,981,594 (Okamoto et al.) relates to usually classified into insulin-dependent and non-insulin a method of treatment of diabetic neuropathy using com dependent types. Both types may be managed by diet, in bined administration of a formulation including as an active combination with insulin in the first type and a variety of ingredient, a prostaglandin I derivative with an anti-diabetic drugs in the Second type. However, while the changes in agent in order to improve nerve conduction Velocities. blood glucose associated with diabetes can usually be man Suitable anti-diabetic agents include oral hypoglycemic aged reasonably Satisfactorily by conscientious patients and agents and insulin. doctors, this does not prevent long term damage to many 0012. The Okamoto patent also contains a detailed dis tissueS as a result of the disease. This damage may take cussion of the various types of neuropathy that may be many forms but the major types are damage to the eyes asSociated with diabetes. According to this patent, nerve (retinopathy), nerves (neuropathy), kidneys (nephropathy) conduction velocity (NCV) is the most widely used method and cardiovascular System, of objectively evaluating the Severity of diabetic neuropathy. 0005 There are many approaches to reducing or prevent This patent also mentions that current methods of treating ing these forms of damage, which are collectively known as diabetic neuropathy Such as dietetic therapy, administration the long-term complications of diabetes. One approach is of insulin, administration of aldose reductase inhibitors or based on damage that results from over-production of the aminoguaninidine to improve abnormal glucose metabo glucose metabolite, Sorbitol, in the cells of the body, Glucose lism, administration of troglitaZone or agents for the can be converted to Sorbitol by the enzyme aldose reductase. improvement of blood flow have been tested but found to be High levels of Sorbitol may be among the causes of diabetic insufficient when a Single drug was used. Also, according to complications Such as diabetic neuropathy. As a result, a this patent, methods of treatment by combined use of number of pharmaceutical companies have been developing different therapeutic agents which have different functions aldose reductase inhibitors for the purpose of reducing had yet to be established. The patent concludes that com diabetic neuropathy. bined drug therapies for diabetic neuropathy, aiming at recovering once reduced nerve conduction Velocity, have not 0006. It has been established that a wide variety of yet been confirmed. flavanoids are effective inhibitors of aldose reductase, including Such flavanoids as quercetin, quercetin and myre 0013 There remains a need in the art for an effective cetrin. However, U.S. Pat. No. 4,232,040 discloses that treatment for diabetic neuropathy that does not suffer from despite the fact that these flavanoids have been shown in in the disadvantage that it causes Severe side effects, as do Vitro Studies to be among the most potent flavanoids for many aldose reductase inhibitors, for example. aldose reductase inhibition, a need exists for aldose reduc 0014. Accordingly, it is the primary object of the present tase inhibitors that can be more effectively used and in lower invention to provide a topical composition that is effective doses than the prior art compounds, including these fla for the treatment of diabetic neuropathy. Vanoids. 0015. It is another object of the present invention to 0007. In fact, numerous patents are devoted to goal of provide a topical composition for the treatment of diabetic developing improved aldose reductase inhibitors. Among neuropathy which does not cause Serve side effects in the these patents are U.S. Pat. Nos. 6,069,168; 5,011,840; 4,210, patients treated with the composition. 667; 4,147,795; 5,866,578; and 5,561,110. Numerous other patents also exist which relate to aldose reductase inhibitors. 0016. These and other objects of the present invention will be apparent from the Summary and detailed descriptions 0008 Another approach to the treatment of neuropathy is of the invention which follow. disclosed in U.S. Pat. No. 5,840,736 (Zelle et al.). In this method, pharmaceutical compositions for Stimulating the SUMMARY OF THE INVENTION growth of neurites in nerve cells comprising a neurotrophic amount of a compound and a nerve growth factor. These 0017. In a first aspect, the present invention relates to a compositions may be administered in a number of ways topical composition for the treatment of diabetic neuropathy. including orally and topically. The composition comprises a cold compounded mixture of US 2002/0115618 A1 Aug. 22, 2002 a compound that promotes Synthesis of nerve growth factor, (19)-triene. The preferred nerve growth factor used in the an aldose reductase inhibitor and an antioxidant formulated topical composition is Vitamin D. Also, pharmaceutically in a pharmaceutically acceptable carrier. It has been found acceptable Salts of the compounds that promote Synthesis of that this combination of active agents provides significant, nerve growth factor may be employed. effective relief of the Symptoms of diabetic neuropathy, as well as at least partial recovery of lost neurological function 0023 The compound that promotes synthesis of nerve in Some cases. In View of the consensus in the art that growth factor is used in an amount effective to promote the effective combinations of various active agents have not synthesis of nerve growth factor of about 10,000 to about 3 been demonstrated to be effective for the treatment of million IU. per kg of the composition. More preferably, the diabetic neuropathy, the present invention provides a Sur compound that promotes Synthesis of nerve growth factor is prising and unexpected effect. In addition, the topical com employed in an amount of about 50,000 to about 2 million positions of the present invention, when used in effective IU per kg of the composition, and most preferably an amounts to treat diabetic neuropathy, do not exhibit the amount of 100,000 to about 1 million IU is used per kg of Severe side effects of many prior art compositions proposed the composition. for treatment of this ailment, 0024. The preferred compounds that induce synthesis of 0.018. In a second aspect, the present invention relates to nerve growth factor may, in addition to this activity, also a method for the topical administration of a composition in function to prevent neurotrophic deficits. This additional accordance with the present invention for the treatment of effect of the preferred compounds may also contribute to the diabetic neuropathy. In the method, an effective amount of overall beneficial effect of the topical composition of the the composition of the invention is topically administered to present invention. the areas of the body that have been adversely affected by 0025. In order to formulate the compound that promotes the diabetic neuropathy on a regular basis over a period of Synthesis of nerve growth factor in the topical composition time sufficient to provide the beneficial effects of relief from of the present invention, it may be necessary to use a the Symptoms and at least Some recovery of the damaged dispersant. Suitable dispersant materials are known to per nerve tissues. Sons Skilled in the art. A particularly Suitable dispersant for 0019. In a third aspect, the present invention relates to a the compounds that promote Synthesis of nerve growth pharmaceutically acceptable carrier for topical compositions factor is corn oil. Corn oil also has the advantage that it is that provides excellent dispersions and/or Solutions of active a natural product. The amount of corn oil used is an amount ingredients and good penetration through the skin to the Sufficient to disperse the compound that promotes Synthesis areas to be treated. The carrier for topical compositions may of nerve growth factor. also include one or more materials that provide beneficial 0026. The second active ingredient of the topical com properties to the skin Since many Sufferers from diabetic position of the present invention is an aldose reductase neuropathy develop skin problems. Such as ulcers, lesions or inhibitor. Numerous Suitable aldose reductase inhibitors are cell damage. known to perSons skilled in the art. Again, Suitable aldose reductase inhibitors are those that do not induce Significant, DETAILED DESCRIPTION OF THE adverse side effects when topically applied to a patient in an PREFERRED EMBODIMENTS amount effective for aldose reductase inhibition, and which do not react with one or more of the ingredients of the topical 0020. In a first aspect, the present invention relates to a composition resulting in a Substantial loSS of activity of one topical composition for the treatment of diabetic neuropathy. or more active ingredients of the composition. Preferred The composition includes a compound that promotes Syn aldose reductase inhibitors are those that occur naturally in thesis of nerve growth factor, an aldose reductase inhibitor the human body and/or materials obtained from plants or and an antioxidant formulated in a pharmaceutically accept animal which may be ingested or topically applied by able carrier for a topical composition. humans without Significant, adverse Side effects in the 0021. The compound that promotes synthesis of nerve amounts used or derivatives thereof growth factor may be Selected from Suitable compounds that 0027 AS mentioned above, numerous aldose reductase have been shown to have this activity. Suitable compounds inhibitors are known to persons skilled in the art. However, that promote Synthesis of nerve growth factor are those that Significant adverse side effects are associated with the use of do not induce Significant, adverse Side effects when topically many aldose reductase inhibitors in humans. Thus, it is applied to a patient in amounts that promote Synthesis of important to Select one or more aldose reductase inhibitors nerve growth factor, and which do not react with one or for use in the topical composition of the present invention more of the ingredients of the topical composition resulting based on minimizing the risk associated with use of the in a Substantial loSS of activity of one or more active aldose reductase inhibitor taking into account the amount of ingredients. Preferred compounds for promoting Synthesis that particular inhibitor that must be employed to achieve the of nerve growth factor are those that occur naturally in the desired level of aldose reductase inhibition. Different aldose human body and/or materials obtained from plants or animal reductase inhibitors exhibit different levels of inhibition. which may be ingested or topically applied by humans With this in mind, the preferred aldose reductase inhibitors without significant, adverse Side effects in the amounts used for use in the topical compositions of the present invention or derivatives thereof are flavonoids and flavonoid derivatives. Exemplary aldose 0022 Exemplary compounds that promote synthesis of reductase inhibitors include (-)-epigallocatechin; (-)-epi nerve growth factor are Vitamin D, Vitamin D derivatives gallocatechin-gallate, 1,2,3,6-tetra-O-gallyol-B-d-glucose, such as 1(S), 3(R)-dihydroxy-20(R)-(1-ethoxy-5-ethyl-5- 2'o-acetylacetoside, 3,3',4-tri-o-methyl-elagic acid; 6,3',4'- hydroxy-2-heptyn-1-yl)-9, 10-seco-pregna-5(Z), 7(E), 10 trihydroxy-5,7,8-trimethoxyflavone; 6-hydroxy-luteolin; US 2002/0115618 A1 Aug. 22, 2002

6-hydroxykaempferol-3,6-dimethyl ether, 7-O-acetyl-8-epi Vitamin E acetate, C-lipoic acid, especially DL-C-lipoic loganic acid; acacetin; acetoside; acetyl trisulfate quercetin; acid, coenzyme Q10, glutathione, catechin, glangin, rutin, amentoflavone, apilin; astragalin, avicularin; axillarin, baica luteolin, morin, fisetin, Sillymerin, apigenin, gingkolides, lein; brazilin; brevifolin carboxylic acid; caryophyllene; hesperitin, cyanidin, citrin and derivatives thereof which chrysin-5,7-dihydroxyflavone, chrySoeriol, chrysosplenol; exhibit antioxidant activity. Even more preferably, mixtures chrysosplenoside-a; chrysosplenoside-d; cosmosiin, of two or more antioxidants are employed in the composi 6-cadinene; dimethylmusSaenoside; diacerylcirSimaritin; tion of the present invention. Particularly preferred antioxi dioSmetin; doSmetin; ellagic acid; ebinin; ethyl brevifolin dant mixtures are ascorbyl palmitate with one or both of carboxylate; flavocannibiside; flavoSativaside; genistein; Vitamin A and Vitamin E acetate. The antioxidants may also gossypetin-8-glucoside; haematoxylin; hispiduloside; be used in the form of their pharmaceutically acceptable hyperin; indole, iridine, isoliquiritigenin, isoliquiritin; iso Salts and this may be preferred in Some cases to increase quercitrin; ionoside, juglanin; kaempferol-3-rhamnoside; Solubility or dispersability, to reduce adverse side effects, kaempferol-3-neohesperidoside, kolaviron; licuraside; etc. linariin; linarin; lonicerin; luteolin, luetolin-7-glucoside; luteolin-7-glucoside, luetolin-7-glucoronide; macrocarpal-a; 0033. The antioxidant is used in an amount of about 1 to macrocarpal-b; macrocarpal-d; macrocarpal-g; maniflavone; about 50 grams per kg of the composition. More preferably, methy Scutellarein, maringenin, naringin; nelumboside; the antioxidant is employed in an amount of about 2 to about nepetin, nepetrin; nerolidol; oxyayanin-a; pectolinarigenin, 30 grams, and most preferably an amount of about 5 to about pectolinarin, quercetagetin, quercetin, quercimertrin; quer 20 grams per kg of the composition. citrin; quercitryl-2" acetate, reynoutrin; rhamnetin, rhoifo 0034. The antioxidants used in the composition of the lin, rutin, Soutellarein; Sideritoflavone, Sophoricoside, Sor present invention are preferably Selected not only for their barin; Spiraeoside; trifolin; Vitexin, and Wogonin, The most antioxidant activity, but also based on other beneficial effects preferred flavonoid and/or flavonoid derivative aldose that particular compounds may provide. For example, ascor reductase inhibitors are quercetin, quercetrin, myricetin, byl palmitate not only has antioxidant activity, but also may kaempferol and myrecetrin Since these compounds exhibit a act as an aldose reductase inhibitor and may help prevent high level of aldose reductase inhibition in combination with degradation of nitric oxide (NO) and thus is a particularly a relatively low toxicity. Also, pharmaceutically acceptable preferred antioxidant for the present invention. Similarly, Salts of these aldose reductase inhibitors may be employed. Vitamin E may also help prevent degradation of nitric oxide 0028. The flavonoids and flavonoid derivatives are also and is thus a preferred antioxidant. Vitamin A is a fat-Soluble preferred since Some of these compounds may provide material and thus is preferred for use due to this additional additional beneficial effects in the composition of the present beneficial property. However, due to its Solubility charac invention. For example, quercetin may act as a chelator for teristics, Vitamin A may need to be formulated in a Suitable transition metals that Some Studies have linked to certain dispersant Such as corn oil in much the same manner as Symptoms of diabetic neuropathy. Flavonoids may also have Vitamin D as described above, Some anti-inflammatory activity and/or may help Stabilize 0035) Suitable additional beneficial properties for com cell membranes, both of which activities may be beneficial pounds useful in the compositions of the present invention in the treatment of diabetic neuropathy. include absorbability when applied topically, aldose reduc 0029. The aldose reductase inhibitor is used in an amount tase inhibition, antioxidant properties, free radical Scaveng of about 2 to about 40 grams per kg of the composition. ing, transition metal chelation, nitric oxide Stabilization, and More preferably, the aldose reductase inhibitor is employed anti-inflamatory activity. in an amount of about 5 to about 30 grams and most preferably an amount of 8 to about 20 grams per kg of the 0036) The compositions in accordance with the present composition. invention may provide one or more of the following ben eficial effects to a patient when topically applied in effective 0.030. Another active ingredient in the composition of the amounts, relief of pain, burning, tingling, electrical Sensa present invention is the antioxidant. The antioxidant may be tions and/or hyperalgesia, increased microcirculation, nitric a single compound or a mixture of two or more compounds. oxide Stabilization, promotes healing of skin ulcers and Also, the antioxidant may include one or more compounds lesions, protein kinase C inhibition, decreased oxidative that provide additional beneficial effects beyond the anti StreSS, anti-inflammation, protection against radiation dam oxidant activity, Such as aldose reductase inhibition, age, particularly ultraViolet radiation, blockage of the for 0.031 Compounds which may be used as antioxidants are mation of leukotrienes, Stabilization of cell membranes, and those which exhibit antioxidant activity when administered promotion of the Synthesis of nerve growth factor. topically without causing any Severe adverse Side affect when used in an amount effective to provide Sufficient 0037. The method of the present invention involves the antioxidant activity, and which do not react with one or more topical application of a composition of the present invention of the ingredients of the topical composition resulting in a to areas of the skin in the vicinity of tissue that suffers from Substantial loSS of activity of one or more active ingredients. diabetic neuropathy. In particular, the present invention is Preferred antioxidants are those that occur naturally in the useful on the patients extremities Such as the fingers, toes, human body and/or materials obtained from plants or animal hands and feet where diabetic neuropathy is often the most which may be ingested or topically applied by humans pervasive. without significant, adverse Side effects in the amounts used 0038. In the method, a suitable amount of the composi or derivatives thereof tion of the invention is applied one to Six times daily as 0.032 More preferred antioxidants are selected from needed to relieve pain and other Symptoms of the diabetic ascorbyl palmitate, ascorbic acid (vitamin C), Vitamin A, neuropathy. Preferably, the composition is applied two to US 2002/0115618 A1 Aug. 22, 2002

four times daily, as needed for pain. A Sufficient amount be employed to facilitate wound healing, for the treatment of should be applied to cover the area afflicted with the diabetic skin cancer and/or one or more Symptoms thereof or as a neuropathy with a thin layer of the composition and the composition for protecting skin from the harmful effects of composition should be rubbed into the skin until little or no radiation Such as radiation breakdown. residue remains on the skin. Treatment begins initially to 004.5 The composition of the present invention is made treat acute Symptoms but may be continued indefinitely to by cold compounding. This is an important feature of the relieve pain, prevent Symptoms of diabetic neuropathy from invention Since one or more of the compounds employed in returning and possibly restore Some nerve and/or skin func the topical composition are Sensitive to heat or other types tion. of energy and thus the activity of the composition may be 0.039 The method of the present invention may provide detrimentally affected as a result of the formulation of the one or more of the beneficial effects described above for the compositions in other manners. Thus, the ingredients of the compositions of the invention. In addition, the method of the topical composition the present invention are merely mixed present invention may provide Some additional beneficial together, without heating using a Sufficient amount of the effects due to one or more of the ingredients contained in the carrier to provide a Substantially homogeneous cream or pharmaceutically acceptable carrier as described in more ointment. It may be necessary to dissolve, disperse or detail below, Suspend one or more of the ingredients prior to cold com pounding in order to ensure Substantially homogeneous 0040. The pharmaceutically acceptable carrier of the distribution of the active ingredients in the composition. present invention is Suitable for use as a carrier for topical compositions wherein the active ingredients are dissolved, 0046) A preferred composition of the invention can be dispersed and/or Suspended in the composition. The carrier made using the following ingredients, all based on use of of the present invention contains at least a hydrophilic one pound of hydrophilic ointment base. 25-35 cc of a 50% ointment base, panthenol or a panthenol derivative and a aqueous Solution of Sodium acid phosphate moisturizing dispersant if needed to disperse one or more insoluble or agent, 5-10 cc of D- or DL-panthenol, 5-10 cc of glycerine, partially insoluble active ingredients in the carrier. 1-3 cc of apricot kernal oil, 3-5 cc of a dispersion of Vitamins A and D in a corn oil base, 10-20 cc of witch hazel extract, 0041) Suitable hydrophilic ointment bases are known to 0.5-2 cc of Vitamin E acetate, 2-4 grams of ascorbyl palpitate perSons Skilled in the art. Exemplary hydrophilic ointment and 4-8 grams of quercetin powder. Optionally, one or more bases suitable for use in the present invention are non-U.S.P. of the glycerin, witch hazel extract, Vitamins A and E and/or hydrophilic ointment bases Such as those made by Fougera, the ascorbyl palmitate can be reduced or eliminate from a Inc. Sufficient hydrophilic ointment base is employed to act particular composition, if desirable or larger amounts of one as a Garrier for the active ingredients of the composition. type of component, i.e. antioxidant, can be employed while Typically the hydrophilic ointment base will make up more reducing the amount of another component of the same type than about 80% of the total composition and more preferably or having a similar type of activity, about 80-90% of the composition is the hydrophilic oint ment base. The hydrophilic ointment base functions as a 0047. The invention will now be further illustrated by the carrier and enhances penetration into the skin. following example. 0042. The panthenol or panthenol derivatives useful in EXAMPLE 1. the present invention include at least D-panthenol, DL 0048. A topical composition including a mixture of an panthenol and mixtures hereof This component of the carrier hydrophilic ointment base, Sodium acid phosphate moistur has skin moisturizing properties and acts as a quick, deep izing agent, a Witch hazel extract carrier, glycerine, apricot penetrating component of the carrier that helps deliver the kernal oil and DL-panthenol as the pharmaceutically accept active ingredients through the skin to the area to be treated able carrier and Vitamins A and D, ascorbyl palmitate, and imparts a healing effect to damaged tissue. The amount quercetin and Vitamin E acetate was prepared by cold of panthenol or panthenol derivative to be employed is from compounding. The formulation of the composition is given about 0.25 to about 10 weight percent, more preferably from in Table 1, about 0.5 to about 5 weight percent and most preferably from about 1 to about 2 weight percent, based on the total 0049. The composition was prepared by first placing the weight of the composition. hydrophilic ointment base in a Stainless Steel bowl and mixing briskly until the ointment becomes creamy. Then, the 0043. The carrier of the present invention may also Sodium acid phosphate, panthenol, ascorbyl palmitate, glyc include additional ingredients Such as other carriers, mois erine, apricot kernal oil, Vitamins A and D, witch hazel turizers, humectants, emollients dispersants, radiation extract, Vitamin E acetate and quercetin are added in that blocking compounds, particularly UV-blockers, as well as order. After each ingredient is added, mixing is continued other Suitable materials that do not have a significant adverse until all traces of dry ingredients have disappeared and a effect on the activity of the topical composition. Preferred Substantially homogeneous mixture is obtained. The final additional ingredients for inclusion in the carrier are Sodium color should be a consistent yellow and the cream should acid phosphate moisturizer, witch hazel extract carrier, glyc have the consistency of cake frosting. The mixture is then erine humectant, apricot kernal oil emollient, and corn oil placed in a Sterile container. All containers which contact the dispersant. composition during mixing must also be Sterilized with, for 0044) Other materials which may optionally be included example, Zephiran choride or a chlorox Solution Such as in the topical compositions of the present invention include betadine. inositol, other B-complex Vitamins, and anti-inflammatory 0050. This composition was topically administered, agents. The composition of the present invention may also under the Supervision of a physician, to Several patients US 2002/0115618 A1 Aug. 22, 2002 diagnosed with the most difficult cases of diabetic peripheral 8-epi-loganic acid; acacetin; acetoside; acetyl trisulfate neuropathy. The topical composition was applied twice daily quercetin; amentoflavone, apilin; astragalin; avicularin; in the morning and afternoon, except that patients were axillarin, baicalein; brazilin; brevifolin carboxylic acid; permitted to apply the composition up to Six times daily, as caryophyllene, chrysin-5,7-dihydroxyflavone, chrySo needed for pain relief over a period of a few days. All of the eriol, chrysosplenol; chrysosplenoside-a; chrysosple eight patients treated experienced immediate positive results noside-d, cosmosiin, Ö-cadinene; dimethylmusSaenos that lasted up to a day or two after treatment was discon ide; diacerylcirSimaritin; dioSmetin; doSmetin; elagic tinued. The effects noted by the patients included the relief acid; ebinin; ethyl brevifolin carboxylate; flavocanni of burning pain, tingling, healing of damaged skin, and biside, flavoSativaside; genistein; goSSypetin-8-gluco reversal of skin discoloration due to impaired circulation. Side; haematoxylin; hispiduloside; hyperin; indole, iri dine, isoliquiritigenin, isoliquiritin; isoquercitrin; TABLE 1. ionoside; juglanin; kaempferol-3-rhamnoside; kaempferol-3-neohesperidoside, kolaviron; licuraside; Ingredient Amount Employed linariin; linarin; lonicerin; luteolin, luetolin-7-gluco Hydrophilic ointment base 1 pound Side; luteolin-7-glucoside; luetolin-7-glucoronide; 50% aqueous solution of Sodium acid phosphate 25 cc macrocarpal-a, macrocarpal-b; macrocarpal-d; macro DL-panthenol 5 cc carpal-g; maniflavone, methy Scutellarein; maringenin, Glycerine 5 cc Apricot kernal oil 3 cc naringin, nelumboside; nepetin, nepetrin; nerolidol; Witch hazel extract 12 cc OXyayanin-a; pectolinarigenin, pectolinarin, quercetag Vitamin E acetate 1 cc etin, quercetin, quercimertrin; quercitrin; quercitryl-2" Ascorbyl Palmitate 2 grams acetate; reynoutrin; rhamnetin, rhoifolin, rutin, Scutel Quercetin powder 4 grams larein; Sideritoflavone, Sophoricoside, Sorbarin; Spi raeoside, trifolin; Vitexin, Wogonin; pharmaceutically 0051. The foregoing detailed description of the invention acceptable Salts thereof, and mixtures thereof. and examples are not intended to limit the Scope of the 5. A topical composition as claimed in claim 3, wherein invention in any way and should not be construed as limiting the aldose reductase inhibitor comprises at least one com the Scope of the invention. The Scope of the invention is to pound Selected from the group consisting of; be determined from the claims appended hereto. quercetin, quercetrin, myricetin, kaempferol and myre What is claimed is: cetrin. 1. A topical composition for the treatment of diabetic 6. A composition as claimed in claim 1, wherein tie neuropathy which comprises a cold compounded mixture of antioxidant comprises at least one compound Selected from an amount of a compound that promotes Synthesis of nerve the group consisting of: growth factor which is effective when administered topically ascorbyl palmitate, ascorbic acid (vitamin C), Vitamin A, in the topical composition to promote Synthesis of nerve Vitamin E acetate, C-lipoic acid, especially DL-C-lipoic growth factor, an amount of an aldose reductase inhibitor acid, coenzyme Q10, glutathione, catechin, glangin, which is effective when administered topically in the topical rutin, luteolin, morin, fisetin, Sillymerin, apigenin, composition to inhibit aldose reductase and an effective gingkolides, hesperitin, cyanidin, citrin, derivatives amount of an antioxidant, formulated in a pharmaceutically thereof which exhibit antioxidant activity, and pharma acceptable carrier for a topical composition. ceutically acceptable Salts thereof. 2. A topical composition as claimed in claim 1, wherein 7. A topical composition as claimed in claim 6, wherein the compound that promotes the Synthesis of nerve growth the antioxidant comprises a mixture of at least two different factor is Selected from the group consisting of: compounds. vitamin D, 1(S), 3(R)-dihydroxy-20(R)-(1 -ethoxy-5- 8. A topical composition as claimed in claim 1, wherein ethyl-5-hydroxy-2-heptyn-1 -yl)-9, 10-seco-pregna the antioxidant comprises Vitamin E acetate. 5(Z), 7(E), 10 (19)-triene, and other vitamin D deriva 9. A topical composition as claimed in claim 1, wherein tives which promote the Synthesis of nerve growth the antioxidant comprises Vitamin A. factor, pharmaceutically acceptable Salts thereof and 10. A topical composition as claimed in claim 1, wherein mixtures thereof. the antioxidant comprises ascorbyl palmitate. 3. A topical composition as claimed in claim 1, wherein 11. A topical composition as claimed in claim 8, wherein the aldose reductase inhibitor is Selected from the group the antioxidant further comprises at least one compound consisting of: Selected from the group consisting of ascorbyl palmitate and Vitamin A. flavonoids, flavonoid derivatives which exhibit aldose 12. A topical composition as claimed in claim 5, wherein reductase inhibiting properties, pharmaceutically the compound that promotes the Synthesis of nerve growth acceptable Salts thereof and mixtures thereof. factor comprises vitamin D. 4. A topical composition as claimed in claim 3, wherein 13. A topical composition as claimed in claim 12, wherein the aldose reductase inhibitor is Selected from the group the antioxidant comprises at least one compound Selected consisting of: from the group consisting of Vitamin A, Vitamin E acetate, (-)-epigallocatechin, (-)-epigallocatechin-gallate, 1,2,3, and ascorbyl palmitate. 6-tetra-O-gallyol-B-d-glucose, 2'o-acetylacetoside; 3,3', 14. A topical composition as claimed in claim 13, wherein 4-tri-o-methyl-elagic acid; 6,3',4'-trihydroxy-5,7,8-tri the antioxidant comprises vitamin A, Vitamin E acetate and methoxyflavone; 6-hydroxy-luteolin; ascorbyl palmitate and the aldose reductase inhibitor com 6-hydroxykaempferol-3,6-dimethyl ether; 7-O-acetyl prises quercetin. US 2002/0115618 A1 Aug. 22, 2002

15. A topical composition as claimed in claim 1, wherein ide; diacerylcirSimaritin; dioSmetin; doSmetin; elagic the pharmaceutically acceptable carrier comprises an acid; ebinin; ethyl brevifolin carboxylate; flavocanni amount of an additive Selected from the group consisting of: biside, flavoSativaside; genistein; goSSypetin-8-gluco Side; haematoxylin; hispiduloside; hyperin; indole, iri D-panthenol, DL-panthenol and mixtures thereof, that is dine, isoliquiritigenin, isoliquiritin; isoquercitrin; Sufficient to promote penetration of the topical compo ionoside; juglanin; kaempferol-3-rhamnoside; Sition into the skin. kaempferol-3-neohesperidoside, kolaviron; licuraside; 16. A topical composition as claimed in claim 1, wherein linariin; linarin; lonicerin; luteolin, luetolin-7-gluco the pharmaceutically acceptable carrier comprises a Suff Side; luteolin-7-glucoside; luetolin-7-glucoronide; cient amount of at least one non-U.S.P. hydrophilic ointment base to form an homogeneous mixture of the active ingre macrocarpal-a, macrocarpal-b; macrocarpal-d; macro dients of the topical composition. carpal-g; maniflavone, methy Scutellarein; maringenin, 17. A topical composition as claimed in claim 16, wherein naringin, nelumboside; nepetin, nepetrin; nerolidol; the pharmaceutically acceptable carrier fiber comprises OXyayanin-a; pectolinarigenin, pectolinarin, quercetag Sodium acid phosphate,. etin, quercetin, quercimertrin; quercitrin; quercitryl-2" 18. A method for the treatment of diabetic neuropathy acetate; reynoutrin; rhamnetin, rhoifolin, rutin, Scutel comprises the Step of applying to the skin of an area afflicted larein; Sideritoflavone, Sophoricoside, Sorbarin; Spi with diabetic neuropathy, an effective amount of a mixture raeoside, trifolin; Vitexin, Wogonin; pharmaceutically which comprises an amount of a compound that promotes acceptable Salts thereof, and mixtures thereof. synthesis of nerve growth factor which is effective when 22. A method as claimed in claim 18, wherein the anti administered topically in the topical composition to promote oxidant comprises at least one compound Selected from the Synthesis of nerve growth factor, an amount of an aldose group consisting of reductase inhibitor which is effective when administered ascorbyl palmitate, ascorbic acid (vitamin C), Vitamin A, topically in the topical composition to inhibit aldose reduc Vitamin E acetate, C-lipoic acid, especially DL-C-lipoic tase and an effective amount of an antioxidant formulated in acid, coenzyme Q10, glutathione, catechin, glangin, a pharmaceutically acceptable carrier for a topical compo rutin, luteolin, morin, fisetin, Sillymerin, apigenin, Sition. gingkolides, hesperitin, cyanidin, citrin, derivatives 19. A method as claimed in claim 18, wherein the com thereof which exhibit antioxidant activity, and pharma pound that promotes the Synthesis of nerve growth factor is ceutically acceptable Salts thereof. Selected from the group consisting of: 23. A method as claimed in claim 18, wherein the com vitamin D, 1(S), 3(R)-dihydroxy-20(R)-(1-ethoxy-5- pound that promotes the synthesis of nerve growth factor ethyl-5-hydroxy-2-heptyn-1-yl)-9, 10-Seco-pregna comprises Vitamin D, the aldose reductase inhibitor com 5(Z), 7(13), 10 (19)-triene, and other vitamin D. prises at least one compound Selected from the group derivatives which promote the synthesis of nerve consisting of: growth factor, pharmaceutically acceptable Salts quercetin, quercetrin, myricetin, kaempferol a-ad myre thereof and mixtures thereof. cetrin, and the antioxidant comprises at least one com 20. A method as claimed in claim 18, wherein the aldose pound Selected from the group consisting of Vitamin A, reductase inhibitor is Selected from the group consisting of Vitamin E acetate, and ascorbyl palmitate. flavonoids, flavonoid derivatives which exhibit aldose 24. A method as claimed in claim 23, wherein the anti reductase inhibiting properties, pharmaceutically oxidant comprises VitaminA, Vitamin B acetate and ascorbyl acceptable Salts thereof and mixtures thereof. palmitate and the aldose reductase inhibitor is quercetin. 21. A method as claimed in claim 18, wherein the aldose 25. A pharmaceutically acceptable carrier for the formu reductase inhibitor is Selected from the group consisting of lation of a topical composition for the treatment of diabetic (-)-epigallocatechin, (-)-epigallocatechin-gallate, 1,2,3, neuropathy which comprises a Sufficient amount of an 6-tetra-O-gallyol-B-d-glucose, 2'o-acetylacetoside; hydrophilic ointment base, and an amount of panthenol or a 3.31,4-tri-o-methyl-ellagic acid; 6.3',4'-trihydroxy-5,7, panthenol derivative Sufficient to promote penetration of one 8-trimethoxyflavone; 6-hydroxy-luteolin; 6-hydroxy or more active ingredients of the topical composition into kaempferol-3,6-dimethyl ether; 7-O-acetyl-8-epi-lo the skin. ganic acid; acacetin; acetoside; acetyl trisulfate 26. A carrier as claimed in claim 25, wherein the hydro quercetin; amentoflavone, apin, astragalin; avicularin; philic ointment base is a non-U.S.P. hydrophilic ointment axillarin; baicalein, brazilin; brevifolin carboxylic acid; base and the panthenol is Selected from D-panthenol and caryophyllene, chrysin-5,7-dihydroxyflavone, chrySo DL-panthenol. eriol, chrysosplenol; chrysosplenoside-a; chrysosple noSide-d; cosmosiin, Ö-cadinene, dimethylmusSaenos