MXPA96004387A - Complexes metal starch for skin and head - Google Patents

Abstract

Methods for preparing suitable compositions for protecting damaged or irritated skin against additional oxidative and biochemical damage are provided, thereby allowing the natural healing process to progress, to accelerate the healing rate of burns and surgical wounds, and to increase the size of the follicles of the hair and the speed of hair growth. The composition comprises, in general, precipitates formed by the complexation of starch from different plants with ionic metals, such as copper (II) and tin (I) salts.

Description

COMPLEXES STALK-GOAL FOR SKIN AND HAIR BACKGROUND OF THE INVENTION Restoring the function of damaged and injured skin continues to be a major health problem despite the development of various medications. Many approaches to skin healing, which are currently being developed, such as the production of growth factor proteins and pharmaceutical drugs with wound healing and occlusive wound healing properties, are beyond the economic reach of many patients. There is a major need for improved, low-cost, skin care products and medicines for less developed countries, particularly in tropical regions, where inadequate health care conditions cause fungal diseases to spread. skin, and the use of flammable cooking agents, such as kerosene, and similar conditions, give rise to the high risk of serious damage to the skin. For these countries, there is a critical need in the production of effective medicines that can be produced at very low cost and that use readily available materials. Even in more developed countries the demand for cost restriction in medical services has increased, necessitating the development of low-cost products for skin care and pharmaceutical agents for wound healing. The procedures, such as hospitalization, for the treatment of skin ulcers in diabetics has been greatly restricted, therefore, for the future, improved and low-cost treatments for wound healing are required. Delayed healing or incomplete healing in humans and other animals causes additional pain and suffering to the patient and markedly increases the complication of injuries and medical costs. Normally the wound continues as chronic pain that requires great attention and medical care to control infection and tissue necrosis. Even when these wounds finally heal, the area of the wound is often free of ability to respond to tactile stimulation and is usually filled with excessive deposits of immature collagen that produces permanent scars. The urgent need for improved compositions that heal wounds extends to wounds generated by surgical procedures. The success of surgical procedures, especially in very ill or elderly patients, is typically a function of the suitability and speed of post-surgical healing. Another aspect that may impede the normal healing response is excessive inflammation of the damaged or injured skin. While the inflammatory process and its concomitant influx of white cells into the affected area are an integral part of the natural healing process, in some cases the inflammatory process becomes excessive and delays healing. The wounded tissue remains static at an early stage of the healing process and can not proceed until its completion. In these cases, compounds with anti-inflammatory activities are used to allow the process to happen normally. A promising approach for the therapeutic treatment of conditions associated with inflammation and preventing the healing of wounds has been the use of metal ions complexed with organic molecules or amino acids, amino acid derivatives and peptides. Some of these complexes have anti-inflammatory activity, while others possess both anti-inflammatory activity and healing actions. Still other complexes have been reported. with actions to stimulate hair growth in addition to anti-inflammatory and / or healed activities, as described, for example, by the applicant in the United States Patent 5,382,431 which is hereby incorporated by reference in its entirety. The use of copper salts or complexes as anti-inflammatory agents for the healing of stomach ulcers in the treatment of patients suffering from acute or chronic arthritis dates from 1940 and 1950 (see for example the reviews of Sorenson, Inflammation, 3: 317 -331 (1976); Agents and Actions 8: 305-331 (1981) and Comprehensive Therapy 11: 49-64 (1985)). The use of copper salts and complexes, such as copper-salicylate complexes, seems to have been abandoned, apparently due to the early promise of steroidal anti-inflammatories, such as hydrocortisone. Other copper complexes with amino acids (tryptophan, lysine), with non-steroidal anti-inflammatory drugs (indomethacin, ketoprofen, acetylsalicylic acid), or with fatty acids (oleic, lauric and caprylic acids) have been studied but, despite being promising , on rare occasions they were developed beyond the pre-clinical phases, apparently due to problems of irritation, toxicity and inadequate efficiency. While many copper complexes have been reported with anti-inflammatory properties, a more limited group has also been reported with curing actions. Heintze (U.S. Patent No. 4,123,511) reported that a copper oleate complex had anti-inflammatory activity and skin healing. Sorenson (US Patent No. 4,440,754) describes the use of complexes of copper (II) salts and amino acids, such as tryptophan or lysine, or with organic molecules such as 3,5-diisopropylsalicylic acid, acetylsalicylic acid or salicylic acid, for avoid and heal gastrointestinal ulcers. Using a wound healing model, Townsend and Sorenson (Sorenson et al., Agents and Actions 8: 305-325 (1981)), found that salicylate-copper accelerates the rate of healing and improves the quality of healing of ulcers surgically induced in rats.

Sorenson also wrote (ibid. And Inflammation 3: 317-331 (1976) that Townsend demonstrated that copper (II) (tryptophan) 2 increased the speed of ulcer healing in a surgically induced ulcer model. The increase in healing apparently was due to a faster repitelialization of the wound and an increase in the quantity or quality of the collagen. Fine collagen fibers, in a normal orientation, developed in treated animals, in contrast to untreated animals in which the new collagen was very dense and composed of disoriented bundles of thick interwoven, resembled the scar tissue. Federici and Bertolotto (EP 450,398 and IT 9,019,948) report that the chondroitin-copper (II) sulfate complexes have anti-inflammatory activity. European Patent No. EP 66,283 discloses that "eustatic" compositions containing a non-toxic metal ion (including copper) and a glycosamino-glycan of hyaluronic acid or chondroitin sulfate are useful as a healing (wound healing by closure). Patent Application UK GB 2 044 265 discloses metal complexes (including copper) of adenosine triphosphate, as auxiliaries in the recovery of bone tissue in cases of fracture, as well as in osteoporosis and bone cysts. Konishi (U.S. Patent No. 4,461,724) reports that the tetrapeptide Gly-Ser-His-Lys and the peptides of related structures possess anti-inflammatory and healing actions when complexed with metals such as ionic copper and zinc. Yu (U.S. Patent No. 4,053,630) discloses the use of cysteic acid and its cysteic sulfinic acid or homocysteic acid derivatives, chelated with metal ions such as ferric, cupric, zinc or aluminum ion, to form compositions that dampen the symptoms of diseases characterized by keratinization defects and a remission of ichthyosis, dandruff and acne was achieved. Bertilli (U.S. Patent No. 4,156,737) suggests that copper complexes of p-aminomethyl-benzene sulfonamide have curative and protective effects on skin burns. Van Scott (U.S. Patent No. 4,283,386) reports that metal salts (copper, zinc or aluminum) formed from cysteic acid, cysteinsulfinic acid and homocysteic acid, have therapeutic actions to produce remissions in dry and brittle skin, warts and keratoses. palmar and plantar hyperkeratosis. Niwa (Dermatological 179 SI: 101-106 (1989)) and Bergren et al. (Am. Surg., 54: 333-336 (1988)) found that the anti-inflammatory protein Cu, Zn-superoxide dismutase also acts to improve the healing process. Pickart (see, for example, PCT Publications WO 91/14437, WO 91/12267, WO 91/05797, WO 91/03488, WO 89/12441, WO 88/26448, WO 88/08851, EP Patents EP 190,736, EP 189,182; and U.S. Patent No. 4,767,753) describe the synthesis and use of metal complexes of Gly-His-L-Lys as anti-inflammatory and curing agents. A number of metal complexes have been used to promote hair growth. Yamashiki (Japanese Patent 70018997) used a copper-pantothenate complex to intentionally promote the growth of hair roots and promote skin functions. Morelle (UK Patent GB 2097256, Patent DE 32212448) used amino acid derivatives (amino acids N-butyryl) complexed with copper and other metals for cosmetic and therapeutic purposes, including their use as hair and skin stimulants. Banfi et al.

(U.S. Patent No. 4,503,047) discloses a composition containing mainly one or more sulfur-containing amino acids and copper (II) ions plus small amounts of allyl isothiocyanate and rhodanide ions to produce hair growth stimulating actions. Pickart (for example, WO 91/07431, 88/08695 and EP 288,278) found a number of metal complexes of Gly-L-His-L-Lys derivatives to increase the size of the hair follicle and the speed of hair growth . Despite the therapeutic promises of the aforementioned metal complexes, toxicity and tissue irritation with many metal complexes occur (see, for example, Johnson et al., Inorg, Chem. Acta. 67: 159-165 (1982); Pickart et al., Biochem. Pharm .. 32: 3868-3871 (1983), Pickart et al., Lymphokines 8: 428-446 (1983)). For example, while the copper-salicylate complexes and various copper-salicylate analogues possess anti-inflammatory activities, other salicylate analogs such as the copper (II) complex of salicylaldehyde benzoylhydrazone are highly toxic to tissues. Similarly, copper (II) - Gly-L-His-L-Lys supports cell viability and possesses anti-inflammatory and healing actions, even when synthetic analogs close to aroylhydrazone in its copper binding region are extremely toxic to cells and tissues. Another problem with copper complexes for therapeutic use relates to the binding affinity of the copper ion with the complexing molecule. While a defined copper complex can be synthesized, its therapeutic use causes the complex to be in the physiological environment of the tissues, where a plethora of virtually hundreds of compounds competes to bind to the copper ion, which can form electrostatic bonds of up to six separate molecules. If the copper is removed from the complex and loosely bound, then tissue irritation occurs (see Raju et al., J. Nati, Cancer Ins .. 69: 1183-1188 (1982)). Other complications arise when these metal complexes are formulated in creams or carrier ointments. Several chemical agents are added to the formulations to increase the adhesion to the skin and to the surfaces of the wound and to improve the penetration of the complexes into the target tissue. Still, because many of these substances also bind to metals, the expected therapeutic benefits can be significantly nullified or attenuated. Also, detergents such as sodium dodecyl sulfate are used to aid in the mixing of the water and oil phases of the emulsions and to stabilize the formulations. However, these detergents by themselves are irritating to the tissues and can delay healing.

Another problem encountered with many of the metal complexes intended for therapeutic use is that they can not be thermally sterilized, therefore, to meet safety requirements, high concentrations of chemical antimicrobial agents must be added, during manufacture, to inhibit the growth of microorganisms and the transmission of viruses. These antimicrobial agents can also inhibit the viability and function of a host cell, such as macrophages and fibroblasts that are involved in the maintenance and repair of the skin and other tissues, and in this way agents can delay the healing response. What is needed in the art are compositions useful in protecting the tissues, healing the tissues and / or stimulating hair growth, wherein the compositions are produced conveniently and at a low cost. Preferably, the compositions can be sterilized without loss of bioactivity and can be formulated for topical application without the use of detergents or other potentially irritant compounds.

The ideal composition should also adhere well to the skin and other materials such as wound healing (for example adhesive bandages). To accelerate the time and cost required for regulatory approvals, compositions must be prepared from materials that are generally recognized as safe by regulatory agencies and can thus be used with minimal safety concerns and minimal regulatory barriers. It is quite surprising that the present invention meets all these needs and with other related ones.

SUMMARY OF THE INVENTION The present invention provides compositions and methods for accelerating the healing of topical wounds and skin irritation, to protect the skin from harmful effects of oxidation and to increase the size of the hair follicles and the speed of hair growth. in warm-blooded animals. The compositions useful in these methods, including the pharmaceutical compositions, are prepared from starch pastes that are complexed with an ionic metal. Thus, in one aspect of the invention there are provided methods for preparing pharmaceutical compositions useful in accelerating topical wound healing or increasing hair follicle size and hair growth in a warm-blooded animal. A starch is combined with a useful amount of an aqueous solution of an ionic metal salt, and then adjusted to a range of acidity useful for products for application to the skin. Typically, the starch is conveniently obtained from plant products such as wheat, corn or potato. The starch is then complexed with an ionic metal such as copper (II), tin (II) or zinc (II). The resulting aqueous mixture is composed of complexes of starch and metal ions. The mixture can be adjusted, for example with water or the like, to produce a mixture similar to a sticky paste. The mixture can be used directly or combined with a pharmaceutically acceptable carrier to form a cream or lotion, in a concentration of between about 10% and about 50% of the starch-ionic metal complex or more. The preparation can be used or pasteurized, as desired, without destroying the healed or hair growth stimulating activity of the metal starch-ion complex. In other embodiments, the invention provides methods for improving the recovery of the skin of a warm-blooded animal that has wounds, such as surgical incisions, burns, inflammation or minor irritation due to oxidative damage, etc. The methods comprise administering to the wound or irritation of the skin a therapeutically effective or, in some cases prophylactically effective amount of a composition comprising metal starch-ion complex.

Due to the paste-like adhesiveness of the compositions of the invention, the replication to the skin is decreased in comparison with other topical formulations and topical compositions. Still other modalities are related to compositions and methods for increasing the size of the hair follicle and the speed of hair growth in warm-blooded animals, such as humans. The methods comprise administering to the skin, in the area in which the hair growth is desired, an amount of the metal starch-ion complex sufficient to increase the size of the hair follicle and the speed of hair growth in the animal. Typically, the composition will be administered topically as a cream, and will be applied daily until hair growth is observed and for a sufficient time afterwards to maintain the desired amount of hair growth.

DESCRIPTION OF SPECIFIC MODALITIES By means of the present invention, compositions and methods are provided for treatments for protection of damaged skin and thus allow the process of natural healing to proceed, to improve the regenerative processes of the tissue in the skin of warm-blooded animals., and to stimulate hair growth in warm-blooded animals. The composition is formed by the complexing of starches from various sources (for example wheat, corn, potatoes) and metals in ionic form such as copper, zinc, indium or tin. The metal starch-ion complexes of the present invention are prepared from starches extracted from any of the variety of sources. Most conveniently, starches are those that are widely available at a relatively low cost, such as wheat, corn, potatoes, oats, peas, beans, rice, soybeans and barley. These starches are widely available from commercial sources. By "starch" is meant, in general, a high molecular weight carbohydrate polymer, usually in the form of amylose or amylopectin, with a molecular weight typically in excess of 100,000 Daltons. To produce the useful metal starch-ion complexes of the present invention, the starch is complexed with one or more metal ions, such as copper, indium, tin, zinc or the salts thereof, such as sulfate, acetate, phosphate, chloride, citrate, succinate, oxalate, cinnamate, tartrate, fumarate, maleate, glutarate, etc. By complexed it is understood that starches and metal ions form electrostatic bonds, although this mechanism is offered only as an explanation and not as a limitation. In a method for preparing the metal starch-ion complex, the starch is mixed with sufficient water (at an ambient temperature of about 22-25 ° C) to form a thick paste. To obtain this paste, wheat starch (1 gram) is mixed with approximately 10 ml of water, while corn starch (1 gram) and potato starch (1 gram) require only about 3 ml of water. Then, the paste is mixed with aqueous solution of a metal salt, copper (II) chloride or tin (II) chloride, tin chloride (IV), indium (III) chloride or zinc (II) chloride, at a salt concentration of about 10 to 50% (w / v), more preferably about 20% (w / v). The volume of the added metal salt solution corresponds to the amount that is needed to obtain a final metallic concentration in the paste of 0.3 to 1.2% (w / w), although this concentration can vary considerably. The addition of the metal salt can reduce the pH of the paste by about 3.0 and thus the pH of the paste can be raised to 6.5, for example, by the careful addition of 1N sodium hydroxide or the like. This pH is useful for skin preparations but other pH levels close to neutrality, or in a slightly acidic range, may also be effective. The sticky paste can be applied directly to the skin or formulated into creams and skin lotions at concentrations typically of 5 to 20% (w / w) although higher concentrations are also effective. The thick paste can also be diluted with water to form a workable paste that spreads easily on the skin, but does not drip. The metallic starch-ion complexes of the invention can be administered for a variety of uses, therapeutic, prophylactic or cosmetic, in humans or in veterinary applications for other warm-blooded animals. Among the veterinary animals particularly suitable for treatment with the present composition are the equine, bovine, porcine, ovine, caprine, canine, avian, feline, etc. species. The pharmaceutical preparations and compositions thereof are intended to be used locally, topically, orally or parenterally (for example subcutaneous injection) for prophylactic and / or therapeutic or cosmetic treatment. Preferably, the pharmaceutical compositions are administered locally, for example topically as a paste, cream or ointment. To be administered to warm-blooded animals, the metal ion-starch composition will typically be sterilized and incorporated into pharmaceutical or veterinary formulations. The compositions comprising the metal starch-ion complexes can be sterilized by well-known conventional sterilization techniques, or by pasteurization or boiling, without appreciably adversely affecting the biological activity of the metal starch-ion complexes. The compositions may contain pharmaceutically acceptable excipients such as those required to approximate physiological conditions and as necessary to prepare compositions for convenient administration, such as pH adjustment and pH regulating agents, and delivery vehicles. Current methods for preparing pharmaceutically administrable compounds will be known and apparent to those skilled in the art and are described in detail in, for example, Re-ington's Pharmaceutical Science, Mack Publishing Co. Easton, PA (1985), which is incorporated herein by reference. reference. Depending on the intended mode of administration and the intended use, the composition can be converted into a solid, semi-solid or liquid dosage forms, such as powders, granules, crystals, liquids, suspensions, liposomes, pastes, creams, ointments, etc. ., and may be in the form of suitable unit doses for the administration of relatively precise doses. The composition may include a conventional pharmaceutical carrier or excipient, and in addition, may include other medicinal agents, growth factors, wound sealants, carriers, etc., as will be described below. For semi-solid compositions, as will be suitable for pastes and creams intended for topical administration, metal starch-ion complexes may be provided separately or may form compounds with conventionally non-toxic carriers, such as, for example, aloe vera gel , squalene, glycerol stearate, polyethylene glycol, cetyl alcohol, stearic acid and propylene glycol, among others. These compositions may contain between about 5-100% of the active ingredient, and more preferably between about 20-40%. The concentration of metal starch-ion complexes in these formulations can vary widely, and will be selected primarily for their intended use, viscosities, etc., according to the particular mode of administration that is selected. Current methods for preparing these dosage forms are well known, or will be apparent to those with expertise in this field; for example, see Remington's Pharmaceutical Science, supra. The composition or formulation to be administered, in any case, will contain a sufficient amount of metallic starch-ion complexes to achieve the desired therapeutic or prophylactic effect in the subject being treated. The tissue healing compositions of the invention are administered to a warm-blooded animal, for example, humans, suffering from a wound, oxidative damage to the skin, inflammatory lesions on the skin, as described above, in a sufficient amount. to allow the healing process to proceed more quickly than if the patient did not receive treatment. In the case of an animal suffering from decreased size in the hair follicle and hair growth prevented, the compositions of the invention are administered in an amount sufficient to increase the size of the hair follicle and the speed of hair growth. The amounts adequate to achieve these effects are defined as "therapeutically effective doses". The amounts effective for this use will depend on the severity of the wound, irritation, etc., in the case of wound healing, and the degree of decrease in the size of the follicle in the case of impaired growth of the hair and the general condition of the hair. health of the patient being treated, but generally ranges from about 1 mg to about 25 mg per day of the starch-metal complex per day per square centimeter of the wound site, doses of between about 5 mg being most commonly used to approximately 10 mg per day per square centimeter of the wound site. Maintenance doses over a prolonged period of time can be adjusted as necessary. For veterinary uses, higher levels may be administered as necessary. The determination of the actual amounts of metal starch-ion complexes necessary to treat a particular wound or particular conditions as described above, will be done by typical empirical methods well known in the art. In prophylactic applications, the compositions containing the metal starch-ion complexes are administered to a host susceptible to skin lesions or the like, or at risk of presenting them, to improve the own anti-oxidative and wound-healing capabilities of the host. This amount is defined as a "prophylactically effective dose" in this use, the precise amount again depends on the condition of the host and the general state of health, but in general it varies from about 0.1 mg to about 10 mg per day per centimeter square of skin, more commonly from about 1 mg to about 3 mg per cm2 of skin per day. Simple or multiple administrations of the composition can be effected.

The metal starch-ion complexes of the invention can be administered in relatively large amounts without serious side effects, although indiscriminate use can cause discoloration of the skin. In cases where the compositions are administered to inhibit oxidative or biochemical damage to the skin or to those suffering from only mild irritation or inflammation of the skin, the dose may be adjusted in accordance with the low maintenance levels. The composition of the invention, including the pharmaceutical compositions, can be administered alone or as adjunctive therapy or prophylaxis. The metallic starch-metal compositions can be used in combination with other compositions, as described in co-pending, jointly owned US Patent No. 5,382,431 and USSN Patent Application 08 / 218,392 and 08 / 219,047, each of which is incorporated herein by reference. which is incorporated herein by reference in its entirety, or with other known growth factors to improve other aspects of healing. In this way, a synergistic effect can be achieved that leads to a higher clinical efficiency than that obtained with any simple factor. In addition, while the compositions described herein stimulate one aspect of the healing process, clinical wounds can differ considerably in their properties and healing patterns, causing a combination of a composition described herein and another factor to be used. For example, nerve regeneration is defective in many burns and, therefore, a specific nerve growth factor can be added to supplement the composition and improve recirimetre of the nerve in the burned area. Examples of factors with other healing properties reported include epidermal growth factor, fibroblast growth factor, nerve growth factor, transformation growth factors, angiogenic growth factors, heparin, fibronectin, fibrin, growth factors. platelet derivatives, enzymatic superoxide dismutase, blood extracts or factors from the blood, and other similar factors. The following examples are offered by way of illustration and not as limitation of the invention.

EXAMPLE I PREPARATION OF ACTIVE COMPONENTS STARCH-METAL This Example describes the methods used for the preparation of the starch-metal complexes having biological activities described below. Wheat starch, corn starch, and potato starch were purchased from Sigma Chemical Company, St. Louis, MO, as well as cupric chloride hydrate ((# C 6641).) Tin (II) chloride, 99% pure, was purchased from Aldrich Chemical Company, Milwaukee, WI In a method to prepare the metal starch-ion complex, a starch was mixed with water (at about 23 ° C) to form a thick paste. , the wheat starch (1 gram) was mixed with 10 ml of water, while the corn starch (1 gram) and the potato starch (1 gram) required only about 3 ml of water. with an aqueous solution of copper (II) chloride or tin (II) chloride, at a salt concentration of 20% (w / v), where the volume of the added metal salt solution was the amount needed to obtain a final metallic concentration in the paste of approximately 0.3 to 1.2% (w / w). the metal salt reduced the pH of the paste by about 3.0. The pH of the pulp was then raised to 6.5 by the careful addition of 1N sodium hydroxide. This pH is useful for preparations for the skin but other pH levels close to neutrality, or in a slightly acidic range, are also effective. The starch-copper complexes are used as skin protective agents that serve as a barrier in irritated or damaged skin. The paste resembling a rubber adheres to the skin and forms a protective barrier. Damaged or irritated skin heals remarkably quickly after treatment with this type of composition. As described below, starch-er and starch-tin complexes were used to promote hair growth and enlargement of hair follicles. In hair growth models in mice, the application of these complexes to the skin produced a marked stimulation of hair growth after 8 to 12 days. Other types of starch-metal complexes, where the starch comes from plants, and other metal salts such as sulfate, acetate, phosphate and etc., would be expected to work in a similar manner.

EXAMPLE II HEALING OF SURGICAL WOUNDS WITH STARCH-COPPER COMPLEXES This Example describes the use of a paste prepared with starch-copper complexes to accelerate the healing of surgical incisions in animals. Surgical incisions (1.25 cm) were made on the back of anesthetized 35 gram Swiss-Webster mice. Immediately after the surgical incision and 24 hours later, the wounds were covered with a thin film of the paste containing the active starch-copper complexes of Example I above. The control wounds were left untreated or they received starch without the complexed metal. As seen in Table 1, the wounds treated with the starch-copper active complex healed faster than the control wounds. Because wounds that heal quickly tend to contract and become rounder, the healing activity can be related to the length of the wound after 9 days. Each group consisted of eight mice.

Table 1: Effect of the Starch-Copper Complex on the Incision Length Test Group Length of the wound after 9 days (cm.) Control 0.91 ± 0.12 Wheat starch-without copper 0.88 ± 0.19 Wheat-copper starch complex 1.0% 0.25 ± 0.09 Wheat-copper starch complex 0.3% 0.37 ± 0.09 Corn starch-without copper 0.98 ± 0.23 Corn starch complex - copper 1.0% 0.31 ± 0.14 Corn starch complex - copper 0.3% 0.40 ± 0.06 Potato starch-without copper 0.92 ± 0.19 Potato-copper starch complex 1.0% 0.41 + 0.15 Potato-copper starch complex 0.3% 0.47 ± 0.14 EXAMPLE III HEALING OF WOUNDS PRODUCED BY BURNING, WITH THE ALMIDÓ -COBRE COMPLEX This example demonstrates the increase in wound healing produced by burning in animals when using starch-copper compositions applied topically. Second degree burns were induced in the shaved backs of anesthetized mice, placing a circular brass rod (1.25 cm diameter, area of the wound = 1.22 cm) (temperature 100 ° C) in contact with the skin for 7 seconds. Immediately after burning, and 24 and 48 hours later, the wounds were covered with a thin film of the paste containing the active starch-copper complex of Example I above. The control wounds were left untreated. The wounds were plotted on the anesthetized mice and digitized from a computerized scanning bed, and the area was calculated from the computerized number of pixels. The wounds treated with the active starch-copper complexes showed less post-burn inflammation and healed much faster than untreated control wounds. Each group that consisted of 8 mice.

Table 2: Effect of the Starch-Copper Complex on Burn Wounds Test Group Wound Area after 15 days (cm) Control 0. 90 + 0 17 Wheat-copper starch complex 0.3% 0.34 ± 0.13 Cornstarch-copper complex 0.3% 0.33 ± 0.09 Potato-copper starch complex 0.3% 0.42 ± 0.12 EXAMPLE IV REDUCTION IN THE INFLAMMATION OF THE SKIN AFTER A BURN This Example demonstrates the ability of the copper-starch complex to reduce the inflammation associated with minor skin burns. Very mild thermal burns were induced in the shaved backs of anesthetized mice (8 mice in each group) by placing a circular brass rod (1.25 cm in diameter, irritated area = 1.22 cm) (60 ° C) in contact with the skin. for 5 seconds. This produced a slight irritation of the skin characterized by redness in swelling, but very rarely a loss of skin tissue. Immediately after the induction of thermal damage, the irritated area was covered with a thin film of the paste containing one of the following active complexes of Example I: wheat starch with 0.3% copper, corn starch with 0.3% copper ion , or potato starch with 0.3% copper ion. The control wounds were left untreated or they received only starch that did not contain the metal complex. Wounds were observed at daily intervals. On day 3, the thermal wounds of the controls were still red and swollen while the skin with any of the three starch-copper complexes had minimal redness and swelling.

EXAMPLE V PASTERIZATION OF ACTIVE COMPOSITION ALMIDÓ -COBRE Pasteurization consists of heating a solution at 160 ° F for 30 minutes, which practically exterminates all microorganisms except the most resistant ones. For this test, several starches were complexed with copper chloride by the methods described above in Example I. The resulting paste was mixed vigorously, the pH was raised to a pH of 6.5 and then heated to 160 ° F for 30 minutes.

After cooling to room temperature, the pastes were applied to surgical incision wounds in mice in the manner described in Example II. The healing activity was similar to that observed with the unpasteurized active compositions as shown in Table 3. Each group had six mice.

Table 3: Effect of pasteurization on the active complex Test group 'Length of the wound after 9 days (cm) Control 0.89 ± 0.15 Wheat-copper starch complex 1.0% 0.29 ± 0.13 Corn-copper starch complex 1.0% 0.35 + 0.16 Potato-copper starch complex 1.0% 0.47 + 0.21 EXAMPLE VI STERILIZATION OF THE ACTIVE COMPOSITION BY BOILING This Example demonstrates that the starch-copper complex can be sterilized by boiling and with this still retains practically all the activity of an unsterile formulation. This results in a considerable advantage in that the need to include sensitizing antimicrobial agents in the compositions is avoided. Sterilization by boiling exterminates practically all microorganisms. For this test, 10 grams of soy starch were complexed with copper chloride by the procedure described above in Example I. After adding the copper chloride solution to the soy starch solution, the resulting solution was mixed vigorously, the pH was raised to 6.5 and then heated in a boiling water bath for 10 minutes. After cooling to room temperature, the active composition was prepared as described in Example I, then applied to the surgical wounds in mice in the manner described in Example II. The healing activity observed with the sterilized starch-copper complexes was similar to the results obtained with the active compositions without sterilization. Each group was composed of six mice.

Table 4: Effect of sterilization on active broths Test group Wound length after 9 days (cm) Control 0.89 ± 0.15 Wheat-copper starch complex 1.0% 0.31 ± 0.16 Corn-copper starch complex 1.0% 0.39 ± 0.19 Potato-copper starch complex 1.0% 0.42 ± 0.18 EXAMPLE VII ADHERENCE OF STEM-COPPER TO SKIN PASTE This Example describes the use of an active starch-copper complex to improve the adherence of wound healing on the surface of the skin. Copper starch complexes can therefore be used to more effectively cover wounds and seal them with cures. Also, many tapes that are used to hold medical detectors to the skin or catheters in the veins, cause skin irritation. The incorporation of the starch-copper complex in the adhesive used for these tapes would reduce that irritation in the skin and the damage to it. As evidence, the portion covering the wound of an adhesive band (Band Aid ™ brand) was cut and removed from the adhesive portion. The wound coverage portion of the band, which had no adhesive qualities to the skin, was covered with wheat starch complexed with 0.3% copper ion. The band covered with paste was applied to the upper arm of humans and left in place during normal work duties in an office. The band adhered well to the skin during the subsequent 8-hour test. This showed that these wound healing pastes have significant adhesive properties on the skin of humans.

EXAMPLE VIII STIMULATION OF HAIR GROWTH This Example describes the use of compositions containing starch-metal complexes to stimulate the growth of hair follicles in warm-blooded animals. The model used in this test was a mouse model that had been found to successfully predict the therapeutic response in humans (see, for example, U.S. Patent No. 5,118,665, which is incorporated herein by reference). Hair growth in mammals is carried out through active growth stages (anagen) followed by lethargic stages (telogen). The test method generally involves applying hair growth stimulant to the skin of the mice in the telogen phase. The Swiss-Webster mice initiate a telogen phase at approximately 45 days of age and the phase lasts until approximately 90 days of age. After application of the active substance, improved hair growth was noted in a period of 10 to 14 days. For this test, 50-day-old mice were used. The starch compositions containing copper (II) and tin (II) were tested. To test them, the starch-metal pastes were mixed with saline solution (composition of 25% starch and 75% by weight physiological saline). The mice were shaved, and then 0.05 ml of mixture was infiltrated under the skin, by injection. The control mice were injected with an equal volume of saline or with starch without metal. Each group contained 10 mice. After 12 days, the groups were compared. The percentage of mice with hair growth at the injection site and the relative resistance of the hair growth response (on a scale of 1 to 5, where 1 is hardly noticeable growth and 5 is very hair growth). notorious) were determined. The results, shown in Table 7, indicate that all the compositions were active stimulants of hair growth, starch (II) complexes being the most effective agents.

Table 5: Stipulation of the Hair Strand for Completed Alptirrji-Mgtal. By cié - 4Xnto dntensidad growth of the hair average in the growth site of hair injection Control mice 0 0 Wheat Starch - without copper (II) 0 0 Wheat Starch - copper 1% (II) 90 2 .5 Wheat - tin starch (II) 1% 100 4 ^ 0 EXAMPLE IX STIMULATION OF HAIR GROWTH BY TOPICAL APPLICATION The model used in this Example was as described in Example X with the exception that the active starch-metal pastes were applied topically to the skin. The animals were shaved, and then applied 0. 10 grams of the dough to the shaved area, as gently as possible for four consecutive days. The control animals were cleaned with saline or starch not complexed with metal. Each group contained ten mice. After 14 days, groups of mice were compared. The percentage of mice with hair growth in the center of the shaved area and the relative resistance of the hair growth response (on a scale of 1 to 5, where 1 is very little remarkable growth and 5 is quite remarkable growth) were determined. All the compositions were active, tin is the most effective agent (II).

Topical Application of Starch-Metal Complexes to Stimulate Hair Growth. Percent with Intensity Average hair growth in the center growth of shaved hair area.

Control mice 10 0. 2 Wheat starch 10 0. 0 Wheat-copper (II) starch 1% 90 2. 0 Wheat-tin starch (II) 1% 100 4_ 0 It is evident from the above results that the present invention provides complexes of ionic metal-starch complexes for topical skin treatments, wounds and surgical wounds in order to protect damaged skin and facilitate natural healing processes, to improve the regenerative processes of the tissue in the epidermis and to stimulate hair growth in warm-blooded animals. The invention also provides inexpensive methods for preparing and formulating compositions for topical administration. Although the foregoing invention has been described with some details by way of illustration and example, in order to give clarity to its understanding, it will be obvious that certain changes and modifications may be made that fall within the scope of the appended claims.

Claims (25)

1. NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and, therefore, the content of the following CLAIMS is claimed as property; A method for accelerating the healing of topical wounds in a warm-blooded animal, comprising: administering to the wound a therapeutically effective amount of a composition comprising a starch complexed with an ionic metal.
2. 2. The method according to claim 1, wherein the ionic metal is copper (II), and the therapeutically acceptable salts thereof.
3. 3. The method according to claim 1, wherein the ionic metal is tin (II).
4. 4. The method according to claim 1, wherein the starch is obtained from wheat, corn, potato or soybean.
5. A method for improving the recovery of the skin of a warm-blooded animal suffering from irritation, which comprises administering to the skin irritation a therapeutically effective amount of a composition comprising a starch complexed with an ionic metal.
6. 6. The method according to claim 5, wherein the ionic metal is copper (II).
7. 7. The method according to claim 5, wherein the starch complexed with ionic metal is obtained from wheat, corn, potato or soybean.
8. 8. A method for protecting the skin from oxidative damage and helping to recover skin wounds in a warm-blooded animal, comprising: administering to the skin or wound site a prophylactically or therapeutically effective amount of a composition that comprises a starch complexed with an ionic metal.
9. The method according to claim 8, wherein the ionic metal is copper (II), and the therapeutically acceptable salts thereof.
10. The method according to claim 8, wherein the starch is prepared from wheat, corn, potato or soybean.
11. A method for increasing the size of the hair follicles and the hair growth rate in a warm-blooded animal, comprising: administering to the animal's skin a composition comprising a starch complexed with an ionic metal in an amount enough to increase the size of the hair follicle and the speed of hair growth in the animal.
12. The method according to claim 11, wherein the composition is topically administered to the skin.
13. The method according to claim 11, wherein the composition is administered by subcutaneous injection.
14. The method according to claim 12, wherein the composition is administered topically, on a daily basis, to the area of the skin where improved hair growth is desired.
15. 15. The method according to claim 11, wherein the ionic metal is copper (II) or tin (II), and the therapeutically acceptable salts thereof.
16. 16. The method according to claim 11, wherein the ionic metal is tin (II).
17. 17. The method according to claim 11, wherein the starch is prepared from wheat, potato or soybean.
18. 18. A pharmaceutical composition useful for accelerating the healing of topical wounds of a warm-blooded animal, comprising a therapeutically effective amount of an animal complexed with an ionic metal and a pharmaceutically acceptable carrier.
19. 19. The pharmaceutical composition according to claim 18, wherein the ionic metal is copper (II) or tin (II), and the therapeutically acceptable salts thereof.
20. 20. The pharmaceutical composition according to claim 18, wherein the starch comes from wheat, corn, soybean or potato.
21. The pharmaceutical composition according to claim 18, wherein the ionic metal starch complex is present in the composition at a concentration of 10% to 50%.
22. 22. A pharmaceutical composition for increasing hair follicle size and hair growth rate in a warm-blooded animal, comprising a hair growth stimulating amount of an ionic metal-starch complex and a pharmaceutically acceptable carrier.
23. 23. The pharmaceutical composition according to claim 22, wherein the starch-metal complex is present in the composition at a concentration of 5% to 25%.
24. 24. The pharmaceutical composition according to claim 22, wherein the ionic metal is copper (II) or tin (II), and the therapeutically acceptable salts thereof.
25. 25. The pharmaceutical composition according to claim 22, wherein the starch comes from wheat, corn, soy or potato.