MXPA97003694A

MXPA97003694A - Profilactico and therapeutic treatment of the sensitization and irritation of the p

Info

Publication number: MXPA97003694A
Application number: MXPA/A/1997/003694A
Authority: MX
Inventors: Kydonieus Agis; J Wille John
Original assignee: Er Squibb & Sons Inc
Priority date: 1994-11-22
Filing date: 1997-05-20
Publication date: 1998-02-01

Abstract

Methods and devices are described for preventing and / or treating an adverse skin reaction in the presence of skin sensitizing or skin irritant agents by administering an effective amount of a diuretic alone or in combination with at least one skin degranulator. mast cells or at least one glucocorticosteroi

Description

PROPHYLACTIC AND THERAPEUTIC TREATMENT OF SENSITIZATION AND SKIN IRRITATION RELATED REQUESTS This is a continuation in part of the US Patent Application Serial No. 08 / 343,156, filed on November 22, 1994.

FIELD OF THE INVENTION The present invention relates to methods and compositions for preventing or treating adverse reactions of the skin or skin sensitizing or skin irritating agents.

BACKGROUND OF THE INVENTION The skin is susceptible to penetration by agents that sensitize the skin or irritate the skin. As used herein, the term "skin sensitizing agent" is a substance that generally causes the formation of memory cells that recognize future contact with the sensitizing agent. This future contact can give by REF: 24760 An adverse reaction results, both locally and in distant places in the body. In general, a "skin irritant" is a substance, (for example, soap) that causes an adverse response, -mediate and generally localized. The response is typically in the form of redness and / or inflammation and does not extend beyond the immediate area of contact, nor does it cause the formation of memory cells. As used herein, the term "agent for prevention or treatment of adverse skin reaction" should collectively mean agents used in the present invention against skin sensitizing agents and / or skin irritants. Allergic reactions of the skin to skin sensitizing agents, known as allergic contact dermatitis (ACD), are immune responses that occur on the skin. The response is the result of the penetration of the skin by a foreign substance, (for example hapten or antigen) that causes a skin sensitization reaction. The ACD is a two-phase process comprising an initial phase of induction followed by an extraction or provocation phase. The induction phase occurs immediately after the first exposure of the hapten skin or antigen and is characterized by the formation of immune memory cells that can subsequently recognize the hapten or specific antigen that was previously introduced to the skin during the first time. The extraction or provocation phase occurs when the skin is subsequently re-exposed to the original hapten or antigen. In the extraction phase, the skin provides an obvious reaction to the presence of the hapten or antigen in the form of an inflammatory response of the skin. The ACD generally results in a persistent, prolonged memory for the hapten or specific antigen. In this way, when the skin is exposed to the hapten or antigen in a subsequent time, there is typically an immediate and often severe inflammatory skin response. The agents that cause allergic contact dermatitis are varied and numerous and include, for example, metals (eg, nickel, chromium, cobalt and the like), fragrances, chemicals, cosmetics, textiles, pesticides, plastics, pollen and the like ( see, for example RJGRycroft et al. "Textbook of Contact Dermatitis"). Therapeutic agents such as drugs can also cause allergic contact dermatitis, particularly when administered transdermally. The transdermal distribution of drugs provides many advantages over alternative routes of administration. Transdermal distribution routes (TDS) for distributing drugs or other beneficial agents are well known (see, for example, US Patent Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454, 4,599,222 and 4,573,995, which are incorporated herein by reference). incorporated herein by reference). A TDS is generally composed of the following components: (a) "building blocks" that include backing, matrix deposit, and an optional layer of separate adhesive; (b) the drug or other therapeutic agent; (c) "additives", which include solubilizers, plasticizers and permeation enhancers; and (d) "impurities" such as residual amounts of monomers, initiators, crosslinking agents, etc., from the polymerization process during the manufacture of the basic components. The conditions under which the TDS are administered are highly favorable to the induction of allergic reactions of the skin, and the following skin reactions may be expected to occur: 1. Irritant reactions to the drug, an additive, an impurity, or a combination thereof; 2. Allergic reactions, especially to low molecular weight components (drug, additive, impurity, adhesive); 3. Local perspiration retention syndrome that results in prolonged occlusion of the skin that causes the blockage of the transpiration ducts. Allergic contact dermatitis presents a significant problem in the transdermal administration of therapeutic agents. It is well known that many drugs, including some commonly sold in the United States of America (eg, clonidine), sensitize the skin when used in a transdermal delivery system. Skin sensitization can occur not only by the transdermally distributed drug, but also by the non-sensitizing drug combined with the permeation enhancers, skin sensitizers, or a combination of a sensitizing drug and an enhancer. of the permeation, sensitizer. The penetration of these sensitizing agents into the skin and the resulting reaction of the skin may persist beyond the time the transdermal skin patch is removed. The reaction of the skin can be a source of discomfort and a clinical complication in a patient suffering from this reaction. Unlike the response induced by skin sensitizing agents, the non-allergic response to skin irritants is immediate and localized and does not involve the activation of the immune system through the production of immune memory cells. The most common response associated with skin irritants is the onset of inflammation. The main steps of the inflammatory response include, the neurological phase, the vascular phase, and the cellular phase. In the neurological phase, transient vasoconstriction typically occurs in the space of approximately 30 seconds of contact with the skin irritant. In the space of approximately one to six minutes of contact, vasodilation occurs followed by the marginalization of neutrophils in the vessels and diapedesis, the passage exterior of the corpuscular elements through the intact walls of the vessels. The non-immune response to an irritant to the skin is the result of a substance that causes direct toxic damage to the skin without the occurrence of allergic sensitization. The response to contact is dependent on the nature of the skin, the skin irritant, its concentration, the contact site in the body and environmental factors such as humidity and temperature. Examples of potential skin irritant agents include water, skin cleansers, industrial cleansing agents, alkalis, acids, oils, organic solvents, oxidizing agents, reducing agents, vegetable matter, animal matter, combinations thereof and the like. Efforts have been made to address the problem of allergic contact dermatitis by prophylactically treating the skin to prevent the onset of the ACD induction phase and / or to prevent therapeutically or reduce the adverse effects of the ACD extraction phase. . For example, U.S. Patent No. 5,202,130 describes which lotions of the lanthanides and organic blockers of the calcium channel can be use individually for the treatment of allergic contact dermatitis. Worfgang Diezel et al., J. Invest. Derm. , Vol. 93, No. 3, pp. 322-326 (September 1989) describes the sensitization of the mice with 1-chloro-2,4-dinitrobenzene and the subsequent treatment with lanthanum citrate and diltiazem hydrochloride to prevent the start of the induction phase of the sensitizing agent. Philip. Ledger, et al., US Patent No. 5, 120,545 describes the prevention of skin sensitization by the administration of an agent that inhibits the process of the antigen such as ammonium chloride. For example, a method for preventing contact sensitization using steroids (eg esters of carboxylic acids of corticosteroids and glucocorticoids) is described in Alfred Amkraut, US Pat. No. 5,118,509 and Peter M. Ross, et al., US Pat. No. 4,897,260. A method for reducing the adverse effects of administering a sensitizing or irritant drug by using methyl nicotinate is described in Michel Cormier et al., US Patent No. 5,451,407.

Methods for treating ACD through blocking the extraction phase after initial exposure to a drug are described, for example, in John McFadden, et al., J. Invest. Derm., Vol. 99, No. 6, pp. 784-786 (December 1992). The delayed-type, tuberculin-induced hypersensitivity reaction in human skin was inhibited by topical application of verapamil hydrochloride prior to or concurrent with tuberculin stimulation. Also, Richard, L. Gallo, et al., Arch. Dermatol., Vol. 125, pp. 502-506 '(April 1989) describes the administration of amiloride hydrochloride, a diuretic as a topical anti-inflammatory agent for the treatment of ACD, particularly in mice sensitized with 2,4,6-trinitrobenzene. As described in the commonly assigned US Patent Application Serial No. 08 / 198,003 filed on February 17, 1994, and references cited therein, irradiation of the skin with intra-violet light B (UVB) is known to be immunosuppressant These effects of UVB are thought to be mediated, in part, by the UVB-induced isomerization of trans-urocanic acid (trans-UCA), a molecule that constitutes approximately 0.5% of the total dry weight in the upper layers of the human epidermis, to cis-urocanic acid (cis-UCA, for its acronym in English). Cis-UCA is known to have several immunosuppressive actions in vivo in a number of experimental systems and is believed to act through histamine-like receptors in the skin. More recently, it has been shown that the impairment by UVB of the induction phase of allergic contact dermatitis to the epicutaneous haptens applied in certain mouse races depends on the participation of the cytokine, tumor necrosis factor-a. (TNFa). It has been suggested that local release of TNFα can inhibit sensitization by trapping Langerhans epidermal cells and preventing them from reaching the drain lymph node where they activate T cells. As described in US Patent Application Serial No. 08 / 198,003, mast cell degranulators such as cis-urocanic acid are effective to prevent or inhibit the skin sensitizing effect of a therapeutic agent administered transdermally. Despite these efforts and the knowledge gained regarding the cause of ACD, there remains a need to develop compositions that effectively prevent the onset of ACD or reduce the adverse effects of ACD after the person has been sensitized to an agent, such as, for example, a transdermally administered agent such as a drug. Likewise, there is a need to develop compositions that effectively prevent reactions for skin irritants. The applicants have gained the knowledge that there is a distinct process step involved in the immune response associated with allergic contact dermatitis, which when interfered with, results in the prevention and / or treatment of, the ACD. This process step is referred to herein as the translation of cellular signals, it is believed to be responsible for the acquisition of memory by T-lymphocytes, for cytokine-mediated regulation of antigen presentation and for other cellular processes as well. Also, applicants have discovered that a particular class of compounds having diuretic properties referred to herein as high limit or loop diuretics alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid achieves a Significant improvement in the desensitization of a patient's skin and prevents and / or treats inflammation of the skin. As a result, the reaction of the skin to skin sensitizing agents or skin irritants is better controlled. The present invention therefore provides prevention and / or treatment of an adverse skin reaction, as well as transdermal therapy that reduces discomfort to the patient.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates in general to methods for preventing or treating allergic contact dermatitis (ACD) and irritation of the skin and to compounds and systems, especially transdermal systems, used in these methods. In one aspect of the invention, there is provided a method for preventing or treating an adverse reaction of the skin caused by the presence of skin sensitizing agents such as therapeutic agents (eg, drug), metals, fragrances, cosmetics, textiles, pollen. , pesticides, plastics, combinations thereof and the like, or skin irritants such as cleansers, cleaning agents, alkalis, acids, oils and the like. The present invention is also applicable to ACD induced by the transdermal administration of an agent, such as, for example, a therapeutic agent such as a drug. In general, the present invention includes a method for preventing or treating an adverse reaction of the skin in the presence of at least one of a skin sensitizing agent and a skin irritating agent comprising administering to a warm-blooded animal a effective amount of an agent preventing or treating the adverse reaction of the skin, comprising at least one loop diuretic alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid. The skin sensitizing or skin irritating agents employed in the present invention can be prepared in the form of a composition containing one or more additives including skin permeation enhancers, excipients and the like. These agents for the prevention or treatment of adverse skin reaction can be administered topically in the form of lotions, creams, sprays and the like, by non-cutaneous routes as well as through the use of transdermal patches. In transdermal applications, the agents can be administered from an individual reservoir that also contains a therapeutic agent or preferably from a separate reservoir and a transdermal patch.

DETAILED DESCRIPTION OF THE INVENTION The present invention is in part directed to methods and systems for preventing the onset of skin sensitization reactions caused by allergic contact dermatitis by treatment before, after or during the induction phase of sensitization and to alleviate this condition once the ACD has progressed to the extraction phase. In one aspect of the invention, the skin is treated with at least one high-limit loop diuretic alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid. The use of a composition containing these agents for treating or preventing the adverse reaction of the skin provides the desensitization of the skin to the presence of the skin sensitizing agents as found from a variety of sources including transdermal systems before, after or during the transdermal administration of the therapeutic agent. These agents for preventing the adverse reaction of the skin provide the inhibition of the immune response and the specific immunotolerance to the provocative antigen. More specifically, an individual administration to the skin of a high-limit or loop diuretic alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid renders the warm-blooded animal specifically insensitive to an antigen, a been known as immunological tolerance. Three known immunosuppressive agents that induce immunotolerance are UVB radiation, cytokine TNF-α and cis-urocanic acid. It is thought that a number of mechanisms are responsible for the induction and maintenance of this tolerant state. Regardless of the mechanism, it is well known that tolerance to an antigen that stimulates a sensitization response can be induced first by presenting the antigen in a tolerogenic form or via a tolerogenic route. The present invention encompasses a method wherein the immune response of an antigen is suppressed and a state of prolonged immunological tolerance is achieved.

High-limit or loop diuretics of the type employed in the present invention affect signal translation. In the renal tubule, these compounds completely interfere with the reabsorption and / or retention of potassium ions by blocking the action of the channels of potassium ions in the loop of Henle. It is believed that these compounds function as pumping contaminants of potassium ions since they directly interfere with the homeostatic regulated ion balance in other cells. The balance of hydrogen, sodium and calcium ions is disturbed by changing the net flux of intracellular potassium ions. Consequently, all cellular processes that depend on the maintenance of intracellularly regulated homeostatic ions are interrupted. In particular, it is known that the process of the translation of cellular signals is highly sensitive to changes in the level of intracellular ions, particularly potassium ions. In another aspect of the present invention, the agents and compositions containing the same are also effective in the prevention and / or treatment of adverse responses caused by skin irritants such as household and industrial cleaners, organic solvents and the like. These agents are effective in disrupting the inflammatory response by limiting the ability of the skin irritant to cause or produce the neurological, vascular and / or cellular phase of inflammation. Examples of loop diuretics for use in the present invention include ethacrynic acid, fluorocemide and butenamide. Ethacrynic acid is preferred for the loop diuretic. The mast cell degranulatory agents useful in the present invention are preferably selected from the group consisting of: cis-urocanic acid, or an analogue or metabolite thereof, PUVA, chloroquine, histamine, capsaicin, morphine sulfate, an ionophore sodium channel, an ionophore of the potassium channel, an inhibitor of the ATPase of the Na + / K + channel, quinine, 4-aminopyridine, and an anti-human IgE antibody, compound 48/80, substance P, estradiol, so atostatin, clonidine , progesterone, carbachol, and frightful. Some mast cell degranulants may be therapeutic agents, in appropriate concentrations. These agents include, for example, capsaicin and clonidine. The cis-urocanic acid analogues, preferred for use in the present invention, include, but are not limited to: (a) a cis or isomer trans-1-furanocrylic acid; (b) a cis or trans isomer of 2-pyrrole acrylic acid; (c) a cis or trans isomer of 2-thiopheneacrylic acid; and (d) dihydrourocanic acid. Preferred cis-urocanic acid metabolites for use in the present invention include, but are not limited to: (a) hista ina; (b) N 1 -ethylhistamine; (c) N: -methylhistidine; (d) histidine; (e) imidazolyrirovic acid; (f) N3-methylhistidine; (g) imidazoleacetic acid; (h) hydantoin-5-propionic acid; e (i) imidazolonapropionic acid. Glucocorticosteroids for use in the present invention, include, for example, (a) hydrocortisone and analogs thereof, (b) beclomethasone, (c) betamethasone and analogs thereof, (d) clobetasol and analogs thereof, ( e) desonide, (f) dexamethasone, (g) fluocinonide, (h) prednisone, and (i) triamcinolone. Hydrocortisone is the preferred glucocorticosteroid. The above methods are useful for preventing or treating the sensitization or inflammation of the skin produced by a variety of skin sensitizing agents such as, for example, a drug selected from, but not limited to, the following group: (a) an inhibitor of the enzyme that converts angiotensin; (b) a beta-adrenergic receptor blocker; (c) an antihypertensive drug other than an enzyme inhibitor that converts angiotensin or a beta-adrenergic receptor blocker; (d) an anti-histamine; (e) an antiasthmatic; (f) a non-anti-inflammatory spheroidal drug; (g) an active drug in the central nervous system, (h) a weight control drug; (i) an anticoagulant; (j) a potassium control drug; (k) an immunomodulatory drug; (1) a decongestant; and (m) proteins and peptides such as insulin and the thyrotropin releasing hormone. More specifically, the therapeutic agents for administration in accordance with the present invention include all major therapeutic areas, including, but not limited to: anti-infectives, such as antibiotics and antivirals; analgesics and analgesic combinations; (such as capsaicin); anorexics; anti-arthritic; anti-asthmatics (such as albuterol), metaproterenol, ketotifen and terbutaline); anticoagulants (such as urokinase); anticonvulsants, antidepressants; antidiabetics; antidiarrheals; antihistamines (such as chlorpheniramine and diphenhydramine); anti-inflammatory agents (such as ketoprofen, prostaglandins, flurbiprofen, diclofenac, indomethacin, piroxicam and ibuprofen); antimigraine agents; anti-movement disease preparations; anti-nauseating; antineoplastic; antiparkinson drugs; antipruritics; antipsychotics; antipyretics; Odic antispas, including gastrointestinal and urinary; anticholinergic; athomimetics, xanthine derivatives, cardiovascular agents, which include inhibitors of the enzyme they convert. angiotensin, such as captropril and fosinopril); beta-blockers (such as nadolol, timolol, propranolol, and alprenolol); antiarrhythmics; anti-hypertensive (such as clonidine); vasodilators, which include general, coronary, peripheral and cerebral; agents acting in the central nervous system (such as fluofenazine, trifluoperazine, haloperidol, Xanax®, Librium®, Valium®); preparations against cough and cold; decongestants; diagnostics; hormones, hypnotics; muscle relaxants, paraatholytics; parasimpatomimetics; psychostimulants, sedatives; appetite suppressant and weight control drugs (such as mazindol) and tranquilizers. The above methods are also useful to prevent or treat irritation of the skin produced by a variety of skin irritants as previously described including, but not limited to household and industrial cleaners, water, organic solvents, re-oxidizing and / or reducing agents, alkalis, acids, oils, vegetable matter, animal matter and Similar . The present invention further provides a useful article for preventing or treating the sensitizing or inflammatory effect of the skin of a component of a transdermal drug delivery system, wherein the component is either a drug, a permeation enhancer in the skin or a combination of the two and similar. The article comprising: (a) a transdermal delivery system comprising a therapeutic agent (e.g., a drug) of interest; and (b) an effective amount of at least one high boundary diuretic or loop diuretic alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid. The agents for prevention and treatment of adverse skin reaction can also be administered in a controlled or transdermal delivery device. The examples of devices Transdermal and distribution systems that can be used are described in Bodde, H.E. and collaborators, Crit. Rev. Ther. Drug Carrier Syst. 6: 87-115 (1989); and in U.S. Patent Nos. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454, 4,559,222, 4,573,995, references which are incorporated herein by reference. The delivery system may include a first transdermal device comprising a matrix for placing the agents for preventing or treating the adverse reaction of the skin in transmission relationship to the skin. A second transdermal device can be used to place the therapeutic agent in transmission relationship to the skin after the agent for prevention or treatment of the adverse reaction has been transdermally administered to the skin. The first and second transdermal devices can be incorporated into an individual transdermal patch. The agents for preventing or treating the adverse reaction of the skin are administered by themselves, or, in transdermal systems in combination with a therapeutic agent of interest. These agents can be administered topically or non-cutaneously such as intradermally, intravenously, intramuscularly, orally or intraperitoneally. In the agents of the present invention they can be incorporated in a pharmaceutically acceptable composition for topical application to the skin in the form of lotions, creams and gels and the like. Useful carriers for the preparations of these compositions include water, gels and the like. The precise formulation of the therapeutic agent administered transdermally, (for example, a drug) and the agents for preventing or treating the adverse skin reaction of the present invention can be designed to distribute the drug and agents in the desired fluxes and can be in numerous forms, including, without limitation, ointments, gels and creams. Aqueous formulations, in particular gels, typically comprise water and from about 1 to 2.5% (w / w) a gel-forming agent such as hydroxyethylcellulose or hydroxypropylmethylcellulose (HPMC). Typical non-aqueous gels comprise silicone fluid or mineral oil. The mineral oil may have from about 1 to 2% (w / w) of a gel-forming agent such as colloidal silicon dioxide. The suitability of a particular gel composition it depends on the compatibility of its constituents with the drug (with or without enhancer to the permeation) and the prevention agents to the treatment of the adverse reaction of the skin. In another embodiment, the agents of the present invention are distributed to the skin alone to prevent skin sensitization and / or skin irritation or prior to the administration of the therapeutic drug or drugs. This prior administration can be via transdermal application using a device as described above, via topical application, intracutaneous injection, and the like. In yet another embodiment, agents are distributed by another non-cutaneous route and the distribution method, either concurrently with, or prior to, the transdermal administration of the therapeutic drug. In embodiments of the invention wherein the agent for preventing or treating the adverse reaction of the skin is administered to prevent or treat skin irritation, the composition containing the skin is preferably in the form of a lotion, cream or other topical formulation easily applied. In all the above modalities, the doses of the prevention or treatment agents of the adverse reaction of the skin, administered will depend on the agent, the age, health and weight of the recipient, class of concurrent treatment, if any, and the frequency of treatment. The methods and compositions within the scope of this invention include all compositions and methods wherein the agents for preventing or treating the adverse reaction of the skin are contained in an effective amount to achieve their intended purpose. While the individual needs vary, the determination of the optimum intervals of the effective amounts of each component is within the experience of the technique. For transdermal administration, the effective doses, typical of the agents for preventing and / or treating ACD by a sensitizing drug will depend on its permeation through the human skin, and are a function of the physical properties of the permeant, including the coefficient of partition of the permeant between the solvent and the skin, the molecular weight and the melting point. In general, the maximum flow that can be obtained from any permeant occurs from saturated solutions. Equations have been derived that accurately predict the maximum flow given the partition coefficient, molecular weight and the point of fusion of the permeant as described in for example; "TREATISE ON CONTROLLEN DRUG DELIVERY", A. Kydonieus, ed., Marcel Dekker, Inc., New York, 1991, in particular, p. 370, equations 3a and 4a and p. 34, Figure 2, incorporated herein by reference. For example, for the transdermal distribution of loop diuretics alone or in combination with mast cell degranulators including the preferred agents, ethacrynic acid and cis-urocanic acid, the maximum expected flow that can be achieved locally to the skin is in the range from about 1 to 50 μg / cm2 / hr. For the transdermal distribution of the glucocorticosteroid, including the preferred hydrocortisone agent, the maximum expected flow that can be achieved locally to the skin is in the range from about 0.005 to 5 μg / cm2 / hr. These values are dependent, for example on the variation of skin age, skin type and skin condition, the preferred range for maximum flow for ethacrynic acid and cis-urocanic acid is from about 5 to 25 μg / cm2 / hr. For the administration of hydrocortisone, the preferred range for maximum flow is from about 0.01 to 1.0 μg / cm2 / hr. Therefore, as It will be understood by those skilled in the art, the distribution of a particular agent, is controlled by the percent saturation of that agent in the chosen vehicle. The amount of loop diuretic agent, mast cell degranulant or glucocorticosteroid that can be distributed to prevent ACD will vary from patient to patient. For example, the amount of the loop diuretic, (eg, ethacrynic acid) distributed from a gel formulation (2.5% HPMC in 75% in ethanol) is from about 0.1 to 10% by weight, and preferably from about 0.25% to 2.0% by weight. The amount of the degranulator in mast cells (eg, cis-uracanic acid), which is preferably employed from the same gel formulation in the present invention is in the range of from about 0.1 to 20% by weight, preferably from about 1. up to 10% by weight. The amount of the glucocorticosteroid (e.g., hydrocortisone) that is preferably employed from the same gel formulation in the present invention is in the range of from about 0.05% to 5% by weight. For the administration of the administration of the agents of prevention of the adverse reaction of the skin to prevent or treat skin irritation, the dose will vary as described. For example for topical application, the preferred agents are loop diuretics alone (e.g., ethacrynic acid) or in combination with a mast cell degranulator (e.g., cis-urocanic acid). In general, the amount of the loop diuretic (eg, ethacrynic acid) is from about 0.1 to 2.0% by weight, preferably from about 0.25 to 1.0% by weight based on the total weight of the composition. The amount of the mast cell degranulator (eg, cis-urocanic acid) is typically from about 1.0 to 20 weight percent, preferably from about 2.0 to 10 weight percent based on the total weight of the composition. The amount of the glucocorticosteroid for the prevention or treatment of skin irritation is from about 0.1 to 5.0 percent by weight, preferably from about 0.5 to 2.0 percent by weight.

EXAMPLE 1 Etacrinic Acid as a Counter Sensitizer for DNCB A 0.5% (w / v) solution of ethacrylic acid in a gel formulation (2.5% HPMC in 75% ethanol) was prepared. The same gel formulation served as a negative control. For sensitization, a 1% (w / v) dinitrochlorobenzene (DNCB) solution was prepared in acetone. Twenty-four (24) Balb / c mice had their abdominal skin shaved. The mice were divided into three equal groups. The first group acted as a negative control and received on day 0 an application of 0.2 mL of hydroxypropylmethylcellulose (HMPC) on their exposed abdominal skin. The second group acted as a positive control when receiving, on day 0, 0.2 mL of HPMC gel in the exposed abdominal skin. The third group of mice was treated with 0.2 mL of the HPMC gel containing ethacrynic acid on day 0. Twenty-four (24) hours later, the mice in Groups II and III received 10 μL of the solution.

DNCB at 1% on the area of skin portrayed with the gel, while mice in Group I received 10 μL of acetone. The three groups were stimulated in the right ear with 20 μL of 1% DNCB in acetone five (5) days after sensitization. The adverse reaction to stimulation to stimulation with DNCB was determined by measuring the thickness of the ears of the mice before and after the stimulation to determine the amount of swelling, and then comparing the degree of swelling for the treated mice according to the invention (Group III) with Groups I and Groups II. The results are shown in Table 1.

As shown in Table I, the Group II mice exhibited a significant swelling of the ear when they were sensitized to DNCB. The loop diuretic, ethacrynic acid alone, which constitutes an agent for preventing the adverse reaction of the skin when administered prophylactically, limits the adverse reactions induced by the sensitization with DNCB.

Example 2 Fluorosemide as a Counter Sensitizer for DNCB The procedures of Example 1 were repeated except that the agents for prevention or treatment of the adverse reaction of the skin was a fluorosemide formulation at 1.0% (w / w). The results are shown in Table II As shown in Table II, Group II mice exhibited significant swelling when desensitized to DNCB. Fluorocemide, which is an agent for the prevention of adverse skin reaction when administered prophylactically limits adverse skin reactions induced by sensitization to DNCB.

EXAMPLE 3 Etacrinic Acid and Cis-urocanic Acid as Sensitizers Counters for DNCB The procedures of Example 1 were repeated except that the agents for prevention or treatment of the adverse reaction of the skin was a combination of a 2.5% (w / v) solution of cis-urocanic acid and a 0.25% solution (p / v) of ethacrynic acid, prepared in the previous HPMC gel. The results are shown in Table III.

As shown in Table III, Group II mice exhibited significant swelling of the ear when they were sensitized with DNCB. The combination of cis-urocanic acid and ethacrynic acid which constitutes an agent for preventing or treating the adverse reaction of the skin according to the present invention suppresses the adverse reactions induced by the sensitization with DNCB.

EXAMPLE 4 Etacrinic acid and Hydrocortisone as Sensitizers Counters for DNCB The procedures of Example 1 were repeated except that the agent for prevention or treatment of the adverse skin reaction was a combination or a 1% (w / v) solution of hydrocortisone, and a 0.25% (w / v) solution. of ethacrynic acid, prepared in the previous gel formulation. The results are shown in Table IV As shown in Table IV, Group II mice showed significant swelling of the ear when they were sensitized with DNCB. The combination of hydrocortisone and ethacrynic acid that constitutes a The agent preventing or treating the adverse reaction of the skin according to the present invention suppresses the adverse reactions induced by the sensitization with DNCB.

EXAMPLE 5 Etacrinic Acid as a Sensitizer for Albuterol Forty (40) CBA / J female mice were obtained from Jackson Labs. A 0.5% (w / v) solution of ethacrynic acid was prepared in a gel formulation (HPMC at 2.5% to 75% ethanol). A solution at 5% (w / v) and a 1% (w / v) solution of albuterol was also prepared. In addition, a 2.5 percent HPMC solution was prepared as a placebo. The mice were shaved on his back. The positive control mice (10) received the placebo and the 5% albuterol solution on alternating days for three weeks. The experimental mice (10) received the ethacrynic acid solution and the 5% albuterol solution on alternating days for three weeks.

A negative control group of mice (20) received the placebo gel every day for three weeks. Five days after the last application each group of mice was stimulated in the right ear with albuterol solution at 1% and in the left ear with placebo gel. The thickness of the ears was measured after 24, 48 and 72 hours. The results are shown in Table V.

As shown in Table V, Group II mice exhibited significant swelling of the ear when sensitized to albuterol. Ethacrynic acid, which is only an agent for the prevention or treatment of adverse skin reactions, limited the adverse reactions induced by albuterol sensitization.

EXAMPLE 6 Etacrinic Acid as a Counter Sensitizer for Chlorpheniramine The procedures of Example 5 were repeated except that the mice were sensitized with chlorpheniramine in an amount of 5% (w / v). The results are shown in Table VI.

As shown in Table VI, the Group II mice exhibited significant swelling of the ear when sensitized to chlorpheniramine. Ethacrynic acid alone, which constitutes an agent for the prevention or treatment of adverse skin reaction, limited the adverse reactions induced by chlorpheniramine sensitization.

EXAMPLE 7 Etacrinic Acid as a Counter Sensitizer to Clonidine The procedures of Example 5 were repeated, except that the mice were sensitized with clonidine in an amount of 5% (w / v). The results are shown in Table VII.

As shown in Table VII, Group II mice exhibited significant swelling of the ear when sensitized to clonidine. The acid Ethacrynic that constitutes only an agent of prevention or treatment of the adverse reaction of the skin limited the adverse reactions induced by the sensitization with clonidine.

EXAMPLE 8 Etacrinic Acid as a Counter Sensitizer for Nadolol The procedures of Example 5 were repeated, except that the skin sensitizing agent was nadolol in an amount of 5% (w / v). The results are shown in Table VIII.

As shown in Table VIII, Group II mice exhibited significant swelling of the ear when sensitized to nadolol. The acid Ethacrynic alone, which constitutes an agent for the prevention or treatment of adverse skin reaction, limited the adverse reactions induced by sensitization with nadolol.

EXAMPLE 9 Etacrinic Acid As a Counter Sensitizer to Mice Already Sensitized with Qxazolone In this example, it is considered a question as to whether ethacrynic acid could result in an adverse reaction after the mice were sensitized by a primary exposure to oxazolone and then treated immediately after stimulation with the sensitizing agent. Thirty (30) male Balb / c mice were obtained from Sprague Dawley Labs. A 1.0% (w / v) solution of ethacrynic acid was prepared in a gel formulation (1.0% HPMC in 75% ethanol). A 1% (w / v) solution of oxazolone in acetone was also prepared. In addition, a 1% HPMC solution was prepared as a placebo. The mice were shaved on their back and divided into three groups. Group II (10 mice) they act as a positive control and receive 10 μl of the oxazolone solution. Group III (10 mice) was designated as the experimental mice were received 10 μl of the oxazolone solution. Group I (10 mice) acted as a negative control group and received 10 μL of acetone. Five days after the last application, mice from Group I, II and III received 20 μL of the oxazolone solution to the right ear. Five minutes after the stimulation, 100 μL of placebo was applied to the right ears of Groups I and II and 100 μL of the.

EXAMPLE 10 Etacrinic Acid Inhibits Irritation Induced by Lactic Acid Thirty (30) female Balb / c mice were obtained from Sprague Dawley Labs. A 1.0% (w / v) solution of ethacrynic acid was prepared in a gel formulation (2.5% HPMC in 75% ethanol). A 25% (w / v) solution of lactic acid (sufficient to elicit a strong irritant response) was also prepared. In addition, a 0.1% HPMC solution was prepared as a placebo. The mice were shaved on his back. Group I (10 mice) received only placebo. The positive control mice (10) designated as Group II received the lactic acid solution to the right ear and five minutes later 50-100 μL of the placebo. Experimental mice (10) (Group III) received the ethacrynic acid solution to the ear right followed five minutes later by the lactic acid solution. The thickness of the ears was measured after 2 hours when the maximum redness and the maximum swelling of the lactic acid were observed. The results are shown in Table X.

As shown in Table X, the Group II mice exhibited a significant swelling of the ear when they were put in contact with lactic acid. Ethacrynic acid, which constitutes an agent for preventing or treating the adverse reaction of the skin, suppressed the inflammation induced by contact with lactic acid.

EXAMPLE ^ 11 Etacrinic Acid Inhibits Capsaicin-Induced Irritation The procedures of Example were repeated , excthat the lactic acid was replaced by capsainal in an amount of 5% (w / v) in a 1% HPMC gel. The results are shown in the Table XI.

As shown in Table XI, Group II mice exhibited significant swelling of the ear when contacted with capsain. Ethacrynic acid, which constitutes an agent for preventing or treating the adverse reaction of the skin, suppressed the inflammation induced by capsaicin.

EXAMPLE 12 Etacrinic Acid Inhibits Irritation Induced by Arachidonic Acid The procedures of Example 10 were repeated excthat the lactic acid was replaced by arachidonic acid in an amount of 5% (w / v) in a 1% HPMC gel. The results are shown in Table XII.

As shown in Table XII, Group II mice exhibited significant swelling of the ear when contacted with arachidonic acid. Ethacrynic acid, which constitutes an agent for preventing or treating the adverse reaction of the skin, suppressed the inflammation induced by contact with arachidonic acid.

EXAMPLE 13 Etacrinic Acid Inhibits PMA-Induced Irritation The procedures of Example 10 were repeated excthat the lactic acid was replaced with phorbol-12-myristate-13-acetate (PMA) in an amount of 0.1%% (w / v) in a 1% HPMC gel.

The results are shown in Table XII.

As shown in Table XIII, Group II mice exhibited significant swelling of the ear when contacted with phorbol-12-myristate-13-acetate. Ethacrynic acid, which constitutes an agent for preventing or treating the adverse reaction of the skin, suppressed the inflammation induced by contact with PMA.

It is noted that in relation to this date, the best method known by the applicant to carry out the present invention is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property:

Claims

1. A method for preventing or treating an adverse reaction of the skin of a warm-blooded animal in the presence of at least one of a skin sensitizing agent or skin irritant, characterized in that it comprises administering to the warm-blooded animal a effective amount of an agent for preventing or treating the adverse skin reaction comprising at least one loop diuretic alone or in combination with at least one mast cell degranulator or glucocorticosteroid to the warm-blooded animal.

2. The method according to claim 1, characterized in that the skin sensitizing agent is selected from the group consisting of therapeutic agents, metals, fragrances, cosmetics, textiles, pollen, pesticides, plastics and combinations thereof.

3. The method according to claim 1, characterized in that the skin irritant is selected from the group consisting of water, cleansers, alkalis, acids, oils, organic solvents, oxidizing agents, reducing agents, vegetable matter, animal material and combinations thereof.

4. The method according to claim 1, characterized in that it comprises administering the agent preventing or treating the adverse reaction of the skin topically to the skin.

5. The method according to claim 4, wherein the agent for preventing or treating the adverse reaction of the skin is administered transdermally.

6. The method according to claim 5, characterized in that the skin sensitizing agent is a therapeutic agent, the method comprising administering the agent for preventing or treating the adverse reaction of the skin of the therapeutic agent from a transdermal patch.

7. The method according to claim 1, characterized in that the diuretic of loop is selected from the group consisting of ethacrynic acid, furosemide and bumetanide.

8. The method according to claim 7, characterized in that the loop diuretic is ethacrynic acid.

9. The method according to claim 1, characterized in that the mast cell degranulator is selected from the group consisting of cis-urocanic acid, analogues and metabolites thereof, PUVA, chloroquine, histamine, capsaicin, morphine sulfate, an ionophore of the sodium channel, a calcium channel ionophore, an ATPase inhibitor of the NA + / K + channel, quinine, 4-aminopyridine, anti-human IgE antibody, compound 48/80, substance P, estradiol, somatastatin, carbacol, progesterone, frightening, and clonidine.

10. The method according to claim 1, characterized in that the cis-urocanic acid analogues are selected from the group consisting of 1-furanacrylyl acid, 2-pyrol-acrylic acid, 2-thiopheneacrylic acid, dihydrouracanic acid and trans-acid. urocanic

11. The method according to claim 9, characterized in that the mast cell degranulator is cis-urocanic acid.

12. The method according to claim 1, characterized in that the glucocorticosteroid is selected from the group consisting of hydrocortisone of analogues thereof, beclomethasone, betamethasone and analogs thereof, clobetasol and analogs thereof, desonide, dexamethasone, fluocinonide, Prednisone, and triaminolone.

13. The method according to claim 12, characterized in that the glucocorticosteroid is hydrocortisone.

14. The method according to claim 5, characterized in that the maximum flow of the loop diuretic alone or in combination with the mast cell degranulator is from about 1 to 50 μg / cm 2 / hr.

15. The method according to claim 14, characterized in that the maximum setting of the loop diuretic alone or in combination with the mast cell degranulator is from about 5 to 25 μg / cm 2 / hr.

16. The method according to claim 5, characterized in that the maximum flow rate of the glucocorticosteroid is from about 0.005 to 5 μg / cm2 / hr.

17. The method according to claim 16, characterized in that the maximum flux of the glucocorticosteroid is from about 0.1 to 1.0 μg / cm2 / hr.

18. The method according to claim 1, characterized in that it comprises administering to the warm-blooded animal an amount of the agent preventing or treating the adverse reaction of the skin sufficient to treat or prevent allergic contact dermatitis caused by a sensitizing agent. the skin in the form of a gel, the amount of the loop diuretic which is from about 0.1 to 10% by weight, the amount of the mast cell degranulator which is from about 0 to 20% by weight and the amount of the glucocorticosteroid which is from about 0 to 5% by weight.

19. The method according to claim 18, characterized in that the amount of the loop diuretic is from about 0.25 to 2.0% by weight, the amount of the mast cell degranulator is from about 1 to 10% by weight.

20. The method according to claim 1, characterized in that it comprises administering to the warm-blooded animal an amount of the prevention or treatment agent of the adverse reaction of the skin sufficient to treat or prevent allergic contact dermatitis caused by a sensitizing agent of the skin in the form of a gel, the amount of the loop diuretic which is from about 0.1 to 2.0% by weight, the amount of the mast cell degranulator which is from about 0 to 20% by weight in the amount of the glucocorticosteroid which is from about 0 to 5% by weight.

21. The method according to claim 20, characterized in that the amount of the loop diuretic is from about 0.25 to 1.0% by weight, the amount of the mast cell degranulator is from about 2.0 to 10% by weight and the amount of the glucocorticosteroid is from approximately 0.5 to 2.0 5 in weight.

22. A transdermal delivery system for transdermally administering an effective amount of an agent preventing or treating the adverse reaction of the skin comprising a loop diuretic alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid, the The system is characterized in that it comprises: (a) a first transdermal device comprising a matrix for placing the agent for prevention or treatment of the adverse reaction of the skin in transmission relation to the skin; and (b) a second transdermal device comprising a matrix for placing a therapeutic agent in transmission relation to the skin after the agent has been transdermally administered. prevention or treatment of the adverse reaction of the skin, to the skin from the first transdermal device.

23. The transdermal distribution system according to claim 22, characterized in that the first and second transdermal devices are contained within a single transdermal patch.

24. A method for transdermally administering a warm-blooded animal, a therapeutic agent without thereby causing an adverse reaction of the skin, characterized in that it comprises administering transdermally, before, after and during administration of the therapeutic agent, an effective amount of a adverse skin reaction prevention agent comprising a loop diuretic alone or in combination with at least one mast cell degranulator or at least one glucocorticosteroid to the warm-blooded animal.

25. The method according to claim 24, characterized in that the diuretic of loop is selected from the group consisting of ethacrynic acid, furosemide or bumetanide.

26. The method according to claim 24, characterized in that the mast cell degranulator is selected from the group consisting of cis-urocanic acid, analogues and metabolites thereof, PUVA, chloroquine, histamine, capsaicin, morphine sulfate, an ionophore of the sodium channel, a calcium channel ionophore, an ATPase inhibitor of the Na + / K + channel, quinine, 4-amino-pyridine, anti-human IgE antibody, compound 48/80, substance P, estradiol, somatastatin, carbachol, progesterone, frightening, and clonidine.

27. The method according to claim 26, characterized in that cis-urocanic acid analogs are selected from the group consisting of 1-furanacrylic acid, 2-pyrolacrylic acid, 2-thiopheneacrylic acid, dihydrourocanic acid and trans-urocanic acid. .

28. The method according to claim 24, characterized in that the glucocorticosteroid is selected from the group which consists of hydrocortisone and analogs thereof, beclomethasone, betamethasone and analogues thereof, clobetasol and analogs thereof, desonide, dexamethasone, fluocinonide, prednisone, and triamcinolone.