MXPA97003693A - Profilactic treatment of allergic dermatitis by conta - Google Patents

Abstract

Methods and devices are described to prevent an adverse reaction of the skin to the presence of a skin sensitizing agent to administer an effective amount of a diuretic that saves potassium

Description

PROPHYLATIC TREATMENT OF ALLERGIC DERMATITIS BY CONTACT 1. Field of the invention The present invention relates to methods and compositions for preventing adverse reactions of the skin in general to skin sensitizing agents and especially to adverse reactions caused by cutaneous administration of a therapeutic agent for transdermal applications. 2. BACKGROUND OF THE INVENTION Allergic skin reactions to several agents are known as allergic contact dermatitis (ACD), an immune response that occurs on the skin. The response is the result of penetration of the foot by a foreign substance (for example, hapten or antigen) that causes a sensitization reaction to the skin. 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 skin to the hapten REF: 24759 or antigen and is characterized by the formation of immune memory cells that can subsequently recognize the hapten or specific antigen that previously entered the skin the first time. The extraction or provocation phase occurs when the skin is subsequently exposed again 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. ACD is generally a persistent, long-lasting memory for the specific hapten or antigen. In this way, when the skin is exposed to the hapten or antigen in a subsequent time, there is typically an inflammatory response of the skin, immediately and often severe. The agents that cause allergic contact dermatitis are varied and numerous and include, for example, metals (e.g., nickel, chromium, cobalt and the like) fragrances, chemicals, cosmetics, textiles, pesticides, plastics, pollen and the like (see , for example RJG Rycroft and collaborators "Textbook of Contact Dermatitis"). Therapeutic agents such as drugs can also cause allergic contact dermatitis, particularly when administered transdermally. The transdermal route of parenteral drug distribution provides many advantages over alternative routes of administration. Transdermal distribution systems (TDS) for distributing drugs or other beneficial agents are well known (see, for example, U.S. Patent Nos. 3,598,122, 3,598.1.23, 4,286,592, 4,314,557, 4,379,454, 4,599,222 and 4,573,995, which are incorporated herein by reference). A TDS is generally composed of the following components: (a) "building blocks" including 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. However, TDS provides highly favorable conditions for the induction of allergic skin reactions, and the following skin reactions may be expected to occur: 1. Irritant reactions to the drug, an additive, an impurity, or a combination of the same 2. Allergic reactions, especially to low molecular weight components (drug, additive, impurity, adhesive); 3. Prolonged occlusion of the skin causes blockage of the transpiration channels that favor the local sweat retention syndrome. 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 (for example, clonidine) sensitize the skin when used in a transdermal distribution system. Inflammation of the skin can occur not only by the transdermally distributed drug, but also by a non-sensitizing drug combined with permeation enhancers, skin sensitizers, or a combination of a sensitizing drug and a permeation enhancer, sensitizer. The penetration of these sensitizing agents into the skin and the resulting irritation of the skin may persist beyond the time that the transdermal patch is removed from the skin. Local inflammation can be a source of discomfort and a clinical complication in a patient suffering from this reaction. 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 therapeutically prevent or reduce the adverse effects of the ACD extraction phase. For example, U.S. Patent No. 5,202,130 discloses that the ions of the lanthanides and the organic calcium channel blockers can be used 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 W. Ledger, et al., US Patent No. 5,120,535 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 corticosteroid and glucocorticoid) is described in Alferd Amkraut, US Pat. No. 5,118,509 and Peter M. Ross, et al., US Pat. No. 4,897,260. 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) and O / 09792 published September 7, 1990 describe 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. 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 in a person who has been sensitized to an agent, such as a transdermally administered agent. such as a drug. Applicants have discovered that a particular class of compounds having diuretic properties, referred to herein as potassium-sparing diuretics, achieve significant prevention against sensitization of a patient's skin. As a result, an adverse reaction of the skin to the skin sensitizing agent such as the therapeutic agents, administered transdermally, is prevented or minimized, allowing the administration of agents that could not be previously administered and / or have longer dose regimens . The present invention therefore provides prevention of an adverse reaction of the skin, as well as a transdermal therapy that reduces discomfort to the patient.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates generally to methods for preventing allergic contact dermatitis (ACD) and compounds and systems, especially transdermal systems, used in these methods. In one aspect of the invention, there is provided a method for preventing an adverse reaction of the skin caused by the presence of skin sensitizing agents such as metals, fragrances, cosmetics, textiles, pollen, pesticides, plastics 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. The method of the present invention comprises administering to the skin of a warm-blooded animal an effective amount of at least one potassium-sparing diuretic. The agents employed herein to prevent skin irritation or inflammation of the skin of the ACD caused by any skin sensitizing agent can be prepared in the form of a composition containing one or more additives including skin improvers. permeation in the skin, excipients and the like.

These agents for preventing the adverse reaction of the skin can be administered topically in the form of lotions, creams, sprays and the like, or non-cutaneous routes as well as through the use of transdermal patches. In transdermal applications, the agents may be administered from an individual reservoir that also contains the therapeutic agent or preferably from a separate reservoir of a transdermal patch.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates in general to methods and systems for preventing the onset of irritation or inflammation of the skin caused by allergic contact dermatitis. In one aspect of the invention, the skin is treated with a prophylactically effective amount of at least one potassium-sparing diuretic. The use of a composition containing these agents for preventing the adverse reaction of the skin provides the inhibition of the immune response and the specific immune tolerance to the provoking antigen. More specifically, an individual administration to the skin of the potassium-sparing diuretic renders the warm-blooded animal specifically insensitive to an antigen, a condition known as immunological tolerance. The immunosuppressive agents known to induce immune tolerance are UVB radiation, cytokine TNF-α, and cis-urocanic acid. A number of mechanisms are known that are responsible for the induction and maintenance of this state of tolerance. 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 reached. Potassium-sparing diuretics of the type used herein to achieve the state of prolonged immune tolerance such as amiloride, inhibit the transport processes of sodium ions and hydrogen ions in the cell membrane. They alter these signal translation processes necessary for the acquisition of the immunological memory of the cells, a vital aspect of the induction phase of the sensitization response. A known mechanism of action that is encompassed is the selective inhibition of the ATPase enzyme from the sodium / hydrogen ion channels. The inhibition of this enzyme results in an elevation of the intracellular pH, and finally a blockage in the intracellular production of the second messenger and / or transcription of the gene initiated by the signal translation mechanisms. Examples of potassium-sparing diuretics for use herein include amiloride and triamterene, and analogs thereof. Amiloride is the potassium-sparing diuretic, preferred. Amiloride and its analogs are described in WO 09792 published September 7, 1990 and are incorporated herein by reference. The above methods are useful for preventing inflammation or skin irritation caused 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-steroidal anti-inflammatory 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; anorexics; antiarrhythmics, antiasthmatics (such as albuterol, etaproterenol, 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; or antipruritics; antipsychotics; antipyretics, antispasmodics, including gastrointestinal and urinary; anticholinergic; sympathomimetics, xanthine derivatives, cardiovascular agents, which include the angiotensin-converting enzyme inhibitors, such as captropril and fosinopril); beta-blockers (such as nadolol, timolol, propanolol, and alprenolol); antiarrhythmics; antihypertensive agents (such as clonidine); vasodilators, which include general, coronary, peripheral and cerebral; agents that act on the central nervous system (such as fluofenazine, trifluoperazine, haloperidol, Xanax®, Librium®, Valium®); preparations against cough and cold; decongestants; diagnostics; hormones, hypnotics; muscle relaxants, parasympatholytics; parasimpatomimetics; psychostimulants, sedatives; appetite suppressant and weight control drugs (such as mazindol) and tranquilizers. The present invention further provides a useful article for preventing the skin irritation or inflammation effect of a component of a transdermal drug delivery system, wherein the component is either a drug, a skin permeation enhancer or a combination of the two and the like, the article comprises: (a) a transdermal delivery system comprising a therapeutic agent (e.g., a drug) of interest and (b) an effective amount of at least one and potassium-sparing diuretic. Agents that prevent the adverse reaction of the skin can also be administered in a controlled or transdermal delivery device. Examples of transdermal devices 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 potassium-sparing diuretic in transmission relation to the skin. A second transdermal device can be used to place the therapeutic agent in transmission relationship to the skin after the potassium-sparing diuretic has been transdermally administered to the skin. The first and second transdermal devices can be incorporated into a single transdermal patch.

Potassium-sparing diuretics are administered by themselves, or, in transdermal systems in combination with the therapeutic agent of interest. These agents can be administered topically or non-cutaneously, such as intradermally, intravenously, intramuscularly, orally or intraperitoneally. The agents of the present invention can be incorporated into a pharmaceutically acceptable composition for topical application to the skin in the form of lotions, creams, gels, and the like. Useful carriers for the preparations of these compositions include water, ethanol, gels and the like. The precise formulation of the therapeutic agent administered transdermally, (eg, a drug) and the potassium-sparing diuretics of the present invention can be designed to distribute the drug and the diuretics in the desired flows 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 also have from 1 to 2% (w / w) of a gel-forming agent such as colloidal silicon dioxide. The suitability of a particular gel composition depends on the compatibility of its constituents with the drug (without or with a permeation enhancer) and the agent that prevents the adverse reaction of the skin. In another modalityPotassium-sparing diuretics are distributed to the skin before administration of the drug or therapeutic 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 modality, potassium-sparing diuretics are distributed by another non-cutaneous route and the distribution method, either concurrently with, or with prior to, the transdermal administration of the therapeutic drug. In all the above modalities, the doses of potassium-sparing diuretics administered will depend on the agent, the age, health and weight of the recipient, class of concurrent treatment, and if any, the frequency of treatment.

The methods and compositions within the scope of this invention include all compositions and methods wherein potassium-sparing diuretics are contained in an effective amount to achieve their intended purpose. While individual needs vary, the determination of optimal ranges of effective amounts of each component is within the skill of the art. For transdermal administration, the effective doses, typical of potassium-sparing diuretics to prevent ACD by a sensitizing drug will depend on its permeation through human skin, and is a function of the physical properties of the permeant, which includes 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 predict the maximum flow in an exact manner given the partition coefficient, molecular weight and melting point of the permeant as described in for example; "TREATISE ON CONTROLLEN DRUG DELIBERY", 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 potassium-sparing diuretics, which include the preferred compound, amiloride, the expected maximum flow that can be locally distributed to the skin is in the range of about 1 to 50 ug / cm / hr. This value is dependent, for example, on the variation of the age of the skin, skin type and skin condition. The preferred range for maximum flow is from about 5 to. 25 μg / cm2 / hr. Accordingly, as will be understood by those skilled in the art, the distribution of a particular potassium-sparing diuretic is controlled by the percent saturation of that agent in the chosen vehicle. The amount of potassium-sparing diuretic that can be distributed to prevent ACD will vary from patient to patient. For example, the amount of amiloride distributed from a gel formulation (2.5% HPMC in 75% in ethanol and 5% in dimethyl sulfoxide (DMSO)) is from about 0.5 to 5% by weight.

EXAMPLE 1 A 1.0% (w / v) solution of amiloride was prepared in gel formulation (2.5% HPMC in 75% ethanol and 5% DMSO). The same gel formulation served as a negative control. For sensitization, a 1% (w / v) dinitrochlorobenzene (DNCB) solution was prepared in acetone. (24) Twenty-four balb / c mice had their abdominal skin shaved. The mice were divided into three equal groups. The first group acted as the 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 HPMC gel containing amiloride on day 0. Twenty-four hours later (24), mice in Group II and Group III received ten (10) microliters of DNCB solution at 1 % on the area of the skin pretreated with the gel, while the mice in Group I received ten (10) microliters of acetone. The three groups were stimulated in the right ear with twenty (20) microliters of 1% NCB in acetone five (5) days after sensitization. The adverse reaction 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 mice treated according to the invention ( Group III) with Groups I and Groups II. The results are shown in Table 1.

As shown in Table 1, Group II mice exhibited significant swelling of the ear when sensitized with DNCB. The potassium-sparing diuretic which constitutes an agent for preventing the adverse reaction of the skin of the present invention when administered prophylactically limits the inflammation induced by DCNB.

Example 2 Induction of Immunotolerance by Amiloride The procedures used for Example 1 were repeated, except that forty-eight (48) animals had their abdominal skin shaved. The mice were then divided into six (6) equal groups. The first three groups, I, II, and III, were treated exactly equal to the numbers numbered correspondingly of Example 1. The last three numbers IV, V and VI were pre-treated with gel on day 0 equal to Groups I, II, and III, and groups V and VI were sensitized with ten (10) microliters of 1% DNCB over the area of the pre-treated gel area. However, when Groups I, II and III were stimulated five (5) days after sensitization, Groups IV, V and VI received twenty (20) microliters of acetone in their right ears.

The adverse reaction to stimulation with 1% DNCB in acetone for Groups I, II and III was measured by the same procedures used in Example 1. The results of the stimulation in the swelling of the ear for Groups I, II and III are shown in Table 2. Group II mice exhibited significant swelling of the ear when sensitized to DNCB. Potassium-sparing diuretic (1% amiloride), when administered prophylactically, limited inflammation of the skin. In order to demonstrate that potassium-sparing diuretics (eg, amiloride) produce a state of immune non-sensitivity, ie immunotolerance, the backs of animals IV, V and VI were shaved eighteen days after receiving on day 0 either the gels that contain the control or amiloride. Animals in Group IV received ten (10) microliters of acetone in their exposed back skin, and animals in Groups V and VI were re-sensitized in the second skin site by applying 1% DNCB in acetone on his exposed skin on his back. The three groups in the left ear were sensitized with twenty (20) microliters of 1% DNCB in acetone, five (5) days after sensitization in the back. The results of the ear swelling stimulation for Groups VI, V and VI are shown in Table 2. As shown in Table 2, the Group V mice exhibited a significant swelling of the ear similar to Group II. of this example. The potassium-sparing diuretic constituting an agent that prevents the adverse reaction of the present invention when administered prophylactically to the main site of the skin (abdomen) on day 0, and when these same animals were re-sensitized at a secondary site of the skin (back) limits the inflammation of the skin twenty-four (24) hours after the stimulation. This example provides clear evidence that the individual topical application of the potassium-sparing diuretic (eg, amiloride) produces immunotolerance to the sensitizing agent.

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 (14)

1. A method for an adverse reaction of the skin of a warm-blooded animal in the presence of a skin sensitizing agent, characterized in that it comprises administering to the warm-blooded animal an effective amount of at least one potassium-sparing diuretic.

2. The method according to claim 1, characterized in that the skin sensitizing agent is a drug.

3. The method according to claim 1, characterized in that the skin sensitizing agent is administered transdermally.

4. The method according to claim 1, characterized in that the potassium-sparing diuretic is administered transdermally.

5. The method according to claim 3, characterized in that the potassium-sparing diuretic is administered transdermally.

6. The method according to claim 1, characterized in that the potassium-sparing diuretic is selected from the group consisting of amiloride, triamterene and analogs thereof.

7. The method according to claim 6, characterized in that the potassium-sparing diuretic is amiloride.

8. The method according to claim 5, characterized in that it comprises administering the potassium-sparing diuretic and skin sensitizing agent from a transdermal patch.

9. The method according to claim 4, characterized in that the maximum flow of the potassium-sparing diuretic is from about 1 to 50 μg / cm 2 / hr.

10. The method according to claim 1, characterized in that the maximum flow of the potassium-sparing diuretic is from about 5 to 25 μg / cm 2 / hr.

11. A transdermal delivery system for transdermally administering an effective amount of a potassium-sparing diuretic, characterized in that: (a) a first transdermal device comprising a matrix for placing the potassium-sparing diuretic in transmission relation to the skin; and (b) a second transdermal device comprising a matrix for placing a therapeutic agent in relation to transmission to the skin after the potassium-sparing diuretic has been transdermally administered to the skin from the first transdermal device.

12. A transdermal delivery system according to claim 11, characterized in that the first and the second transdermal device are maintained within an individual transdermal route.

13. A method for transdermally administering to a warm-blooded animal a therapeutic agent without producing an adverse reaction of the skin, characterized in that it comprises administering transdermally, before, after or during administration of a therapeutic agent an effective amount of a potassium-sparing diuretic. outgoing blood animal.

14. The method according to claim 13, characterized in that the potassium-sparing diuretic is selected from the group consisting of amiloride, triamterene analogs thereof.