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WO1997018782A1 - Traitement de l'hypersensibilite medicamenteuse par des inhibiteurs des canaux calciques - Google Patents

Traitement de l'hypersensibilite medicamenteuse par des inhibiteurs des canaux calciques Download PDF

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Publication number
WO1997018782A1
WO1997018782A1 PCT/US1996/018760 US9618760W WO9718782A1 WO 1997018782 A1 WO1997018782 A1 WO 1997018782A1 US 9618760 W US9618760 W US 9618760W WO 9718782 A1 WO9718782 A1 WO 9718782A1
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Prior art keywords
skin
diuretic
adverse
calcium channel
agent
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Application number
PCT/US1996/018760
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English (en)
Inventor
John J. Wille
Agis Kydonieus
Frank S. Castellana
Original Assignee
Bristol-Myers Squibb Company
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Filing date
Publication date
Application filed by Bristol-Myers Squibb Company filed Critical Bristol-Myers Squibb Company
Priority to AU10587/97A priority Critical patent/AU1058797A/en
Publication of WO1997018782A1 publication Critical patent/WO1997018782A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • the present invention relates to methods and compositions for preventing or treating adverse reactions of the skin in general to skin-sensitizing agents and especially adverse reactions occasioned by the cutaneous administration of a therapeutic agent for transdermal applications.
  • ACD allergic contact dermatitis
  • the induction phase occurs immediately after first time exposure of the skin to the hapten or antigen and is characterized by the formation of immune memory cells that can subsequently recognize the specific hapten or antigen which previously entered the skin for the first time.
  • the elicitation phase occurs when the skin is subsequently re-exposed to the original hapten or antigen. In the elicitation phase, the skin provides an overt reaction to the presence of the hapten or antigen in the form of a skin inflammatory response.
  • ACD generally results in a life-time persistent memory for the specific hapten or antigen.
  • the skin is exposed to the hapten or antigen at a subsequent time, there is typically an immediate and often severe skin inflammatory response.
  • 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, R.J.G. Rycroft et al. "Textbook of Contact Dermatitis") .
  • Therapeutic agents such as drugs may also cause allergic contact dermatitis particularly when administered transdermally.
  • TDS Transdermal delivery systems
  • a TDS is generally composed of the following components: (a) “basic components”, including backing, matrix reservoir, and an optional separate adhesive layer; (b) the drug or other therapeutic agent; (c) “additives”, including solubilizers, plasticizers and permeation enhancers; and (d) "impurities” such as residual amounts of monomers, initiators, cross-linkers, etc., from the polymerization process during fabrication of the basic components.
  • basic components including backing, matrix reservoir, and an optional separate adhesive layer
  • additives including solubilizers, plasticizers and permeation enhancers
  • impurities such as residual amounts of monomers, initiators, cross-linkers, etc.
  • TDS provide conditions highly conducive for the induction of skin allergic reactions, and the following skin reactions may be expected to occur:
  • Prolonged skin occlusion causes blocking of sweat ducts favoring local sweat retention syndrome.
  • Allergic contact dermatitis presents a significant problem in the transdermal administration of therapeutic agents.
  • drugs including some currently marketed in the United States (e.g. clonidine) sensitize the skin when used in a transdermal delivery system.
  • Skin inflammation may be produced not only by the transdermally delivered drug, but also by a non-sensitizing drug combined with skin sensitizing permeation enhancers, or a combination of a sensitizing drug and a sensitizing permeation enhancer. Penetration of these sensitizing agents into the skin and the resulting skin irritation may persist well beyond the time that the transdermal patch is removed from the skin.
  • the local inflammation may be a source of discomfort and a clinical complication in a patient suffering from such a reaction.
  • Efforts have been made to address the problem of allergic contact dermatitis by prophylactically treating the skin to prevent the onset of the induction phase of ACD and/or to therapeutically prevent or reduce the adverse effects of the elicitation phase of ACD.
  • U.S. Patent No. 5,202,130 discloses that lanthanide ions and organic calcium channel blockers individually can be used for the treatment of contact allergic dermatitis.
  • corticosteroid and glucocorticoid carboxylic acid esters is disclosed, for example, in Alfred Amkraut, U.S. Patent No. 5,118, 509 and Peter M. Ross, et al., U.S. Patent No. 4,897,260.
  • UVB ultraviolet light B
  • trans-UCA trans-urocanic acid
  • cis-UCA cis-urocanic acid
  • TNFa tumor necrosis factor-a
  • mast cell degranulators such as cis-urocanic acid are effective for preventing or inhibiting the skin sensitizing or irritating effect of a transdermally administered therapeutic agent.
  • compositions which effectively prevent the onset of ACD or reduce the adverse affects of ACD after the person has been sensitized to an agent, as for example, a transdermally administered agent such as a drug.
  • Applicants have gained the knowledge that there is a distinct process step implicated in the immune response associated with allergic contact dermatitis, which when interfered with, results in the prevention and/or treatment of ACD.
  • This process step referred to herein as cellular signal transduction, is believed responsible for the acquisition of memory by T-lymphocytes, for the cytokine-mediated regulation of antigen presentation and for other cellular processes as well.
  • a particular class of compounds having anti-hypertensive properties referred to herein as calcium channel blocking agents alone or in combination with at least one diuretic, or at least one glucocorticosteroid achieves significant improvement in the desensitization of a patient's skin.
  • a skin- sensitizing agent such as therapeutic agents administered transdermally is better controlled allowing for the administration of agents that could not previously be administered and/or have longer dosage regimens.
  • the present invention therefore provides prevention and/or treatment of an adverse reaction to the skin, as well as a transdermal therapy which reduces discomfort to the patient.
  • the present invention is generally directed to methods and compositions of preventing or treating allergic contact dermatitis (ACD) and compounds and systems, especially transdermal systems, used in said methods.
  • ACD allergic contact dermatitis
  • a method and composition is provided for preventing or treating 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, 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 calcium channel blocking agent alone or in combination with at least one diuretic, and/or at least one glucocorticosteroid.
  • agents employed in the present invention for preventing or treating skin irritation or inflammation from ACD caused by any skin-sensitizing agent can be prepared in the form of a composition containing one or more additives including skin permeation enhancers, excipients and the like.
  • These adverse skin reaction preventing or treating agents may 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.
  • the agents may be administered from a single reservoir also containing a therapeutic agent or preferably from a separate reservoir of a transdermal patch.
  • the present invention is generally directed to methods and systems for preventing the onset of skin irritation or inflammation caused by allergic contact dermatitis by treatment before, after or during the induction phase of sensitization and for alleviating this condition once ACD has progressed to the elicitation phase.
  • the skin is treated with at least one calcium channel blocking agent alone or in combination with at least one diuretic, or at least one glucocorticosteroid.
  • calcium channel blocking compounds belonging to four classes of compounds with diverse chemical structures have been approved for clinical use in the United States. They are: the arylalkylamines (e.g., verapa il) , the dihydropyridines (nicardipine, nifedipine, and ni oldipine) , the benzothiazepines (diltiazem) , and diphenylpiperazines (e.g., cinnarizine) .
  • a number of calcium channel blockers are also diuretics (e.g., perhexiline) .
  • Examples of calcium channel blockers for use in the present invention include: nifedipine, verapamil, diltiazem, isradipine, bepridil, niludipine, becyclone, etafenone, perhexiline, nicardipine, flunarizine, nilvadipine, nisoldipine, nitrendipine, felodipine, cinnarazine, and nimoldipine.
  • Diuretics useful in the present invention include loop diuretics and potassium-sparing diuretics.
  • the loop diuretics useful in the present invention are preferably selected from a group consisting of ethacrynic acid, furosemide and bumetanide.
  • Potassium-sparing diuretics useful in the present invention include amiloride and triamterene.
  • compositions containing such adverse reaction skin preventing or treating agents provides desensitization of the skin to the presence of skin-sensitizing agents as encountered from a variety of sources including transdermal systems before, after or during the transdermal administration of the therapeutic agent.
  • Such adverse skin reaction preventing agents provide inhibition of the immune response and specific immune tolerance to the provoking antigen. More specifically, a single administration to the skin of at least one calcium channel blocker alone or in combination with at least one diuretic, or at least one glucocorticosteroid renders a warm-blooded animal specifically unresponsive to an antigen, a state known as immunological tolerance.
  • UVB radiation Three immunosuppressive agents known to induce immune tolerance are UVB radiation, the cytokine TNF- ⁇ and cis-urocanic acid. A number of mechanisms are thought to be responsible for the induction and maintenance of this tolerant state. Regardless of the mechanism, it is well-known that tolerance to an antigen which 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.
  • Calcium channel blockers employed in the present invention affect signal transduction. It is believed that these compounds function as calcium ion pump poisons in that they indirectly interfere with the homeostatically regulated ion balance in other cells. The balance of hydrogen, sodium and potassium ions is upset by changing the net flux of intracellular calcium ions. Consequently, all those cellular processes dependent on the maintenance of homeostatically regulated intracellular ions are disrupted. In particular, the process of cellular signal transduction is known to be highly sensitive to changes in the level of intracellular ions, particularly calcium ions.
  • 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 gulcocorticosteroid.
  • the above methods are useful for preventing or treating skin sensitization or inflammation 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 angiotensin converting enzyme inhibitor; (b) a beta adrenergic receptor blocker; (c) an anti-hypertensive drug other than an angiotensin converting enzyme inhibitor or a beta adrenergic receptor blocker; (d) an anti-histamine; (e) an anti-asthmatic; (f) a non- steroidal anti-inflammatory drug; (g) a central nervous system active drug; (h) a weight control drug; (i) an anticoagulant; (j) a potassium control drug; (k) an immunomodulatory drug; (1) a decongestant; and ( ) proteins and peptides such as insulin and thyrotropin-releasing hormone.
  • a drug selected from, but not limited to, the following group: (a) an angio
  • the therapeutic agents for administration in accordance with the present invention include all of the major therapeutic areas, including, but not limited to: anti- infectives, such as antibiotics and antivirals; analgesics and analgesic combinations; anorexics; antiarthritics; anti- asthmatics (such as albuterol, metaproterenol, ketotifen and terbutaline) ; anticoagulants (such as urokinase) ; anticonvulsants; antidepressants; anti-diabetics; antidiarrheals; antihistamines (such as chlorpheniramine and diphenhydramine) ; anti-inflammatory agents (such as ketoprofen, prostaglandins, flurbiprofen, diclofenac, indomethacin, piroxicam and ibuprofen) ; antimigrane agents; anti-motion sickness preparations; antinauseants; antineoplastics; antiparkinsonism drugs; antipruritics; anti-in
  • the present invention further provides an article useful for preventing or treating the skin sensitizing or inflammatory effect of a component of a transdermal drug delivery system, where the component is either a drug, a skin permeation enhancer or a combination of the two and the like, the article comprising:
  • transdermal delivery system comprising a therapeutic agent (e.g. a drug) of interest; and (b) an effective amount of at least one calcium channel blocking agent alone or in combination with at least one loop diuretic, or at least one glucocorticosteroid.
  • a therapeutic agent e.g. a drug
  • the adverse skin reaction preventing or treating agents can also be administered in a transdermal or a controlled-release device.
  • transdermal devices and delivery systems which may be used are disclosed in Bodde, H.E. et al . , Crit. Rev. Ther. Drug Carrier Syst. 6:87-115 (1989) ; and in U.S. Patents No. 3,598,122, 3,598,123, 4,286,592, 4,314,557, 4,379,454, 4,559,222, 4,573,995, which references are hereby incorporated by reference.
  • the delivery system may include a first transdermal device comprising a matrix for placing the adverse skin reaction preventing or treating agents in transmitting relationship to the skin.
  • a second transdermal device may be used to place the therapeutic agent in transmitting relationship to the skin after the adverse reaction preventing or treating agent has been transdermally administered to the skin.
  • the first and second transdermal devices may be incorporated into a single transdermal patch.
  • the adverse skin reaction preventing or treating agents are administered by themselves or, in transdermal systems in combination with a therapeutic agent of interest. These agents may be administered topically or non-cutaneously such as by intradermally, intravenously, intramuscularly, orally or intra ⁇ peritoneally.
  • 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 such compositions include water, ethanol, gels and the like.
  • the precise formulation of the transdermally administered therapeutic agent (e.g. a drug) and the adverse skin reaction preventing or treating agents of the present invention can be designed to deliver the drug and the agents at 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) of a gelling agent such as hydroxyethylcellulose or hydroxypropylmethylcellulose (HPMC) .
  • Typical non-aqueous gels comprise silicone fluid or mineral oil.
  • the mineral oil may also have from about 1 to 2% (w/w) of a gelling agent such as colloidal silicon dioxide.
  • the suitability of a particular gel composition depends on the compatibility of its constituents with the drug (with or without a permeation enhancer) and the adverse skin reaction preventing or treating agents.
  • the agents of the present invention are delivered to the skin prior to the administration of the therapeutic drug or drugs.
  • Such prior administration can be via transdermal application using a device as described above, via topical application, intracutaneous injection, and the like.
  • the agents are delivered by another non-cutaneous route and method of delivery, either concurrently with, or prior to, the transdermal administration of the therapeutic drug.
  • the dosage of the adverse skin reaction preventing or treating agents administered will be dependent upon the agent, the age, health, and weight of the recipient, kind of concurrent treatment, if any, and frequency of treatment.
  • compositions within the scope of this invention include all compositions and methods wherein the adverse skin reaction preventing or treating agents are contained in an amount effective to achieve their intended purpose. While individual needs vary, determination of optimal ranges of effective amounts of each component is within the skill of the art.
  • typical effective dosages of the agents to prevent and/or treat ACD by a sensitizing drug will depend on their permeation through human skin, and are a function of the physical properties of the permeant, including the partition coefficient of the permeant between solvent and skin, molecular weight and melting point.
  • the maximum flux that can be obtained from any permeant occurs from saturated solutions. Equations have been derived that predict accurately the maximum flux given the partition coefficient, molecular weight and melting point of the permeant as described in, for example, "TREATISE ON CONTROLLED DRUG DELIVERY", A. Kydonieus, ed. , Marcel Dekker, Inc., New York, 1991, in particular, p.
  • the expected maximum flux that can be delivered locally to skin is in the range of from about 0.1 to 20 ⁇ g/cm 2 /hr.
  • the expected maximum flux for the diuretic e.g. ethacrynic acid
  • the expected maximum flux that can be delivered locally to the skin is from about 0.005 to 5 ⁇ g/cm 2 /hr.
  • the preferred range for the maximum flux for the calcium channel blocker, e.g. nifedipine, is from about 0.5 to 5 ⁇ g/cm 2 /hr.
  • the preferred range for the diuretic is from about 10 to 25 ⁇ g/cm 2 /hr.
  • the preferred maximum flux is from about 0.01 to 1.0 ⁇ g/cm 2 /hr. Accordingly, as will be understood by those skilled in the art, the delivery of a particular agent, is controlled by the percent saturation of that agent in the chosen vehicle.
  • the amount of the calcium channel blocker, diuretic e.g. loop diuretic and/or potassium-sparing diuretic, or glucocorticosteroid which can be delivered to prevent or treat ACD will vary from patient to patient.
  • the amount of nifedipine delivered from a gel formulation (2.5% HPMC in 75% ethanol) is from about 0.1 to 5% by weight, and preferably from about 0.25% to 2.0% by weight.
  • the amount of diuretic e.g. loop diuretic such as ethacrynic acid, which is preferably used from the same gel formulation is in the range of from about 0.25% to 10% by weight.
  • the amount of glucocorticosteroid which is preferably employed from the same gel formulation in the present invention is in the range of from about 0.1% to 5% by weight.
  • the dosage will vary as described.
  • the preferred agents are calcium channel blockers alone (e.g. nifedipine) or in combination with a diuretic (e.g. ethacrynic acid) .
  • the amount of the calcium channel blockers (e.g. nifedipine) is from about 0.1 to 10% by weight, preferably from about 0.1 to 1.0% by weight based on the total weight of the composition.
  • the amount of the optional diuretic is typically from about 0.5 to 5% by weight, preferably from about 0.1 to 1.0% by weight based on the total weight of the composition.
  • the amount of the optional glucocorticosteroid is up to about 2.0% by weight, preferably from about 0.05 to 1.0% by weight.
  • Example 1 Nifedipine as a Counter Sensitizer to DNCB
  • a 0.5% (w/v) solution of nifedipine was prepared in a gel formulation (2.5% HPMC in 75% ethanol) .
  • the same gel formulation served as a negative control.
  • a 1% (w/v) solution of dinitrochlorobenzene (DNCB) was prepared in acetone.
  • mice 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 L of hydroxypropylmethylcellulose (HPMC) on their exposed abdominal skin. The second group acted as a positive control by receiving on day 0, 0.2 mL of HPMC gel on exposed abdominal skin. The third group of mice was treated with 0.2 mL of HPMC gel containing nifedipine on day 0.
  • HPMC hydroxypropylmethylcellulose
  • mice in Groups II and III received ten (10) microliters of 1% DNCB ⁇ olution over the skin area pretreated with gel, while the mice in Group I received ten (10) microliters of acetone. All three groups were challenged on the right ear with twenty (20) microliters of 1% DNCB in acetone five (5) days after ⁇ en ⁇ itization.
  • Adverse reaction to the challenge with DNCB was determined by measuring the thickness of the mice ears before and after challenge to determine the amount of swelling, and then comparing the degree of swelling for mice treated in accordance with the invention (Group III) with Groups I and Groups II. The results are shown in Table 1.
  • NIFEDIPINE 1 HG (IN HPMC GEL) (PRE ONLY) + DNCB (100 ⁇ g) 24 HOURS 254 t 7 4 88
  • Example 2 The procedures of Example 1 were repeated except that the adverse skin reaction preventing or treating agent was a combination of a 1% (w/v) solution of hydrocortisone, and a 0.25% (w/v) solution of nifedipine, prepared in the above gel formulation. The results are shown in Table II.
  • the Group II mice showed significant ear swelling when sen ⁇ itized with DNCB.
  • the combination of hydrocorti ⁇ one and nifedipine constituting an adverse skin reaction preventing or treating agent in accordance with the present invention suppressed adverse reactions induced by sensitization with DNCB.
  • Example 1 The procedures of Example 1 were repeated except that the adverse skin reaction preventing or treating agent was a combination of a 2.5% (w/v) solution of ethacrynic acid and a
  • mice exhibited significant ear swelling when sensitized with DNCB.
  • the combination of nifedipine and ethacrynic acid constituting an adverse skin reaction preventing or treating agent in accordance with the present invention ⁇ uppre ⁇ sed adverse reactions induced by sensitization with DNCB.
  • a 0.5% (w/v) solution of nifedipine was prepared in a gel formulation (2.5% HPMC in 75% ethanol) .
  • a 5% (w/v) solution and a 1% (w/v) solution of nadolol were also prepared.
  • a 2.5% HPMC solution was prepared as a placebo.
  • mice were shaved on their back. Positive control mice
  • mice As shown in Table IV, the Group II mice exhibited significant ear swelling when sensitized to nadolol. Nifedipine alone constituting an adverse skin reaction preventing or treating agent limited adverse reactions induced by sensitization with nadolol.
  • Example 5
  • Verapamil as a Counter Sensitizer to Nadolol
  • Example 4 The procedures of Example 4 were repeated except that a 0.5% (w/v) solution of verapamil was used in place of nifedipine. The results are shown in Table V.
  • mice As shown in Table V, the Group II mice exhibited significant ear swelling when sensitized to nadolol. Verapamil alone constituting an adverse skin reaction preventing or treating agent limited adverse reactions induced by sensitization with nadolol .

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Abstract

Procédés, compositions et dispositifs de prévention et/ou de traitement d'une réaction secondaire de la peau à la présence d'un agent sensibilisant la peau par administration d'une dose efficace d'un inhibiteur de canaux calciques seul ou en combinaison avec au moins un diurétique et/ou au moins un glucocorticostéroïde.
PCT/US1996/018760 1995-11-22 1996-11-20 Traitement de l'hypersensibilite medicamenteuse par des inhibiteurs des canaux calciques WO1997018782A1 (fr)

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AU10587/97A AU1058797A (en) 1995-11-22 1996-11-20 Treatment with calcium channel blockers for drug-induced hypersensitivity

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US56181495A 1995-11-22 1995-11-22
US08/561,814 1995-11-22

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WO1997018782A1 true WO1997018782A1 (fr) 1997-05-29

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EP1053745A1 (fr) * 1999-05-18 2000-11-22 L'oreal Utilisation d'au moins un inhibiteur d'au moins un canal calcique dans le traitement des rides
FR2866810A1 (fr) * 2004-03-01 2005-09-02 Oreal Utilisation d'au moins un inhibiteur des canaux calciques pour prevenir et/ou traiter la peau grasse.
US7399493B2 (en) 2004-07-16 2008-07-15 Wille John J Anti-irritant botanicals
USRE46217E1 (en) 2005-05-24 2016-11-29 Chrono Therapeutics Inc. Portable drug delivery device including a detachable and replaceable administration or dosing element
US9555227B2 (en) 2004-09-13 2017-01-31 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery
US9669199B2 (en) 2004-09-13 2017-06-06 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US9700549B2 (en) 2013-10-03 2017-07-11 David Wise Compositions and methods for treating pelvic pain and other conditions
US10105487B2 (en) 2013-01-24 2018-10-23 Chrono Therapeutics Inc. Optimized bio-synchronous bioactive agent delivery system
US10213586B2 (en) 2015-01-28 2019-02-26 Chrono Therapeutics Inc. Drug delivery methods and systems
US10653686B2 (en) 2011-07-06 2020-05-19 Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
US10679516B2 (en) 2015-03-12 2020-06-09 Morningside Venture Investments Limited Craving input and support system
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US11596779B2 (en) 2018-05-29 2023-03-07 Morningside Venture Investments Limited Drug delivery methods and systems

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FR2793681A1 (fr) * 1999-05-18 2000-11-24 Oreal Utilisation d'au moins un inhibiteur d'au moins un canal calcique dans le traitement des rides
US6344461B1 (en) 1999-05-18 2002-02-05 Societe L'oreal S.A. Treating skin wrinkles/fine lines with calcium channel inhibitors
US6908925B2 (en) 1999-05-18 2005-06-21 L'oreal Treating skin wrinkles/fine lines with calcium channel inhibitors
EP1053745A1 (fr) * 1999-05-18 2000-11-22 L'oreal Utilisation d'au moins un inhibiteur d'au moins un canal calcique dans le traitement des rides
US9555226B2 (en) 2003-10-27 2017-01-31 Chrono Therapeutics Inc. Transdermal drug delivery method and system
US10716764B2 (en) 2003-10-27 2020-07-21 Morningside Venture Investments Limited Transdermal drug delivery method and system
FR2866810A1 (fr) * 2004-03-01 2005-09-02 Oreal Utilisation d'au moins un inhibiteur des canaux calciques pour prevenir et/ou traiter la peau grasse.
EP1570841A1 (fr) * 2004-03-01 2005-09-07 L'oreal Utilisation d'au moins un inhibiteur des canaux calciques pour prevenir et/ou traiter la peau grasse
US7399493B2 (en) 2004-07-16 2008-07-15 Wille John J Anti-irritant botanicals
US9555227B2 (en) 2004-09-13 2017-01-31 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery
US9669199B2 (en) 2004-09-13 2017-06-06 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US11471424B2 (en) 2004-09-13 2022-10-18 Morningside Venture Investments Limited Biosynchronous transdermal drug delivery
US10258778B2 (en) 2004-09-13 2019-04-16 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, aids, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
US10258738B2 (en) 2004-09-13 2019-04-16 Chrono Therapeutics Inc. Biosynchronous transdermal drug delivery for longevity, anti-aging, fatigue management, obesity, weight loss, weight management, delivery of nutraceuticals, and the treatment of hyperglycemia, alzheimer's disease, sleep disorders, parkinson's disease, AIDs, epilepsy, attention deficit disorder, nicotine addiction, cancer, headache and pain control, asthma, angina, hypertension, depression, cold, flu and the like
USRE46217E1 (en) 2005-05-24 2016-11-29 Chrono Therapeutics Inc. Portable drug delivery device including a detachable and replaceable administration or dosing element
US10653686B2 (en) 2011-07-06 2020-05-19 Parkinson's Institute Compositions and methods for treatment of symptoms in parkinson's disease patients
US10105487B2 (en) 2013-01-24 2018-10-23 Chrono Therapeutics Inc. Optimized bio-synchronous bioactive agent delivery system
US9700549B2 (en) 2013-10-03 2017-07-11 David Wise Compositions and methods for treating pelvic pain and other conditions
US10543201B2 (en) 2013-10-03 2020-01-28 David Wise Compositions and methods for treating pelvic pain and other conditions
US10232156B2 (en) 2015-01-28 2019-03-19 Chrono Therapeutics Inc. Drug delivery methods and systems
US11400266B2 (en) 2015-01-28 2022-08-02 Morningside Venture Investments Limited Drug delivery methods and systems
US10213586B2 (en) 2015-01-28 2019-02-26 Chrono Therapeutics Inc. Drug delivery methods and systems
US12011560B2 (en) 2015-01-28 2024-06-18 Morningside Venture Investments Limited Drug delivery methods and systems
US10679516B2 (en) 2015-03-12 2020-06-09 Morningside Venture Investments Limited Craving input and support system
US11285306B2 (en) 2017-01-06 2022-03-29 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US12042614B2 (en) 2017-01-06 2024-07-23 Morningside Venture Investments Limited Transdermal drug delivery devices and methods
US11596779B2 (en) 2018-05-29 2023-03-07 Morningside Venture Investments Limited Drug delivery methods and systems
US12017029B2 (en) 2018-05-29 2024-06-25 Morningside Venture Investments Limited Drug delivery methods and systems

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