WO2016142946A1 - Système pour le traitement d'infections dermatologiques - Google Patents

Système pour le traitement d'infections dermatologiques Download PDF

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Publication number
WO2016142946A1
WO2016142946A1 PCT/IL2016/050263 IL2016050263W WO2016142946A1 WO 2016142946 A1 WO2016142946 A1 WO 2016142946A1 IL 2016050263 W IL2016050263 W IL 2016050263W WO 2016142946 A1 WO2016142946 A1 WO 2016142946A1
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WO
WIPO (PCT)
Prior art keywords
composition
econazole
mometasone
days
subject
Prior art date
Application number
PCT/IL2016/050263
Other languages
English (en)
Inventor
Mori Arkin
Murielle AGASSI
Ofer Toledano
Ofra LEVY HACHAM
Original Assignee
Sol-Gel Technologies Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sol-Gel Technologies Ltd. filed Critical Sol-Gel Technologies Ltd.
Publication of WO2016142946A1 publication Critical patent/WO2016142946A1/fr

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Classifications

    • 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
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the present invention provides a system comprising econazole and mometasone and a pharmaceutically acceptable salt thereof for topical treatment of dermatological infections and regiments for using such.
  • Econazole is an imidazole antifungal agent (l-[2- ⁇ (4-chlorophenyl)methoxy ⁇ -2- (2,4-dichlorophenyl)ethyl]-lH-imidazole), sold as a 1% active mono nitrate cream, in a water-miscible base for topical use only. Econazole nitrate was shown to be as effective antifungal drug. It is dermatologically administered on the affected areas once daily in patients with tinea pedis, tinea cruris, tinea corporis, and tinea versicolor, and twice daily (morning and evening) in patients with cutaneous candidiasis.
  • Mometasone furoate is a glucocorticosteroid used topically to reduce inflammation of the skin or in the airways. It is a prodrug of the free form mometasone (( 11 ⁇ , 16 ⁇ )-9,21 -dichloro- 11 -hydroxy- 16-methyl-3 ,20-dioxopregna- 1 ,4-dien- 17-yl) .
  • Mometasone furoate is used in the treatment of inflammatory skin disorders (such as eczema and psoriasis), allergic rhinitis (such as hay fever), asthma for patients unresponsive to less potent corticosteroids, and penile phimosis.
  • steroid strength In terms of steroid strength, it is a medium strength steroid (for example it is more potent than hydrocortisone, and less potent than dexamethasone). Mometazone furoate was shown to reduce inflammation by causing several effects: reversing the activation of inflammatory proteins, activating the secretion of anti-inflammatory proteins, stabilizing cell membranes and decreasing the influx of inflammatory cells. Many methods are known for the topical treatment of fungal infections, including the use of antibiotics (e.g.
  • imidazole antifungal agents such as miconazole, clotrimazole, econazole and sulconazole, and non-imidazole fungal agents such as the allylamine derivatives terbinafine and naftifine, and the benzylamine butenafine.
  • imidazole antifungal agents such as miconazole, clotrimazole, econazole and sulconazole
  • non-imidazole fungal agents such as the allylamine derivatives terbinafine and naftifine, and the benzylamine butenafine.
  • imidazole antifungal agents such as miconazole, clotrimazole, econazole and sulconazole
  • non-imidazole fungal agents such as the allylamine derivatives terbinafine and naftifine, and the benzylamine butenafine.
  • Steroids can penetrate the skin and cause undesirable side effects, including skin atrophy, suppression of the hypothalamic -pituitary-adrenal axis, Cushing's syndrome, glucosuria, hyperglycemia, etc. Furthermore, the addition of a steroid decreases the effectiveness of some antifungal compounds, because of the potential of steroids to function as a deactivating agent.
  • corticosteroids in the treatment of topical indications has been connected with several sever harmful effects including hypothalamic pituitary adrenal axis (HPA) suppression, Cushing's syndrome, diabetes mellitus, osteoporosis, topical steroid addiction, allergic contact dermatitis, steroid allergy, steroid atrophy, perioral dermatitis, ocular effects (such as high intra-ocular pressure (IOP) and increase risk of glaucoma, cataract, retinopathy, tachyphylaxis, delivery-related adverse effects, and other local adverse effects (such as for example facial hypertrichosis, folliculitis, miliaria, genital ulcers, and granuloma gluteale infantum.
  • HPA hypothalamic pituitary adrenal axis
  • Lotrisone® cream clotrimazole 1 /betamethasone dipropionate 0.05%)
  • paraesthesia maculopapular rash
  • edema secondary infection
  • Lotrisone cream can cause reversible hypothalamic - pituitary-adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. This may occur during treatment or after withdrawal of treatment. Cushing's syndrome and hyperglycemia may also occur due to the systemic effect of corticosteroids while on treatment.
  • Factors that predispose a patient to HPA axis suppression include the use of high-potency steroids, large treatment surface areas, prolonged use, use of occlusive dressing, altered skin barrier, liver failure, and young age.
  • Canesten® hydrocortisone clotrimazole 1 percent /hydrocortisone 1 percent
  • Lotriderm® clotrimazole 1% percent /betamethasone dipropionate 0.05%) are local mild burning, irritation and hypersensitivity reactions.
  • such combination products sometimes fail to provide the fast relief of the inflammatory symptoms which is normally desired for the treatment of a fungal infection.
  • the system of the invention is useful in the treatment of dermatological fungal infections, such as for example tinea pedis, when administered to a subject for a treatment period of up to 7 days (either once or twice daily doses - the administration period), however having a therapeutic effect for at least 14 days past last administration of the system (post administration period).
  • the present invention relates to a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof.
  • the present invention provides a method of treating a dermatological fungal infection (including symptoms thereof) in a subject in need thereof comprising administering to a subject in need thereof a system comprising as active agents econazole or a pharmaceutically acceptable salt thereof and mometasone or a pharmaceutically acceptable salt thereof for a period of up to 7 days.
  • the present invention relates to a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof, for use in the treatment of dermatological fungal infection (including symptoms thereof), wherein said system is administered to a subject in need thereof for a period of up to 7 days.
  • system as used herein should be understood to relate to an arrangement representing a product or kit made up by at least one component, at least two components, at least three components and so forth, wherein said component represents a pharmaceutical composition comprising one or two active pharmaceutical agents.
  • a system of the invention may further comprise a composition that comprises a dermatological cosmetic agent (i.e. none pharmaceutical active agent), such as for example toning agent, moisturizing agent, hydrating agent and so forth.
  • econazole and mometasone constitute two separate compositions in a system of the invention.
  • a system of the invention comprises a composition comprising econazole and a composition comprising mometasone.
  • the econazole and mometasone constitute a single composition in a system of the invention.
  • the composition comprising econazole is a water based composition.
  • composition comprising mometasone is an oil based composition.
  • the system of the invention comprises a composition comprising econazole in the range of 0.5 to 2 weight percent of the composition. In some other embodiments, the econazole is at least 0.5 weight percent of the composition. In further embodiments, the econazole is about 1 weight percent of the composition.
  • the system of the invention comprises a composition comprising mometasone in the range of 0.05 to 0.2 weight percent of the composition.
  • the mometasone is at least 0.05 weight percent of the composition.
  • the mometasone is 0.1 weight percent of the composition.
  • a system comprises 1 % by weight econazole and 0.1 % by weight of mometasone.
  • the invention provides a unique method of treating a dermatological fungal infection in a subject in need thereof comprising administering to the subject a system of the invention (as described herein above and below) comprising as active agents econazole or a pharmaceutically acceptable salt thereof and mometasone or a pharmaceutically acceptable salt thereof for a period of up to 7 days.
  • the invention further provides a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof, for use in the treatment of dermatological fungal infection, wherein said system is administered to a subject in need thereof for a period of up to 7 days.
  • the invention further provides a system comprising econazole or any pharmaceutically acceptable salt or ester thereof and mometasone or any pharmaceutically salt or ester thereof, for use in the treatment of tenia pedis, wherein said system is administered to a subject in need thereof for a period of up to 7 days.
  • the system is administered to the subject for 1, 2, 3, 4, 5, 6 or 7 days. In some embodiments, the system is administered to the subject for 7 days. In certain embodiments, the system is administered to the subject once daily. In certain other embodiments, the system is administered to the subject twice daily.
  • each of the active agents of a system of the invention is contained in a separate composition for administration.
  • At least one of the compositions of a system of the invention is a dermatological/topical composition.
  • the system comprises a single composition comprising said active agents.
  • the single composition is a dermatological/topical composition.
  • the system comprises a composition comprising econazole in a water based composition. In some other embodiments of a method or use of the invention said system comprises a composition comprising mometasone in an oil based composition.
  • the system comprises a composition comprising econazole in the range of between 0.5 to 2 weight percent of the composition.
  • the econazole is at least 0.5 weight percent of the composition.
  • the econazole has a weight percent of about 1 % weight of the composition.
  • the system comprises a composition comprising mometasone in the range of between 0.05 to 0.2 weight percent of the composition.
  • the mometasone is at least 0.05 weight percent of the composition.
  • the mometasone has a weight percent of 0.1 % of the composition.
  • a method or use of the invention is intended for the treatment of a dermatological fungal infection selected from a skin mycosis including any disorders, symptoms or conditions associated thereof, tinea pedis, tinea corporis, tinea cruris, jock itch, tinea and ringworm.
  • the dermatological fungal infection is a mild to moderate infection. In other embodiments, the dermatological fungal infection is a moderate to severe infection.
  • moderate topical fungal infection symptoms or “moderate to severe topical fungal infection symptoms” relate to the intensity of the dermatological symptoms shown on the skin of said subject at the infection site which include at least one of erythema, scaling, maceration, burning and pruritus or any combinations thereof.
  • intensity of infectious symptoms are determined by a medical practitioner, e.g. as defined in the FDA "Draft Guidance on Econozole Nitrate”.
  • the subject has sensitivity to steroid exposure. It should be understood that the subject was either previously diagnosed as suffering from steroid sensitivity or is being diagnosed as having steroid sensitivity by a medical practitioner based on symptoms and conditions exhibited by the subject. It should be further understood that steroid sensitivity in a subject can be caused by several causes including, but not limited to another disease or disorder the subject is suffering from making him or her more sensitive to exposure of severe agents such as steroid, especially for a long period of exposure time, such disease include for example glaucoma, high-blood pressure, heart disease, diabetes mellitus, obesity, acid reflux/GERD, osteoporosis, cushing syndrome, fibromyalgia and so forth.
  • Subjects that have gone through severe surgery, including bypass surgery, transplant surgery, cancer removing surgery and so forth are also more susceptible to the side effects of steroids.
  • Patient populations having extreme skin sensitivity are also included in the definition of sensitivity to steroid exposure. Such populations include, but are not limited to infants between the age of 0 to 12 months, fibromyalgia patients, patients having skin allergies, patients suffering from skin cancer and so forth.
  • the therapeutic efficacy is retained for at least additional 14 days.
  • therapeutic efficacy it should be understood that the combined effect of the antifungal agent and steroid agent is evident even for at least 14 days after the last day of administration of the system of the invention to the subject. The evidence for the therapeutic effectiveness is shown by the reduction in fungal infection signs and dermatological symptoms thereof (mycological signs and symptoms of the infection) at the site of treatment.
  • the therapeutic efficacy is retained for at least additional 21 days.
  • the therapeutic efficacy is retained for at least additional 28 days. In some embodiments of a method or use of the invention, after the treatment (administration) period of 7 days the therapeutic efficacy is retained for at least additional 35 days.
  • the subject shows improved signs and symptoms of the fungal infection as compared with the single treatment with compositions comprising econazole or momethasone alone.
  • the improved signs and symptoms are selected from at least one of reduced erythemia, scaling, fissuring, maceration, vesiculation, pruritus and any combinations thereof.
  • the subject is a child between the ages of 0 to 5. In some embodiments, the subject is a child between the ages of 0 to 12.
  • a method or use of the invention is intended for the treatment of tinea pedis in a subject.
  • the system comprising 1% by weight of econazole and 0.1% by weight of mometasone is administered to a subject in need for a period of up to 7 days.
  • Treating a disease or disorder includes treating a symptom and/or reducing the symptoms of the disease.
  • a "pharmaceutically acceptable salt” is intended to mean a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable.
  • a compound for use in the invention may possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of inorganic or organic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • Exemplary pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a mineral or organic acid or an inorganic base, such as salts including sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrophosphates, dihydrophosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caproates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4 dioates, hexyne-l,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates,
  • a "pharmaceutically acceptable carrier” refers to a non-API (API refers to Active Pharmaceutical Ingredient) substances such as disintegrators, binders, fillers, and lubricants used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards, including those promulgated by the United States Food and Drug Administration and the European Medical Agency.
  • Topical administration examples include nasal, bucal, mucosal, rectal, or vaginal applications.
  • the compositions and system of the invention can be formulated into lotions, creams, ointments, gels, powders, pastes, sprays, suspensions, drops and aerosols.
  • one or more thickening agents, humectants, and stabilizing agents can be included in the formulations. Examples of such agents include, but are not limited to, polyethylene glycol, sorbitol, xanthan gum, petrolatum, beeswax, or mineral oil, lanolin, squalene, and the like.
  • a special form of topical administration is delivery by a transdermal patch. Methods for preparing transdermal patches are disclosed, e.g., in Brown, et al. (1988) Ann. Rev. Med. 39:221-229 which is incorporated herein by reference.
  • the system of the invention can also be administered parenterally in the form of solution or suspension, or in lyophilized form capable of conversion into a solution or suspension form before use.
  • diluents or pharmaceutically acceptable carriers such as sterile water and physiological saline buffer can be used.
  • Other conventional solvents, pH buffers, stabilizers, anti-bacteria agents, surfactants, and antioxidants can all be included.
  • useful components include sodium chloride, acetates, citrates or phosphates buffers, glycerin, dextrose, fixed oils, methyl parabens, polyethylene glycol, propylene glycol, sodium bisulfate, benzyl alcohol, ascorbic acid, and the like.
  • the parenteral formulations can be stored in any conventional containers such as vials and ampoules.
  • Clinical evaluation score included 5 parameters: Erythema, scaling, maceration, burning and pruritus (score between 0-3) Global assessment (global response scale) (% of clearing; 1.100%, 5. ⁇ 25%) Statistical analysis was performed on the total score, each parameter, the change from baseline of total score & global response rate for all visits.
  • the primary efficacy endpoints are the eradication of infection (evaluated at Week 1 and Days 21, 28 and 36 from end-of-treatment) and no evidence of clinical disease as indicated by complete resolution of all signs and symptoms (i.e., scores of 0 for erythemia, scaling, fissuring, maceration, vesiculation and pruritus) (evaluated at Week 1 and Days 21, 28 and 36 from start of study).
  • Complete cure defined as a negative KOH and negative fungal culture and no evidence of clinical disease as indicated by scores of 0 (none, complete absence of any signs or symptoms) for each clinical sign or symptom at Week 1 and Days 21, 28 and 36 from start of study.
  • a target lesion is identified, and patients undergo a mycological test (positive KOH and fungal culture). Patients return to the clinic following Week 1 and Days 21, 28 and 36, (follow-up visit through 29 days after end of treatment). Mycological test is performed on week 1 and day 36. A follow-up visit is performed five weeks following the completion of the treatment. During this visit safety and efficacy parameters are assessed including mycological test.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Dermatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne un système comprenant de l'éconazole et de la mométasone, y compris des utilisations et des méthodes de traitement de symptômes, de troubles et de maladies infectieuses associés.
PCT/IL2016/050263 2015-03-12 2016-03-10 Système pour le traitement d'infections dermatologiques WO2016142946A1 (fr)

Applications Claiming Priority (2)

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US201562131950P 2015-03-12 2015-03-12
US62/131,950 2015-03-12

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WO2016142946A1 true WO2016142946A1 (fr) 2016-09-15

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2341814A1 (fr) * 2000-03-27 2001-09-27 Taro Pharmaceutical Industries Ltd. Dispositif d'administration d'agents antifongiques et keratolytiques pour le traitement local d'infections fongiques de l'ongle et des tissus avoisinants
CN1931165A (zh) * 2006-09-21 2007-03-21 西北农林科技大学 一种硝酸益康唑纳米乳抗真菌药物及其制备方法
WO2012083341A1 (fr) * 2010-12-20 2012-06-28 Le Andrew Tuan Anh Composition pour le traitement d'états pathologiques de la peau

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2341814A1 (fr) * 2000-03-27 2001-09-27 Taro Pharmaceutical Industries Ltd. Dispositif d'administration d'agents antifongiques et keratolytiques pour le traitement local d'infections fongiques de l'ongle et des tissus avoisinants
CN1931165A (zh) * 2006-09-21 2007-03-21 西北农林科技大学 一种硝酸益康唑纳米乳抗真菌药物及其制备方法
WO2012083341A1 (fr) * 2010-12-20 2012-06-28 Le Andrew Tuan Anh Composition pour le traitement d'états pathologiques de la peau

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
HENG-LEONG CHAN, M.D: "An Open Study Evaluating Efficacy and Safety of Mometasone Furoate Cream, 0.1%, Once A Dayin the Treatment of A Variety of Dermatoses", DERMATOL SINICA, vol. 13, 31 December 1995 (1995-12-31), pages 87 - 92, XP055310283 *
N. SHARMA: "Validated Stability-indicating High-performance Liquid Chromatographic Method for Estimation of Degradation Behaviour of Eberconazole Nitrate and Mometasone Furoate in Cream Formulation", INDIAN J PHARM SCI., vol. 75, no. 1, 28 February 2013 (2013-02-28), pages 76 - 82, XP055310279 *

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