WO2020049327A1 - Méthodes et composition pharmaceutique pour le traitement de l'hidradénite suppurée chez des patients en ayant besoin - Google Patents

Méthodes et composition pharmaceutique pour le traitement de l'hidradénite suppurée chez des patients en ayant besoin Download PDF

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Publication number
WO2020049327A1
WO2020049327A1 PCT/IB2018/001127 IB2018001127W WO2020049327A1 WO 2020049327 A1 WO2020049327 A1 WO 2020049327A1 IB 2018001127 W IB2018001127 W IB 2018001127W WO 2020049327 A1 WO2020049327 A1 WO 2020049327A1
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WO
WIPO (PCT)
Prior art keywords
channel blocker
calcium channel
verapamil
treatment
hidradenitis suppurativa
Prior art date
Application number
PCT/IB2018/001127
Other languages
English (en)
Inventor
Marie-Laure LAROCHE
Marianne TESTE
Original Assignee
INSERM (Institut National de la Santé et de la Recherche Médicale)
Université De Limoges
Centre Hospitalier Régional Universitaire De Limoges
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 INSERM (Institut National de la Santé et de la Recherche Médicale), Université De Limoges, Centre Hospitalier Régional Universitaire De Limoges filed Critical INSERM (Institut National de la Santé et de la Recherche Médicale)
Priority to PCT/IB2018/001127 priority Critical patent/WO2020049327A1/fr
Publication of WO2020049327A1 publication Critical patent/WO2020049327A1/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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents

Definitions

  • the present invention relates to methods and pharmaceutical composition for the treatment of Hidradenitis suppurativa in patients in need thereof.
  • the present invention is defined by the claims.
  • a “therapeutically effective amount” is meant a sufficient amount of the calcium channel blocker to treat Hidradenitis suppurativa at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the agent for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the agent, preferably from 1 mg to about 100 mg of the agent.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • Topical formulation refers to a formulation that may be applied to skin. Topical formulations can be used for both topical and transdermal administration of substances.
  • topical administration is used in its conventional sense to mean delivery of a substance, such as a therapeutically active agent, to the skin or a localized region of a subject's body.
  • transdermal administration refers to administration through the skin. Transdermal administration is often applied where systemic delivery of an active is desired, although it may also be useful for delivering an active to tissues underlying the skin with minimal systemic absorption.
  • the topical pharmaceutically acceptable carrier is any substantially nontoxic carrier conventionally usable for topical administration of pharmaceuticals in which the calcium channel blocker of the present invention will remain stable and bioavailable when applied directly to skin surfaces.
  • carriers such as those known in the art effective for penetrating the keratin layer of the skin into the stratum corneum may be useful in delivering the calcium channel blocker of the present invention to the area of interest.
  • Such carriers include liposomes.
  • the calcium channel blocker can be dispersed or emulsified in a medium in a conventional manner to form a liquid preparation or mixed with a semi-solid (gel) or solid carrier to form a paste, powder, ointment, cream, lotion or the like.
  • Suitable cosmetically acceptable carriers include, but are not limited to, cosmetically acceptable liquids, creams, oils, lotions, ointments, gels, or solids, such as conventional cosmetic night creams, foundation creams, suntan lotions, sunscreens, hand lotions, make-up and make-up bases, masks and the like.
  • Any suitable carrier or vehicle effective for topical administration to a patient as known in the art may be used, such as, for example, a cream base, creams, liniments, gels, lotions, ointments, foams, solutions, suspensions, emulsions, pastes, aqueous mixtures, sprays, aerosolized mixtures, oils such as Crisco®, soft-soap, as well as any other preparation that is pharmaceutically suitable for topical administration on human and/or animal body surfaces such as skin or mucous membranes.
  • Topical acceptable carriers may be similar or identical in nature to the above described topical pharmaceutically acceptable carriers.
  • Sustained or delayed release of the calcium channel blocker provides a more efficient administration resulting in less frequent and/or decreased dosage of the calcium channel blocker and better patient compliance.
  • suitable carriers for sustained or delayed release in a moist environment include gelatin, gum arabic, xanthane polymers.
  • thermoplastic or flexible thermoset resin or elastomer including thermoplastic resins such as polyvinyl halides, polyvinyl esters, polyvinylidene halides and halogenated polyolefins, elastomers such as brasiliensis, polydienes, and halogenated natural and synthetic rubbers, and flexible thermoset resins such as polyurethanes, epoxy resins and the like. Controlled delivery systems are described, for example, in U.S. Pat. No.
  • “penetration enhancer” refers to an agent that improves the transport of molecules such as an active agent (e.g., a drug) into or through the skin. Various conditions may occur at different sites in the body either in the skin or below creating a need to target delivery of compounds. Thus, a“penetration enhancer” may be used to assist in the delivery of an active agent directly to the skin or underlying tissue or indirectly to the site of the disease or a symptom thereof through systemic distribution.
  • a penetration enhancer may be a pure substance or may comprise a mixture of different chemical entities.
  • HS also named“Vemeuil’s disease” or acnea inversa
  • HS is a chronic inflammatory skin disease (prevalence 0.25%-5%), with a major impact on the quality of life.
  • HS is sometimes associated with Crohn’s disease, arthropathy, metabolic syndrome and migraine (1).
  • the pathogenesis is not still understood; genetic predisposition, bacterial infection, hormones, obesity and smoking play a role.
  • an immune response dysfunction has been identified, involving pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a), interleukin (IL)-lp, IL-10, IL-12/23 and IL-17 (3).
  • TNF-a tumor necrosis factor-a
  • IL interleukin
  • adalimumab anti-TNF-a
  • anti-ILl anakinra
  • anti-IL23 ustekinumab
  • adalimumab was the first TNF-a inhibitor approved for moderate to severe HS.
  • biologic therapies are at increased risk of infections, malignancies, and hypersensitivity reactions (5).
  • Verapamil inhibits the growth and proliferation of fibroblasts, the synthesis of extracellular matrix proteins (collagen, fibronectin, proteoglycans), and reduces cytokines (IL-6, VEGF and TGF-bl) often elevated in keloids; so the intralesional injection of verapamil is a therapeutic option to treat keloid scars and other fibrosing diseases (e.g. Peyronie’s disease) (6-8).
  • verapamil has been shown to inhibit TNF-a-induced activation of NF-kB signaling both in vitro and in arthritis mice models, and to suppress IF- 1 b and TNF-a production by human peripheral blood mononuclear cells (9-10).
  • verapamil inhibits the inflammatory process through the TNF-a/IF-l pathway involved in the HS physiopathology.
  • both the HS relapse after the verapamil dechallenge and the regression after the verapamil rechallenge suggest a positive effect of verapamil on HS.

Landscapes

  • 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)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'hidradénite suppurée (HS) est une maladie cutanée chronique, inflammatoire, récurrente et débilitante qui apparaît généralement après la puberté. Elle se caractérise par des lésions douloureuses, profondes et enflammées, le plus souvent dans les régions axillaires, inguinales et anogénitales. Les inventeurs rapportent un traitement réussi de la HS avec un inhibiteur calcique, le vérapamil. Par rapport aux agents biologiques, le vérapamil est plus sûr et moins onéreux. Étant donné leur rôle possible sur TNF-α/IL-1, les inhibiteurs calciques représentent ainsi une option thérapeutique alternative dans le cas de la HS bénigne et modérée. Ainsi, la présente invention concerne une méthode de traitement de l'hidradénite suppurée chez un patient le nécessitant, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un inhibiteur calcique.
PCT/IB2018/001127 2018-09-05 2018-09-05 Méthodes et composition pharmaceutique pour le traitement de l'hidradénite suppurée chez des patients en ayant besoin WO2020049327A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/IB2018/001127 WO2020049327A1 (fr) 2018-09-05 2018-09-05 Méthodes et composition pharmaceutique pour le traitement de l'hidradénite suppurée chez des patients en ayant besoin

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IB2018/001127 WO2020049327A1 (fr) 2018-09-05 2018-09-05 Méthodes et composition pharmaceutique pour le traitement de l'hidradénite suppurée chez des patients en ayant besoin

Publications (1)

Publication Number Publication Date
WO2020049327A1 true WO2020049327A1 (fr) 2020-03-12

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Country Status (1)

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WO (1) WO2020049327A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5427778A (en) 1987-09-18 1995-06-27 Ethicon, Inc. Gel formulations containing growth factors and acrylamide polymer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5427778A (en) 1987-09-18 1995-06-27 Ethicon, Inc. Gel formulations containing growth factors and acrylamide polymer

Non-Patent Citations (12)

* Cited by examiner, † Cited by third party
Title
ALAVI A ET AL: "Approach to the management of patients with hidradenitis suppurativa: A consensus document", JOURNAL OF CUTANEOUS MEDICINE AND SURGERY 20170601 SAGE PUBLICATIONS INC. USA, vol. 21, no. 6, June 2017 (2017-06-01), pages 513 - 524, XP009513276, ISSN: 1203-4754 *
BADAVANIS G; PASMATZI E; MONASTIRLI A ET AL.: "Biologic agents in systemic dermatotherapy: cutaneous and systemic side effects", CURR DRUG SAF, 18 May 2017 (2017-05-18)
BERMAN B; MADERAL A; RAPHAEL B: "Keloids and Hypertrophic Scars: Pathophysiology, Classification, and Treatment", DERMATOL SURG, vol. 43, no. 1, 2017, pages S3 - S18
CANOUI-POITRINE F; LE THUAUT A; REVUZ JE ET AL.: "Identification of three hidradenitis suppurativa phenotypes: latent class analysis of a cross-sectional study", J INVEST DERMATOL, vol. 133, 2013, pages 1506 - 11
D'ANDREA F; BRONGO S; FERRARO G; BARONI A: "Prevention and treatment of keloids with intralesional verapamil", DERMATOLOGY, vol. 204, 2002, pages 60 - 2
FAVILLA V; RUSSO GI; ZUCCHI A ET AL.: "Evaluation of intralesional injection of hyaluronic acid compared with verapamil in Peyronie's disease: preliminary results from a prospective, double-blinded, randomized study", ANDROLOGY, vol. 5, 2017, pages 771 - 775
HOFFMAN LK; GHIAS MH; LOWES MA: "Pathophysiology of hidradenitis suppurativa", SEMIN CUTAN MED SURG, vol. 36, 2017, pages 47 - 54
MARIE-LAURE LAROCHE ET AL: "Successful control of hidradenitis suppurativa with verapamil: a case report", WILEY ONLINE LIBRARY, 19 July 2018 (2018-07-19), pages 1 - 7, XP055589527, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/10.1111/fcp.12403> [retrieved on 20190516] *
MATSUMORI A; NISHIO R; NOSE Y: "Calcium channel blockers differentially modulate cytokine production by peripheral blood mononuclear cells", CIRC J, vol. 74, 2010, pages 567 - 71
VAN DER ZEE HH; DE RUITER L; VAN DEN BROECKE DG ET AL.: "Elevated levels of tumour necrosis factor (TNF)-a, interleukin (IL)- 1 β and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-a and IL-Iβ", BR J DERMATOL, vol. 164, 2011, pages 1292 - 8
WANG W; LI Z; MENG Q; ZHANG P ET AL.: "Chronic Calcium Channel Inhibitor Verapamil Antagonizes TNF-a-Mediated Inflammatory Reaction and Protects Against Inflammatory Arthritis in Mice", INFLAMMATION, vol. 39, 2016, pages 1624 - 34, XP036055442, DOI: doi:10.1007/s10753-016-0396-1
ZOUBOULIS CC; DESAI N; EMTESTAM L ET AL.: "European Sl guideline for the treatment of hidradenitis suppurativa/acne inversa", J EUR ACAD DERMATOL VENEREOL, vol. 29, 2015, pages 619 - 44

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