WO2014049044A1 - Méthodes et compositions pharmaceutiques pour le traitement de la colite ulcéreuse - Google Patents

Méthodes et compositions pharmaceutiques pour le traitement de la colite ulcéreuse Download PDF

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Publication number
WO2014049044A1
WO2014049044A1 PCT/EP2013/070050 EP2013070050W WO2014049044A1 WO 2014049044 A1 WO2014049044 A1 WO 2014049044A1 EP 2013070050 W EP2013070050 W EP 2013070050W WO 2014049044 A1 WO2014049044 A1 WO 2014049044A1
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WIPO (PCT)
Prior art keywords
sulforaphane
subject
analog
ulcerative colitis
isothiocyanato
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PCT/EP2013/070050
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English (en)
Inventor
Eric Ogier-Denis
Xavier Treton
Eric PEDRUZZI
Yannick LADEIRO
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paris Diderot - Paris 7
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Publication of WO2014049044A1 publication Critical patent/WO2014049044A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/26—Cyanate or isocyanate esters; Thiocyanate or isothiocyanate esters
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the present invention relates to methods and pharmaceutical compositions for the treatment of ulcerative colitis.
  • Ulcerative colitis is a chronic intermittent and relapsing inflammatory bowel disease (IBD) of the colon characterized by superficial mucosal lesions that extend through the rectum and progress upstream.
  • IBD inflammatory bowel disease
  • the natural history of UC is characterized by the progression of colonic lesions in up to 50% of subjects.
  • colonic mucosa samples from patients with UC have defects in the eIF2a pathway, which controls protein translation and the cell stress response (Treton X, Pedruzzi E, Cazals-Hatem D, Grodet A, Panis Y, Groyer A, Moreau R, Bouhnik Y, Daniel F, Ogier-Denis E. Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis. Gastroenterology. 201 1 Sep;141(3): 1024-35. Epub 201 1 May 26.). Restoration of eIF2a phosphorylation was thus suggested as a therapeutic target for the treatment of UC so as to achieve a potential cure and/or more profound remission.
  • Nrf2-ARE Nuclear factor (erythroid-derived 2)-like 2-Antioxidant Response Element
  • inflammation-associated pathogenesis such as autoimmune diseases, rheumatoid arthritis, asthma, emphysema, gastritis, colitis, and atherosclerosis 9 .
  • Sulforaphane that is an organosulfur compound that is obtained from cruciferous vegetables such as broccoli, Brussels sprouts or cabbages is a potent activator of Nrf2 and thus was suggested for the treatment of inflammatory disease (US 2011/0245213).
  • beneficial regulatory effect of sulforaphane on ulcerative colitis and its possible link with the ER stress-dependent eIF2a pathway remains unknown.
  • the present invention relates to methods and pharmaceutical compositions for the treatment of ulcerative colitis.
  • sulforaphane While the connection between ER stress and the subsequent induction of oxidative stress has been appreciated for several years, the data accumulated by the inventors with sulforaphane offer a new mechanism for the intersection of these two signaling pathways and reveal an unexpected effect on colitis. They indeed show that sulforaphane may prevent and protect mice from colitis by regulating eIF2 phosphorylation but also by activating Nrf2 pathway which participate to the fine tuning of ER stress. Accordingly, sulforaphane thus represents a new therapeutic molecule for the treatment (e.g.
  • Sulforaphane may also be suitable for the prevention of the main complications of ulcerative colitis such as primary sclerosing cholangitis and colorectal cancer.
  • An object of the present invention is a method for the treatment of ulcerative colitis in a subject in need thereof comprising administering the subject with a therapeutically effective amount of sulforaphane or an analog thereof.
  • Treatment is herein defined as the application or administration of the active ingredient according to the invention (i.e. sulforaphane or an analog thereof) to a subject, or application or administration a pharmaceutical composition comprising said active ingredient, with the purpose to cure, heal, alleviate, relieve, alter, remedy, ameliorate, improve the disease (i.e ulcerative colitis), or to prevent the development of the disease.
  • the tern thus encompasses the prophylactic treatment.
  • the term “prevent” refers to the reduction in the risk of acquiring or developing a given condition, or the reduction or inhibition of the recurrence or said condition in a subject who is not ill, but who has been or may be near a subject with the disease.
  • sulforaphane has its general meaning in the art and refers to l-Isothiocyanato-4-methylsulfinylbutane (CAS Number: 4478-93-7). Sulforaphane may be isolated from Brussels sprouts, cabbage, cauliflower, bokchoy, kale, collards, Chinese broccoli, broccoli raab, kohlrabi, mustard, turnip, radish, arugula, and watercress. Sulforaphane is typically orally given in capsules.
  • the term "sulforaphane analog" refers to any molecule selected from the group consisting of 6-isothiocyanato-2-hexanone, exo-2-acetyl-6- isothiocyanatonorbornane, exo-2-isothiocyanato-6-methylsulfonyinorbornane, 6- isothiocyanato-2-hexanol, l-isothiocyanato-4-dimethylphosphonylbutane, exo-2-(l- hydroxyethyl)-5-isothiocyanatonorbornane, exo-2-acetyl-5-isothiocyanatonorbornane, 1 - isothiocyanato-5-methylsulfonylpentane, cis-3- (methylsulfonyl)cyclohexylmethylisothiocyanate and trans-3- (methylsulfonyl)cyclohexylmethylisothiocyanate and trans
  • a “therapeutically effective amount” is meant a sufficient amount of the sulforaphane or the analog thereof to treat the disease at a reasonable benefit/risk ratio applicable to any medical treatment.
  • 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 specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific polypeptide employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • 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 active ingredient 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 active ingredient, preferably from 1 mg to about 100 mg of the active ingredient.
  • 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.
  • a further object of the invention is a method for maintaining a subject suffering from ulcerative colitis in a long term remission comprising administering the subject with a therapeutically effective amount of sulforaphane or an analog thereof.
  • a further object of the invention is a method for treating an ulcerative colitis in a subject in need thereof comprising i) a first step consisting of administering the subject with a a standard treatment and ii) second step consisting of administering the subject with a therapeutically effective amount of sulforaphane or an analog thereof for maintaining the subject in a long term remission after the standard treatment of step i).
  • step i) and ii) are performed concomitantly or preferably step ii) is performed sequentially after step i).
  • the standard treatment is selected from the group consisting of corticosteroids, immunosuppressive drugs, aminosalicylates sulfasalazine, such as Mesalazine (also known as 5 -amino salicylic acid, mesalamine, or 5 -ASA.
  • Brand name formulations include Apriso, Asacol, Pentasa, Mezavant, Lialda, Fivasa, Rovasa and Salofalk.), Sulfasalazine (also known as Azulfidine), Balsalazide (also known as Colazal or Colazide (UK)), Olsalazine (also known as Dipentum), immuno suppressors (azathioprine, 6- mercaptopurine, methotrexate, rapamycine, cyclosporine and tacrolimus) or biological treatments such as Infliximab, Visilizumab, Adalimumab, or Vedolizumab, golimumab, tofacitinib.
  • An object of the present invention is a method for the prevention of primary sclerosing cholangitis and colorectal cancer in a subject suffering from ulcerative colitis comprising administering the subject with a therapeutically effective amount of sulforaphane or an analog thereof.
  • the sulforaphane or the analog thereof may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms (suppository and enemas).
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the sulforaphane or the analog thereof of the invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active polypeptides in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered so lution thereo f.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • parenteral administration in an aqueous solution for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure.
  • one dosage could be dissolved in 1 ml of isotonic NaCl solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the sulforaphane or the analog thereof of the invention may be formulated within a therapeutic mixture to comprise about 0.0001 to 1.0 milligrams, or about 0.001 to 0.1 milligrams, or about 0.1 to 1.0 or even about 10 milligrams per dose or so. Multiple doses can also be administered.
  • parenteral administration such as intravenous or intramuscular injection
  • other pharmaceutically acceptable forms include, e.g. tablets or other solids for oral administration; liposomal formulations; time release capsules; and any other form currently used.
  • the invention will be further illustrated by the following figures and examples.
  • EXAMPLE 1 SULFORAPHANE PREVENTS AND TREATS ULCERATIVE COLITIS THROUGH A DUAL EFFECT ON NRF2 AND E I F 2a PHOSPHORYLATION (EX VIVO STUDIES)
  • sulforaphane SFN was tested on isolated colon loops from anesthetized WT mice for 1 to 3h.
  • ER stress was evaluated by qPCR (XBP-1 splicing, Grp78/Grp94, EDEM, PDI, AGR2, ATF4, CHOP, GADD34 mRNA levels), Western blot (Grp78/Grp94, phospho-eIF2a, eIF2a, ATF4, GADD34, CHOP).
  • Nrf2/ARE-dependent pathway was evaluated by qPCR and Western blots (Nrf2, Keapl, HO-1, NQOl, GST).
  • the anti-inflammatory effects of sulforaphane was studied by Western blot of phospho- ⁇ ,phospho-lKBa, p65 subunit of NF- ⁇ and by qPCR (TNFa, IL-8, ILl , IL10; iNOS, COX, MCP1/CCL2).
  • mice (see patent PCT/FR2012/050822 ) (3/4 weeks of age) were treated for 3 weeks with sulforaphane (IP 10 ⁇ g/g or 25 ⁇ g/g of body) and sacrificed at 6 weeks of age.
  • DAI Clinical disease activity index
  • Histological grading was performed blindly by the same expert Gl-pathologist (DCH) and intestinal inflammation was characterized by loss of goblet cells, mucosal thickening, presence of inflammatory cells, loss of epithelial architecture, ulcers, and crypt abscesses.
  • DCH Gl-pathologist
  • Colonic inflammatory response was analysed by qPCR arrays (cytokines). Muco secretion was studied by immunohistochemistry and confocal microscopy associated with alcian blue/periodic acid/Schiff s reagent.
  • the preventive and curative effects of sulforaphane is mediated by increased HO-1 protein expression level and increased phosphorylation of eIF2 after three weeks of treatment.
  • Cigarette smoke induces endoplasmic reticulum stress and the unfolded protein response in normal and malignant human lung cells. BMC Cancer 8, 229 (2008).
  • Nrf2-deficient mice have an increased susceptibility to dextran sulfate sodium-induced colitis. Cancer Res 66, 11580-11584 (2006).
  • Nrf2 is a direct PERK substrate and effector of PERK- dependent cell survival. Mol Cell Biol 23, 7198-7209 (2003).
  • Nrf2-ARE pathway An important role of Nrf2-ARE pathway in the cellular defense mechanism. J Biochem Mol Biol 37, 139-143 (2004).

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Abstract

La présente invention concerne des méthodes et des compositions pharmaceutiques pour le traitement de la colite ulcéreuse. En particulier, la présente invention vise à fournir une méthode de traitement de la colite ulcéreuse chez un sujet en ayant besoin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace de sulforaphane ou d'un analogue de celui-ci.
PCT/EP2013/070050 2012-09-26 2013-09-26 Méthodes et compositions pharmaceutiques pour le traitement de la colite ulcéreuse WO2014049044A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070042061A1 (en) * 2005-08-18 2007-02-22 Ribnicky David M Anti-inflammatory activity of phenethylisothiocyanate (PEITC) and the Barbarea verna seed preparation containing this compound
WO2009087602A1 (fr) * 2008-01-10 2009-07-16 Geiszt Miklos Compositions et procédés de traitement et de prévention de la rectocolite hémorragique
WO2010001119A2 (fr) * 2008-07-01 2010-01-07 Plant Bioscience Limited Utilisation
WO2010001096A2 (fr) * 2008-07-01 2010-01-07 Provexis Natural Products Limited Traitement
WO2010140902A1 (fr) * 2009-06-02 2010-12-09 Mark Hampton Inhibiteurs du facteur d'inhibition de la migration des macrophages

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070042061A1 (en) * 2005-08-18 2007-02-22 Ribnicky David M Anti-inflammatory activity of phenethylisothiocyanate (PEITC) and the Barbarea verna seed preparation containing this compound
WO2009087602A1 (fr) * 2008-01-10 2009-07-16 Geiszt Miklos Compositions et procédés de traitement et de prévention de la rectocolite hémorragique
WO2010001119A2 (fr) * 2008-07-01 2010-01-07 Plant Bioscience Limited Utilisation
WO2010001096A2 (fr) * 2008-07-01 2010-01-07 Provexis Natural Products Limited Traitement
US20110245213A1 (en) 2008-07-01 2011-10-06 Provexis Natural Products Limited Treatment
WO2010140902A1 (fr) * 2009-06-02 2010-12-09 Mark Hampton Inhibiteurs du facteur d'inhibition de la migration des macrophages

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Title
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CULLINAN, S.B.; DIEHL, J.A.: "PERK-dependent activation of Nrf2 contributes to redox homeostasis and cell survival following endoplasmic reticulum stress", JBIOL CHEM, vol. 279, 2004, pages 20108 - 20117
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TRETON, X. ET AL.: "Altered endoplasmic reticulum stress affects translation in inactive colon tissue from patients with ulcerative colitis", GASTROENTEROLOGY, vol. 141, 2011, pages 1024 - 1035
VAN LIESHOUT E M M ET AL: "Effects of the sulforaphane analog compound 30, indole-3-carbinol, d-limonene or relafen on glutathione S-transferases and glutathione peroxidase of the rat digestive tract", BIOCHIMICA ET BIOPHYSICA ACTA - GENERAL SUBJECTS, ELSEVIER SCIENCE PUBLISHERS, NL, vol. 1379, no. 3, 2 March 1998 (1998-03-02), pages 325 - 336, XP004276055, ISSN: 0304-4165, DOI: 10.1016/S0304-4165(97)00112-8 *
YANAKA A ET AL: "Daily intake of sulphoraphane-rich broccoli sprouts prevents colon tumor formation in mice treated with dextran sodium sulfate and azoxymethane via stimulating nrf2-dependent antioxidant enzymes", GASTROENTEROLOGY, ELSEVIER, PHILADELPHIA, PA, vol. 132, no. 4, Suppl. 2, 1 April 2007 (2007-04-01), pages A23, XP008112107, ISSN: 0016-5085 *

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