WO2012069842A1 - Combinaison d'un antagoniste de cyslt1 et d'un médicament anti-arthrite pour le traitement d'un trouble arthritique - Google Patents

Combinaison d'un antagoniste de cyslt1 et d'un médicament anti-arthrite pour le traitement d'un trouble arthritique Download PDF

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WO2012069842A1
WO2012069842A1 PCT/GB2011/052317 GB2011052317W WO2012069842A1 WO 2012069842 A1 WO2012069842 A1 WO 2012069842A1 GB 2011052317 W GB2011052317 W GB 2011052317W WO 2012069842 A1 WO2012069842 A1 WO 2012069842A1
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derivative
acceptable salt
pharmaceutically acceptable
composition
cyslti
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Stephen Alan John Kilfeather
Elaine Lee
Alberto Taurozzi
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Xaragen Pharma Limited
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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/573—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 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine

Definitions

  • This invention relates to the treatment of arthritic conditions.
  • Arthritic conditions are typically those affecting joints of human and other mammals. Arthritic conditions are most often characterised by symptoms of joint inflammation including joint pain, swelling and stiffness. Additionally, arthritic conditions involve destructive changes in joint architecture. These conditions include the following: rheumatoid arthritis, osteoarthritis, psoriatic arthritis, gout, pseudogout, juvenile arthritis, Still's disease, ankylosing spondylitis, fibromyalgia and tennis elbow, Septic arthritis, chronic reactivated streptococcal cell wall (SCW)-induced arthritis.
  • SCW streptococcal cell wall
  • Arthritic conditions are also those inflammatory joint conditions occurring secondary to the following conditions: Ehlers-Danlos Syndrome, Sarcoidosis, Henoch- Schonleinpurpura, Reactive arthritis, Haemochromatosis, Hepatitis, Wegener's granulomatosis (and many other vasculitis syndromes), Lyme disease, Familial Mediterranean fever, Hyperimmunoglobulinemia D with recurrent fever, TNF receptor associated periodic syndrome, Inflammatory bowel disease (Including Crohn's Disease and Ulcerative Colitis).
  • Treatment of arthritic conditions currently involves administration of a range of classes of compounds to treat both symptoms and underlying cause. Treatment is far from optimal as demonstrated by the large number of synovectomy procedures, together with the number of large and small joint replacements conducted in osteoarthritis and rheumatoid arthritis; the most prevalent forms of arthritis.
  • Analgesics are administered ubiquitously within arthritic conditions as an adjunct therapy.
  • Prostaglandins and leukotrienes are metabolic byproducts derived from the same cell membrane precursor and are involved in many cellular functions; particularly mediation of inflammatory responses.
  • Prostaglandins are produced by the action of cycloxygenase (COX) on arachidonic acid, whereas leukotrienes are produced by the action of 5-lipoxygenase (5-LO) on arachidonic acid.
  • COX cycloxygenase
  • 5-LO 5-lipoxygenase
  • Prostaglandins mediate certain pain signals and hence, compounds that inhibit prostaglandin production through inhibition of the enzyme cycloxygenase (COX) have established themselves as an analgesic class.
  • Non-steroidal anti-inflammatory drugs such as naproxen of the non-selective COX-1 and COX -2 isoenzyme inhibiting class
  • NSAIDs are administered for analgesic purposes in treatment of symptoms of pain in patients with arthritis.
  • COX-1 inhibition is associated with gastric side effects.
  • COX-2 selective inhibitors such as celecoxib
  • Analgesics that have been designed on the basis of inhibition of prostaglandin production, pain swelling and inflammation, and those compounds that are administered for treatment of arthritis include those of the following classes: non-steroidal anti-inflammatory drugs (NSAIDS) (e.g.
  • detoprofen diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, meclofenameate, mefenamic acid, meloxicam, nabumeone, naproxen sodium, oxaprozin, piroxicam, sulindac, tolmetin, aspirin, choline salicylate, salsalate, and sodium and magnesium salicylate), COX-2 selective inhibitors (e.g., celecoxib, rofecoxib,valdecoxib and lumiracoxib).
  • COX-2 selective inhibitors e.g., celecoxib, rofecoxib,valdecoxib and lumiracoxib.
  • DMARDS disease modifying anti-rheumatic drugs
  • Glucocorticoids are also administered during periods of increased inflammatory activity, often termed 'flare ups' (e.g.
  • TNFa anti-tumor necrosis factor alpha
  • ENBREL(R) etanercept, a soluble TNFa receptor
  • REMICADE(R) infliximab
  • All of the above classes can be administered simultaneously within arthritic conditions, such is the debilitating nature of the conditions.
  • Combination therapy is valuable therefore when it comprises a therapy targeting the underlying cause and a different therapy targeting the symptoms through an adjunct therapy.
  • Another example is the treatment of cancer with chemotherapeutic agents together with adjunct analgesics such as NSAIDs or opioid analgesics. This is also observed in treatment of asthma, in which glucocorticoids treat the underlying immune cause, while beta-adrenergic receptor agonists treat the bronchoconstricting inflammatory responses.
  • Combination therapy is also valuable when targeting a single biological event, where a single agent has a limited capacity to affect the target, independent of the concentration of compound administered. Under these circumstances, addition of another compound exerting a similar action can add efficacy to the first compound's efficacy ('additive effect'). Combination of compounds within a therapy can also result in a 'synergistic action' in which the combined efficacy is greater than the sum of the individual component efficacies.
  • Combination therapy can also reduce the problem of dose limiting toxicity.
  • additive actions of compounds against a single target within a disease can permit the dose reduction or 'sparing' of one of the components in a combination used to treat the disease; thereby reducing side effects.
  • addition of a compound to a regimen within a combination can result in alleviation of a side effect of a compound to which a side-effect-alleviating compound is added within a combination.
  • This subject of this invention concerns the capacity of compounds within the COX inhibiting classes and the cysteinyl leukotriene receptor 1 (CysLTi) antagonists to provide components of a pharmaceutical preparation combination that will provide (1) a novel treatment for the reduction of increased synoviocyte numbers in the treatment of arthritic conditions, and (2) an improvement in the adjunct use of analgesic therapy of COX inhibitors through the additive effect of the combination in treatment of arthritic conditions.
  • CysLTi cysteinyl leukotriene receptor 1
  • Synoviocytes are the cell type that produce the synovial tissue matrix of the synovial tissue within which they reside.
  • the synoviocytes contained within the joint synovium are critical for the maintenance of joint inflammation in arthritic conditions. Synoviocytes release a range of pro-inflammatory cytokines and destructive enzymes such as matrix metalloproteinases. Additionally, a reflection of the increased inflammatory activity of synoviocytes is their excessive division in arthritis.
  • Synoviocyte activation and hyperplasia are present in all major forms of arthritic conditions. Synoviocyte activation and proliferation (hyperplasia) results in inflammation and hypertrophy of the synovium (synovitis) and is accompanied by release of immune/inflammatory signals, angiogenic factors, joint destructive enzymes and invasive behaviour leading to impedance of joint function and joint destruction. The Synoviocyte is therefore an established target in the treatment of arthritic conditions. (Bartok et al., Immunol Rev. 233(1):233, 2010; Noss et al., Immunol Rev. 223:252, 2008; Iwanaga et al., Arch HistolCytol.
  • Osteoarthritis is the most common arthritic condition and synovial hyperplasia leading to synovial hypertrophy is a common feature of the condition (Iagnocco et al., ClinExpRheumatol. 28(5):643, 2010; Furuzawa-Carballeda et al., ClinExpRheumatol.26(4):554, 2008; Ju et al., J Ultrasound Med. 27(5):729, 2008; Migliore et al., Reumatismo.59(1):57 ' , 2007; Jung et al. ClinExpRheumatol. 24(3):253, 2006. Conaghan et al., Ann Rheum Dis.
  • Synovial hypertrophy is closely associated with pain in osteoarthritic joints (Wenham et al., Nat ClinPractRheumatol. 5(3): 149, 2009; Conaghan et al., Novartis Found Symp. ; 260: 191, 2004).
  • the release of prostaglandins by the hypertrophied synovium would therefore contribute to the source of pain in arthritic joints, and would provide a route for NSAID efficacy against arthritis-derived pain through their targeting of the synovial source of prostaglandin production (Nah et al., Rheumatol Int.30 (4):443, 2010).
  • VEGF vascular endothelial growth factor
  • Tumor necrosis factor alpha induces synoviocyte divisions and VEGF production from synoviocytes, contributing to the synoviocyte importance in anti-TNF therapy in arthritis and the associated reduction in inflammatory angiogenesis in the joint (Cha et al., J Rheumatol. 34(1): 16, 2007).
  • Rheumatoid arthritis has a lower prevalence than osteoarthritis, but exhibits an even more aggressive synovial hyperplasia and hypertrophy compared with osteoarthritis; with associated pain, angiogenesis, joint impedance and secretion of a plethora of synoviocyte-derived immune/inflammatory signals and destructive enzymes (Noss et al., Immunol Rev. 223:252, 2008; Seemayer et al., Z Rheumatol. 60(5):309, 2001). Synovial hyperplasia is also sufficiently advanced in early stages of rheumatoid arthritis to be detected macroscopically (McQueen, Rheumatology (Oxford).
  • compositions comprising the cysteinyl leukotriene 1 receptor (CysLTi) antagonist class with other compounds used in treatment of arthritic conditions.
  • CysLTi antagonists generate an additive inhibitory effect on synoviocyte division when in combination with NSAIDs, COX-2 selective inhibitors, DMARDS and glucocorticoids.
  • the CysLTi antagonists are a class of compounds that have been developed for use in treatment of asthma.
  • the CysLTi antagonists have been classified based on their high affinity for and capacity to antagonise, the CysLTi receptor.
  • cysteinylleukotrienes C4 (LTC4) and D4 (LTD4) with the CysLTi receptor is competed for by the CysLTi antagonist class.
  • Cysteinylleukotrienes are highly inflammatory lipid-derived products, produced along with prostaglandins from the arachidonic cascade at cell membranes.
  • the CysLTi antagonists have demonstrated a capacity to inhibit LTC4 and LTD4-induced inflammatory responses (Yuanet al., JPharmacol Sci.
  • montelukast has been found to have a significant effect on the clinical disease score of an established model of arthritis, namely collagen-induced arthritis in small mammals (Shiota et al., Eur J iarmaco/.548(l-3):158, 2006).
  • This action included a reduction in arthritic paw swelling and x-ray-determined bone erosion in affected limbs.
  • the action of the CysLTi antagonists against a principle cell type underlying arthritic joint inflammation, namely, the synoviocyte has not previously been determined.
  • the combined action of CysLTi antagonists with other drug classes used to treat arthritic conditions in either models of arthritis or inflammatory cell types within arthritis has not been determined.
  • the subject of this invention utilises the combined action of CysLTi antagonist compounds against synoviocyte function with the following classes of drugs commonly used in treatment of arthritic conditions: nonsteroidal anti-inflammatory drugs (NSAIDS), COX-2 selective inhibitor compounds, DMARDs and glucocorticoids.
  • NSAIDS nonsteroidal anti-inflammatory drugs
  • COX-2 selective inhibitor compounds COX-2 selective inhibitor compounds
  • DMARDs DMARDs
  • glucocorticoids glucocorticoids
  • cystLTl receptor antagonists produce an additive action in inhibition of human joint-derived synoviocyte division when in combination with any of the following class of compounds: NSAIDs, COX-2 selective inhibitors, DMARDSs and glucocorticoids. This discovery can be utilised in the treatment of arthritic conditions.
  • CysLTi antagonists against synoviocyte cell division that is additive with the same inhibitory action of NSAIDs, COX-2 selective inhibitors, DMARDS and glucocorticoids.
  • compositions for treatment of arthritic conditions in which the composition comprises a member of the class of compounds known as the CysLTi antagonists together with a member of any one of the following classes of compounds: NSAIDS, COX-2 selective inhibitors, DMARDS and glucocorticoids.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a member of the class of compounds known as the CysLTi antagonists together with a member of any one of the following classes of compounds: NSAIDS, COX-2 selective inhibitors, DMARDS and glucocorticoids.
  • This composition is for treatment of arthritic conditions.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of a CysLTi antagonist and/or a derivative thereof and a NSAID and/or a derivative of, or COX-2 selective inhibitor and/or a derivative of, or a DMARD and/or a derivative of, or a glucocorticoid and/or a derivative of, which together with a pharmaceutically acceptable adjuvant, diluents or carrier form a pharmaceutical composition for the treatment of arthritis.
  • Said pharmaceutical composition can also be used as an adjunct to administration of a DMARD or glucocorticoid.
  • compositions for treatment of arthritic conditions in which the composition comprises a member of the class of compounds known as the CysLTi antagonists together with a member of any one of the following classes of compounds: NSAIDS; and COX-2 selective inhibitors is used as an adjunctive therapy to administration of compounds within the following classes of compounds: DMARDs; and glucocorticoids.
  • CysLTi antagonists or a derivative thereof in combination with a NSAID, or COX-2 selective inhibitor, or DMARD, or glucocorticoid for the treatment of arthritic conditions is advantageous, inter alia, because it shows reduced toxicity, and/or reduced side effects, and/or increased efficacy.
  • the NSAID, or COX-2 selective inhibitor, or DMARD, or glucocorticoid may be administered with the CysLTi antagonist, or a salt or derivative or a derivative thereof, separately, simultaneously or sequentially.
  • effective therapeutic amounts of the compounds as described herein are to be administered as part of the same medicaments or are provided as separate medicaments to be administered at the same time or at different times.
  • compositions for treatment of arthritic conditions in which the composition comprises a member of the class of compounds known as the CysLTi antagonists together with a member of any one of the following classes of compounds: NSAIDS, COX-2 selective inhibitors, DMARDS and glucocorticoids is administered to a patient suffering with an arthritic condition in order to exert an additive inhibitory effect against synoviocyte division.
  • CysLTi antagonists a member of the class of compounds known as the CysLTi antagonists together with a member of any one of the following classes of compounds: NSAIDS, COX-2 selective inhibitors, DMARDS and glucocorticoids
  • the treatment of an arthritic condition according to the invention may comprise separately, simultaneously or sequentially inhibition of a synoviocyte cell division by providing to the cell a CysLTi antagonist, or derivative of, in combination with a NSAID or derivative of, or a COX-2 selective inhibitor or derivative of, or a DMARD or derivative of, or a glucocorticoid or derivative of.
  • CysLTi antagonists or derivatives thereof, separately, simultaneously or sequentially in combination with a second therapeutic agent classed as a NSAID or derivative of, or a COX-2 selective inhibitor or derivative of, or a DMARD or derivative of, or a glucocorticoid or derivative of, for the treatment of an arthritic condition.
  • a second therapeutic agent classed as a NSAID or derivative of, or a COX-2 selective inhibitor or derivative of, or a DMARD or derivative of, or a glucocorticoid or derivative of, for the treatment of an arthritic condition.
  • a method of treatment or alleviation of arthritic conditions which comprises contacting a synoviocyte with a therapeutically effective amount of a CysLTi antagonist, or a derivative thereof, separately, simultaneously or sequentially in combination with an effective amount of an NSAID or a derivative thereof, or COX-2 selective inhibitor or a derivative thereof, or a DMARD or derivative of, or a glucocorticoid or derivative of.
  • the second therapeutic agent may be a NSAID.
  • the second therapeutic agent may be a COX-2 selective inhibitor, the second agent may be a DMARD, the second agent may be a glucocorticoid.
  • the present invention provides a use of a CysLTi antagonist and/or a derivative thereof in combination with either a NSAID, or COX-2 selective inhibitor, or a DMARD, or a glucocorticoid in methods for treating an arthritic condition.
  • NSAID NSAID
  • a NSAID or derivative in the manufacture of a medicament for the treatment or alleviation of arthritic conditions by combination therapy with a CysLTi antagonist or derivative thereof.
  • a CysLTi antagonist for the treatment of an arthritic condition.
  • COX-2 selective inhibitor or derivative in the manufacture of a medicament for the treatment or alleviation of arthritic conditions by combination therapy with a CysLTi antagonist or derivative.
  • a COX-2 selective inhibitor separately, simultaneously or sequentially in combination with a CysLTi antagonist for the treatment of arthritic conditions.
  • a DMARD or derivative in the manufacture of a medicament for the treatment or alleviation of arthritic conditions by combination therapy with a CysLTi antagonist or derivative.
  • a CysLTi antagonist for the treatment of arthritic conditions.
  • glucocorticoid or derivative in the manufacture of a medicament for the treatment or alleviation of arthritic conditions by combination therapy with a CysLTi antagonist or derivative for the treatment or alleviation of arthritic conditions.
  • a glucocorticoid separately, simultaneously or sequentially in combination with a CysLTi antagonist for the treatment of arthritic conditions.
  • a DMARD or derivative in the manufacture of a medicament for the treatment or alleviation of arthritic conditions by combination therapy with both a NSAID or derivative and a CysLTi antagonist or derivative.
  • a DMARD separately, simultaneously or sequentially in combination with a NSAID, separately, simultaneously or sequentially and a CysLTi antagonist separately, simultaneously or sequentially for the treatment of arthritic conditions.
  • glucocorticoid or derivative in the manufacture of a combination therapy with both a NSAID or derivative and a CysLTi antagonist or derivative for the treatment or alleviation of arthritic conditions.
  • a glucocorticoid separately, simultaneously or sequentially in combination with a NSAID, separately, simultaneously or sequentially and a CysLTi antagonist separately, simultaneously or sequentially for the treatment of arthritic conditions.
  • a DMARD or derivative in the manufacture of a combination therapy with both a COX-2 selective inhibitor or derivative and a CysLTi antagonist or derivative for the treatment or alleviation of arthritic conditions.
  • a DMARD separately, simultaneously or sequentially in combination with a COX-2 selective inhibitor, separately, simultaneously or sequentially and a CysLTi antagonist separately, simultaneously or sequentially for the treatment of arthritic conditions.
  • glucocorticoid or derivative in the manufacture of a combination therapy with both a COX-2 selective inhibitor or derivative and a CysLTi antagonist or derivative for the treatment or alleviation of arthritic conditions.
  • a glucocorticoid separately, simultaneously or sequentially in combination with a COX- 2 selective inhibitor, separately, simultaneously or sequentially and a CysLTi antagonist separately, simultaneously or sequentially for the treatment of arthritic conditions.
  • glucocorticoid or derivative in the manufacture of a combination therapy with both a DMARD or derivative and a CysLTi antagonist or derivative for the treatment or alleviation of arthritic conditions.
  • a glucocorticoid separately, simultaneously or sequentially in combination with a DMARD, separately, simultaneously or sequentially and a CysLTi antagonist separately, simultaneously or sequentially for the treatment of arthritic conditions.
  • therapeutic agents that are CysLTi antagonists include: montelukast or any other pharmaceutically acceptable salt or derivative thereof, pranlukast or any other pharmaceutically acceptable salt or derivative thereof, pibulokast or any pharmaceutically acceptable salt or derivative thereof, zafirlukastor any other pharmaceutically acceptable salt or derivative thereof, cinalukastor any other pharmaceutically acceptable salt or derivative thereof, tomelukastor any other pharmaceutically acceptable salt or derivative thereof or pobilukastor any other pharmaceutically acceptable salt or derivative thereof.
  • therapeutic agents that are NSAIDs include: naproxen sodium or any other pharmaceutically acceptable salt or derivative thereof, or diclofenac sodium or any other pharmaceutically acceptable salt or derivative thereof, meloxicam or any pharmaceutically acceptable salt or derivative thereof, ibuprofen any pharmaceutically acceptable salt or derivative thereof, ketoprofen or any pharmaceutically acceptable salt or derivative thereof, or flurbiprofen or any pharmaceutically acceptable salt or derivative thereof, or oxaprozin or any pharmaceutically acceptable salt or derivative thereof, indomethacin or any pharmaceutically acceptable salt or derivative thereof, sulindac or any pharmaceutically acceptable salt or derivative thereof, or etodolac or any pharmaceutically acceptable salt or derivative thereof, or ketorolac or any pharmaceutically acceptable salt or derivative thereof, nabunetone or any pharmaceutically acceptable salt or derivative thereof, piroxicam or any pharmaceutically acceptable salt or derivative thereof, or tenoxicam or any pharmaceutically acceptable salt or derivative thereof, droxicam or any pharmaceutically acceptable salt or derivative thereof, lornoxi
  • therapeutic agents that are COX-2 selective inhibitors are: celecoxib or any pharmaceutically acceptable salt or derivative thereof, celecoxib or any pharmaceutically acceptable salt or derivative thereof, rofecoxib or any pharmaceutically acceptable salt or derivative thereof, valdecoxib or any pharmaceutically acceptable salt or derivative thereof, or lumiracoxib or any pharmaceutically acceptable salt or derivative thereof, or firocoxib or any pharmaceutically acceptable salt or derivative thereof.
  • therapeutic agents that are DMARDS include the following: cyclosporine or any pharmaceutically acceptable salt or derivative thereof, azathioprine or any pharmaceutically acceptable salt or derivative thereof, methotrexate or any pharmaceutically acceptable salt or derivative thereof, leflunomide or any pharmaceutically acceptable salt or derivative thereof, cyclophosphamide or any pharmaceutically acceptable salt or derivative thereof, hydroxychloroquine or any pharmaceutically acceptable salt or derivative thereof, sulfasalazine or any pharmaceutically acceptable salt or derivative thereof, D- penicillamine or any pharmaceutically acceptable salt or derivative thereof, minocycline or any pharmaceutically acceptable salt or derivative thereof, and gold or any pharmaceutically acceptable salt or derivative thereof.
  • therapeutic agents that are glucocorticoids include cortisone or any pharmaceutically acceptable salt or derivative thereof, dexamethasone or any pharmaceutically acceptable salt or derivative thereof, hydrocortisone or any pharmaceutically acceptable salt or derivative thereof, methylprednisolone or any pharmaceutically acceptable salt or derivative thereof, prednisolone or any pharmaceutically acceptable salt or derivative thereof, prednisone or any pharmaceutically acceptable salt or derivative thereof, triamcinolone or any pharmaceutically acceptable salt or derivative thereof.
  • derivative used herein shall include any conventionally known derivatives of CysLTi antagonist, NSAID, COX-2 selective inhibitor, DMARD, or glucocorticoid, such as, inter alia, solvates. It may be desirable to prepare, purify, and/or handle a corresponding solvate of the compound described herein, which may be used in any one of the uses/methods described.
  • solvate is used herein to refer to a complex of solute, such as a compound or salt or derivative of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc, depending on the number of water molecules present per molecule of substrate.
  • aspects of this invention include the administration of a single formulation containing a composition of two or more compounds in which one is a member of the CysLTi receptor antagonist class and the other(s) is a member of one of the following classes: NSAID, COX-2 selective inhibitor, DMARD and glucocorticoid.
  • Embodiments of this invention include the formulation of compositions for administration through the following routes: oral buccal, oral sublingual, inhalation, subcutaneous, topical or transdermal, pessary, suppository, intravenous, intramuscular, intraarticular.
  • the administration of the compounds is conducted separately in a kit containing instruction for the administration of the compounds separately simultaneously or at a separate time; up to 14 days apart (e.g., within 10 days, within five days, twenty-four hours, or one hour of each other).
  • CysLTi antagonist, NSAID, COX-2 selective inhibitor, DMARD and glucocorticoid administered depend on the specific combination of components (i.e., the specific CysLT ⁇ antagonist/NSAID combination; CysLTi antagonist /COX-2 selective inhibitor combination; CysLTi antagonist /DMARD combination; CysLTi receptor antagonist/glucocorticoid combination; CysLTiantagonist/NSAID/DMARD combination; CysLTiantagonist/NSAID/glucocorticoid combination; CysLTi antagonist /COX-2 selective inhibitor/DMARD combination; CysLTi antagonist /COX-2 selective inhibitor/glucocorticoid combination; glucocorticoid/DMARD/CysLTiantagonistcombination) and can be determined by one skilled in the art.
  • Embodiments of the invention include administration of compounds separately and in different formulations, such as, but not limited to, tablet for the CysLTi antagonist and injection for DMARD or glucocorticoid.
  • systemic administration is meant administration of a compound within the invention by any route (e.g., oral, rectal, intravenous, intramuscular, subcutaneous, inhalation, transdermal, vaginal, intraperitoneal, interarticular or ophthalmic) such that the compound is absorbed into the bloodstream of the patient.
  • route e.g., oral, rectal, intravenous, intramuscular, subcutaneous, inhalation, transdermal, vaginal, intraperitoneal, interarticular or ophthalmic
  • a “low dosage” is meant less than 10 mg per day of CysLTi antagonist, NSAID, COX- 2 selective inhibitor, DMARD and glucocorticoid.
  • a “moderate dosage” is meant 10 mg to 20 mg per day of CysLTi antagonist, NSAID, COX-2 selective inhibitor, DMARD and glucocorticoid.
  • a “high dosage” is meant greater than about 20 mg per day of CysLTi antagonist, NSAID, COX-2 selective inhibitor, DMARD and glucocorticoid.
  • treating is meant administering a pharmaceutical composition for the treatment or prevention of an arthritic condition.
  • treating disease or use for “therapeutic treatment” refers to administering treatment to a patient already suffering from an arthritic condition to improve the patient's condition (i.e., relieve pain and inflammation, prevent joint destruction, preserve or improve functional ability, and maintain a patient's normal lifestyle).
  • patient is meant any animal (e.g., a human).
  • an effective amount is meant the amount of a compound, in a combination of the invention, required to treat or prevent an arthritic condition.
  • the effective amount of active compound(s) used to practice the present invention for therapeutic treatment of conditions caused by or contributed to by the arthritic condition varies depending upon the manner of administration, the age, body weight, and general health of the patient. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an effective amount.
  • compound is also interchangeable with the term “drug” or “component” where a component is one of the active molecules within a pharmaceutical combination preparation or kit.
  • compositions described herein are intended here to cover any pharmaceutically acceptable salt, ester, solvate, hydrate which, upon administration to the recipient is capable of providing (directly or indirectly) the compound as described herein.
  • non- pharmaceutically acceptable salts also fall within the scope of the invention since these may be useful in the preparation of pharmaceutically acceptable salts.
  • the preparation of salts can be carried out by methods known in the art.
  • the pharmaceutical composition described herein is for use in the treatment of an arthritic condition.
  • a combination for use in the treatment of an arthritic condition comprising a member of the class of compounds known as the CysLTi antagonists together with a NSAIDS, COX-2 selective inhibitors, DMARDS or glucocorticoid compound.
  • the invention also provides the use of a CysLTi antagonists in combninaiton with a NSAIDS, COX-2 selective inhibitors, DMARDS or glucocorticoid compound for the reduction of synoviocyte division and/or increase in synoviocyte apoptosis in vivo.
  • FIG1 demonstrates the capacity of montelukast to provide an additive inhibition of synoviocytedivision in combination with a glucocorticoid, namely, prenisolone.
  • FIG2 demonstrates the capacity of montelukast to provide an additive action against synoviocyte function in combination with an NSAID, namely, diclofenac.
  • FIG3 demonstrates the capacity of montelukast to provide an additive inhibition of synoviocytedivision in combination with a COX-2 selective compound, namely, celecoxib
  • FIG4 demonstrates the capacity of montelukast to provide an additive inhibition of synoviocytedivision in combination with a DMARD, namely, methotrexate.
  • FIG5 demonstrates the capacity of montelukast to provide an additive inhibition of synoviocytedivision in combination with a DMARD, namely, sulfasalazine.
  • FIG1-5 provide a graphical representation of examples of the additive effect of montelukast, over a wide range of concentrations, in combination with, a wide range of concentrations ofat least one compound from each of the following classes:NSAID, COX-2- selective, DMARD and glucocorticoid.
  • NSAID a compound from each of the following classes: COX-2- selective, DMARD and glucocorticoid.
  • the additive action between the CysLT ! antagonists and all other compounds examined in the other compound classes is observed over the examined concentration range of CysLTi antagonists and the examined range of concentrations of the compounds of the other classes.
  • CysLT ! antagonist class members in their recognised function as CysLTi antagonists and among the other compound classes of NSAIDs, COX-2 selective inhibitors and glucocorticoids, it would be clear to anyone skilled in the art that any member of those classes examined in the present examples could be replaced by another member of that class in the combination.
  • the CysLTiantagonist may be selected from any the following: zafirlukast or any pharmacologically acceptable salt thereof, pranlukast or any pharmaceutically acceptable salt or derivative thereof, cinalukast or any pharmaceutically acceptable salt or derivative thereof, tomelukast or any pharmaceutically acceptable salt or derivative thereof, or pobilukast or any pharmaceutically acceptable salt or derivative thereof.
  • the NSAID in each CysLTiantagonist/NSAID combination or composition may be selected from any the following: naproxen sodium or any other pharmaceutically acceptable salt or derivative thereof, or diclofenac sodium or any other pharmaceutically acceptable salt or derivative thereof, meloxicam or any pharmaceutically acceptable salt or derivative thereof, ibuprofen any pharmaceutically acceptable salt or derivative thereof, ketoprofen or any pharmaceutically acceptable salt or derivative thereof, or flurbiprofen or any pharmaceutically acceptable salt or derivative thereof, or oxaprozin or any pharmaceutically acceptable salt or derivative thereof, indomethacin or any pharmaceutically acceptable salt or derivative thereof, sulindac or any pharmaceutically acceptable salt or derivative thereof, or etodolac or any pharmaceutically acceptable salt or derivative thereof, or ketorolac or any pharmaceutically acceptable salt or derivative thereof, nabunetone or any pharmaceutically acceptable salt or derivative thereof, piroxicam or any pharmaceutically acceptable salt or derivative thereof, or tenoxicam or any pharmaceutically acceptable salt or derivative thereof, droxicam or any pharmaceutically acceptable
  • the COX-2-selective inhibitor in each CysLTiantagonists/COX-2-selective inhibitor combination or composition may be selected from any the following: rofecoxib or any pharmaceutically acceptable salt or derivative thereof, valdecoxib or any pharmaceutically acceptable salt or derivative thereof or lumiracoxib or any pharmaceutically acceptable salt or derivative thereof.
  • the DMARD in each CysLTiantagonist/DMARD combination or composition may be selected from any the following: cyclosporine or any pharmaceutically acceptable salt or derivative thereof, azathioprineor any pharmaceutically acceptable salt or derivative thereof, methotrexateor any pharmaceutically acceptable salt or derivative thereof, leflunomideor any pharmaceutically acceptable salt or derivative thereof, cyclophosphamideor any pharmaceutically acceptable salt or derivative thereof, hydroxychloroquineor any pharmaceutically acceptable salt or derivative thereof, sulfasalazineor any pharmaceutically acceptable salt or derivative thereof, D-penicillamine or any pharmaceutically acceptable salt or derivative thereof, minocyclineor any pharmaceutically acceptable salt or derivative thereof, and goldor any pharmaceutically acceptable salt or derivative thereof.
  • the glucocorticoid in each cystLTl receptor antagonist/glucocorticoid combination may be selected from any the following: budesonide and analogs of budesonide (e.g., budesonide (11- beta, 16-alpha(R)), budesonide (11-beta, 16-alpha(S)), flunisolide, desonide, triamcinolone acetonide, halcinonide, flurandrenolide, fluocinoloneacetonide, triamcinolone hexacetonide, triamcinolone diacetate, flucinonide, triamcinolone, amcinafal, deflazacort, algestone, procinonide, flunisolide, hyrcanoside, descinolone, wortmannin, formocortal, tralonide, flumoxonide, triamcinolone acetonide 21-palmitate, and flucinolone, deson
  • the corticosteroid is selected from cortisone, dexamethasone, hydrocortisone, methylpredmsolone, prednisone, traimcinolone, and diflorasone.
  • the CysLTiantagonist is normally administered alone or in combination at a dosage of lmg to lOOmg per day, desirably l-40mg per day, more desirably 1-1 Omg per day.
  • the NSAID is normally administered alone or in a composition at a dosage of lmg to 4000mg per day, desirably about 50mg to 500mg per day, more desirably, 50-200mg per day.
  • the COX-2 selective inhibitor is normally given alone or in a composition at a dosage of lmg to lOOOmg, desirably 20mg to 500mg per day, more desirably 20mg to 200mg per day.
  • the DMARD is usually given alone or in composition at a dosage of lmg to 3000mg per day, desirably 3mg to lOOOmg per day, most preferably 3mg to 500mg per day.
  • a DMARD could be given once per week at 3mg-20mg.
  • the steroid is normally administered alone or in a composition at a dosage of about 0.1 mg to 1500 mg per day, desirably about 0.5 mg to 10 mg per day, and more desirably about 0.5 mg to 5 mg per day. Dosages of up to 3000 mg per day may be necessary.
  • the arthritic condition is selected from one of the following: rheumatoid arthritis, osteoarthritis, psoriatic arthritis, gout, pseudogout, juvenile arthritis, Still's disease, ankylosing spondylitis, fibromyalgia and tennis elbow, Septic arthritis, chronic reactivated streptococcal cell wall (SCW)-induced arthritis.
  • arthritic conditions are also those inflammatory joint conditions that occurring secondary to the following conditions: Ehlers-Danlos Syndrome, Sarcoidosis, Henoch- Schonleinpurpura, Reactive arthritis, Haemochromatosis, Hepatitis, Wegener's granulomatosis (and many other vasculitis syndromes), Lyme disease, Familial Mediterranean fever, Hyperimmunoglobulinemia D with recurrent fever, TNF receptor associated periodic syndrome, Inflammatory bowel disease (Including Crohn's Disease and Ulcerative Colitis).
  • the arthritic condition is selected from rheumatoid arthritis, osteoarthritis, psoriatic arthritis, gout, pseudogout, juvenile arthritis, Still's disease, ankylosing spondylitis, fibromyalgia and tennis elbow.
  • the administration of the combination therapy as described herein is additive.
  • Combination therapy according to the invention may be performed alone or in conjunction with another therapy and may be provided at a hospital, a hospital's outpatient department, a doctor's office a clinic, or at the recipient's home.
  • Treatment could commence at a hospital, or clinic where the patient is resident or remains for a period of time, so that a doctor can observe the patient's response to the therapy (effect of the therapy) and make any adjustments to the therapy that are required.
  • each compound of the claimed combinations depends on several factors, including but not limited to: the route of administration, the arthritic condition and its severity, whether the treatment is prophylactic or for a diagnosed condition, and patient age, weight, health and co-morbidity, pharmacogenomic status and concomitant therapy.
  • the time course and treatment regimen of the combination therapy is dependent upon the type of disease or disorder being treated, the age and condition of the patient, the stage of the patient's disease, other treatments that the patient is receiving and the patient's response to the combination therapy. Additionally, a person having a greater risk of developing an arthritic condition (e.g., a person who has a family history of an arthritic condition or is classified as 'at risk' for development of an arthritic condition for any other reason) may receive treatment to prevent, inhibit or delay the onset of the disease or symptoms.
  • the compounds may also be formulated together such that a single administration delivers both compounds.
  • each component of the combination can be adjusted independently. For example, one compound may be administered four times per day, while the second compound may be administered once per week.
  • Combination therapy may be given in On(administration)-and-off (intervals of non-administration)' periods.
  • compositions are desirably administered systemically.
  • Suitable modes of administration include, but are not limited to inhalation, intra- articular, intramuscular, intraperitoneal (IP), intravenous (IV), ophthalmic, oral, rectal, subcutaneous, topical or transdermal and vaginal.
  • the combination/composition of the invention can also be provided as components of a pharmaceutical kit.
  • the two drugs (one from each class within the class combinations described above) can be formulated together, or separately and in individual dosage amounts.
  • the compounds of the invention are also useful when formulated as salts.
  • each compound of the combination may be by any suitable means that results in a systemic concentration of the compound that, combined with the other compound, is effective for the treatment of arthritic conditions.
  • Each compound is admixed with a suitable carrier substance, and is generally present in an amount of 1-98% by weight of the total weight of the composition formulation.
  • the composition may be provided in a dosage form that is suitable for, but not limited toinhalation, intra-articular, intramuscular, intra-peritoneal (IP), intravenous (IV), ophthalmic, oral, rectal, subcutaneous, topical or transdermal and vaginal administration.
  • the composition may include, but are not limited toaerosols, capsules, creams, delivery devices, drenches, emulsions, enemas, gels including hydrogels, granulates, injectables, implants, ointments, pastes, pills, plasters, powders, suspensions, solutions, sprays, suppositories or tablets.
  • the pharmaceutical compositions may be formulated according to conventional pharmaceutical practice (see, e.g., Remington: The Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro, 2000, Lippincott Williams & Wilkins, Philedelphia, Pa. and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan, 1988-2002, Marcel Dekker, New York).
  • compositions according to the invention may be formulated to release the active compound substantially immediately upon administration, in a delayed manner or at any predefined time after administration, using controlled release formulations.
  • Administration of compounds in controlled release formulations is useful where the compound, either alone or in combination exhibits (i) a small difference between the plasma concentration leading to harmful side effects or toxic reactions and the plasma concentration leading to a therapeutic effect
  • delaying formulations include, but are not limited to emulsions, liposomes, microcapsules, microspheres, nanoparticles, oil solutions, patches, single or multiple unit tablet or capsule compositions and suspensions.
  • Formulations for oral use include tablets containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients.
  • excipients may be, for example, anti-adhesives (such as, but not limited to magnesium stearate, silicas, stearic acid, talc, vegetable oils or zinc stearate) inert diluents or fillers (such as, but not limited to sucrose or sorbitol), lubricating agents and glidants.
  • the two compounds can be mixed together in a tablet or other vehicle, or be partitioned.
  • the first compound is contained on the outside of the tablet, and the second compound is on the inside, such that a substantial portion of the first compound is released prior to the release of the second compound.
  • Formulations for oral use may also be provided as hard gelatin, or as chewable tablets capsules wherein the active ingredient is mixed with a solid inert diluent, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil solvent.
  • synoviocyte number was conducted by seeding 3000 isolated human synoviocytes per well in a 48 well tissue culture-treated plate. The synoviocytes were allowed to attach for 2 days. The synoviocytes were then exposed to the compound(s) as described in example 1. The synoviocytes were incubated with the compound(s) for 7 days at 37°C in a humidified atmosphere of 95% air 15% C02. Synoviocyte number was calculated by performing cell counts using an inverted microscope. A minimum of 5 separate fields of view were counted per well. All counts were performed using xlOO magnification in a blinded fashion.

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Abstract

L'invention concerne des compositions pharmaceutiques comprenant un antagoniste du récepteur des cystéinyl-leukotriènes 1 (CysLT1) et un deuxième composé. Elle concerne également des procédés pour le traitement de l'arthrite par un traitement combiné.
PCT/GB2011/052317 2010-11-26 2011-11-25 Combinaison d'un antagoniste de cyslt1 et d'un médicament anti-arthrite pour le traitement d'un trouble arthritique WO2012069842A1 (fr)

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US20220047570A1 (en) * 2018-11-26 2022-02-17 Mmc Intellectual Property Institute, S.L. Montelukast for the treatment of erosive hand osteoarthritis
RU2809024C2 (ru) * 2018-11-26 2023-12-06 Фармалидер, С.А. Монтелукаст для лечения эрозивного остеоартрита кистей рук

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102920676A (zh) * 2012-12-04 2013-02-13 山东省立医院 一种塞来昔布咀嚼片及其制备方法
US20220047570A1 (en) * 2018-11-26 2022-02-17 Mmc Intellectual Property Institute, S.L. Montelukast for the treatment of erosive hand osteoarthritis
RU2809024C2 (ru) * 2018-11-26 2023-12-06 Фармалидер, С.А. Монтелукаст для лечения эрозивного остеоартрита кистей рук

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