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WO2013084182A1 - Composition pharmaceutique comprenant un inhibiteur de l'enzyme pde4 et un agent analgésique - Google Patents

Composition pharmaceutique comprenant un inhibiteur de l'enzyme pde4 et un agent analgésique Download PDF

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Publication number
WO2013084182A1
WO2013084182A1 PCT/IB2012/057022 IB2012057022W WO2013084182A1 WO 2013084182 A1 WO2013084182 A1 WO 2013084182A1 IB 2012057022 W IB2012057022 W IB 2012057022W WO 2013084182 A1 WO2013084182 A1 WO 2013084182A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
revamilast
pain
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Inventor
Srinivas Gullapalli
Maulik Nitinkumar GANDHI
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Ichnos Sciences SA
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Glenmark Pharmaceuticals SA
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    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered 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
    • A61K31/33—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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present patent application relates to a pharmaceutical composition that includes a phosphodiesterase-4 ("PDE4") enzyme inhibitor and an analgesic agent.
  • PDE4 phosphodiesterase-4
  • the present patent application relates to a pharmaceutical composition that includes a benzofuropyridine compound as a PDE4 enzyme inhibitor and an analgesic agent, a process for preparing such composition and its use for the treatment of pain related disorder in a subject.
  • Pain is described as a complex constellation of unpleasant sensory, emotional and cognitive experiences provoked by real or perceived tissue damage and manifested by certain autonomic, psychological and behavioral reactions and is a disease of epidemic proportions. From a neurobio logical perspective, pain is believed to be of three different aspects: first, 'nociceptive pain' - an early warning to physiological protective system, essential to detect and minimize contact with damaging or noxious stimuli; second, 'inflammatory pain' which is adaptive and protective, by heightening sensory sensitivity after unavoidable tissue damage, and mainly caused by activation of the immune system by tissue injury or infection; and the third 'pathological pain' which is not protective, but maladaptive resulting from abnormal functioning of the nervous system.
  • This pain is not a symptom of some disorder but rather a disease state of the nervous system, which can occur after damage to the nervous system (neuropathic pain) or a situation where there is no such damage or inflammation (dysfunctional pain - like fibromyalgia, irritable bowel syndrome, temporomandibular joint disease, interstitial cystitis and other syndromes where there is substantial pain but no noxious stimulants and minimal/no peripheral inflammatory pathology).
  • Analgesic agents include a group of drugs used to relieve pain and thus achieve analgesia.
  • Analgesic drugs act in various ways on the peripheral and central nervous systems and can be divided into 2 general classes: non-opioid analgesics and opioid analgesics.
  • Opioid analgesics include but are not limited to morphine, oxycodone, hydromorphone, hydrocodone, and the like or salts thereof.
  • Non-opioid analgesics include various drugs such as acetaminophen (also called paracetamol), non-steroidal anti-inflammatory drugs (NSAID) that inhibit mainly the enzyme cyclooxygenase (COX) and in turn reduce the synthesis of prostaglandins, adjuvant medications that help in reduction of pain such as serotonin-norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake inhibitors (SSRI), norepinephrine reuptake inhibitors (NERIs), tricyclic
  • drugs such as acetaminophen (also called paracetamol), non-steroidal anti-inflammatory drugs (NSAID) that inhibit mainly the enzyme cyclooxygenase (COX) and in turn reduce the synthesis of prostaglandins, adjuvant medications that help in reduction of pain such as serotonin-norepinephrine reuptake inhibitors (SNRI), selective serotonin reuptake
  • non-opioid analgesic agents include acetaminophen, aspirin, diflunisal, ibuprofen, naproxen, fenoprofen, fenbuten, flurbiprofen, indoprofen, ketoprofen, indomethacin, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, mefenamic acid, tolfenamic acid, meclofenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, nimesulide, licofenole, phenylbutazone, oxphenbutazone, antipyrine, aminopyrine, thiocolchicoside, duloxetine, milnacipran, amitriptylene,
  • Naproxen is chemically called (S)-6-methoxy-a methyl-2-naphthaleneacetic acid.
  • NAPROSYN ® - oral tablets As 250 mg, 375 mg and 500 mg; EC-NAPROSYN ® - oral delayed-release tablets as 375 mg and 500 mg and as oral suspension - 125 mg/5 mL), and as sodium salt (ANAPROX ® - oral tablets as 225 mg and ANAPROX DS ® - 500 mg). It is also available in the oral suspension form (NAPROSYN ® ). Naproxen is indicated for the relief of the signs and symptoms of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis and juvenile arthritis.
  • Diclofenac is chemically known as 2-[(2, 6-dichlorophenyl) amino] benzeneacetic acid, monosodium salt, and is commercially available in the United states VOLTAREN ® -XR (100 mg extended-release tablets). It is approved for the relief of the signs and symptoms of osteoarthritis and rheumatoid arthritis.
  • Pregabalin is chemically known as (S)-3-(aminomethyl)-5-methylhexanoic acid, and is commercially available as LYRIC A ® (25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg, and 300 mg capsules). It is approved for the management of neuropathic pain associated with diabetic peripheral neuropathy and
  • Duloxetine is chemically known as (+)-(S)-N-methyl-y-(l-naphthyloxy)-2- thiophenepropylamine hydrochloride, and is commercially available as
  • CYMBALTA ® (Eq. 20 mg base, Eq. 30 mg base and Eq. 60 mg base capsule, delayed release pellets). It is approved for the management of neuropathic pain (DPNP) associated with diabetic peripheral neuropathy and for the management of chronic musculoskeletal pain.
  • DPNP neuropathic pain
  • 3'-5'-cyclic adenosine monophosphate (cAMP) and 3 '- '-cyclic guanosine monophosphate (cGMP) are intracellular cyclic nucleotides that are believed to have regulatory effect on various functions of the cell.
  • the phosphodiesterase (PDE) enzymes convert the cAMP and/or cGMP into the inactive products, 5'- AMP and 5'-GMP, respectively.
  • PDE4 is an isozyme of PDE enzymes that is specific to cAMP and is found mostly in inflammatory cells.
  • the inhibition of the PDE4 enzyme is believed to regulate the cytokine activity by T-cells; inhibit the release of inflammatory mediators like tumor-necrosis factor-a (TNF-a), interlukin-2, iterlukin-12 and interferon- ⁇ ; and lead to smooth muscle relaxation, bronchodilation, inhibition of mast cells, monocyte and macrophage activation, and suppression of neutrophil degranulation.
  • TNF-a tumor-necrosis factor-a
  • interlukin-2 interlukin-2
  • iterlukin-12 interferon- ⁇
  • the inventors of the present invention have invented a pharmaceutical composition that includes a PDE4 enzyme inhibitor and an analgesic agent.
  • Rl is alkyl or alkyl substituted by one or more halogen groups
  • R2 is hydrogen
  • R3 is hydrogen
  • Ar is a heteroaryl ring or a heteroaryl ring substituted by one or more halogen groups
  • n 2;
  • p 3;
  • T, V and W are C;
  • X is O
  • Y is -C(0)NR4
  • R4 is hydrogen
  • the preferred compound of formula (I) is N9-(3,5-dichloro-4-pyridyl)-6- difluoromethoxybenzo[4,5]furo[3,2-c]pyridine-9-carboxamide -N-oxide [INN: Revamilast] or its pharmaceutically acceptable salt.
  • the present invention relates a pharmaceutical composition
  • a pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the analgesic agent suitable for use in the present invention is an opioid or a non-opioid analgesic.
  • the analgesic agent includes acetaminophen, aspirin, diflunisal, ibuprofen, naproxen, fenoprofen, fenbuten, flurbiprofen, indoprofen, ketoprofen, indomethacin, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, mefenamic acid, tolfenamic acid, meclofenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, nimesulide, licofenole, phenylbutazone, oxphenbutazone, antipyrine, aminopyrine, thiocolchicoside, duloxetine, milnacipran, amitriptylene, desipramine, imipramine, bupropion
  • the analgesic agent is a non- opioid agent selected from acetaminophen, aspirin, naproxen, ibuprofen, ketoprofen, indomethacin, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, mefenamic acid, celecoxib, rofecoxib, nimesulide, duloxetine, thiocolchicoside, ilnacipran, amitriptylene, desipramine, imipramine, bupropion, lefetamine, methylphenidate, pregabalin, paroxetine, citalopram, tizaidine or salt thereof. More preferably, the non-opioid analgesic agent includes naproxen, diclofenac, pregabalin, duloxetine or a salt thereof.
  • the present invention relates a pharmaceutical composition
  • a pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent, wherein the weight ratio of revamilast or its pharmaceutically acceptable salt to the analgesic agent ranges from about 1 : 100000 to about 1 :0.01. In an aspect of the embodiment, the weight ratio of revamilast or its pharmaceutically acceptable salt to the analgesic agent ranges from about 1 : 7500 to about 1 : 10.
  • the present invention relates a pharmaceutical composition for oral administration comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the analgesic agent is a non-opioid analgesic agent.
  • the therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day ranges from about 0.01 mg to about 50 mg, preferably from about 0.1 mg to about 30 mg and more preferably from about 2 mg to about 20 mg.
  • composition of the present invention may optionally comprise one or more pharmaceutically acceptable excipients.
  • the present invention relates a pharmaceutical composition for oral administration comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent selected from,
  • the pharmaceutical composition comprises from about 1 mg to about 20 mg or about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 500 mg of pregabalin or its pharmaceutically acceptable salt.
  • the pharmaceutical composition comprises from about 1 mg to about 20 mg or from about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 100 mg of duloxetine or its pharmaceutically acceptable salt.
  • the present invention relates a pharmaceutical composition for oral administration comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent selected from,
  • the weight ratio of revamilast or its pharmaceutically acceptable salt to analgesic agent or its pharmaceutically acceptable salt ranges from about 1 : 1 to about 1 :300.
  • the composition comprises from about 1 mg to about 20 mg or from about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 15 mg to about 200 mg of diclofenac or its pharmaceutically acceptable salt.
  • the composition comprises from about 1 mg to about 20 mg or from about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 100 mg to about 1000 mg of naproxen or its pharmaceutically acceptable salt.
  • the therapeutically effective amount of the active ingredient can be administered as a single dose or in divided doses, either once daily or
  • the pharmaceutical composition of the present invention is in the form of a fixed dose combination formulation containing revamilast or its pharmaceutically acceptable salt and the analgesic agent.
  • the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations containing revamilast or its pharmaceutically acceptable salt and the analgesic agent.
  • the present invention relates to a method of treating a pain related disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the pain related disorder is neuropathic pain.
  • the neuropathic pain is diabetic peripheral neuropathy.
  • the pain related disorder may be acute pain, chronic pain, mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, postoperative pain, inflammatory pain, rheumatoid arthritis pain, osteoarthritis pain, back pain such as acute low back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states,
  • polyneuropathy pain states such as diabetic peripheral neuropathy or
  • PNS peripheral nervous system
  • CNS central nervous system
  • PNS peripheral nervous system
  • CNS central nervous system
  • polyradiculopathies of cervical, lumbar or sciatica type cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia
  • PNS peripheral nervous system
  • CNS central
  • the present invention relates to a method of alleviating mechanical allodynia and/or thermal hyperalgesia in a subject having a pain related disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the analgesic agent is selected from, pregabalin or duloxetine or diclofenac or naproxen or pharmaceutically acceptable salts thereof.
  • the present invention relates to use of revamilast or its pharmaceutically acceptable salt and an analgesic agent in the preparation of a pharmaceutical composition for treatment of a pain related disorder in a subject.
  • the analgesic agent is selected from, pregabalin or duloxetine or diclofenac or naproxen or
  • the present invention provides a process for the preparing a pharmaceutical composition that includes revamilast or its
  • the process comprises admixing revamilast or its pharmaceutically acceptable salt with the analgesic agent. Alternately, the process comprises formulating revamilast or its
  • the invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, and an analgesic agent, wherein the composition is in the form of a kit comprising two or more separate formulations of revamilast or its
  • Figure 1 is a bar graph showing the effect of naproxen on revamilast sodium mediated reversal of Freund's Complete Adjuvant induced mechanical hyperalgesia in male SD rats.
  • Figure 2 is a bar graph showing the effect of diclofenac sodium on revamilast sodium mediated reversal of Freund's Complete Adjuvant induced mechanical hyperalgesia in male SD rats.
  • Figure 3 is a bar graph showing the effect of pregabalin on revamilast sodium mediated reversal of CCI induced mechanical hyperalgesia in male SD rats.
  • the inventors of the present invention have invented a pharmaceutical composition that includes a PDE4 enzyme inhibitor and an analgesic agent.
  • the term "effective amount” or "therapeutically effective amount” denotes an amount of an active ingredient that, when administered to a subject for treating a state, disorder or condition, produces an intended therapeutic benefit in a subject.
  • the therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day ranges from about 0.01 mg to about 50 mg, preferably from about 0.1 mg to about 20 mg and more preferably from about 2 mg to about 10 mg.
  • the therapeutically effective amount of naproxen or its salt is present in an amount ranging from about 100 mg to about 1000 mg, and preferably from about 125 mg to about 750 mg.
  • the therapeutically effective amount of diclofenac or its salt is present in an amount ranging from about 15 mg to about 200 mg and preferably from about 25 mg to about 100 mg.
  • the therapeutically effective amount of pregabalin or its salt is present in an amount ranging from about from about 10 mg to about 500 mg and preferably from about 20 mg to about 300 mg.
  • the therapeutically effective amount of duloxetine or its salt is present in an amount ranging from about from about 10 mg to about 100 mg and preferably from about 15 mg to about 75 mg.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes a PDE4 enzyme inhibitor, an analgesic agent and a pharmaceutically acceptable salt thereof.
  • the PDE4 enzyme inhibitor is N9-(3,5-dichloro-4-pyridyl)-6-difluoromethoxybenzo [4,5]furo[3,2-c]pyridine-9-carboxamide-N-oxide [INN: Revamilast] or its pharmaceutically acceptable salt. All stereoisomers including enantiomers and diastereomers are separately contemplated.
  • the analgesic agent is preferably naproxen or diclofenac or pregabalin or duloxetine a salt thereof.
  • salts and esters are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
  • Representative acid additions salts include the hydrochloride, hydrobromide, sulphate, bisulphate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, mesylate, citrate, maleate, fumarate, succinate, tartrate, ascorbate, glucoheptonate, lactobionate, and lauryl sulphate salts.
  • Representative alkali or alkaline earth metal salts include the sodium, calcium, potassium and magnesium salts.
  • treating also covers the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder modulated by the PDE4 enzyme, or the analgesic agent which acts by various mechanisms including but not limited to modulation of cyclooxygenase (COX) and lipoxygenase pathway, prostaglandin synthesis, opioid receptors, serotonin and nor-epinephrine receptors, a-2 adrenergic receptors, or by a combination of the two in a mammal.
  • COX cyclooxygenase
  • lipoxygenase pathway prostaglandin synthesis
  • opioid receptors serotonin and nor-epinephrine receptors
  • a-2 adrenergic receptors a combination of the two in a mammal.
  • the term “synergistic” or “synergy”, as used herein, refers to the combination of the PDE4 enzyme inhibitor (preferably revamilast or its pharmaceutically acceptable salt) with an analgesic agent which is used in the treatment of a pain related disorder either in the form of the pharmaceutical composition, combination product or a kit according to the invention having an efficacy for the treatment of pain related disorder that is greater than would be expected from the sum of their individuals effects.
  • the synergistic effects of the embodiments of the present invention encompass additional unexpected advantages for the treatment of pain related disorder.
  • Such additional advantages may include, but are not limited to, lowering the required dose of one or more of the active compounds of the combination, reducing the side effects of one or more of the active compounds of the combination or rendering one or more of the active compounds more tolerable to the subject in need of treatment of pain related disorder.
  • the "pain related disorder” includes but is not limited to acute pain, chronic pain, mild pain, moderate pain, severe pain, musculoskeletal pain, complex regional pain syndrome, neuropathic pain, postoperative pain, inflammatory pain, rheumatoid arthritis pain, osteoarthritis pain, back pain such as acute low back pain, visceral pain, cancer pain, neuralgia, migraine, neuropathies, acute trauma, chemotherapy - induced mononeuropathy pain states, polyneuropathy pain states (such as diabetic peripheral neuropathy & chemotherapy induced neuropathy), autonomic neuropathy pain states, PNS lesion or CNS lesion or disease related pain states, polyradiculopathies of cervical, lumbar or sciatica type, cauda equina syndrome, piriformis syndrome, paraplegia, quadriplegia, pain states related to various Polyneuritis conditions underlying various infections, chemical injuries, radiation exposure, underlying disease or deficiency conditions such as beriberi, vitamin deficiencies, hypothyroidism, porphyri
  • pharmaceutically acceptable excipient any of the components of a pharmaceutical composition other than the actives and which are approved by regulatory authorities or are generally regarded as safe for human or animal use.
  • PDE4 inhibitors have demonstrated anti-inflammatory properties from elevations in intracellular cAMP levels secondary to the induction of adenylate cyclase.
  • cAMP broadly suppresses the activity of immune and inflammatory cells whereas cGMP has not been shown to play a substantial role in inflammatory cells.
  • PDE4 inhibitor potentiate hyperalgesic effects induced by PGE 2 , dopamine, carrageenan, bradykinin, TNFa, IL- ⁇ , IL-6 and IL-8.
  • neuronal cyclic AMP mediates the prostanoid and sympathetic components of mechanical hyperalgesia.
  • the intracellular levels of cyclic AMP that enhance hyperalgesia are controlled by the PDE4 isoform and appear to result in activation of protein kinase A whereas the intracellular levels of cyclic GMP results from activation of a soluble guanylate cyclase.
  • Analgesic agents mainly NSAIDs, exert their analgesic effect not only through peripheral inhibition of prostaglandin synthesis but also through a variety of other peripheral and central mechanisms. Inhibition of COX-2 activity represent the most likely mechanism of action for NSAID-mediated analgesia. In addition, some NSAIDs inhibit the lipoxygenase pathway, which may itself result in the production of algogenic metabolites. Interference with G-protein-mediated signal transduction by NSAIDs may form the basis of an analgesic mechanism unrelated to inhibition of prostaglandin synthesis ("The mechanisms of action of NSAIDs in analgesia", Drugs, 1996; 52 Suppl. 5: 13-23).
  • a pharmaceutical composition that includes a compound of formula (I) (particularly, revamilast or its pharmaceutically acceptable salt) and an analgesic agent are more effective in the treatment of pain related disorders, and provide better therapeutic value when compared to the actives alone (when administered individually) for the treatment of pain related disorders.
  • the present invention relates a pharmaceutical composition
  • a pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the analgesic agent suitable for use in the present invention is an opioid or a non-opioid analgesic.
  • the analgesic agent includes acetaminophen, aspirin, diflunisal, ibuprofen, naproxen, fenoprofen, fenbuten, flurbiprofen, indoprofen, ketoprofen, indomethacin, ketorolac, diclofenac, nabumetone, piroxicam, meloxicam, tenoxicam, mefenamic acid, tolfenamic acid, meclofenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, nimesulide, licofenole, phenylbutazone, oxphenbutazone, antipyrine, aminopyrine, thiocolchicoside, duloxetine, milnacipran, amitriptylene, desipramine, imipramine, bupropion
  • the analgesic agent is a non- opioid agent selected from acetaminophen, aspirin, naproxen, ibuprofen, ketoprofen, indomethacin, ketorolac, diclofenac, aceclofenac, nabumetone, piroxicam, meloxicam, mefenamic acid, celecoxib, rofecoxib, nimesulide, duloxetine, thiocolchicoside, ilnacipran, amitriptylene, desipramine, imipramine, bupropion, lefetamine, methylphenidate, pregabalin, paroxetine, citalopram, tizaidine or salt thereof. More preferably, the non-opioid analgesic agent includes naproxen, diclofenac, pregabalin, duloxetine or a salt thereof.
  • the present invention relates a pharmaceutical composition
  • a pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent, wherein the weight ratio of revamilast or its pharmaceutically acceptable salt to the analgesic agent ranges from about 1 : 100000 to about 1 :0.01. In an aspect of the embodiment, the weight ratio of revamilast or its pharmaceutically acceptable salt to the analgesic agent ranges from about 1 : 7500 to about 1:10.
  • the specific weight ratios of revamilast or its pharmaceutically acceptable salt to the analgesic agent are about 1:100000, 1:10000, 1:5000,1: 2500, 1:2000, 1:1500, 1:1200, 1:1000, 1:900, 1:850, 1:800, 1:750, 1:700, 1:650, 1:600, 1:550, 1:500, 1:450, 1:400, 1:350, 1:300, 1:250, 1:200, 1:175, 1:150, 1:125, 1:100, 1:90, 1:80, 1:75, 1:70, 1:60, 1:50, 1:40, 1:30, 1:25, 1:20, 1:18, 1:15, 1:12, 1:10, 1:9, 1:8, 1:7.5, 1:7, 1:6.5, 1:6, 1:5, 1:4.5, 1:4, 1:3.5, 1:3, 1:2.5, 1:2, 1:1.5, 1:1, 1:0.5, 1:0.1, 1:0.05 and about 1:0.01.
  • the present invention relates a pharmaceutical composition for oral administration comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the analgesic agent is a non-opioid analgesic agent. More preferably, the non-opioid analgesic agent includes naproxen, diclofenac, pregabalin, duloxetine or a salt thereof.
  • the therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day ranges from about 0.01 mg to about 50 mg, preferably from about 0.1 mg to about 30 mg and more preferably from about
  • the discrete dosage strengths of revamilast (or its pharmaceutically acceptable salt) to be administered may be about 0.1 mg, about 0.2 mg, about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about
  • the therapeutically effective amount of diclofenac or its salt is present in an amount ranging from about 15 mg to about 200 mg and preferably from about 25 mg to about 100 mg.
  • the discrete dosage strengths of diclofenac or its salt to be administered are 25 mg, 50 mg, 75 mg, 100 mg, 150 mg or 200 mg.
  • the therapeutically effective amount of naproxen or its salt is present in an amount ranging from about 100 mg to about 1000 mg and preferably from about 125 mg to about 750 mg.
  • the discrete dosage strengths of naproxen or its salt to be administered are 250 mg, 375 mg or 500 mg.
  • the therapeutically effective amount of pregabalin or its salt is present in an amount ranging from about 10 mg to about 500 mg and preferably from about 20 mg to about 300 mg.
  • the discrete dosage strengths of pregabalin or its salt to be administered are 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 225 mg or 300 mg.
  • the therapeutically effective amount of duloxetine or its salt is present in an amount ranging from about 10 mg to about 100 mg and preferably from about 15 mg to about 75 mg.
  • the discrete dosage strengths of duloxetine or its salt to be administered are 20 mg, 30 mg or 60 mg.
  • the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 2 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 125 mg to about 750 mg of naproxen or its salt.
  • the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 2 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 25 mg to about 100 mg of diclofenac or its salt.
  • the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 2 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 20 mg to about 300 mg of pregabalin or its salt.
  • the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises about 2 mg to about 20 mg of revamilast or its pharmaceutically acceptable salt and about 15 mg to about 75 mg of duloxetine or its salt.
  • These dosage strengths can be administered either once daily or two/three/four times a day.
  • the present invention relates a pharmaceutical composition for oral administration comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent selected from,
  • the pharmaceutical composition comprises from about 1 mg to about 20 mg or about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 500 mg of pregabalin or its pharmaceutically acceptable salt.
  • the pharmaceutical composition comprises from about 1 mg to about 20 mg or from about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 10 mg to about 100 mg of duloxetine or its pharmaceutically acceptable salt.
  • the present invention relates a pharmaceutical composition for oral administration comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent selected from,
  • the weight ratio of revamilast or its pharmaceutically acceptable salt to analgesic agent or its pharmaceutically acceptable salt ranges from about 1 : 1 to about 1 :300.
  • the composition comprises from about 1 mg to about 20 mg or from about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 15 mg to about 200 mg of diclofenac or its pharmaceutically acceptable salt.
  • the composition comprises from about 1 mg to about 20 mg or from about 2 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt, and from about 100 mg to about 1000 mg of naproxen or its pharmaceutically acceptable salt.
  • the therapeutically effective amount of the active ingredient can be administered as a single dose or in divided doses, either once daily or
  • the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations containing revamilast or its pharmaceutically acceptable salt and the analgesic agent.
  • the pharmaceutical composition of the present invention is in the form of a fixed dose combination formulation containing revamilast or its pharmaceutically acceptable salt and the analgesic agent.
  • the active ingredient may be in the form of a single dosage form (i.e., fixed-dose formulation in which both the active ingredients are present together) or they may be divided doses, formulated separately, each in its individual dosage forms but as part of the same therapeutic treatment, program or regimen, either once daily or two/three/four times a day.
  • the pharmaceutical composition of the present invention is in the form of a fixed dose combination formulation containing revamilast or its pharmaceutically acceptable salt and the analgesic agent.
  • the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations containing revamilast or its pharmaceutically acceptable salt and the analgesic agent.
  • the two or more separate formulations are to be administered by same or different routes, either separately, simultaneously, or sequentially, where the sequential administration is close in time or remote in time.
  • the period of time may be in the range from 10 min to 12 hours.
  • the active ingredients may be administered together in a single dosage form or they may be administered in different dosage forms. They may be administered at the same time or they may be administered either close in time or remotely, such as, where one drug is administered in the morning and the second drug is administered in the evening. The combination may be used prophylactically or after the onset of symptoms has occurred.
  • the pharmaceutical composition of the present invention may be administered orally, nasally, intra-tracheally, parenterally, transdermally, transmucosal, inhalation or by any other route that a physician or a health-care provider may determine to be appropriate.
  • the route of administration is oral.
  • compositions of the invention include those for oral, parenteral, intra-tracheal, transdermal, transmucosal and nasal administration, or by inhalation route among others.
  • pharmaceutical composition of present invention is for oral administration.
  • both the active ingredients i.e. revamilast or its salt and the analgesic agent are formulated as a pharmaceutical composition suitable for oral administration.
  • the pharmaceutical compositions for oral administration may be in conventional forms, for example, tablets, capsules, granules (synonymously, "beads” or “particles” or “pellets”), suspensions, emulsions, powders, dry syrups, and the like.
  • the capsules may contain granule/pellet/particle/mini-tablets/mini- capsules containing the active ingredients.
  • the amount of active that may be incorporated in the pharmaceutical composition may range from about 1% w/w to about 98% w/w; or from about 5% w/w to about 90% w/w.
  • compositions for parenteral administration include but are not limited to solutions for intravenous, subcutaneous or intramuscular injection/infusion, suspensions for intramuscular or subcutaneous injection, emulsions for intramuscular or subcutaneous injection and implants.
  • compositions for transdermal or transmucosal administration include but are not limited to patches, gels, creams, ointments and the like.
  • the pharmaceutical composition of the present invention may optionally comprise one or more pharmaceutically acceptable excipients, which includes but is not limited to one or more of the following; diluents, glidants and lubricants, preservatives, buffering agents, chelating agents, polymers, gelling
  • agents/viscosifying agents surfactants, propellants, solvents and the like.
  • the present invention relates to a pharmaceutical composition that includes therapeutically effective amount of revamilast or its pharmaceutically acceptable salt; an analgesic agent and a pharmaceutically acceptable excipient.
  • the analgesic agent is selected from naproxen, diclofenac, pregabalin, duloxetine or a salt thereof.
  • the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, naproxen or its salt and a pharmaceutically acceptable excipient.
  • the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, diclofenac or its salt and a pharmaceutically acceptable excipient.
  • the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, pregabalin or its salt and a pharmaceutically acceptable excipient.
  • the present invention relates to a pharmaceutical composition for oral administration that includes revamilast or its pharmaceutically acceptable salt, duloxetine or its salt and a pharmaceutically acceptable excipient.
  • the present invention relates to a method of treating a pain related disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the pain related disorder is neuropathic pain.
  • the neuropathic pain is diabetic peripheral neuropathy.
  • the present invention relates to a method of treating a pain related disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and diclofenac or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating inflammatory pain such postoperative pain, rheumatoid arthritis pain or osteoarthritis pain in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and diclofenac or its
  • the present invention relates to a method of treating a pain related disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and naproxen or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating a inflammatory pain such postoperative pain, rheumatoid arthritis pain or osteoarthritis pain in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and naproxen or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating a pain related disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and pregabalin or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating neuropathic pain in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and pregabalin or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating diabetic peripheral neuropathy in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and pregabalin or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating a pain related disorder in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and duloxetine or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating a neuropathic pain in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and duloxetine or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating a diabetic peripheral neuropathy in a subject, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and duloxetine or its pharmaceutically acceptable salt.
  • the present invention relates to a method of alleviating mechanical allodynia and/or thermal hyperalgesia in a subject having a pain related disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and an analgesic agent.
  • the present invention relates to a method of alleviating mechanical allodynia and/or thermal hyperalgesia in a subject having a pain related disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and pregabalin or its pharmaceutically acceptable salt.
  • the present invention relates to a method of alleviating mechanical allodynia and/or thermal hyperalgesia in a subject having a pain related disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and duloxetine or its pharmaceutically acceptable salt.
  • the present invention relates to a method of alleviating mechanical allodynia and/or thermal hyperalgesia in a subject having a pain related disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and diclofenac or its pharmaceutically acceptable salt.
  • the present invention relates to a method of alleviating mechanical allodynia and/or thermal hyperalgesia in a subject having a pain related disorder, said method comprising administering to the subject the pharmaceutical composition comprising synergistic effective amount of revamilast or its pharmaceutically acceptable salt and naproxen or its pharmaceutically acceptable salt.
  • the present invention relates to use of revamilast or its pharmaceutically acceptable salt and an analgesic agent in the preparation of a pharmaceutical composition for treatment of a pain related disorder in a subject.
  • the present invention relates to use of revamilast or its pharmaceutically acceptable salt and pregabalin or its pharmaceutically acceptable salt in the preparation of a pharmaceutical composition for treatment of a pain related disorder in a subject.
  • the present invention relates to use of revamilast or its pharmaceutically acceptable salt and duloxetine or its pharmaceutically acceptable salt in the preparation of a pharmaceutical composition for treatment of a pain related disorder in a subject.
  • the present invention relates to use of revamilast or its pharmaceutically acceptable salt and diclofenac or its pharmaceutically acceptable salt in the preparation of a pharmaceutical composition for treatment of a pain related disorder in a subject.
  • the present invention relates to use of revamilast or its pharmaceutically acceptable salt and naproxen or its
  • Various animal models can be used for the evaluation of the therapeutic efficacy of drug candidates for pain-related disorders such as inflammatory disorders, nerve injury, and central injury models of pain.
  • pain-related disorders such as inflammatory disorders, nerve injury, and central injury models of pain.
  • Each model mirrors the clinical appearance of many features of the pain disorder, and human conditions such as rheumatoid arthritis and osteoarthritis related pain states, diabetic neuropathy, nerve injury models of mononeuropathies, chemotherapy and immunotherapy related pain states. All these models have allowed for the comparison of certain behavioral, cellular, biochemical, and molecular mechanisms with human patient populations.
  • Models to best describe acute pain are acute tests, such as hot-plate, tail- flick, and paw pressure tests. There are a few models that used for tonic pain that use long-duration stimuli tests.
  • Intraperitoneal injection of acetic acid provokes a stereotypical behavior in rodents that is characterized by abdominal contractions, whole body movements, contortions of the abdominal muscles, and reduced motor activity and in coordination.
  • the behaviors are considered reflexive, and are evidence of peritoneovisceral or visceral pain associated with visceral chemoreceptors.
  • Chronic inflammatory pain models use the intracapsular/inraplantar/ intradermal/intra-articular administration of urate crystals, Freund's adjuvant, monosodium iodoacetate (MIA), lipopolysaccharide (LPS), or carrageenan.
  • MIA monosodium iodoacetate
  • LPS lipopolysaccharide
  • carrageenan Such long-term tonic pain in rats has been used to model human arthritis and to examine the safety and efficacy of various NSAIDs including the COX-1 and COX-2 inhibitors commonly used by patients for inflammatory pain.
  • the present invention provides a process for the preparing a pharmaceutical composition that includes revamilast or its
  • the process comprises admixing revamilast or its pharmaceutically acceptable salt with the analgesic agent. Alternately, the process comprises formulating revamilast or its
  • the invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, and an analgesic agent, wherein the composition is in the form of a kit comprising two or more separate formulations of revamilast or its
  • the present invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its
  • the present invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, and diclofenac or its salt.
  • the present invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, and pregabalin or its salt.
  • the present invention relates to a process for preparing a pharmaceutical composition that includes revamilast or its pharmaceutically acceptable salt, and duloxetine or its salt.
  • the process for making the pharmaceutical composition may include (1) granulating either or both the active ingredients, combined or separately, along with pharmaceutically acceptable carriers so as to obtain granulates, and (2) converting the granulates into suitable dosage forms for oral administration.
  • the typical processes involved in the preparation of the pharmaceutical compositions include various unit operations such as mixing, sifting, solubilizing, dispersing, granulating, lubricating, compressing, coating, and the like. These processes, as contemplated by a person skilled in the formulation art, have been incorporated herein for preparing the pharmaceutical compositions of the present invention.
  • EXAMPLE 1 Effect of revamilast and naproxen in a Freund's Complete Adjuvant (FCA) model of inflammatory pain in Sprague - Dawley (SD) rats.
  • FCA Freund's Complete Adjuvant
  • Revamilast sodium (1 mg/kg) and naproxen (3 mg/kg) produced only moderate effect with a maximal of 14 and 15 % reversal of hyperalgesia across course of the study, respectively.
  • the combination of revamilast sodium and naproxen produced significantly superior efficacy across the course of study compared to the sum of efficacies of individual agents as shown in Figure 1.
  • the combination has produced a maximum of 81% reversal of hyperalgesia.
  • EXAMPLE 2 Effect of revamilast and diclofenac in FCA - induced inflammatory mechanical hyperalgesia in male SD rats.
  • revamilast sodium (1 mg/kg) and diclofenac sodium (6 mg/kg) produced only moderate effect with a maximal of 15 and 14 % reversal of hyperalgesia across course of the study, respectively.
  • the combination of revamilast sodium and diclofenac sodium produced a synergistic effect (maximum of 87%o reversal of hyperalgesia) across the course of study compared to the sum of efficacies of individual agents as shown in Figure 2.
  • EXAMPLE 3 Effect of revamilast and pregabalin in chronic constriction injury - induced neuropathic hyperalgesia in male Sprague - Dawley (SD) rats. Rats were anesthetized using ketamine / xylazine (40 / 5 mg/kg, i.p.) and the left sciatic nerve was exposed at mid thigh level through a small incision. Four loose ligatures of 4-0 chromic cat gut (Ethicon - Johnson & Johnson) at 1 mm space were placed around the sciatic nerve after the bifurcation of common sciatic nerve. After 6-7 days, mechanical hyperalgesia was assessed by measuring hind paw withdrawal thresholds to an increasing pressure (g) stimulus, using the Randall-Sellitto analgesymeter (Ugo Basile, Italy), fitted with a wedge-shaped probe.
  • Revamilast sodium (0.1 mg/kg) and pregabalin (1 mg/kg) produced only moderate effect with a maximal of 10 and 11 % reversal of hyperalgesia across course of the study, respectively.

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Abstract

La présente invention concerne une composition pharmaceutique comprenant un inhibiteur de l'enzyme phosphodiestérase-4 (« PDE4 ») et un agent analgésique. En particulier, la présente invention concerne une composition pharmaceutique comprenant un composé benzofuropyridine en tant qu'inhibiteur de l'enzyme PDE4 et un agent analgésique. L'invention a également trait à un procédé de préparation d'une telle composition et à son utilisation dans le traitement de trouble lié à la douleur chez un sujet.
PCT/IB2012/057022 2011-12-08 2012-12-06 Composition pharmaceutique comprenant un inhibiteur de l'enzyme pde4 et un agent analgésique Ceased WO2013084182A1 (fr)

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WO2016016824A1 (fr) 2014-07-29 2016-02-04 Fundacio Hospital Universitari Vall D' Hebron-Institut De Recerca Diagnostic différentiel et choix de thérapie pour la polyarthrite rhumatoïde et l'arthrite psoriasique

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Publication number Priority date Publication date Assignee Title
WO2016016824A1 (fr) 2014-07-29 2016-02-04 Fundacio Hospital Universitari Vall D' Hebron-Institut De Recerca Diagnostic différentiel et choix de thérapie pour la polyarthrite rhumatoïde et l'arthrite psoriasique

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