WO2012110946A1 - Composition pharmaceutique comprenant l'inhibiteur d'enzyme pde4 révamilast et un agent de modification pathologique, de préférence, le méthotrexate - Google Patents

Composition pharmaceutique comprenant l'inhibiteur d'enzyme pde4 révamilast et un agent de modification pathologique, de préférence, le méthotrexate Download PDF

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Publication number
WO2012110946A1
WO2012110946A1 PCT/IB2012/050657 IB2012050657W WO2012110946A1 WO 2012110946 A1 WO2012110946 A1 WO 2012110946A1 IB 2012050657 W IB2012050657 W IB 2012050657W WO 2012110946 A1 WO2012110946 A1 WO 2012110946A1
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WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
revamilast
methotrexate
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PCT/IB2012/050657
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English (en)
Inventor
Neelima Khairatkar-Joshi
Raghuram ANUPINDI
Thamil Selvan VAIYAPURI
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Glenmark Pharmaceuticals Sa
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Publication of WO2012110946A1 publication Critical patent/WO2012110946A1/fr

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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
    • A61K31/33—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
    • 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
    • A61K31/42—Oxazoles
    • 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
    • A61K31/655—Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis

Definitions

  • the present patent application relates to a pharmaceutical composition
  • the application relates to a pharmaceutical
  • composition comprising a benzoiuropyridine compound as a PDE4 enzyme inhibitor and a disease modifying agent; a process for preparing such composition; and its use in treating an autoimmune disease in a subject.
  • Autoimmune diseases are a set of diseases believed to be manifestations of the body's over-active immune system.
  • Diseases or disorders that are believed to be of autoimmune origin include rheumatoid arthritis, multiple sclerosis, Type I diabetes mellitus, psoriasis, psoriatic arthritis and ankylosing spondylitis.
  • autoimmune diseases Numerous treatment options are available for the treatment of autoimmune diseases.
  • DMARDs, NSAIDs, and steroids have been employed in the treatment of autoimmune disease (e.g., rheumatoid arthritis) which may be generally referred to as "disease modifying agents".
  • Disease modifying agents such as methotrexate, cyclophosphamide, hydroxychloroquine, sulfasalazine, leflunomide, or their pharmaceutically acceptable salts have been approved to treat certain autoimmune diseases.
  • Methotrexate is chemically, N-[4-[[(2,4-diamino-6-pteridinyl)methyl]methyl -amino]benzoyl] L-glutamic acid and is commercially available as TREXALLTM oral tablets (strengths: 5mg, 7.5mg, lOmg and 15 mg).
  • neoplastic diseases gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole
  • psoriasis symptomatic control of severe recalcitrant disabling psoriasis that is not adequately responsive to other forms of therapy, but only when the diagnosis has been established, as by biopsy and/or after dermatological consultation
  • rheumatoid arthritis rheumatoid arthritis
  • Leflunomide is known chemically as N-(4'-trifluoromethylphenyl)-5- methylisoxazole-4-carboxamide. It is commercially available in the United States as ARAVA® oral tablets (strengths: lOmg, 20mg, or 100 mg) and is approved for the treatment of active rheumatoid arthritis (RA).
  • RA active rheumatoid arthritis
  • Hydroxychloroquine sulfate is chemically 2-[[4-[(7-Chloro-4-quinolyl) amino]pentyl] ethylamino] ethanol sulfate (1: 1) and is commercially available as PLAQUENIL oral tablets (200mg). It is approved for the treatment of discoid and systemic lupus erythematosus, and rheumatoid arthritis. It is also indicated for the suppressive treatment and treatment of acute attacks of malaria due to Plasmodium vivax, P. malariae, P. ovale, and susceptible strains of P. falciparum.
  • the present invention relates to a pharmaceutical composition
  • a PDE4 enzyme inhibitor e.g., benzofuropyridine compound
  • a disease modifying agent e.g., benzofuropyridine compound
  • a preferred PDE4 enzyme inhibitor is 3,5-dichloro-4-(6- difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-l-pyridiniumolate) [INN: Revamilast] or its pharmaceutically acceptable salt.
  • a pharmaceutical composition comprising a PDE4 enzyme inhibitor of the present invention (particularly, revamilast or its pharmaceutically acceptable salt) and a disease modifying agent is more effective in the treatment of autoimmune disease and provides better therapeutic value than both the actives alone (when administered individually) for the treatment of autoimmune diseases.
  • a pharmaceutical composition comprising:
  • R 1 is alkyl or alkyl substituted by one or more halogen groups
  • R 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;
  • each dotted line [— ] in the ring represents a bond
  • X is O
  • Y is -C(0)NR 4 ;
  • R 4 is hydrogen
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • Suitable disease modifying agents include, but are not limited to, methotrexate, cyclophosphamide, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, minocycline or their pharmaceutically acceptable salts.
  • composition of the present invention may optionally comprise one or more pharmaceutically acceptable excipients.
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent.
  • the therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 50 mg and preferably from about 0.1 mg to about 30 mg.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt.
  • the therapeutically effective amount of methotrexate or its pharmaceutically acceptable salt to be administered per week may range from about lmg to about 50mg, and preferably from about 2.5 mg to about 30 mg.
  • the therapeutically effective amount of the active ingredients can be administered as a single dose or in divided doses, either once weekly or once daily or two/three/four times a day.
  • the PDE4 enzyme inhibitor and the disease modifying agent may be administered in a single dosage form or in separate dosage forms.
  • the PDE4 enzyme inhibitor and the disease modifying agent may be administered by the same or different routes and either separately, simultaneously, or sequentially.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the pharmaceutical composition of the present invention is in the form of a fixed dose combination formulation of revamilast or its pharmaceutically acceptable salt and the disease modifying agent.
  • the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the disease modifying agent.
  • the disease modifying agent includes methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt in a weight ratio that may range from about 0.01 :50 to about 50: 1, and preferably from about 0.1 :30 to about 12:1.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt and a disease modifying agent, wherein the combination exhibits synergy for the treatment of an autoimmune disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of an autoimmune disease.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent for the treatment of an autoimmune disease in a subject in need thereof.
  • the autoimmune disease may be rheumatoid arthritis, multiple sclerosis, Type I diabetes mellitus, psoriasis, psoriatic arthritis and ankylosing spondylitis.
  • the autoimmune disease is rheumatoid arthritis, multiple sclerosis or psoriasis.
  • the present invention relates to a method of treating an autoimmune disease in a subject, the method comprising administering to the subject a pharmaceutical composition of the present invention.
  • the present invention relates to a method of treating an autoimmune disease in a subject, the method including administering to the subject a pharmaceutical composition comprising an effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent to a subject in need thereof.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating an autoimmune disease in a subject comprising administering to the subject a pharmaceutical composition comprising from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt and from about lmg to about 50mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis or psoriasis in a subject comprising administering to the subject a pharmaceutical composition comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 2.5 mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating rheumatoid arthritis in a subject comprising administering to the subject a pharmaceutical composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt, from about 2.5mg to about 20mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating psoriasis in a subject comprising administering to the subject a
  • composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt, from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to use of therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent in the preparation of a pharmaceutical composition for the treatment of an autoimmune disease in a subject in need thereof.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt
  • the present invention provides a process for preparing a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt, a disease modifying agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of a fixed dose combination formulation.
  • the process comprises admixing revamilast or its pharmaceutically acceptable salt with the disease modifying agent.
  • the process comprises formulating revamilast or its pharmaceutically acceptable salt and the disease modifying agent in such a way that they are not in intimate contact with each other.
  • the invention in another embodiment, relates to a process for preparing a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt, a disease modifying agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the disease modifying agent.
  • Figure 1 is a line graph depicting the mean clinical disease score in experimental autoimmune encephalomyelitis in female C57/BL6 mice for different treatment groups and control group.
  • Figure 2 is a bar graph depicting percent change in body weight measurements in experimental autoimmune encephalomyelitis in female C57/BL6 mice for different treatment groups and control group.
  • Figure 3 is a line graph that corresponds to the effect of revamilast and methotrexate on clinical scores in collagen induced arthritis in DBA/1J mice.
  • Figure 4 is a line graph that depicts the effect revamilast and methotrexate on paw thickness in collagen induced arthritis in DBA/1J mice.
  • Figure 5 represents a bar graph depicting the effect of revamilast and methotrexate on histological scores in collagen induced arthritis in DBA/1J mice.
  • the term "effective amount” or "therapeutically effective amount” denotes an amount of an active ingredient that, when administered to a subject for treating an autoimmune disease, produces an intended therapeutic benefit in the subject.
  • the therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 50 mg and preferably from about 0.1 mg to about 30 mg.
  • the therapeutically effective amount of methotrexate or its pharmaceutically acceptable salt to be administered per week may range from about lmg to about 50mg, and preferably from about 2.5 mg to about 30 mg.
  • active ingredient (used interchangeably with “active” or “active substance” or “drug”) as used herein includes a PDE4 enzyme inhibitor and a disease modifying agent.
  • salt or “pharmaceutically acceptable salt” it is meant those salts which 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 addition salts include 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 sodium, calcium, potassium and magnesium salts.
  • treating includes the prophylaxis, mitigation, prevention, amelioration, or suppression of a disorder or its symptoms.
  • the term “synergistic” or “synergy” with regard to the combination of the PDE4 enzyme inhibitor (preferably revamilast or its pharmaceutically acceptable salt) with a disease modifying agent which is used in the treatment of an autoimmune disease either in the form of the pharmaceutical composition, combination product or a kit according to the invention refers to an efficacy for the treatment of the autoimmune disease that is greater than would be expected from the sum of their individuals effects.
  • the advantages for the synergistic combinations of the present invention 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 and/or rendering one or more of the active compounds more tolerable to the subject in need of treatment of the autoimmune disease.
  • autoimmune disease refers to any condition or disease related to immune system such as rheumatoid arthritis, multiple sclerosis, Type I diabetes mellitus, psoriasis, psoriatic arthritis and ankylosing spondylitis.
  • the autoimmune disease is rheumatoid arthritis, multiple sclerosis or psoriasis.
  • Rheumatoid arthritis is believed to be an autoimmune disease that, among other things, is characterized by manifestation in the joints as synovitis. Rheumatoid arthritis is a chronic inflammatory disease with varying course. Despite the various therapeutic efforts, in a great number of cases the disease shows a resistant course with progressive joint destruction and physical disability.
  • Multiple sclerosis is believed to be an autoimmune disease characterized, among other things, by damage to the myelin sheath around the axons in the brain and the spinal cord. Multiple sclerosis alters the ability of the nerve cells to communicate with each other.
  • the neurological symptoms that may manifest in patients suffering from multiple sclerosis include ataxia, dysphagia, and dysarthria, among others.
  • Psoriasis is also believed to be of autoimmune etiology that mainly affects the skin. Psoriasis among other things is characterized by red scaly patches that appear on the skin.
  • subject includes mammals, such as humans and other animals, such as domestic animals (e.g., household pets including cats and dogs) and non- domestic animals (such as wildlife).
  • domestic animals e.g., household pets including cats and dogs
  • non- domestic animals such as wildlife
  • the subject is a human.
  • pharmaceutically acceptable excipients 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.
  • Suitable PDE4 enzyme inhibitors include benzofuropyridine PDE4 enzyme inhibitors, such as those described in WO 2006/064355, which is incorporated herein by reference in its entirety.
  • the PDE4 enzyme inhibitor has the formula:
  • R 1 is alkyl or alkyl substituted by one or more halogen groups
  • R 2 is hydrogen
  • R 3 is hydrogen
  • Ar is a heteroaryl ring or a heteroaryl ring substituted by one or more halogen groups
  • T, V and W are C;
  • each dotted line [— ] in the ring represents a bond
  • X is O
  • Y is -C(0)NR 4 ;
  • R 4 is hydrogen
  • a preferred compound of formula (I) is 3,5-dichloro-4-(6- difluoromethoxybenzo[4,5]furo[3,2-c]pyridin-9-ylcarboxamido)-l-pyridiniumolate) [INN: Revamilast] or its pharmaceutically acceptable salt.
  • Suitable disease modifying agents include, but are not limited to, methotrexate, cyclophosphamide, hydroxychloroquine, sulfasalazine, leflunomide, azathioprine, minocycline or their pharmaceutically acceptable salts.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt.
  • PDE4 enzyme inhibitor / Disease modifying agent combination PDE4 enzyme inhibitor / Disease modifying agent combination
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a
  • PDE4 enzyme inhibitor such as a benzofuropyridine compound of formula (I) above
  • a disease modifying agent such as a benzofuropyridine compound of formula (I) above
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt and a disease modifying agent.
  • the pharmaceutical composition of the present invention may optionally comprise one or more pharmaceutically acceptable excipients.
  • the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent.
  • the therapeutically effective amount of revamilast or its pharmaceutically acceptable salt to be administered per day may range from about 0.01 mg to about 50 mg and preferably from about 0.1 mg to about 30 mg.
  • the discrete dosage strengths of revamilast or its pharmaceutically acceptable salt to be administered per day may be O.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt.
  • the therapeutically effective amount of methotrexate or its pharmaceutically acceptable salt to be administered per week may range from about lmg to about 50mg, preferably from about 2.5 mg to about 30 mg and more preferably from about 5mg to about 30mg.
  • the discrete dosage strengths of methotrexate or its pharmaceutically acceptable salt to be administered per week may be 2.5mg or 5mg or 7.5mg or lOmg or 15 mg or 20mg or 25mg or 30mg.
  • the doses may be administered as a single weekly dose or may be administered as divided doses to be given two/three/four/five/six/seven times in a week.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about O.Olmg to about 50 mg revamilast or its pharmaceutically acceptable salt and from about lmg to about 50mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt and from about 2.5 mg to about 30 mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition for oral administration, wherein unit dose of the composition comprises from about 1 mg to about 10 mg of revamilast or its pharmaceutically acceptable salt and from about 2.5mg to about 15mg of methotrexate or its pharmaceutically acceptable salt.
  • the optimal dose of the active ingredients can vary as a function of the severity of disease, route of administration, composition type, the patient body weight, the age and the general state of mind of the patient, and the response to behavior to the active ingredients.
  • 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 weekly or 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 of revamilast or its pharmaceutically acceptable salt and the disease modifying agent.
  • the pharmaceutical composition of the present invention is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the disease modifying agent.
  • the two or more separate formulations can 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 present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt, and from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt, and about 2.5mg or 5mg or 7.5mg or lOmg or 15mg or 20mg or 25mg or 30mg of methotrexate or its pharmaceutically acceptable salt.
  • a fixed dose combination formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8
  • the present invention relates to a pharmaceutical composition for oral administration wherein the composition is in the form of a kit containing an oral formulation comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and another oral formulation comprising from about 2.5mg to about 30mg methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition for oral administration wherein the composition is in the form of a kit having a unit dose formulation comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg of revamilast or its pharmaceutically acceptable salt, and another unit dose formulation comprising about 2.5mg or 5mg or 7.5mg or lOmg or 15mg of methotrexate or its
  • the present invention relates to a pharmaceutical composition for oral administration, wherein the composition is in the form of a kit containing an oral formulation comprising from about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and another oral formulation comprising from about 2.5mg or 5mg or 7.5 mg or lOmg or 15mg or 20mg or 30mg of methotrexate or its pharmaceutically acceptable salt.
  • an oral formulation comprising from about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or
  • the part of the kit comprising methotrexate or its pharmaceutically acceptable salt may be administered as a single weekly dose or may be administered as divided doses to be administered two or three or four or five or six or seven times in a week.
  • the part of the kit comprising revamilast or its pharmaceutically acceptable salt may be administered once daily or tow/three/four times in a day.
  • a pharmaceutical composition containing revamilast or its pharmaceutically acceptable salt and a disease modifying agent at a weight ratio that may range from about 0.01 :100 to about 100: 1 preferably from about 0.1:50 to about 50: 1, and more preferably from about 1 :30 to about 15: 1.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition including revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt in a weight ratio that may range from about 0.01 :50 to about 50: 1, and preferably from about 0.1 :30 to about 12:1.
  • the weight ratio of revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt may range from about 0.1 :30 to about 12: 1 and preferably from about 1 :30 to about 4: 1.
  • the weight ratio of revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt may be 1 :0.25 or 1 :0.5 or 1 :1 or 1 : 1.5 or 1 :2 or 1:2.5 or 1 :3 or 1:3.7 or 1 :3.75 or 1 :4 or 1 :5 or 1 :6 or 1 :7 or 1 :7.5 or 1 :8 or 1 :9 or 1 : 10 or 1 : 15 or 1 :20 or 1 :25 or 1 :30 or 2:0.5 or 2: 1 or 2: 1.3 or 2:2.5 or 2:3 or 2:5 or 2:7 or 2:9 or 2: 15 or 2:25 or 3:0.5 or 3: 1 or 3:2 or 3:2.5 or 3:4 or 3:5 or 3:7 or 3:10 or 3:20 or 3:25 or 4:0.5 or 4: 1 or 4: 1.5 or 4:2.5 or 4:3 or 4:5 or 4:7.5 4:15 or 4:25 or 5: 1 or
  • 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 pharmaceutical composition is administered by the oral route.
  • 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 e.g., revamilast or its pharmaceutically acceptable salt and the disease modifying 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.
  • pharmaceutical compositions for transdermal or transmucosal administration include but are not limited to patches, gels, creams, ointments and the like.
  • the pharmaceutical composition may include at least one pharmaceutically acceptable excipient, 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, and solvents.
  • diluents include 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, and solvents.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising therapeutically effective amount of revamilast or its pharmaceutically acceptable salt; a disease modifying agent and a pharmaceutically acceptable excipient.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a pharmaceutical composition for oral administration comprising revamilast or its pharmaceutically acceptable salt, methotrexate or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt and a disease modifying agent, wherein the combination exhibits synergy for the treatment of an autoimmune disease in a subject in need thereof.
  • the present invention relates to a
  • composition comprising therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of an autoimmune disease in a subject in need thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of an autoimmune disease in a subject in need thereof.
  • the autoimmune disease is selected from rheumatoid arthritis, psoriasis or multiple sclerosis.
  • the present invention relates to a pharmaceutical composition for oral administration comprising from about lmg to about 20mg of revamilast or a pharmaceutically acceptable salt and from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of an autoimmune disease in a subject in need thereof.
  • the present invention relates to a pharmaceutical composition for oral administration comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 2.5mg to about 20mg of methotrexate or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of rheumatoid arthritis in a subject in need thereof.
  • the present invention relates to a pharmaceutical composition for oral administration comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt and from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt, wherein the combination exhibits synergy for the treatment of psoriasis in a subject in need thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent for the treatment of an autoimmune disease in a subject in need thereof.
  • the autoimmune disease may be rheumatoid arthritis, multiple sclerosis, Type I diabetes mellitus, psoriasis, psoriatic arthritis and ankylosing spondylitis.
  • the autoimmune disease is rheumatoid arthritis, multiple sclerosis or psoriasis.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of revamilast or its pharmaceutically acceptable salt and methotrexate or its pharmaceutically acceptable salt for the treatment of an autoimmune disease in a subject in need thereof.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising from about 0.1 mg to about 30mg of revamilast or its pharmaceutically acceptable salt and from about 2.5 mg to about 30mg of methotrexate or its pharmaceutically acceptable salt for the treatment of an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis or psoriasis in a subject in need thereof.
  • the present invention relates to a pharmaceutical composition for oral administration comprising about 0.5mg or lmg or 1.5mg or 2mg or 2.5 mg or 3mg or 3.5 mg or 4 mg or 4.5 mg or 5mg or 5.5 mg or 6 mg or 6.5 mg or 7mg or 7.5 mg or 8mg or 8.5 mg or 9 mg or 9.5 mg or lOmg or 12mg or 15mg or 20mg of revamilast or its pharmaceutically acceptable salt and about 2.5mg or 5mg or 7.5mg or lOmg or 15mg or 20mg or 25mg or 30mg of methotrexate or its pharmaceutically acceptable salt for the treatment of an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis or psoriasis in a subject in need thereof.
  • an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis or psoriasis in a subject in need thereof.
  • the present invention relates to a method of treating an autoimmune disease in a subject, the method comprising administering to the subject a pharmaceutical composition of the present invention.
  • the present invention relates to a method of treating an autoimmune disease in a subject, the method including administering to the subject a pharmaceutical composition comprising an effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent to a subject in need thereof.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating an autoimmune disease in a subject, the method comprising administering to the subject a pharmaceutical composition comprising from about 0.01 mg to about 50 mg revamilast or its pharmaceutically acceptable salt and from about lmg to about 50mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating an autoimmune disease selected from rheumatoid arthritis, multiple sclerosis or psoriasis in a subject comprising administering to the subject a pharmaceutical composition comprising from about 0.1 mg to about 30 mg of revamilast or its pharmaceutically acceptable salt, from about 2.5 mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating rheumatoid arthritis in a subject comprising administering to the subject a pharmaceutical composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt, from about 2.5mg to about 20mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating psoriasis in a subject comprising administering to the subject a
  • composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt, from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to a method of treating multiple sclerosis in a subject comprising administering to the subject a pharmaceutical composition comprising from about lmg to about 20mg of revamilast or its pharmaceutically acceptable salt, from about 2.5mg to about 30mg of methotrexate or its pharmaceutically acceptable salt.
  • the present invention relates to use of therapeutically effective amount of revamilast or its pharmaceutically acceptable salt and a disease modifying agent in the preparation of a pharmaceutical composition for the treatment of an autoimmune disease in a subject in need thereof.
  • the disease modifying agent is methotrexate or its pharmaceutically acceptable salt.
  • ⁇ arthritis Various animal models of arthritis are used extensively in research on pathogenesis of inflammatory arthritis and in the pharmaceutical industry in the testing of potential anti-arthritic agents.
  • One such model is the adjuvant arthritis model in rat which brings about the disease condition either by Freund' s Complete (FCA) supplemented with mycobacterium or by injection of the synthetic adjuvant N, Ndioctylddecyl-N', N-bis(2-hydroxy-ethyl) propanediamine (LA).
  • FCA Freund' s Complete
  • LA Ndioctylddecyl-N', N-bis(2-hydroxy-ethyl) propanediamine
  • Another commonly used model is antigen arthritis model.
  • Mouse models of antigen arthritis have been used extensively to study efficacy of biologies and the role of specific cytokines in the various aspects of disease pathogenesis.
  • the present invention provides a process for preparing a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt, a disease modifying agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of a fixed dose combination formulation.
  • the process comprises admixing revamilast or its pharmaceutically acceptable salt with the disease modifying agent.
  • the process comprises formulating revamilast or its pharmaceutically acceptable salt and the disease modifying agent in such a way that they are not in intimate contact with each other.
  • the invention in another embodiment, relates to a process for preparing a pharmaceutical composition comprising revamilast or its pharmaceutically acceptable salt, a disease modifying agent and a pharmaceutically acceptable excipient, wherein the composition is in the form of a kit comprising two or more separate formulations of revamilast or its pharmaceutically acceptable salt and the disease modifying agent.
  • 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 these 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 combination of revamilast and methotrexate (MTX) in experimental autoimmune encephalomyelitis in mice.
  • MTX methotrexate
  • EAE experimental autoimmune encephalomyelitis
  • CFA Complete Freund's adjuvant
  • the MOG-CFA emulsion was administered subcutaneously (s.c.) on both sides at the base of the tail (100 ⁇ g/mouse).
  • the additional immune adjuvant pertussis toxin (Sigma-Aldrich) in IX Hanks' balanced salt solution was injected intraperitoneally (200 ng/mouse) on the initial day of immunization and again on day 2.
  • the MOG + CFA immunization was repeated, with two subcutaneous injections into the upper flanks of each mouse.
  • the drugs were administered orally in a vehicle containing carboxymethyl cellulose suspension with Tween 80.
  • the clinical disease scores (Table 1) and body weights (Table 2) were recorded starting from the day of drug treatment (day 7) for a period of 11 days.
  • the clinical disease scoring was done using the following criteria: 0, no clinical signs; 0.5, hook tail; 1, flaccid/floppy tail; 2, beginning of walking deficits; 3, unilateral hind limb paralysis; 4, bilateral hind-limb paralysis; and 5, moribund. Table 1
  • revamilast sodium (equivalent to revamilast 1.5 mg/kg, BID) alone showed reduction in clinical scores (from day 11 to day 17) however this did not reach statistical significance as compared to vehicle controls.
  • Methotrexate (0.3 mg/kg, QD) given singly failed to produce any reduction in clinical disease scores during the course of EAE as compared to vehicle controls.
  • EXAMPLE 2 Effect of combination of revamilast and methotrexate in rheumatoid arthritis.
  • Revamilast (1.2mg/kg p.o.) and methotrexate (lmg/kg p.o.) were administered orally for 17 days to groups 3 and 4 respectively.
  • Clinical score and paw thickness were recorded at regular intervals from day 23 onwards.
  • Clinical scoring for the measurement of severity of arthritis was done on a scale of 0-4 (Table 4), while paw thickness was recorded using cutimeter (Mitituo, Japan).
  • Table 4 Scoring system for subjective evaluation of arthritis severity (clinical scores)

Abstract

La présente demande de brevet concerne une composition pharmaceutique comprenant un inhibiteur d'enzyme PDE4 et un agent de modification pathologique ; un procédé pour la préparer ; et son utilisation pour traiter une maladie auto-immune chez un sujet.
PCT/IB2012/050657 2011-02-17 2012-02-14 Composition pharmaceutique comprenant l'inhibiteur d'enzyme pde4 révamilast et un agent de modification pathologique, de préférence, le méthotrexate WO2012110946A1 (fr)

Applications Claiming Priority (4)

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IN437/MUM/2011 2011-02-17
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IN2301MU2011 2011-08-16

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006064355A2 (fr) 2004-12-17 2006-06-22 Glenmark Pharmaceuticals S.A. Nouveaux composes heterocycliques utiles pour le traitement de troubles inflammatoires et allergiques
WO2008055947A1 (fr) * 2006-11-09 2008-05-15 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006064355A2 (fr) 2004-12-17 2006-06-22 Glenmark Pharmaceuticals S.A. Nouveaux composes heterocycliques utiles pour le traitement de troubles inflammatoires et allergiques
WO2008055947A1 (fr) * 2006-11-09 2008-05-15 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase

Non-Patent Citations (4)

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ANNALS OF THE RHEUMATIC DISEASES, vol. 64, no. 4, April 2005 (2005-04-01), pages 599 - 605, ISSN: 0003-4967 *
ANONYMOUS: "A Phase IIb study to evaluate the efficacy, safety and tolerability of revamilast in patients with active rheumatoid arthritis who have had an inadequate response to methotrexate", INTERNET ARTICLE, 1 September 2011 (2011-09-01), pages 1 - 7, XP002673772, Retrieved from the Internet <URL:http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=3483> [retrieved on 20120412] *
DATABASE BIOSIS [online] BIOSCIENCES INFORMATION SERVICE, PHILADELPHIA, PA, US; April 2005 (2005-04-01), LANGE F ET AL: "Methotrexate ameliorates T cell dependent autoimmune arthritis and encephalomyelitis but not antibody induced or fibroblast induced arthritis", XP002673771, Database accession no. PREV200510000749 *
MÃ Â NICA BOGAS ET AL: "Methotrexate treatment in rheumatoid arthritis: management in clinical remission, common infection and tuberculosis. Results from a systematic literature review", CLINICAL RHEUMATOLOGY ; JOURNAL OF THE INTERNATIONAL LEAGUE OF ASSOCIATIONS FOR RHEUMATOLOGY, SPRINGER-VERLAG, LO, vol. 29, no. 6, 8 February 2010 (2010-02-08), pages 629 - 635, XP019784373, ISSN: 1434-9949 *

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