WO2005055997A1 - Composition medicinale pour traiter et pour prevenir une maladie inflammatoire - Google Patents

Composition medicinale pour traiter et pour prevenir une maladie inflammatoire Download PDF

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WO2005055997A1
WO2005055997A1 PCT/JP2004/018694 JP2004018694W WO2005055997A1 WO 2005055997 A1 WO2005055997 A1 WO 2005055997A1 JP 2004018694 W JP2004018694 W JP 2004018694W WO 2005055997 A1 WO2005055997 A1 WO 2005055997A1
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rheumatism
therapeutic agent
pharmaceutical composition
group
administration
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PCT/JP2004/018694
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English (en)
Japanese (ja)
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Junya Yoneda
Junji Hamuro
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Ajinomoto Co., Inc.
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—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
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic 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
    • 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
    • A61K31/185—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
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • 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
    • A61K31/52—Purines, e.g. adenine
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
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    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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    • A61K31/7135—Compounds containing heavy metals
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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Definitions

  • composition for treatment and prevention of inflammatory diseases comprising:
  • the present invention relates to a novel pharmaceutical composition, particularly preferably a pharmaceutical composition for treating and / or preventing an inflammatory disease such as rheumatism. More specifically, it contains at least one of onorenitine, iso-isocyanate, leucine, and palin, and other therapeutic agents for rheumatism as active ingredients, and can be used for treating or preventing inflammatory diseases such as rheumatism. And a combination of the above two active ingredients.
  • Rheumatoid arthritis is a systemic inflammatory disease mainly caused by polyarticular pain, and is characterized by immunological abnormalities.
  • synovial inflammatory cell infiltration, synovial cell proliferation, stratification and angiogenesis are accompanied by destructive changes in articular cartilage, bone, periosteum, ligaments and tendons.
  • Interaction with macrophage-like type A synovial cells, fibroblast-like type B synovial cells, and various inflammatory cells activates synovial cells to form pannus, a synovial granulation tissue causes cartilage and bone destruction. If inflammation persists, joint destruction and deformation will occur, eventually leading to dysfunction. It may also be associated with a variety of extra-articular symptoms associated with pulmonary fibrosis, amyloidosis and vasculitis.
  • non-steroidal anti-inflammatory drugs Non-Steroidal anti-inflammatory drugs
  • NSAIDs Anti-Inflammatory Drugs
  • DMARDs Disease Modifying Antirheumatics Drugs
  • steroids as a pyramid-type treatment policy.
  • QOL quality of life
  • Multidrug therapy has also been attempted. The idea is that by using drugs with different mechanisms of action together, the dose of each drug can be reduced, thereby reducing side effects.
  • new therapeutic agents such as anti-cytodynamic therapy, oral peptide therapy, antisense therapy, and treatment with anti-adhesion molecules are being developed.
  • Patent Document 1 International Publication No. WO 02/060431 pamphlet
  • Patent Document 2 U.S. Patent Application Publication No. 2002/0119952
  • Non-Patent Document 1 Brian, E. Meyers and two others, Infrastructure (Inflammation), Volume 3 (No. 3), 1979, p. 225—233
  • An object of the present invention is to provide a novel pharmaceutical composition which can solve such problems of rheumatic treatment. Is to provide.
  • the present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, have found that at least one of isoleucine, branched-chain amino acids of oral isin and palin, and ordinine, and other therapeutic agents for rheumatism
  • the present inventors have found that the use of a combination of the above can significantly and effectively treat inflammatory diseases typified by rheumatism and, if preferable, synergistic effects, and can prevent or prevent the disease, and have completed the present invention. .
  • the present invention provides the following pharmaceutical composition from one viewpoint, wherein the pharmaceutical composition is at least selected from the group consisting of ordinine, isoleucine, leucine, and palin. It contains one compound and a therapeutic agent for rheumatism other than the compound as active ingredients.
  • the compound such as orditin may be in any form such as a free form, a pharmacologically acceptable salt, or a derivative which is converted into a free form in the body. Such a compound may be referred to as a “compound used in the present invention”.
  • the ratio of the total amount of the compounds to the amount of the other therapeutic agent for rheumatism is not particularly limited, but is preferably 1: 1 to 10,000: 1, more preferably 1: 1 by mass.
  • the ratio is 5000: 1, more preferably 1: 1 and 2000: 1.
  • the therapeutic agent for rheumatism other than the compound is selected from the group consisting of adrenocortical steroid drugs (steroid drugs), remission-inducing antirheumatic drugs (DMARDs), and nonsteroidal anti-inflammatory drugs (NSAIDs). It is characterized by being at least one selected.
  • steroid drugs adrenocortical steroid drugs
  • DMARDs remission-inducing antirheumatic drugs
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • the steroid drug is at least one selected from the group consisting of hide oral cortisone, cortisone, prednisolone, methylprednisolone, triamcinolone, paramethasone, dexamethasone, and betamethasone.
  • the DMARDs are at least one selected from the group consisting of methotrexate, bucillamine, oranofin, penicillamine, sodium thiomalate, mizoribine, and oral benzaritin sodium.
  • the NSAIDs are at least one selected from the group consisting of aspirin, indomethacin, ibuprofen, mefenamic acid, and piroxicam. Let it be a special feature.
  • the above pharmaceutical composition can be used for the treatment and / or prevention of inflammatory diseases, and particularly preferably for the treatment and / or prevention of rheumatism.
  • the dosage is characterized in that the total amount of ordinine, isoleucine, leucine and palin is 1 mg 60 g, preferably 500 mg 15 g per day.
  • the present invention provides a therapeutic agent for rheumatism, which comprises administering a plurality of drugs, including a drug formulation, simultaneously, sequentially, or separately at intervals.
  • the rheumatic drug is at least one selected from the group consisting of corticosteroids (steroid drugs), remission-inducing antirheumatic drugs (DMARDs), and nonsteroidal anti-inflammatory drugs (NSAIDs). .
  • the mechanism of action of the pharmaceutical composition of the present invention is that any of orditin, isoleucine, leucine, and phosphorus is effective in reducing the number of infiltrating immune cells in the inflamed area by single administration. Therefore, it is considered that the required dose of other concomitant rheumatic drugs can be significantly reduced.
  • the examples are expected to reduce the need for other rheumatic drugs by a factor of five.
  • steroids such as dexamethasone have been reported to cause susceptibility to infection if administered at 40 mg / day (PSL equivalent) or more.
  • steroids may be administered at a dose of 60 mg / day (PSL equivalent), but in the present invention, 12 mg (PSL equivalent) is expected to have the same effect, and thus avoidance of susceptibility can be expected.
  • Methotrexate one of the DMARDs, is given at a dose of 2.5 mg at a time, 5 to 7.5 mg per week. According to the American College of Rheumatology guidelines, a liver biopsy should be performed when the total dose exceeds 1.5 g because of side effects of liver damage.If the patient rejects the biopsy, the administration of methotrexate should be discontinued. I have. If methotrexate is administered at a dose of 5 mg per week for 6 consecutive years, a liver biopsy is required once.
  • the pharmaceutical composition of the present invention can reduce the dose of a conventional therapeutic agent for rheumatism, and thus can reduce side effects and extend the effective period. It is extremely useful for treating complications associated with the disease and improving the condition.
  • a therapeutic agent for rheumatism pharmaceutical composition
  • a therapeutic agent for rheumatism pharmaceutical composition
  • the present invention can be widely practiced particularly in the field of pharmaceuticals, and is extremely useful in industry.
  • FIG. 1 is a graph showing the effect of coadministration of ordinine and methotrexate in a CIA mouse model.
  • FIG. 2 is a graph showing the effect of co-administration of orditin and dexamethasone in a CIA mouse model.
  • FIG. 3 is a daraf showing the effect of coadministration of parin and methotrexate in a CIA mouse model.
  • FIG. 4 is a graph showing the effect of coadministration of parin and dexamethasone in a CIA mouse model.
  • Orditin, palin, leucine and isoleucine used in the present invention may be an animal or an animal.
  • Orditin, valine, leucine, and isopenic isine are optical isomers, and the power of D-form and L-form exists.
  • L-form which is a biological protein
  • Orditin can be used in various salt forms.
  • a salt with an acid is mainly used because onorenitine shows basicity.
  • the acid either an inorganic acid or an organic acid may be used. Examples of the inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid and the like.
  • organic acids examples include formic acid, acetic acid, propionic acid, oxalic acid, succinic acid, maleic acid, fumaric acid, citric acid, glutamic acid, aspartic acid, gamma linolenic acid, succinic acid tocopherolone monoesterol, and tocopherol.
  • Phosphoric acid, ascorbic acid, ascorbic phosphoric acid, tocopherol ascorbyl phosphoric acid, choctoic acid, N-acetyl cysteine, N, N-diacetyl cysteine, lipoic acid and the like can be mentioned.
  • Valine, leucine, and isoleucine belong to a group called a branched-chain amino acid, and are hydrophobic amino acids having a branched alkyl group in a side chain.
  • Molecular amino acids make up about 40% of essential amino acids, and their metabolism is of particular clinical significance.
  • the uptake of branched-chain amino acids from the blood into muscle tissue is likely to increase due to the detoxification of high ammonia blood, rather than simply reducing the intake.
  • albumin and the like synthesized by the liver are increased, and hepatic encephalopathy and cirrhosis are improved.
  • “Libatat” containing L-leucine, L-isoleucine and L-valine (all free forms) is provided to medical sites.
  • the orditin and the branched-chain amino acid used in the present invention may be anything that can be rapidly converted into orditin or a branched-chain amino acid in vivo when ingested.
  • the content of orditin and branched-chain amino acids in the peptide is preferably 10-30% or more.
  • Onolenitine or branched-chain amino acid is essential as a peptide component because it is the active substance, but the type of amino acid is not limited.
  • Peptides can be obtained by various methods such as chemical synthesis, fermentation, hydrolysis of natural proteins, natural peptides, etc., and any of them can be used.
  • the therapeutic agent for rheumatism other than the compound used in the present invention refers to any drug conventionally used as a therapeutic agent for rheumatism. However, for example, the following may be mentioned.
  • Corticosteroids steroids: Hydral cortisone, cortisone, prednisolone, methylprednisolone, triamcinolone, triamcinolone acetonide, paramethasone, dexamethasone, betamethasone, hexestrol, methimazole, fluocinolone, fluocinolone Cetonide, fluorometron, beclomethasone propionate, estriol, etc.
  • DMARDs Remission-inducing antirheumatic drugs: methotrexate, bucillamine, gold preparation auranofin, penicillamine, sodium thiomalate, mizoribine, oral benzaritni sodium, sulfasalazine, antimalarial Clocloquin, pyrimidine synthesis Inhibitor leflunomide, prograf and the like.
  • Non-steroidal anti-inflammatory drugs (i) Classical NSAIDs alkofenac, aceclofenac, sulindac, tonolemetin, etodolac, phenoprofen, thiprofenic acid, meclofenamic acid, meloxicam, teoxicam, lornoxicam, nabumeton, nabumeton Phenacetin, ethenzamide, snorepilin, antipyrine, migrenine, aspirin, mefenamic acid, flufenamic acid, diclofenac sodium, loxoprofen pentane, fenirbutazone, indomethacin, ibuprofen, ketoprofen, naproxen, oxaprofen, flurbifen Fenbufen, pranoprofen, floctafenin, piroxicam, epirizole
  • Cyclooxygenase inhibitors COX-1 selective inhibitor, C ⁇ X-2 selective inhibitor, etc.
  • salicylic acid derivatives eg, celecoxib, oral fuecoxib, aspirin
  • ML-3000 which has both C ⁇ X inhibition and 5-lipoxygenase inhibition p54 (COX inhibition & 5-lipoxygenase inhibition) and the like.
  • Nitric oxide free NSAIDs Nitric oxide free NSAIDs.
  • T cell differentiation regulator 6,7-dimethoxy-1-41 (3,4-dimethoxyphenyl) _2_ (1,2,4_triazonole-1-ylmethyl) Quinoline-3-ethyl carboxylate (JP-A-7-118266)
  • Others methotrexate cyclophosphamide, MX_68, aliprimododihydrate chloride, BMS-188667, CKD-461, rimexolone, cyclosporin , Tacrolimus, dasperimus, azathioprine, antilymphatic serum, dried sulfonated immunoglobulin, erythropoietin, colony stimulating factor, interleukin, interferon and the like.
  • Anti-cytopotency drug (I) protein preparation (i) TNF inhibitor etanercebut, infliximab, D2E7, CDP-571, PASSTNF-a, soluble TNF- ⁇ receptor, TNF-a binding protein , Anti-TNF-H antibodies etc. (Ii) Interleukin-1 inhibitor anakinra (interleukin-1 receptor antagonist), soluble interleukin-11 receptor and the like. (Iii) Interleukin-16 inhibitor MRA (anti-interleukin-16 receptor antibody), anti-interleukin-16 antibody and the like. (Iv) Interleukin-10 drug Interleukin-10 and the like. (V) interleukin-12 inhibitor anti-interleukin-12 antibody and the like.
  • interleukin-8 inhibitor IL-8 antagonist CXCR1 & CXCR2 antagonist and the like.
  • interleukin-12 receptor antagonists denileukin, diftitotutus and the like.
  • Therapeutic vaccines TNF-hi vaccine etc. Gene therapy aimed at enhancing the expression of genes having anti-inflammatory activity such as interleukin-4, interleukin-10, soluble interleukin-1 receptor and soluble TNF-a receptor medicine.
  • antisense compound ISIS-104838 and the like.
  • anti-adhesion molecule therapy, antisense therapy, monoclonal antibody, intracellular signal Can also be used in combination with a drug transmission inhibitor, MHC-binding peptide therapy, or the like.
  • rheumatic means a rheumatic disease, in addition to rheumatoid arthritis, such as rheumatic fever, relapsing rheumatism (palindromic rheumatism) and polymyalgia rheumatica. Including diseases.
  • the pharmaceutical composition of the present invention can be widely applied to these rheumatic diseases and complications associated with the diseases.
  • the pharmaceutical composition of the present invention may be used for autoimmune diseases (collagen diseases) such as osteoarthritis, Wegener's granulomatosis, polyarteritis, Behcet's disease, nephrotic syndrome, and Rubus' disease.
  • nephritis such as nephritis, intestinal diseases such as Crohn's disease and ulcerative colitis, psoriasis, chronic active hepatitis, multiple sclerosis, myasthenia gravis, pulmonary fibrosis, uveitis, inflammatory response during transplantation It is also effective for inflammatory diseases such as.
  • the pharmaceutical composition of the present invention is useful for treating and preventing rheumatic diseases, in particular, rheumatoid arthritis.
  • Rheumatoid arthritis is a polyarthritis that recurs and remits repeatedly, and ranges from mild cases to cases with joint destruction or extra-articular symptoms. The cause has not yet been clarified, but there are currently two ideas. This is the result of abnormal immune responses such as lymphocytes to certain autoantigens present in joints, especially the synovium and cartilage, and the result of increased proliferative activity of synovial cells themselves for some reason. is there.
  • the primary lesion of rheumatism is the synovial tissue, where the synovium overgrows and forms granulation tissue (pannus), which erodes and destroys cartilage and bone.
  • the inflammatory synovium has a large accumulation of T cells, and as the inflammation progresses further, infiltration of B cells also appears.
  • Rheumatism is associated with a number of cytokins, including IL-11 and tumor necrosis factor (TNF) -induced by T cells and inflammation.
  • rheumatoid factors known as antibodies to autologous immunoglobulin (Ig) G which are frequently seen in rheumatic patients, may also play a role in the pathology.
  • monocytes and macrophage cells of rheumatoid patients also release active oxygen-lysosomal enzymes, which may be involved in the pathological conditions such as inflammation seen in rheumatism.
  • the dose of a therapeutic agent for rheumatism is reduced by co-administering at least one of ordinine, isoleucine, leucine, and palin with a therapeutic agent for rheumatism (steroid drug, SMARDs, NSAIDs). Also demonstrated that a similar degree of joint swelling inhibitory effect was obtained using an animal model of arthritis.
  • onorenitine There are two metabolic pathways of onorenitine: a pathway metabolized to polyamine by the action of onorenitine decarboxylase and the like and a pathway of metabolism to proline by the action of ordinine aminotransferase. Isoleucine, leucine, and valine all inhibit ordinine aminotransferase. As a result, the metabolic pathway from ordinine to proline is inhibited, and the amount of onolenitine as a substrate for onorenitine decarboxylase increases. Therefore, administration of iso-oral isine, leucine, and palin is expected to be as effective as administration of onorenitine.
  • the compound used in the present invention By combining the compound used in the present invention with a concomitant drug, it is possible to (1) reduce the dose of the concomitant drug compared to a case where the compound used in the present invention or the concomitant drug is administered alone. (2) The drug used in combination with the compound used in the present invention can be selected according to the patient's symptoms (mild, severe, etc.). (3) The compound used in the present invention and the mechanism of action are The treatment period can be set longer by selecting different concomitant drugs. (4) The therapeutic effect can be maintained by selecting concomitant drugs having a different mechanism of action from the compound used in the present invention.
  • the administration timing of each preparation is not limited, and the compound used in the present invention and the concomitant drug are administered to the subject to be administered. They may be administered simultaneously or at different times. It can also be used after physical therapy or after surgery.
  • Concomitant drug dosage The dose can be appropriately selected according to the administration subject, administration route, disease, combination and the like according to the clinically used dose.
  • the administration form of the pharmaceutical composition of the present invention is not particularly limited as long as the compound used in the present invention and the concomitant drug are combined at the time of administration.
  • Such administration forms include, for example, (1) administration of a single preparation obtained by simultaneously formulating the compound used in the present invention and the concomitant drug, and (2) administration of the compound used in the present invention and the concomitant drug.
  • the pharmaceutical composition of the present invention has low toxicity.
  • the compound used in the present invention and / or the concomitant drug is mixed with a pharmacologically acceptable carrier according to a method known per se.
  • Pharmaceutical compositions such as tablets (including sugar-coated tablets and film-coated tablets), powders, granules, capsules (including soft capsules), liquids, injections, suppositories, sustained-release preparations, etc. It can be safely administered orally (eg, topically, rectally, intravenously, etc.).
  • the injection can be administered intravenously, intramuscularly, subcutaneously or into an organ or directly to a lesion.
  • Pharmaceutically acceptable carriers include various organic or inorganic carrier materials commonly used as drug substances, such as excipients, lubricants, binders and disintegrants in solid preparations, or liquid preparations. Examples include solvents, solubilizing agents, suspending agents, tonicity agents, buffers, and soothing agents. Further, if necessary, usual additives such as preservatives, antioxidants, coloring agents, sweeteners, adsorbents, wetting agents and the like can be used in appropriate amounts.
  • Examples of the excipient include lactose, sucrose, D-mannitol, starch, corn starch, crystalline cellulose, light caffeic anhydride and the like.
  • Examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropylcellulose, hydroxypropylmethylcellulose, polybutylpyrrolidone, And starch, sucrose, gelatin, methylcellulose, sodium carboxymethylcellulose and the like.
  • Disintegrators include, for example, starch, carboxymethylcellulose, calcium carbonate, sodium carboxymethyl starch, L-hydroxypropylcellulose and the like.
  • the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like.
  • the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol monoole, triethanolamine, sodium carbonate, sodium citrate and the like.
  • suspending agent examples include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurinoleamino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate;
  • hydrophilic polymers such as sodium norboxoxy methinoresenolerose, methinoresenolerose, hydroxymethinoresenolerose, hydroxyethyl cellulose, and hydroxypropyl cellulose.
  • tonicity agent examples include glucose, D-sorbitol, sodium salt, dariserin, D-mannitol and the like.
  • buffer examples include buffers such as phosphate, acetate, carbonate, and citrate.
  • Examples of the soothing agent include benzyl alcohol and the like.
  • Examples of the preservative include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • Examples of the antioxidant include sulfite, ascorbic acid, ⁇ -tocopherol and the like.
  • the compounding ratio of the compound used in the present invention and the concomitant drug in the pharmaceutical composition of the present invention can be appropriately selected depending on the administration subject, administration route, disease and the like.
  • the content of ordinine, isoleucine, leucine, norin, or a pharmacologically acceptable salt or derivative thereof in the pharmaceutical composition of the present invention varies depending on the form of the preparation.
  • the content of the concomitant drug in the pharmaceutical composition of the present invention varies depending on the form of the preparation, but is usually about 0.01 to 100% by mass, preferably about 0.1 to 50% by mass, more preferably about 0.1% by mass, based on the whole preparation.
  • the content of additives such as a carrier in the pharmaceutical composition of the present invention is generally about 1 to 99.99% by mass, preferably about 10 to 90% by mass, based on the total strength of the preparation. .
  • the same content may be used when the compound used in the present invention and the concomitant drug are separately formulated.
  • the compound or concomitant drug used in the present invention may be a dispersant (eg, Tween 80 (manufactured by Atlas Powder Co., USA), HCO 60 (manufactured by Nikko Chemicals), polyethylene glycol, carboxymethyl cellulose, sodium alginate, Hydroxypropyl methylcellulose, dextrin, etc.), stabilizers (eg, ascorbic acid, sodium pyrosulfite, etc.), surfactants (eg, polysorbate 80, macrogol, etc.), solubilizers (eg, glycerin, ethanol, etc.) , Buffers (eg, phosphoric acid and its alkali metal salts, citric acid and its alkali metal salts, etc.), tonicity agents (eg, sodium salt of sodium salt, potassium salt of sodium salt, mannitol, sorbitol, glucose, etc.), pH regulator
  • a dispersant eg, Tween 80 (manufactured by Atlas Powder
  • the compound used in the present invention or the concomitant drug can be prepared by, for example, excipients (eg, lactose, sucrose, starch, etc.), disintegrants (eg, starch, Calcium carbonate, etc.), binders (eg, starch, gum arabic, carboxymethyl cellulose, polybutylpyrrolidone, hydroxypropylcellulose, etc.) or Hitoshi Surizawa 1J (eg, tanolek, magnesium stearate, polyethylene glycol 6000, etc.) And then compression-molded.
  • excipients eg, lactose, sucrose, starch, etc.
  • disintegrants eg, starch, Calcium carbonate, etc.
  • binders eg, starch, gum arabic, carboxymethyl cellulose, polybutylpyrrolidone, hydroxypropylcellulose, etc.
  • Hitoshi Surizawa 1J eg, tanolek, magnesium stearate, polyethylene
  • the preparation may be coated by a method known per se for the purpose of taste masking, enteric coating or long-lasting, to give a preparation for oral administration.
  • the coating agent include hydroxypropyl methylcellulose, ethylcellulose, hydroxymethylinoresenorelose, hydroxypropinoresenorelose, and polyoxyethylene glycolonole. , Tween 80, pull mouth nick F68, cellulose acetate phthalate, hydroxypropionylmethylcellulose phthalate, hydroxymethylcellulose acetate succinate, hydragit (manufactured by Rohm, Germany, methacrylic acid 'acrylic acid copolymerization) and dyes (eg, Bengala , Titanium dioxide, etc.).
  • Preparations for oral administration may be immediate release preparations or sustained release preparations.
  • the compound used in the present invention may be formed into a preparation for oral administration such as a solid preparation (eg, powder, granules, tablets, capsules) or a liquid preparation (contained in a liquid component), It is preferable to mold into a preparation for rectal administration such as a suppository. In particular, preparations for oral administration are preferred.
  • the concomitant drug can be in the above-mentioned dosage form depending on the type of the drug.
  • Secondary components such as preservatives, antioxidants, surfactants, thickeners, coloring agents, pH adjusters, flavors, sweeteners or taste-masking agents are contained in the composition.
  • Suitable colorants include red, black and yellow iron oxides and FD & C dyes such as FD & C Blue No. 2 and FD & C Red No. 40 from Ellis 'and' Everard.
  • Suitable flavors include mint, raspberry, licorice, orange, lemon, grapefruit, caramel, vanilla, cherry and grape flavor and combinations thereof.
  • Suitable pH adjusters include citric acid, tartaric acid, phosphoric acid, hydrochloric acid and maleic acid.
  • Suitable sweeteners include aspartame, acesulfame K and thaumatin.
  • Suitable taste masking agents include sodium bicarbonate, ion exchange resins, cyclodextrin inclusion compounds, adsorbate materials, and microencapsulated apomorphine.
  • the formulations usually contain about 0.1 to about 50% by weight, preferably about 0.1 to about 30% by weight, of the compound or the concomitant drug used in the present invention, for about 1 minute to about 60 minutes, preferably A preparation capable of dissolving 90% or more of the compound or concomitant drug used in the present invention (in water) for about 1 minute to about 15 minutes, more preferably for about 2 minutes to about 5 minutes (see above).
  • Sublingual tablets, buccal, etc.) or rapidly disintegrating within the oral cavity within 1 to 60 seconds, preferably within 1 to 30 seconds, more preferably within 1 to 10 seconds The agent prefers.
  • the content in the whole preparation of the excipient is from about 10 to about 99 wt%, preferably from about 30 one to about 90 weight 0/0.
  • the content of the / 3-cyclodextrin or ⁇ -cyclodextrin derivative in the whole preparation is 0 about 30% by mass.
  • Lubricant content in the entire formulation The amount is from about 0.01 to about 10% by weight, preferably from about 1 to about 5% by weight.
  • the content of the isotonic pill in the whole preparation is about 0.1 to about 90% by mass, preferably about 10 to about 70% by mass.
  • the content of the hydrophilic carrier in the whole preparation is about 0.1 to about 50% by mass, preferably about 10 to about 30% by mass.
  • the content of the water-dispersible polymer in the whole preparation is about 0.1 to about 30% by mass, preferably about 10 to about 25% by mass.
  • the content of the stabilizer in the whole preparation is about 0.1 to about 10% by mass, preferably about 1 to about 5% by mass.
  • the above preparations may further contain additives such as coloring agents, sweetening agents, preservatives and the like, if necessary.
  • the dosage of the pharmaceutical composition of the present invention varies depending on the disease state, the age, weight, symptom, constitution, physical condition, drug dosage form, administration method, administration period and the like of the disease of the present invention.
  • Rheumatic patients adults, weighing about 60 kg
  • the compound used in the present invention should be appropriately selected in the range of lmg 60 g, preferably 500 mg-15 g in terms of ordinine.
  • the therapeutic drug for rheumatism as a concomitant drug varies depending on its type, but it is preferable that each drug contains about 20% of the dose at which an effective effect can be obtained by single administration.
  • a dose smaller than the above dose may be sufficient, or may need to be administered outside the range.
  • the compound used in the present invention and the concomitant drug may be administered at the same time.
  • the concomitant drug is administered first and then used in the present invention.
  • the compound may be administered, or the compound used in the present invention may be administered first, and then the concomitant drug may be administered.
  • the time difference varies depending on the active ingredient to be administered, the dosage form, the administration method, and the like.
  • the concomitant drug first it is preferable that the The method includes administering the compound used in the present invention within 10 days, more preferably within 10 minutes to 11 days, and even more preferably within 15 minutes to 1 hour.
  • the compound used in the present invention When the compound used in the present invention is administered first, after administration of the compound used in the present invention, it is preferably within 1 minute to 7 days, more preferably within 10 minutes and 1 day, and still more preferably 15 minutes and 1 day. There is a method of administering the concomitant drug within 6 hours.
  • a compound to be used in the present invention formed into a preparation for administration is administered first, and thereafter, a concomitant drug formed into an oral preparation is orally administered.
  • the concomitant drug formed into an oral administration preparation may be administered first, followed by administration of the compound used in the present invention. They may be administered simultaneously.
  • continuous administration is desirable, etc., such as intravenous, intramuscular, subcutaneous, or joint capsule containing the pharmaceutical composition
  • transdermal absorption preparation such as an ointment or a patch containing the pharmaceutical composition.
  • Collagen-induced arthritis was induced by a standard method using DBA-1 mice, and the effect of co-administration of orditin and methotrexate was examined.
  • Collagen-induced arthritis (CIA) is well known as experimental arthritis induced by sensitizing mice with type II collagen (CIA).
  • Emulsion with an antigen amount of 100 ⁇ g / 0.1 ml per mouse was intradermally injected into the tail.
  • an emulsion of the same composition was injected intradermally at the base of the ridge with an antigen amount of 100 ⁇ g / 0.1 ml as a booster immunization as in the case of the initial sensitization.
  • Arthritis began around 4 days after the booster and was observed as edema with redness. The degree of arthritis peaked about 2 weeks after the boost. The degree of edema was classified into four stages, and each limb was visually judged.
  • FIG. 1 is a graph showing the change in joint score when a combination of onorenitine and methotrexate was administered to CIA mice over time from the day of booster immunization.
  • the joint score of the control group was 3.5, the strength of the group administered orditin alone was about 3 ⁇ 4, and that of the group administered methotrexate (0.2 mg / kg) alone was 2.8.
  • the score of the combined administration group of ornithine and methotrexate was 0.6 which was the same as that of the group administered with methotrexate (lmg / kg) alone.
  • the combined administration of orditin and methotrexate (0.2 mg / kg) showed the same inhibitory effect as the single administration of methotrexate (lmg / kg) administered 5 times the amount of methotrexate used in the combined administration.
  • Example 2 Effect of concurrent administration of onorenitine and dexamethasone to collagen-induced arthritis (CIA) mice
  • Collagen-induced arthritis was induced by a standard method using DBA-1 mice, and the effect of combined administration of orditin and dexamethasone was examined in the same manner as in Example 1.
  • the conditions are the same as above.
  • Orditin (0.03%) is freely available for drinking, and dexamethasone (0. Olmg / kg) or dexamethasone (0.05 mg / kg) is administered orally by gavage 100 / il / animal 5 times a week.
  • single or combined administration of type II collagen and FCA was started simultaneously with intradermal administration of emulsion. The results are shown in FIG. FIG.
  • 2 is a graph showing the change in joint score when a combined administration of orditin and dexamethasone to CIA mice is shown with time-course of booster immunity.
  • score 1 no disease
  • 1 red edema was observed in any of the limbs or finger joints
  • 2 it was recognized that the swelling of the joints was excessively thick twice or more than usual
  • 3 It was determined that the joint was twisted, deformed, etc., and judged visually.
  • the sum of the limb scores of 1 was taken as the mouse score of 1.
  • the joint score of the control group was 3.5, whereas the group administered orditin alone was about 2, and the group administered dexamethasone (0.01 mg / kg) alone was 1.5.
  • the value was 0.6 in the group receiving the combination of orditin and dexamethasone (0.01 mg / kg), which was close to 0.2 in the case of dexamethasone (0.05 mgZkg) alone.
  • the combined administration of orditin and dexamethasone (0.01 mg / kg) was as effective as the single administration of dexamethasone (0.05 mg / kg) given 5 times the amount of dexamethasone used in the combined administration. .
  • Example 3 Effect of combined administration of parin and methotrexate to collagen-induced arthritis (CIA) mice
  • Palin 0.0715%
  • Palin 0.2 mg / kg
  • methotrexate 0.2 mg / kg
  • methotrexate lmg / kg
  • 3 is a graph showing the change in joint score when a combination of palin and methotrexate was administered to CIA mice over time according to the daily strength of the booster immunization.
  • the score 1 0: no disease
  • 1 red edema was observed in either the limb or the finger joint
  • 2 it was recognized that the swelling of the joint was excessively thicker than normal
  • 3 The case where torsion, deformation and the like were recognized in the joint, and the judgment was made with the naked eye.
  • the sum of the limb scores was defined as the mouse score.
  • the control group had a joint score of 5.8, whereas the methotrexate (1 mg / kg) alone administration group had a joint score of 2.2, and palin and methotrexate (0.2 mg). / kg) was 2.6.
  • the combined administration of noklin and methotrexate (0.2 mg / kg) showed the same level of inhibitory effect as the single administration of methotrexate (lmg / kg) administered 5 times the amount of methotrexate used in the combined administration.
  • FIG. 4 is a diagram showing changes in joint scores when C-administered orditin and dexamethasone in combination are shown over time from the day of booster immunization.
  • the control group had a joint score of 5.8, whereas the dexamethasone (0.05 mg / kg) alone group had a joint score of 2.8, and valine and dexamethasone (0 Olmg / kg). ) was 2.4.
  • the combined administration of parin and dexamethasone (0.01 mg / kg) was as effective as dexamethasone (0.05 mgZkg) administered alone at a dose 5 times that of the dexamethasone used in the combined administration.

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Abstract

L'invention concerne une nouvelle composition médicinale permettant de résoudre les problèmes apparaissant dans les traitements classiques des rhumatismes, par exemple, les problèmes qui réduisent les effets thérapeutiques et augmentent les effets secondaires du traitement, en raison d'une administration prolongée. L'invention concerne une composition médicinale caractérisée en ce qu'elle contient au moins un composé sélectionné dans le groupe comprenant: ornithine, isoleucine, leucine et valine, et un remède pour les rhumatismes, autres que ces composés, en tant que principes actifs. Chaque composé susmentionné comprend de l'ornithine, etc., et peut se présenter sous n'importe quelle forme, à savoir, soit un composé libre, un sel pharmacologiquement acceptable, un dérivé pouvant être converti en un composé libre in vivo ou analogue.
PCT/JP2004/018694 2003-12-15 2004-12-15 Composition medicinale pour traiter et pour prevenir une maladie inflammatoire WO2005055997A1 (fr)

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WO2007018278A1 (fr) * 2005-08-05 2007-02-15 Ajinomoto Co., Inc. Inhibiteur de l’apparition et de la progression du cancer hépatique
WO2008072663A1 (fr) 2006-12-12 2008-06-19 Ajinomoto Co., Inc. Composition pour atténuer/prévenir un effet secondaire nuisible dans une thérapie par stéroïdes
WO2013118773A1 (fr) 2012-02-06 2013-08-15 味の素株式会社 Agent prophylactique ou thérapeutique pour myopathies inflammatoires idiopathiques

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KR101239541B1 (ko) * 2007-07-02 2013-03-06 아사히 가세이 메디컬 가부시키가이샤 미조리빈을 함유하는 궤양성 대장염 치료약
EP2461803B1 (fr) * 2009-08-03 2018-10-17 Emisphere Technologies, Inc. Composition de naproxène à action rapide avec effets gastro-intestinaux réduits

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WO2007018278A1 (fr) * 2005-08-05 2007-02-15 Ajinomoto Co., Inc. Inhibiteur de l’apparition et de la progression du cancer hépatique
JP5067160B2 (ja) * 2005-08-05 2012-11-07 味の素株式会社 肝癌発生・進展抑制剤
JP2012214485A (ja) * 2005-08-05 2012-11-08 Ajinomoto Co Inc 肝癌発生・進展抑制剤
WO2008072663A1 (fr) 2006-12-12 2008-06-19 Ajinomoto Co., Inc. Composition pour atténuer/prévenir un effet secondaire nuisible dans une thérapie par stéroïdes
CN103120655A (zh) * 2006-12-12 2013-05-29 味之素株式会社 用于改善/预防类固醇治疗中的不利副作用的组合物
EP2606882A1 (fr) 2006-12-12 2013-06-26 Ajinomoto Co., Inc. Composition pour atténuer/prévenir un effet secondaire nuisible dans une thérapie par stéroïdes
JP5293189B2 (ja) * 2006-12-12 2013-09-18 味の素株式会社 ステロイド療法における副作用の改善・抑制用組成物
JP2013216671A (ja) * 2006-12-12 2013-10-24 Ajinomoto Co Inc ステロイド療法における副作用の改善・抑制用組成物
JP2015166352A (ja) * 2006-12-12 2015-09-24 味の素株式会社 ステロイド療法における副作用の改善・抑制用組成物
CN103120655B (zh) * 2006-12-12 2016-06-01 味之素株式会社 用于改善/预防类固醇治疗中的不利副作用的组合物
WO2013118773A1 (fr) 2012-02-06 2013-08-15 味の素株式会社 Agent prophylactique ou thérapeutique pour myopathies inflammatoires idiopathiques
JPWO2013118773A1 (ja) * 2012-02-06 2015-05-11 味の素株式会社 特発性炎症性筋疾患の予防又は治療剤

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