WO2005055997A1 - Medicinal composition for treating and preventing inflammatory disease - Google Patents

Medicinal composition for treating and preventing inflammatory disease Download PDF

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Publication number
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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French (fr)
Japanese (ja)
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Junya Yoneda
Junji Hamuro
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Ajinomoto Co., Inc.
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Publication of WO2005055997A1 publication Critical patent/WO2005055997A1/en

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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
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    • 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, pantothenic acid
    • A61K31/198—Alpha-aminoacids, e.g. alanine, edetic acids [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.

Abstract

It is intended to provide a novel medicinal composition by which problems occurring in the conventional treatments for rheumatism, for example, lowering in therapeutic effects and increase in side effects due to prolonged administration can be solved. A medicinal composition characterized by containing at least one compound selected from the group consisting of ornithine, isoleucine, leucine and valine and a remedy for rheumatism other than these compounds as the active ingredients. Each of the above-described compounds including ornithine and so on may be in any form, i.e., either a free compound, a pharmacologically acceptable salt, a derivative which can be converted into a free compound in vivo or the like.

Description

明 細 書  Specification
炎症性疾患の治療及び予防用医薬組成物  Pharmaceutical composition for treatment and prevention of inflammatory diseases
技術分野  Technical field
[0001] 本発明は、新規な医薬組成物、特に好ましくは、リウマチ等の炎症性疾患を治療及 び/又は予防するための医薬組成物に関する。さらに詳細には、オノレニチン、イソ口 イシン、ロイシン、及びパリンの少なくとも 1種と、これら以外のリウマチ治療薬とを有効 成分として含み、リウマチ等の炎症性疾患を治療又は予防するために用いることので きる医薬組成物、並びに上記 2種の有効成分の組合せに関する。  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.
背景技術  Background art
[0002] 慢性関節リウマチは多発性関節痛を主症状とする全身性の炎症性疾患で、免疫異 常を伴うことを特徴とする。リウマチでは滑膜の炎症細胞浸潤、滑膜細胞の増殖、重 層化と血管新生を伴い、関節軟骨、骨、骨膜、靭帯、腱の破壊性変化が進行してい く。マクロファージ様の A型滑膜細胞、線維芽細胞様の B型滑膜細胞、種々の炎症性 細胞との相互作用により滑膜細胞の活性化が起こり、滑膜の肉芽組織であるパンヌ スを形成して軟骨、骨破壊を引き起こす。炎症が持続すると関節破壊、変形を来たし 、最終的には機能障害に至る。また、肺線維症、アミロイド一シスや血管炎に伴う多 彩な関節外症状を合併することがある。  [0002] Rheumatoid arthritis is a systemic inflammatory disease mainly caused by polyarticular pain, and is characterized by immunological abnormalities. In rheumatism, 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.
[0003] リウマチの病態形成には遺伝的要因、環境要因が複雑に絡み合って炎症反応を 誘導していると考えられているが、発症機構については不明な点が多い。遺伝要因 として知られているのは、 HLA— DR4、 HLA— DR1等の特定の MHCクラス IIをもつ 患者が多いということである。これは MHCクラス IIに拘束性をもつ T細胞が関節炎の 発症に関与している可能性を示唆している。環境要因としては、ウィルスや細菌、マ ィコプラズマ等の感染が引き金になっているのではないかと考えられている。  [0003] Genetic and environmental factors are thought to induce the inflammatory response intricately inducing the pathogenesis of rheumatism, but the mechanism of the onset is unknown. A known genetic factor is that many patients have specific MHC class II, such as HLA-DR4 and HLA-DR1. This suggests that MHC class II-restricted T cells may be involved in the development of arthritis. It is thought that infections such as viruses, bacteria, and mycoplasmas may be triggered as environmental factors.
[0004] リウマチの従来の治療法においては、まず非ステロイド系抗炎症薬（Non-Steroidal [0004] In the conventional treatment of rheumatism, first, non-steroidal anti-inflammatory drugs (Non-Steroidal
Anti-Inflammatory Drugs； NSAIDs)により炎症を抑えて痛みをとり、効果のない活 動性のリウマチに DMARDs (Disease Modifying Antirheumatics Drugs)やステロイド 薬を使うピラミッド型の治療方針であった。近年は早期から病勢を抑え、骨の破壊を 防ぎ、機能障害に陥らないよう積極的に DMARDsやステロイドを使う Step-down bridge療法が提唱されている。し力し、この療法も 5— 10年という短期的には生活の 質（Quality of Life; QOL)の向上をはかれる力 長期においては効果の低下と副作 用の増大とレ、う問題を残してレ、る。 Anti-Inflammatory Drugs (NSAIDs) were used to suppress inflammation and relieve pain, and to treat inactive and active rheumatism, using DMARDs (Disease Modifying Antirheumatics Drugs) and steroids as a pyramid-type treatment policy. In recent years, the disease has been suppressed from an early stage, Step-down bridge therapy using DMARDs and steroids has been proposed to prevent and prevent dysfunction. This therapy also has the ability to improve quality of life (QOL) in the short term of 5 to 10 years. In the long term, it has a problem of reduced efficacy and increased side effects. Te, ru.
[0005] 多剤併用療法も試みられている。作用機序の異なる薬剤を併用することで、各々の 薬剤の投与量を減少できるので副作用が軽減されるという考え方である。その他、抗 サイト力イン療法、経口ペプチド療法、アンチセンス療法、抗接着分子による治療等 の新治療薬が開発されつつある。  [0005] 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. In addition, new therapeutic agents such as anti-cytodynamic therapy, oral peptide therapy, antisense therapy, and treatment with anti-adhesion molecules are being developed.
[0006] ある種のアミノ酸が抗炎症作用、抗リウマチ作用があることは知られている。本発明 者らは、オル二チンや分枝鎖アミノ酸が関節炎疾患の治療、予防、進展防止、改善 等に優れた効果を有することを報告している (例えば、特許文献 1参照）。また、アル ギニンやその誘導体には抗リウマチ効果があることも知られている（例えば、特許文 献 2参照)。さらに、 L-シスチンとステロイド薬を併用投与すると抗炎症作用が増強さ れるという報告もある (例えば、非特許文献 1参照）。しかし、いずれも実用化には至つ てレ、なレ、。他の抗リウマチ薬に比べて効果が低レ、ためと考えられる。  [0006] It is known that certain amino acids have anti-inflammatory and anti-rheumatic effects. The present inventors have reported that orditin and branched-chain amino acids have excellent effects in treating, preventing, preventing the progress of, and improving arthritis diseases (see, for example, Patent Document 1). It is also known that arginine and its derivatives have an antirheumatic effect (for example, see Patent Document 2). Furthermore, there is a report that the anti-inflammatory effect is enhanced when L-cystine and a steroid are administered in combination (for example, see Non-Patent Document 1). However, all of them have been put to practical use. It is considered that the effect is lower than other antirheumatic drugs.
[0007] 特許文献 1：国際公開第 02/060431号パンフレット [0007] Patent Document 1: International Publication No. WO 02/060431 pamphlet
特許文献 2 :米国特許出願公開第 2002/0119952号明細書  Patent Document 2: U.S. Patent Application Publication No. 2002/0119952
非特許文献 1 :ブライアン、ィー、メイヤーズ (Brian, E. Meyers)外 2名、インフラメーショ ン (Inflammation),第 3卷（No. 3)、 1979年、 p. 225—233  Non-Patent Document 1: Brian, E. Meyers and two others, Infrastructure (Inflammation), Volume 3 (No. 3), 1979, p. 225—233
発明の開示  Disclosure of the invention
発明が解決しょうとする課題  Problems to be solved by the invention
[0008] リウマチ患者への薬剤の投与は長期間に及ぶことが多いが、長期投与は効果の減 少と副作用の増大を招く危険性が高い。例えば、非ステロイド系抗炎症薬は重篤な 胃出血、消化性潰瘍ゃ腎障害等を引き起こすことがあり、ステロイド薬は免疫抑制作 用による感染症の憎悪、消化性潰瘍、骨粗鬆症等多くの副作用を引き起こす。従つ て、これらのリウマチ薬の投与効果を低下させずに極力薬物の投与量を減少させるこ とができれば、長期投与が可能となり、同時に副作用の軽減を達成することができる 。本発明の課題は、このようなリウマチ治療の問題点を解決できる新規な医薬組成物 を提供することにある。 [0008] Administration of drugs to rheumatic patients often extends over a long period of time, but long-term administration has a high risk of reducing effects and increasing side effects. For example, non-steroidal anti-inflammatory drugs may cause severe gastric bleeding, peptic ulcer, renal impairment, etc.Steroidal drugs have many side effects such as hatred of infectious diseases due to immunosuppressive action, peptic ulcer, osteoporosis. cause. Therefore, if the dose of a drug can be reduced as much as possible without lowering the administration effect of these rheumatic drugs, long-term administration becomes possible, and at the same time, reduction of side effects can be achieved. An object of the present invention is to provide a novel pharmaceutical composition which can solve such problems of rheumatic treatment. Is to provide.
課題を解決するための手段  Means for solving the problem
[0009] 本発明者らは、上記課題を解決するために鋭意研究した結果、イソロイシン、口イシ ン及びパリンの分岐鎖アミノ酸、並びにオル二チンの少なくとも 1種と、これら以外のリ ゥマチ治療薬とを併用することにより、リウマチに代表される炎症性疾患が極めて効 果的に、好ましい場合には相乗的効果で治療、及び Z又は予防されることを見出し、 本発明を完成するに至った。  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. .
[0010] すなわち、本発明はその 1つの視点において以下の医薬組成物を提供するもので あって、当該医薬組成物は、オル二チン、イソロイシン、ロイシン、及びパリンからなる 群より選択される少なくとも 1種の化合物と、前記化合物以外のリウマチ治療薬とを有 効成分として含むことを特徴とする。前記オル二チン等の化合物は、それぞれ遊離体 、薬理的に許容される塩、又は体内で遊離体に変換される誘導体等のいずれの形 態であってもよい。このような化合物を「本発明で使用する化合物」と称する場合があ る。この医薬組成物において、前記化合物の合計量とこれら以外のリウマチ治療薬 の量比は、特に制限はなレ、が、好ましくは質量比で 1 : 1一 10000 : 1、より好ましくは 1： 1一 5000 : 1、さらに好ましくは 1： 1一 2000 : 1である。  [0010] That is, 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”. In this pharmaceutical composition, 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.
[0011] 好ましい実施形態において、前記化合物以外のリウマチ治療薬は、副腎皮質ステ ロイド薬 (ステロイド薬）、寛解導入抗リウマチ薬（DMARDs)、及び非ステロイド系消 炎症薬 (NSAIDs)からなる群より選択される少なくとも 1種であることを特徴とする。  [0011] In a preferred embodiment, 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.
[0012] さらに好ましい実施形態において、前記ステロイド薬は、ハイド口コルチゾン、コルチ ゾン、プレドニゾロン、メチルプレドニゾロン、トリアムシノロン、パラメタゾン、デキサメタ ゾン、及びべタメタゾンからなる群より選択される少なくとも 1種であることを特徴とする  [0012] In a further preferred embodiment, the steroid drug is at least one selected from the group consisting of hide oral cortisone, cortisone, prednisolone, methylprednisolone, triamcinolone, paramethasone, dexamethasone, and betamethasone. Feature
[0013] 他の好ましい実施形態において、前記 DMARDsがメトトレキサート、ブシラミン、ォ ーラノフィン、ぺニシラミン、チオリンゴ酸ナトリウム、ミゾリビン、及び口ベンザリットニナ トリウムからなる群より選択される少なくとも 1種であることを特徴とする。 [0013] In another preferred embodiment, the DMARDs are at least one selected from the group consisting of methotrexate, bucillamine, oranofin, penicillamine, sodium thiomalate, mizoribine, and oral benzaritin sodium. And
[0014] 別の好ましい実施形態において、前記 NSAIDsが、アスピリン、インドメタシン、イブ プロフェン、メフヱナム酸、及びピロキシカムからなる群より選択される少なくとも 1種で あることを特 ί数とする。 [0014] In another preferred embodiment, 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.
[0015] 本発明の 1つの好ましい実施形態において、上記医薬組成物は炎症性疾患の治 療及び/又は予防のために使用することができ、特に好ましくは、リウマチの治療及 び/又は予防に使用される。リウマチ治療剤として用レ、る場合には、その投与量が一 日当たり、オル二チン、イソロイシン、ロイシン、及びパリンの合計量として lmg 60g 、好ましくは 500mg 15gであることを特徴とする。  [0015] In one preferred embodiment of the present invention, 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. used. When used as a therapeutic agent for 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.
[0016] 本発明の他の視点において、オル二チン、イソロイシン、ロイシン、バリン、それらの 塩、及びそれらの誘導体からなる群より選択される少なくとも 1種の製剤と、前記化合 物以外のリウマチ治療薬の製剤とを含む複数薬剤であって、それらを同時に、逐次 的に、又は時間を置いて別々に投与することを特徴とするリウマチ治療剤が提供され る。前記リウマチ治療薬は、副腎皮質ステロイド薬 (ステロイド薬)、寛解導入抗リウマ チ薬（DMARDs)、及び非ステロイド系消炎症薬（NSAIDs)力 なる群より選択され る少なくとも 1種であることが好ましい。  [0016] In another aspect of the present invention, at least one preparation selected from the group consisting of ordinine, isoleucine, leucine, valine, a salt thereof, and a derivative thereof, and a treatment for rheumatism other than the above compound 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. Preferably, 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). .
発明の効果  The invention's effect
[0017] 本発明の医薬組成物の作用機作としては、オル二チン、イソロイシン、ロイシン、ノく リンのいずれにも単独投与により炎症局所への浸潤免疫細胞数を減少させる効果が 認められることから、併用されるその他のリューマチ治療薬の必要投与量を著しく低 減することができると考えられる。実施例から、他のリウマチ治療薬の必要量を 5分の 1に減らせることが期待される。例えば、デキサメサゾンなどのステロイド剤は 1日 40m g (PSL換算）以上投与すると、易感染性をもたらすという報告がある。ステロイド剤は 大量療法の場合、 1日 60mg (PSL換算）投与するケースがあるが、本発明において は、 12mg (PSL換算）で同等の効果が期待されるため易感染性の回避が期待でき る。 DMARDsの一つであるメトトレキサートは 1回 2. 5mg、週 5— 7. 5mgの投与が 行なわれている。肝障害の副作用があるためアメリカリウマチ学会ガイドラインにおい て、総投与量が 1. 5gを超えた際には肝生検の実施が必要、患者が生検を拒否した 場合メトトレキサートの投与を中止するとしている。メトトレキサートを週 5mgで 6年間 連続投与した場合、 1度は肝生検の必要が発生する。本発明の医薬組成物では、こ の期間が 30年間に延長することが期待できる。さらに、 NSAIDsの一つであるァスピ リンはリウマチ様関節炎治療には 1日 3gの大量が必要であるが、血中濃度が 20mg /dl以上になると耳鳴りがする。本発明においては 0. 6gで同様な効果が期待できる ため、耳鳴りのために減量、中止を余儀なくされることは回避できるものと期待される 。このように、本発明の医薬組成物は、含有する従来のリウマチ治療薬の投与量を削 減することができるため、副作用の軽減や、有効期間の延長が可能であり、リウマチ 性疾患及び同疾患に伴う合併症の治療、病態改善に極めて有用である。本発明に より、従来のリウマチ治療薬に比較して優れた薬効を有するリウマチ治療剤（医薬組 成物）が提供される。以上、本発明は、特に医薬品分野において広く実施可能であり 、産業上極めて有用である。 [0017] 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. For example, steroids such as dexamethasone have been reported to cause susceptibility to infection if administered at 40 mg / day (PSL equivalent) or more. In the case of high dose therapy, 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. With the pharmaceutical composition of the present invention, this period can be expected to be extended to 30 years. Furthermore, one of the NSAIDs Phosphorus requires a large amount of 3 g per day to treat rheumatoid arthritis, but tinnitus occurs when the blood concentration exceeds 20 mg / dl. In the present invention, a similar effect can be expected at 0.6 g, so that it is expected that it is possible to avoid having to reduce or stop the weight loss due to tinnitus. As described above, 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. According to the present invention, there is provided a therapeutic agent for rheumatism (pharmaceutical composition) having superior efficacy as compared with conventional therapeutic agents for rheumatism. As described above, the present invention can be widely practiced particularly in the field of pharmaceuticals, and is extremely useful in industry.
図面の簡単な説明  Brief Description of Drawings
[0018] [図 1]CIAマウスモデルにおけるオル二チンとメトトレキサートの併用投与効果を示し たグラフである。  FIG. 1 is a graph showing the effect of coadministration of ordinine and methotrexate in a CIA mouse model.
[図 2]CIAマウスモデルにおけるオル二チンとデキサメサゾンの併用投与効果を示し たグラフである。  FIG. 2 is a graph showing the effect of co-administration of orditin and dexamethasone in a CIA mouse model.
[図 3]CIAマウスモデルにおけるパリンとメトトレキサートの併用投与効果を示したダラ フである。  FIG. 3 is a daraf showing the effect of coadministration of parin and methotrexate in a CIA mouse model.
[図 4]CIAマウスモデルにおけるパリンとデキサメサゾンの併用投与効果を示したダラ フである。  FIG. 4 is a graph showing the effect of coadministration of parin and dexamethasone in a CIA mouse model.
符号の説明  Explanation of symbols
[0019] Cont:コントロール（対照） [0019] Cont: control (control)
Orn :ォ/レニチン  Orn: o / renitine
Val :バリン  Val: Valine
MTX :メトトレキサート  MTX: Methotrexate
DEX:デキサメサゾン  DEX: dexamethasone
発明を実施するための最良の形態  BEST MODE FOR CARRYING OUT THE INVENTION
[0020] 以下に本発明の実施の形態について説明する。 Hereinafter, embodiments of the present invention will be described.
(本発明の医薬組成物）  (Pharmaceutical composition of the present invention)
本発明で使用されるオル二チン、パリン、ロイシン、及びイソロイシンは、動物あるい は植物由来の天然タンパク質の加水分解から得られたもの、発酵法あるいは化学合 成法によって得られたものいずれでも良レ、。オル二チン、バリン、ロイシン、及びイソ口 イシンは光学異性体として、 D体と L体が存在する力 本発明に使用するには、生体 タンパク質である L体が望ましレ、。オル二チンは種々の塩の形で用いても良レ、。オル 二チンの塩としては、オノレニチンが塩基性を示すために主に酸との塩が用いられる。 酸としては、無機酸、有機酸いずれでも良い。無機酸の例としては、塩酸、硫酸、硝 酸、燐酸、臭化水素酸、ヨウ化水素酸等があげられる。有機酸の例としては、蟻酸、 酢酸、プロピオン酸、蓚酸、コハク酸、マレイン酸、フマル酸、クェン酸、グルタミン酸 、ァスパラギン酸、ガンマリノレン酸、コハク酸トコフェローノレモノエステノレ、トコフエ口 ール燐酸、ァスコルビン酸、ァスコルビン燐酸、トコフェロールァスコルビル燐酸、チ ォクト酸、 N-ァセチルシスティン、 N，Nしジァセチルシスティン、リポ酸 (lipoic acid)等 が挙げられる。 Orditin, palin, leucine and isoleucine used in the present invention may be an animal or an animal. は 良 で も で も で も で も い ず れ い ず れ い ず れ で も い ず れ い ず れ い ず れ は い ず れ 良 良 良 は は は 植物 植物 植物 は は 植物 天然 天然 天然 い ず れ 良 い ず れ 天然 天然 良 い ず れ は い ず れ は い ず れ 良 天然 良 良 良 は 良 は は は は は は は は は は は は は は は は は は は は は は は. Orditin, valine, leucine, and isopenic isine are optical isomers, and the power of D-form and L-form exists. For use in the present invention, L-form, which is a biological protein, is desirable. Orditin can be used in various salt forms. As the salt of ordinine, a salt with an acid is mainly used because onorenitine shows basicity. As 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. Examples of organic acids 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.
[0021] バリン、ロイシン、及びイソロイシンは、分枝鎖アミノ酸と呼ばれるグループに属し、 側鎖に分枝アルキル基を持つ疎水性アミノ酸である。分子鎖アミノ酸は必須アミノ酸 の約 40%を占め、その代謝は、特に臨床的意義が高い。肝硬変症では摂取量が低 下するだけでなぐ血液中からの筋肉組織への分枝鎖アミノ酸の取り込みが高アンモ ニァ血の解毒のために亢進すると考えられる。そこで、分枝鎖アミノ酸を経口投与し て補充療法することにより肝臓が合成するアルブミン等が上昇し、肝性脳症と肝硬変 症の改善が見られる。低アルブミン血症を呈する非代償性肝硬変患者の低アルブミ ン血症の改善を目的として、 L-ロイシン、 L-イソロイシン、及び L-バリン（何れも遊離 体)を含む「リーバタト」（味の素株式会社登録商標）が医療現場に提供されている。  [0021] 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. In cirrhosis, 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. Thus, by orally administering a branched-chain amino acid and performing replacement therapy, albumin and the like synthesized by the liver are increased, and hepatic encephalopathy and cirrhosis are improved. For the purpose of improving hypoalbuminemia in patients with decompensated cirrhosis presenting with hypoalbuminemia, “Libatat” containing L-leucine, L-isoleucine and L-valine (all free forms) (Ajinomoto Co., Ltd.) (Registered trademark) is provided to medical sites.
[0022] 本発明で使用されるオル二チン、及び分岐鎖アミノ酸は摂取されたときに生体内で オル二チン、又は分岐鎖アミノ酸に速やかに変換されるものなら何でも良レ、が、例え ばペプチドが挙げられる。オル二チン、及び分岐鎖アミノ酸のペプチド中の含量は 1 0— 30%以上であることが望ましい。ペプチド成分としてオノレニチン、又は分岐鎖アミ ノ酸は活性本体であるから必須であるがそれ以外はアミノ酸の種類は問わなレ、。ぺ プチドは化学合成、発酵法、天然タンパク質の加水分解、天然ペプチド等、種々の 方法で入手できるが、いずれでも使用できる。 [0023] 本発明で使用する化合物以外のリウマチ治療薬 (以下、「併用薬物」と略記する場 合もある）とは、従来よりリウマチ治療薬として用いられている医薬であればどのような ものでもよいが、例えば、以下のものが挙げられる。 [0022] 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. Peptides. 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.ぺ 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. [0023] The therapeutic agent for rheumatism other than the compound used in the present invention (hereinafter sometimes abbreviated as "concomitant drug") refers to any drug conventionally used as a therapeutic agent for rheumatism. However, for example, the following may be mentioned.
(1)副腎皮質ステロイド薬（ステロイド薬）：ハイド口コルチゾン、コルチゾン、プレドニ ゾロン、メチルプレドニゾロン、トリアムシノロン、トリアムシノロンァセトニド、パラメタゾ ン、デキサメサゾン、ベタメタゾン、へキセストロール、メチマゾール、フルオシノニド、 フルオシノロンァセトニド、フルォロメトロン、プロピオン酸べクロメタゾン、エストリオ一 ル等。  (1) Corticosteroids (steroids): Hydral cortisone, cortisone, prednisolone, methylprednisolone, triamcinolone, triamcinolone acetonide, paramethasone, dexamethasone, betamethasone, hexestrol, methimazole, fluocinolone, fluocinolone Cetonide, fluorometron, beclomethasone propionate, estriol, etc.
[0024] (2)寛解導入抗リウマチ薬（DMARDs)：メトトレキサート、ブシラミン、金製剤オーラ ノフィン、ぺニシラミン、チオリンゴ酸ナトリウム、ミゾリビン、口ベンザリットニナトリウム、 スルフアサラジン、抗マラリア薬クロ口キン、ピリミジン合成阻害薬レフルノマイド、プロ グラフ等。  (2) Remission-inducing antirheumatic drugs (DMARDs): methotrexate, bucillamine, gold preparation auranofin, penicillamine, sodium thiomalate, mizoribine, oral benzaritni sodium, sulfasalazine, antimalarial Clocloquin, pyrimidine synthesis Inhibitor leflunomide, prograf and the like.
[0025] (3)非ステロイド系消炎症薬（NSAIDs)： (i) Classical NSAIDsアルコフヱナク、 ァセクロフエナク、スリンダク、トノレメチン、エトドラク、フエノプロフェン、チアプロフェン 酸、メクロフエナム酸、メロキシカム、テオキシカム、ロルノキシカム、ナブメトン、ァセト ァミノフェン、フエナセチン、ェテンザミド、スノレピリン、アンチピリン、ミグレニン、ァスピ リン、メフエナム酸、フルフエナム酸、ジクロフエナックナトリウム、ロキソプロフエンナトリ ゥム、フエ二ルブタゾン、インドメタシン、イブプロフェン、ケトプロフェン、ナプロキセン 、ォキサプロジン、フルルビプロフェン、フェンブフェン、プラノプロフェン、フロクタフエ ニン、ピロキシカム、ェピリゾール、塩酸チアラミド、ザルトプロフェン、メシル酸ガべキ サート、メシル酸力モスタツト、ゥリナスタチン、コルヒチン、プロベネシド、スルフィンピ ラゾン、ベンズブロマロン、ァロプリノール、金チオリンゴ酸ナトリウム、ヒアルロン酸ナト リウム、サリチル酸ナトリウム、塩酸モルヒネ、サリチル酸、アト口ピン、スコポラミン、モ ノレヒネ、ペチジン、レボルファノール、ォキシモルフオンまたはその塩等。 （Π)シクロォ キシゲナーゼ抑制薬 (COX - 1選択的阻害薬、 C〇X - 2選択的阻害薬等）サリチル 酸誘導体（例、セレコキシブ、口フエコキシブ、アスピリン）、 MK- 663、バルデコキシブ 、 SC-57666、チラコキシブ、 S-2474,ジクロフエナック、インドメタシン、ロキソプロフエ ン等。 （iii) C〇X阻害と 5—リポキシゲナーゼ阻害を併せ持つ薬物 ML-3000、 p54(COX阻害 & 5-リポキシゲナーゼ阻害)等。 （iv) Nitric oxide遊離型 NSAIDs 等。 [0025] (3) Non-steroidal anti-inflammatory drugs (NSAIDs): (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, tiaramid hydrochloride, zaltoprofen, gabbe mesylate Sart, mesilate power mist, perinastatin, colchicine, probenecid, sulfinpyrazone, benzbromarone, aloprinol, sodium gold thiomalate, sodium hyaluronate, sodium salicylate, morphine hydrochloride, salicylic acid, atopin, scopolamine, monorehine, pethidine. , Levorphanol, oxymorphone or a salt thereof and the like. (Π) Cyclooxygenase inhibitors (COX-1 selective inhibitor, C〇X-2 selective inhibitor, etc.) salicylic acid derivatives (eg, celecoxib, oral fuecoxib, aspirin), MK-663, valdecoxib, SC-57666 , Tilacoxib, S-2474, diclofenac, indomethacin, loxoprofen and the like. (Iii) ML-3000, which has both C〇X inhibition and 5-lipoxygenase inhibition p54 (COX inhibition & 5-lipoxygenase inhibition) and the like. (Iv) Nitric oxide free NSAIDs.
[0026] (4)免疫抑制剤：（i) T細胞分化調節薬 6 , 7—ジメトキシ一 4一（3, 4—ジメトキシフエ二 ノレ）_2_ ( 1， 2, 4_トリァゾーノレ— 1_ィルメチル）キノリン— 3_カルボン酸ェチルエステ ノレ（特開平 7—1 18266号公報）（ii)その他メトトレキサート、シクロフォスフアミド、 MX_68、ァチプリモドディハイド口クロライド、 BMS-188667, CKD-461 ,リメクソロン、 シクロスポリン、タクロリムス、ダスペリムス、ァザチォプリン、抗リンパ血清、乾燥スルホ 化免疫グロブリン、エリスロポイエチン、コロニー刺激因子、インターロイキン、インタ 一フエロン等。  (4) Immunosuppressant: (i) 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) (ii) 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.
[0027] (5)抗サイト力イン薬： (I)タンパク質製剤（i) TNF阻害薬ェタナーセブト、インフリキ シマブ、 D2E7、 CDP-571、 PASSTNF- a、可溶性 TNF- α受容体、 TNF- a結合蛋白 、抗 TNF-ひ抗体等。 （ii)インターロイキン— 1阻害薬アナキンラ (インターロイキン— 1受 容体拮抗薬)、可溶性インターロイキン一 1受容体等。 （iii)インターロイキン一 6阻害薬 MRA (抗インターロイキン一 6受容体抗体)、抗インターロイキン一 6抗体等。 （iv)インタ 一ロイキン- 10薬インターロイキン- 10等。 （V)インターロイキン- 12阻害薬抗インタ 一ロイキン一 12抗体等。 （vi)インターフェロン一 α及び γ阻害、及び TNF- α阻害を併 せ持つ薬物（ポリクローナル抗体) AGT— 1 (II)非タンパク質製剤 G) MAPキナーゼ 阻害薬 PD-98059等。 （ii)遺伝子調節薬 SP_100030、 NF- κ、 NF- κ b、 IKK_1、 IKK-2、 ΑΡ-1等シグナル伝達に関係する分子の阻害薬等。 （iii)サイト力イン産生抑 制薬 T-614、 SR-31747,ソナチモド等。 （iv) TNF_ α変換酵素阻害薬。 （ν)インター口 ィキン一 1 β変換酵素阻害薬 HMR3480/VX-740等。 （vi)インターロイキン一 6拮抗薬 SANT- 7等。 （vii)インターロイキン— 8阻害薬 IL-8拮抗薬、 CXCR1 & CXCR2拮抗薬 等。 （viii)ケモカイン拮抗薬 MCP-1拮抗薬等。 （ix)インターロイキン一 2受容体拮抗 薬デニロイキン、ディフチトツタス等。 （X) Therapeutic vaccines TNF-ひワクチン等 。（xi)遺伝子治療薬インターロイキン— 4、インターロイキン— 10、可溶性インターロイ キン - 1受容体、可溶性 TNF- a受容体等抗炎症作用を有する遺伝子の発現を亢進 させることを目的とした遺伝子治療薬。 （xii)アンチセンス化合物 ISIS-104838等。 その他、抗接着分子療法、アンチセンス療法、モノクローナル抗体、細胞内シグナ ル伝達阻害薬、 MHC結合性ペプチド療法等との併用も可能である。 (5) Anti-cytopotency drug: (I) protein preparation (i) TNF inhibitor etanercebut, infliximab, D2E7, CDP-571, PASSTNF-a, soluble TNF-α 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. (Vi) Drug having both interferon-α and γ inhibition and TNF-α inhibition (polyclonal antibody) AGT-1 (II) Non-protein preparation G) MAP kinase inhibitor PD-98059 and the like. (Ii) Gene modulators Inhibitors of molecules involved in signal transduction, such as SP_100030, NF-κ, NF-κb, IKK_1, IKK-2 and ΑΡ-1. (Iii) Cytoin production inhibitor T-614, SR-31747, sonatimod and the like. (I v) TNF_ α-converting enzyme inhibitors. ( Ν ) inter-kinin-1β-converting enzyme inhibitor HMR3480 / VX-740 and the like. (Vi) Interleukin-16 antagonist SANT-7 and the like. (Vii) interleukin-8 inhibitor IL-8 antagonist, CXCR1 & CXCR2 antagonist and the like. (Viii) Chemokine antagonist MCP-1 antagonist and the like. (Ix) interleukin-12 receptor antagonists denileukin, diftitotutus and the like. (X) Therapeutic vaccines TNF-hi vaccine etc. (Xi) 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. (Xii) antisense compound ISIS-104838 and the like. In addition, 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.
[0028] (本発明の医薬組成物が効果を奏する炎症性疾患）  (Inflammatory diseases for which the pharmaceutical composition of the present invention is effective)
本発明において、用語「リウマチ」とはリウマチ性疾患のことを意味し、リウマチ様関 節炎の他に、リウマチ熱、回帰性リウマチ（palindromic rheumatism)やリウマチ性多発 筋痛症（polymyalgia rheumatica)といった疾患を含む。本発明の医薬組成物は、これ らリウマチ性疾患及び同疾患に伴う合併症に広く適用できる。また、本発明の医薬組 成物はこれらのリウマチ性疾患のほか、変形性関節症やウェジナー肉芽腫症、多発 性動脈炎、ベーチェット病などの自己免疫疾患 (膠原病）、ネフローゼ症候群、ルー ブス腎炎などの各種腎炎、クローン病、潰瘍性大腸炎などの腸疾患、乾癬、慢性活 動性肝炎、多発性硬化症、重症筋無力症、肺繊維症、ぶどう膜炎、移植時の炎症反 応などの炎症性疾患にも効果を奏する。  In the present invention, the term “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. In addition to the rheumatic 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. Various 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.
[0029] 好ましい実施形態において、本発明の医薬組成物はリウマチ性疾患、特に、慢性 関節リウマチの治療及び予防に有用である。慢性関節リウマチは再燃と寛解を繰り返 す多発性関節炎で軽症例から関節破壊あるいは関節外症状をともなう症例まで幅広 い疾患である。その原因はいまだ明らかにされていないが、現在 2つの考え方がある 。関節、特に滑膜や軟骨に存在するある自己抗原に対し、リンパ球等の免疫応答異 常が生じた結果というものと、滑膜細胞自体の増殖活性がなんらかの原因で亢進し た結果というものである。リウマチの主病変は滑膜組織であり、滑膜が異常増殖し、肉 芽組織 (パンヌス）を形成し、これにより軟骨や骨を侵蝕，破壊する。また、炎症滑膜 には T細胞の巨大な集積巣があり、炎症がさらに進展すると B細胞の浸潤巣も現れる 。リウマチの病態には T細胞や炎症によって誘導された IL一 1や腫瘍壊死因子 (tumor necrosis factor: TNF)-ひ等、数多いサイト力インが関わっている。また、リウマチ患 者から頻繁にみられる自己の免疫グロブリン (Ig) Gに対する抗体として知られるリウマ チ因子も病態に関与すると思われる。さらに、リウマチ患者の単球やマクロファージの 細胞からは活性酸素ゃリソソーム酵素の放出も見られ、リウマチで見られる炎症等の 病態にかかわると考えられる。  [0029] In a preferred embodiment, 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. In addition, 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. In addition, 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. In addition, 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.
[0030] (分岐鎖アミノ酸又はオノレニチンとリウマチ治療薬の併用で効果を奏する作用機作） 本発明者らは、以前にポリアミンの原料ともいうべきオル二チンが関節腫脹を抑制 することを 3つの機序の異なる関節炎動物モデルを用いて明らかにした（上記特許文 献 1参照）。ポリアミンはポリアミンォキシデースにより酸化されてできる産物の一つ過 酸化水素を介して IL一 2の産生を抑制する。単核球はこのポリアミンを産生し、活性 化 T細胞の IL—2産生をひいては細胞増殖を抑制することが知られている。 [0030] (Mechanism of Effectiveness When Combined Use of Branched-chain Amino Acid or Onolenitine and Rheumatoid Therapeutic Agent) The present inventors have found that ordinine, which has been previously referred to as a raw material of polyamine, suppresses joint swelling. This was clarified by using animal models of arthritis with three different mechanisms (see Patent Document 1 above). Polyamine suppresses the production of IL-12 via hydrogen peroxide, one of the products oxidized by polyamine oxidase. Monocytes are known to produce this polyamine and suppress IL-2 production by activated T cells, and thus suppress cell proliferation.
[0031] 本発明ではオル二チン、イソロイシン、ロイシン、及びパリンの少なくとも 1種とリウマ チ治療薬 (ステロイド薬、 SMARDs、 NSAIDs)を併用投与することで、リューマチ治 療薬の投与量を減少させても同程度の関節腫脹抑制効果が得られることを関節炎 動物モデルを用いて明らかにした。  [0031] In the present invention, 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.
[0032] オノレニチンの代謝経路はオノレニチンデカルボキシラーゼ等の働きでポリアミンに代 謝される経路とオル二チンアミノトランスフェラーゼの働きでプロリンに代謝される経路 の 2つがある。イソロイシン、ロイシン、及びバリンは、いずれもオル二チンアミノトラン スフヱラーゼを抑制する。結果、オル二チンからプロリンへの代謝経路が阻害され、 オノレニチンデカルボキシラーゼの基質としてのオノレニチン量が増える。よって、イソ口 イシン、ロイシン、及びパリンの投与はオノレニチンを投与するのと同等の効果が期待 される。  [0032] 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.
[0033] (本発明の医薬組成物の投与方法、及び製剤の形態等）  (Method of administering the pharmaceutical composition of the present invention, form of preparation, etc.)
本発明で使用する化合物と併用薬物とを組み合わせることにより、（1)本発明で使 用する化合物または併用薬物を単独で投与する場合に比べて、併用薬物の投与量 を軽減すること力 Sできる、 （2)患者の症状 (軽症、重症等）に応じて、本発明で使用す る化合物と併用する薬物を選択することができる、（3)本発明で使用する化合物と作 用機序が異なる併用薬物を選択することにより、治療期間を長く設定することができ る、（4)本発明で使用する化合物と作用機序が異なる併用薬物を選択することにより 、治療効果の持続を図ることができる、（5)本発明で使用する化合物と併用薬物とを 併用することにより、好ましい場合相乗効果が得られる、等の優れた効果を得ることが できる。本発明で使用する化合物と併用薬物とを複数製剤の形態で使用するに際し ては、それぞれの製剤の投与時期は限定されず、本発明で使用する化合物と併用 薬物とを、投与対象に対し、同時に投与してもよいし、時間差をおいて投与してもよ レ、。また、理学療法後、又は手術療法後等に用レ、ることもできる。併用薬物の投与量 は、臨床上用いられている投与量に準ずればよぐ投与対象、投与ルート、疾患、組 み合わせ等により適宜選択することができる。本発明の医薬組成物の投与形態は、 特に限定されず、投与時に、本発明で使用する化合物と併用薬物とが組み合わされ ていればよい。このような投与形態としては、例えば、（1)本発明で使用する化合物と 併用薬物とを同時に製剤化して得られる単一の製剤の投与、（2)本発明で使用する 化合物と併用薬物とを別々に製剤化して得られる 2種の製剤の同一投与経路での同 時投与、（3)本発明で使用する化合物と併用薬物とを別々に製剤化して得られる 2 種の製剤の同一投与経路での時間差をおいての投与、（4)本発明で使用する化合 物と併用薬物とを別々に製剤化して得られる 2種の製剤の異なる投与経路での同時 投与、（5)本発明で使用する化合物と併用薬物とを別々に製剤化して得られる 2種 の製剤の異なる投与経路での時間差をおいての投与 (例えば、本発明で使用する化 合物；併用薬物の順序での投与、あるいは逆の順序での投与）等が挙げられる。 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. (5) By using the compound used in the present invention in combination with a concomitant drug, it is possible to obtain excellent effects such as obtaining a synergistic effect in a preferable case. When the compound used in the present invention and the concomitant drug are used in the form of a plurality of preparations, 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. (2) Simultaneous administration by the same administration route of the two preparations obtained by separately preparing the two preparations, (3) Same administration of the two preparations obtained by separately preparing the compound used in the present invention and the concomitant drug (4) Simultaneous administration of two formulations obtained by separately formulating the compound used in the present invention and the concomitant drug by different administration routes, (5) The present invention Administration of two preparations obtained by separately formulating the compound used in the above and the concomitant drug at different times by different administration routes (for example, the compound used in the present invention; Administration or administration in the reverse order).
[0034] 本発明の医薬組成物は、毒性が低ぐ例えば、本発明で使用する化合物及び/又 は上記併用薬物をそれ自体公知の方法に従って、薬理学的に許容される担体と混 合して医薬組成物、例えば錠剤（糖衣錠、フィルムコーティング錠を含む）、散剤、顆 粒剤、カプセル剤（ソフトカプセルを含む）、液剤、注射剤、坐剤、徐放剤等として、経 口的又は非経口的 (例、局所、直腸、静脈投与等）に安全に投与することができる。 注射剤は、静脈内、筋肉内、皮下又は臓器内投与あるいは直接病巣に投与すること ができる。薬理学的に許容される担体としては、製剤素材として慣用の各種有機ある いは無機担体物質が挙げられ、例えば固形製剤における賦形剤、滑沢剤、結合剤 及び崩壊剤、あるいは液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、 緩衝剤及び無痛化剤等が挙げられる。更に必要に応じ、通常の防腐剤、抗酸化剤、 着色剤、甘味剤、吸着剤、湿潤剤等の添加物を適宜、適量用いることもできる。 The pharmaceutical composition of the present invention has low toxicity. For example, 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.
[0035] 賦形剤としては、例えば乳糖、白糖、 D—マンニトール、デンプン、コーンスターチ、 結晶セルロース、軽質無水ケィ酸等が挙げられる。滑沢剤としては、例えばステアリ ン酸マグネシウム、ステアリン酸カルシウム、タルク、コロイドシリカ等が挙げられる。結 合剤としては、例えば結晶セルロース、白糖、 D—マンニトール、デキストリン、ヒドロキ シプロピルセルロース.ヒドロキシプロピルメチルセルロース、ポリビュルピロリドン、デ ンプン、ショ糖、ゼラチン、メチルセルロース、カルボキシメチルセルロースナトリウム 等が挙げられる。崩壊剤としては、例えばデンプン、カルボキシメチルセルロース、力 ノレボキシメチルセルロースカルシウム、カルボキシメチルスターチナトリウム、 Lーヒドロ キシプロピルセルロース等が挙げられる。溶剤としては、例えば注射用水、アルコー ノレ、プロピレングリコール、マクロゴール、ゴマ油、トウモロコシ油、ォリーブ油等が挙 げられる。溶解補助剤としては、例えばポリエチレングリコール、プロピレングリコーノレ 、 D—マンニトール、安息香酸べンジル、エタノール、トリスァミノメタン、コレステロ一ノレ 、トリエタノールァミン、炭酸ナトリウム、クェン酸ナトリウム等が挙げられる。懸濁化剤 としては、例えばステアリルトリエタノールァミン、ラウリル硫酸ナトリウム、ラウリノレアミノ プロピオン酸、レシチン、塩化ベンザルコニゥム、塩化べンゼトニゥム、モノステアリン 酸グリセリン等の界面活性剤；例えばポリビュルアルコール、ポリビュルピロリドン、力 ノレボキシメチノレセノレロースナトリウム、メチノレセノレロース、ヒドロキシメチノレセノレロース、 ヒドロキシェチルセルロース、ヒドロキシプロピルセルロース等の親水性高分子等が挙 げられる。等張化剤としては、例えばブドウ糖、 D-ソルビトール、塩ィ匕ナトリウム、ダリ セリン、 D-マンニトール等が挙げられる。緩衝剤としては、例えばリン酸塩、酢酸塩、 炭酸塩、クェン酸塩等の緩衝液等が挙げられる。無痛化剤としては、例えばべンジル アルコール等が挙げられる。防腐剤としては、例えばパラォキシ安息香酸エステル類 、クロロブタノール、ベンジルアルコール、フエネチルアルコール、デヒドロ酢酸、ソル ビン酸等が挙げられる。抗酸化剤としては、例えば亜硫酸塩、ァスコルビン酸、 α -ト コフエロール等が挙げられる。 [0035] 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. Examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil, olive oil and the like. Examples of the solubilizer include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol monoole, triethanolamine, sodium carbonate, sodium citrate and the like. Examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, laurinoleamino propionic acid, lecithin, benzalkonium chloride, benzethonium chloride, and glycerin monostearate; Examples include hydrophilic polymers such as sodium norboxoxy methinoresenolerose, methinoresenolerose, hydroxymethinoresenolerose, hydroxyethyl cellulose, and hydroxypropyl cellulose. Examples of the tonicity agent include glucose, D-sorbitol, sodium salt, dariserin, D-mannitol and the like. Examples of the buffer 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, α-tocopherol and the like.
本発明の医薬組成物における本発明で使用する化合物と併用薬物との配合比は 、投与対象、投与ルート、疾患等により適宜選択することができる。例えば、本発明の 医薬組成物におけるオル二チン、イソロイシン、ロイシン、ノ リン、又はその薬理的に 許容される塩若しくは誘導体の含有量は、製剤の形態によって相違するが、通常製 剤全体に対して約 0. 01ないし 100質量％、好ましくは約 0. 1ないし 50質量％、さら に好ましくは約 0. 5ないし 20質量％程度である。本発明の医薬組成物における併用 薬物の含有量は、製剤の形態によって相違するが、通常製剤全体に対して約 0. 01 ないし 100質量％、好ましくは約 0. 1ないし 50質量％、さらに好ましくは約 0. 5ない し 20質量％程度である。本発明の医薬組成物における担体等の添加剤の含有量は 、製剤の形態によって相違する力 通常製剤全体に対して約 1ないし 99. 99質量％ 、好ましくは約 10ないし 90質量％程度である。また、本発明で使用する化合物及び 併用薬物をそれぞれ別々に製剤化する場合も同様の含有量でよい。 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. For example, 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. About 0.01 to 100% by weight, preferably about 0.1 to 50% by weight, and more preferably about 0.5 to 20% by weight. 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. Is not about 0.5 About 20% by mass. 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.
[0037] これらの製剤は、製剤工程において通常一般に用いられる公知の方法により製造 すること力 Sできる。例えば、本発明で使用する化合物又は併用薬物は、分散剤 (例、 ツイーン（Tween) 80 (アトラスパウダー社製、米国）、 HCO 60 (日光ケミカルズ製）、ポ リエチレングリコール、カルボキシメチルセルロース、アルギン酸ナトリウム、ヒドロキシ プロピルメチルセルロース、デキストリン等）、安定化剤（例、ァスコルビン酸、ピロ亜硫 酸ナトリウム等）、界面活性剤（例、ポリソルベート 80、マクロゴール等）、可溶化剤（例 、グリセリン、エタノール等）、緩衝剤（例、リン酸及びそのアルカリ金属塩、クェン酸及 びそのアルカリ金属塩等）、等張化剤（例、塩ィ匕ナトリウム、塩ィ匕カリウム、マンニトー ノレ、ソルビトール、ブドウ糖等）、 pH調節剤（例、塩酸、水酸化ナトリウム等）、保存剤（ 例、パラォキシ安息香酸ェチル、安息香酸、パラォキシ安息香酸メチル、パラォキシ 安息香酸プロピル、ベンジノレアルコール等）、溶解剤（例、濃グリセリン、メダルミン等 )、溶解補助剤 (例、プロピレングリコール、白糖等）、無痛化剤 (例、ブドウ糖、ベンジ ルアルコール等）等と共に水性注射剤に、あるいはォリーブ油、ゴマ油、綿実油、コ ーン油等の植物油、プロピレングリコール等の溶解補助剤に溶解、懸濁あるいは乳 化して油性注射剤に成形し、注射剤とすることができる。  [0037] These preparations can be manufactured by a known method generally used in the preparation process. For example, 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 regulators (eg, hydrochloric acid, sodium hydroxide, etc.), preservatives (eg, ethyl ethyl paraoxybenzoate, Carboxylic acid, methyl paraoxybenzoate, propyl paraoxybenzoate, benzinole alcohol, etc.), solubilizers (eg, concentrated glycerin, medalmine, etc.), solubilizers (eg, propylene glycol, sucrose, etc.), soothing agents (eg, (E.g., glucose, benzyl alcohol, etc.) in aqueous injections, or dissolved, suspended or emulsified in dissolution aids such as olive oil, sesame oil, cottonseed oil, corn oil, etc., or propylene glycol to form oily injections. It can be molded and used as an injection.
[0038] 経口投与用製剤とするには、公知の方法に従い、本発明で使用する化合物または 併用薬物を例えば、賦形剤 (例、乳糖、白糖、デンプン等）、崩壊剤 (例、デンプン、 炭酸カルシウム等）、結合剤（例、デンプン、アラビアゴム、カルボキシメチルセルロー ス、ポリビュルピロリドン、ヒドロキシプロピルセルロース等）又は滑沢斉 1J (例、タノレク、ス テアリン酸マグネシウム、ポリエチレングリコール 6000等）等を添加して圧縮成形し、 次いで必要により、味のマスキング、腸溶性あるいは持続性の目的のため自体公知 の方法でコーティングすることにより経口投与製剤とすることができる。そのコーティン グ剤としては、例えば、ヒドロキシプロピルメチルセルロース、ェチルセルロース、ヒドロ キシメチノレセノレロース、ヒドロキシプロピノレセノレロース.ポリオキシエチレングリコーノレ 、ツイーン 80、プル口ニック F68、セルロースアセテートフタレート、ヒドロキシプロピ ノレメチルセルロースフタレート、ヒドロキシメチルセルロースアセテートサクシネート、ォ ィドラギット（ローム社製、ドイツ、メタアクリル酸 'アクリル酸共重合)及び色素（例、ベ ンガラ、二酸化チタン等)等が用いられる。経口投与用製剤は速放性製剤、徐放性 製剤のレ、ずれであってもよレ、。 [0038] In order to prepare a preparation for oral administration, 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. If necessary, 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. Examples of 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.
[0039] 本発明で使用する化合物は、固形製剤 (例、散剤、顆粒剤、錠剤、カプセル剤)又 は液体製剤 (液体成分に含有させたもの）等の経口投与用製剤に成型するか、坐剤 等の直腸投与用製剤に成型するのが好ましい。特に経口投与用製剤が好ましい。併 用薬物は、薬物の種類に応じて上記した剤形とすることができる。  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.
[0040] 保存剤、酸化防止剤、界面活性剤、増粘剤、着色剤、 pH調整剤、香味料、甘味料 若しくは食味マスキング剤等の二次成分を組成物中に含有してレ、てよレ、。適当な着 色剤としては、赤色、黒色ならびに黄色酸化鉄類及びエリス'アンド 'エベラールド社 の FD&Cブルー 2号ならびに FD&Cレッド 40号等の FD&C染料が挙げられる。適 当な香味料には、ミント、ラスべリー、甘草、オレンジ、レモン、グレープフルーツ、カラ メル、バニラ、チヱリーならびにグレープフレーバー及びその組合せたものが含まれ る。適当な pH調整剤は、クェン酸、酒石酸、リン酸、塩酸及びマレイン酸が含まれる 。適当な甘味料としてはアスパルテーム、アセスルフエーム Kならびにタウマチン等が 含まれる。適当な食味マスキング剤としては、重炭酸ナトリウム、イオン交換樹脂、シク ロデキストリン包接化合物、吸着質物質ならびにマイクロカプセル化アポモルフインが 含まれる。製剤には通常約 0. 1—約 50質量％、好ましくは約 0. 1—約 30質量％の 本発明で使用する化合物または併用薬物を含み、約 1分一約 60分の間、好ましくは 約 1分一約 15分の間、より好ましくは約 2分一約 5分の間に（水に)本発明で使用する 化合物または併用薬物の 90%以上を溶解させることが可能な製剤（上記、舌下錠、 バッカル等）や、 口腔内に入れられて 1ないし 60秒以内に、好ましくは 1ないし 30秒 以内に、さらに好ましくは 1なレ、し 10秒以内に崩壊する口腔内速崩壊剤が好ましレ、。  [0040] Secondary components such as preservatives, antioxidants, surfactants, thickeners, coloring agents, pH adjusters, flavors, sweeteners or taste-masking agents are contained in the composition. Yeah. 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.
[0041] 上記賦形剤の製剤全体に対する含有量は、約 10—約 99質量％、好ましくは約 30 一約 90質量0 /0である。 /3—シクロデキストリン又は β—シクロデキストリン誘導体の製 剤全体に対する含有量は 0 約 30質量％である。滑沢剤の製剤全体に対する含有 量は、約 0. 01—約 10質量％、好ましくは約 1一約 5質量％である。等張ィ匕剤の製剤 全体に対する含有量は、約 0. 1—約 90質量％、好ましくは、約 10—約 70質量％で ある。親水性担体の製剤全体に対する含有量は約 0. 1—約 50質量％、好ましくは 約 10—約 30質量％である。水分散性ポリマーの製剤全体に対する含有量は、約 0. 1一約 30質量％、好ましくは約 10—約 25質量％である。安定化剤の製剤全体に対 する含有量は約 0. 1—約 10質量％、好ましくは約 1一約 5質量％である。上記製剤 はさらに、着色剤、甘味剤、防腐剤等の添加剤を必要に応じ含有していてもよい。 [0041] 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 β-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.
[0042] 本発明の医薬組成物の投与量は、本発明に係る病気の状態、病人の年齢、体重、 症状、体質、体調、薬剤の剤形、投与方法、投与期間等により異なるが、例えば、リウ マチの患者 (成人、体重約 60kg)—人当たり、一般に 1日当たり、本発明で使用する 化合物に関してはオル二チンに換算して lmg 60g、好ましくは 500mg— 15gの範 囲で適宜選択することができる。また、併用薬物としてのリウマチ治療薬はその種類 によって異なるが、それぞれの単独投与で有効な効果が得られる投与量の 20%程 度を含有することが好ましい。もちろん、前記したように投与量は種々の条件で変動 するので、前記投与量より少ない量で十分な場合もあり、また範囲を超えて投与する 必要のある場合もある。 [0042] 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)-For the compound used in the present invention per person, generally per day, 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. Can be. 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. Of course, as described above, since the dose varies under various conditions, a dose smaller than the above dose may be sufficient, or may need to be administered outside the range.
[0043] 本発明の医薬組成物を投与するに際しては、本発明で使用する化合物と併用薬物 とを同時期に投与してもよいが、併用薬物を先に投与した後、本発明で使用する化 合物を投与してもよいし、本発明で使用する化合物を先に投与し、その後で併用薬 物を投与してもよい。時間差をおいて投与する場合、時間差は投与する有効成分、 剤形、投与方法等により異なるが、例えば、併用薬物を先に投与する場合、併用薬 物を投与した後、好ましくは 1分一 3日以内、より好ましくは 10分一 1日以内、さらに好 ましくは 15分一 1時間以内に本発明で使用する化合物を投与する方法が挙げられる 。本発明で使用する化合物を先に投与する場合、本発明で使用する化合物を投与 した後、好ましくは 1分一 7日以内、より好ましくは 10分一 1日以内、さらに好ましくは 1 5分一 6時間以内に併用薬物を投与する方法が挙げられる。  When administering the pharmaceutical composition of the present invention, the compound used in the present invention and the concomitant drug may be administered at the same time. However, 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. When administration is carried out at different times, the time difference varies depending on the active ingredient to be administered, the dosage form, the administration method, and the like.For example, when administering 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. 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.
[0044] 好ましい投与方法としては、例えば、投与製剤に製形された本発明で使用する化 合物を先に投与し、その後に経口投与製剤に製形された併用薬物を経口投与する 。逆に、経口投与製剤に製形された併用薬物を先に投与し、その後に本発明で使用 する化合物を投与してもよい。また、それらを同時に投与してもよい。また、経口投与 が困難な場合、持続投与が望ましい場合などの理由を問わず、当該医薬組成物を 含有する静脈内投与製剤、筋肉内投与製剤、皮下投与製剤、あるいは関節包内等 リウマチ患部近傍に直接投与する製剤とすることができる。さらには、当該医薬組成 物を含有する軟膏や貼り薬などの経皮吸収製剤として使用することもできる。 [0044] As a preferable administration method, for example, 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. . Conversely, 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. In addition, whether oral administration is difficult, continuous administration is desirable, etc., such as intravenous, intramuscular, subcutaneous, or joint capsule containing the pharmaceutical composition To be administered directly to Furthermore, it can be used as a transdermal absorption preparation such as an ointment or a patch containing the pharmaceutical composition.
実施例  Example
[0045] 以下に実施例を挙げて本発明をより具体的に説明するが、本発明はこれらに限定 されるものではない。  [0045] Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited thereto.
[0046] (実施例 1 )コラーゲン誘導関節炎 (CIA)マウスへのオノレニチンとメトトレキサートの併 用投与効果  (Example 1) Effect of concurrent administration of onolenitine and methotrexate to collagen-induced arthritis (CIA) mice
DBA— 1マウスを用いて定法によりコラーゲン誘導関節炎を誘導し、オル二チンとメ トトレキサートの併用投与効果を検討した。コラーゲン誘導関節炎 (CIA)はマウスを II 型コラーゲンで感作することで誘発する実験的関節炎としてよく知られている（  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 (
Courtenay et al.， Nature, 283, 666-668， 1980参照）。マウス 1匹当たり抗原量 100 μ g/0. 1mlのェマルジヨンを尾根部に皮内注射した。初回感作の 3週間後に追加免 疫として同組成のェマルジヨンを初回感作と同様 1匹当たり抗原量 100 μ g/0. lml を尾根部に皮内注射した。関節炎は追加免疫後 4日目頃から発症し、発赤を伴う浮 腫として観察された。関節炎の程度については追加免疫から約 2週間後にピークとな つた。浮腫の程度は 4段階に分類し四肢各々について肉眼的に判定した。オルニチ ン (0. 03%)は自由飲水にて、また、メトトレキサート(0. 2mg/kg)あるいはメトトレキ サート (lmg/kg)については週 5回 Ι ΟΟ μ Ι/匹、強制経口投与にてそれぞれ II型コ ラーゲンと CFAのェマルジヨン皮内投与と同時に、単独あるいは併用投与を開始し た。その結果を図 1に示した。図 1は CIAマウスにオノレニチンとメトトレキサートを併用 投与した際の関節スコア一の変化を追加免疫を行った日から経時的に示した図であ る。なお、スコア一の内容については 0 :未発症、 1 :手足あるいは指関節の何れかに 赤い浮腫が認められた、 2 :関節の腫れが甚だしぐ太さが通常の 2倍以上であると認 められた、 3 :関節にねじれ、変形等が認められた場合とし、肉眼で判定した。四肢の スコア一の合計をマウスのスコア一とした。 Courtenay et al., Nature, 283, 666-668, 1980). Emulsion with an antigen amount of 100 μg / 0.1 ml per mouse was intradermally injected into the tail. Three weeks after the initial sensitization, an emulsion of the same composition was injected intradermally at the base of the ridge with an antigen amount of 100 μg / 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. Ornithine (0.03%) was given by free drinking water, and methotrexate (0.2 mg / kg) or methotrexate (lmg / kg) was given 5 ΟΟ μΙ / animal by gavage 5 times a week. Intradermal administration of type II collagen and CFA was started at the same time as single or combined administration. The results are shown in FIG. 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. Regarding the content of the score 1, 0: no disease occurred, 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 usual. 3: When the joint was twisted, deformed, etc., it was judged visually. Limb The sum of the scores was defined as the score of the mouse.
[0047] 追加免疫後 17日目の Control群の関節スコア一が 3. 5、オル二チンの単独投与群 力 ¾前後、メトトレキサート(0. 2mg/kg)単独投与群が 2. 8であったのに対して、ォ ルニチンとメトトレキサート (0. 2mg/kg)の併用投与群のスコア一はメトトレキサート（ lmg/kg)単独投与群と同様の 0. 6であった。オル二チンとメトトレキサート (0. 2mg /kg)の併用投与は、併用投与で用いたメトトレキサートの 5倍量を投与したメトトレキ サート (lmg/kg)単独投与と同程度の抑制効果を示した。  [0047] On the 17th day after the booster immunization, the joint score of the control group was 3.5, the strength of the group administered orditin alone was about ¾, and that of the group administered methotrexate (0.2 mg / kg) alone was 2.8. On the other hand, the score of the combined administration group of ornithine and methotrexate (0.2 mg / kg) 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.
[0048] (実施例 2)コラーゲン誘導関節炎 (CIA)マウスへのオノレニチンとデキサメサゾンの併 用投与効果  (Example 2) Effect of concurrent administration of onorenitine and dexamethasone to collagen-induced arthritis (CIA) mice
DBA— 1マウスを用いて定法によりコラーゲン誘導関節炎を誘導し、オル二チンとデ キサメサゾンの併用投与効果を実施例 1と同様に検討した。条件は上記と同様である 。オル二チン (0. 03%)は自由飲水にて、また、デキサメサゾン (0. Olmg/kg)あるい はデキサメサゾン (0. 05mg/kg)については週 5回 100 /i l/匹、強制経口投与にて それぞれ II型コラーゲンと FCAのェマルジヨン皮内投与と同時に単独あるいは併用 投与を開始した。その結果を図 2に示した。図 2は CIAマウスにオル二チンとデキサメ サゾンを併用投与した際の関節スコア一の変化を追加免疫を行った日力 経時的に 示した図である。なお、スコア一については 0 :未発症、 1 :手足あるいは指関節の何 れかに赤い浮腫が認められた、 2 :関節の腫れが甚だしぐ太さが通常の 2倍以上で あると認められた、 3 :関節にねじれ、変形等が認められた場合とし、肉眼で判定した 。 四肢のスコア一の合計をマウスのスコア一とした。  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. At the same time, 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. Regarding the score 1, 0: 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.
[0049] 追加免疫後 17日目の Control群の関節スコア-が 3. 5に対してオル二チンの単独 投与群が 2前後、デキサメサゾン (0. 01mg/kg)の単独投与群が 1. 5前後であった のに対してオル二チンとデキサメサゾン (0. 01mg/kg)の併用投与群では 0. 6と、デ キサメサゾン (0. 05mgZkg)単独投与の 0. 2に近い値を示した。オル二チンとデキ サメサゾン (0. 01mg/kg)の併用投与は,併用投与で用いたデキサメサゾンの 5倍量 を投与したデキサメサゾン (0. 05mg/kg)単独投与と同程度の抑制効果を示した。  [0049] On the 17th day after booster immunization, 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. On the other hand, 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. .
[0050] (実施例 3)コラーゲン誘導関節炎 (CIA)マウスへのパリンとメトトレキサートの併用投 与効果 DBA-1マウスを用いて定法によりコラーゲン誘導関節炎を誘導し、パリンとメトトレ キサートの併用投与効果を検討した。パリン (0. 0715%)は自由飲水にて II型コラー ゲンと FCAのェマルジヨン皮内投与と同時に、単独あるいは併用投与を開始した。ま た、メトトレキサート (0. 2mg/kg)あるいはメトトレキサート (lmg/kg)は週 5回 ΙΟΟ μ 1Ζ匹、強制経口投与にて関節腫脹の発症を確認後、単独あるいは併用投与を開始 した。その結果を図 3に示した。図 3は CIAマウスにパリンとメトトレキサートを併用投 与した際の関節スコア一の変化を追加免疫を行った日力 経時的に示した図である 。なお、スコア一については 0 :未発症、 1 :手足あるいは指関節の何れかに赤い浮腫 が認められた、 2 :関節の腫れが甚だしぐ太さが通常の 2倍以上であると認められた 、 3 :関節にねじれ、変形等が認められた場合とし、肉眼で判定した。四肢のスコア一 の合計をマウスのスコア一とした。 (Example 3) Effect of combined administration of parin and methotrexate to collagen-induced arthritis (CIA) mice Collagen-induced arthritis was induced by a standard method using DBA-1 mice, and the effect of co-administration of palin and methotrexate was examined. Palin (0.0715%) was administered alone or in combination at the same time as intradermal administration of type II collagen and FCA in free water. In addition, methotrexate (0.2 mg / kg) or methotrexate (lmg / kg) was administered ΙΟΟμ 1 ΙΟΟ 5 times a week by gavage to confirm joint swelling. The results are shown in FIG. FIG. 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. Regarding 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.
[0051] 追加免疫後 24日目の Control群の関節スコア—が 5. 8に対して、メトトレキサート（1 mg/kg)単独投与群の関節スコア一は 2· 2、パリンとメトトレキサート (0· 2mg/kg) の併用投与群は 2. 6であった。ノくリンとメトトレキサート (0. 2mg/kg)の併用投与は 、併用投与で用いたメトトレキサートの 5倍量を投与したメトトレキサート (lmg/kg)単 独投与と同程度の抑制効果を示した。  [0051] On the 24th day after the booster immunization, 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.
[0052] (実施例 4)コラーゲン誘導関節炎 (CIA)マウスへのパリンとデキサメサゾンの併用投 与効果  (Example 4) Effect of combined use of palin and dexamethasone on collagen-induced arthritis (CIA) mice
DBA— 1マウスを用いて定法によりコラーゲン誘導関節炎を誘導し、パリンとデキサ メサゾンの併用投与効果を検討した。ノ リン (0. 0715%)は自由飲水にて II型コラー ゲンと FCAのェマルジヨン皮内投与と同時に、単独あるいは併用投与を開始した。ま た、デキサメサゾン (0. 01mg/kg)あるいはデキサメサゾン（0. 05mgZkg)は週 5回 ΙΟΟ μ ΐΖ匹、強制経口投与にて関節腫脹の発症を確認後、単独あるいは併用投与 を開始した。その結果を図 4に示した。図 4は CIAマウスにオル二チンとデキサメサゾ ンを併用投与した際の関節スコア一の変化を追加免疫を行った日から経時的に示し た図である。なお、スコア一については 0 :未発症、 1 :手足あるいは指関節の何れか に赤い浮腫が認められた、 2 :関節の腫れが甚だしぐ太さが通常の 2倍以上であると 認められた、 3 :関節にねじれ、変形等が認められた場合とし、肉眼で判定した。四肢 のスコア一の合計をマウスのスコア一とした。 Collagen-induced arthritis was induced by a standard method using DBA-1 mice, and the effect of co-administration of palin and dexamethasone was examined. Norin (0.0715%) was administered alone or in combination at the same time as intradermal administration of type II collagen and FCA in free water. Dexamethasone (0.01 mg / kg) or dexamethasone (0.05 mgZkg) was administered ΙΟΟμΐΖ 5 5 times a week, by gavage, to confirm the onset of joint swelling. The results are shown in FIG. 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. Regarding the score 1, 0: no disease, 1: red edema was observed in either the limb or 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. limb The sum of the scores of 1 was taken as the score of the mouse.
追加免疫後 24日目の Control群の関節スコア一が 5. 8に対して、デキサメサゾン (0 . 05mg/kg)単独投与群の関節スコア一が 2· 8、バリンとデキサメサゾン (0· Olmg /kg)の併用投与群は 2. 4であった。パリンとデキサメサゾン (0. 01mg/kg)の併用 投与は、併用投与で用いたデキサメサゾンの 5倍量を投与したデキサメサゾン (0. 05 mgZkg)単独投与と同程度の抑制効果を示した。  On the 24th day after the booster, 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.

Claims

請求の範囲 The scope of the claims
[1] オル二チン、イソロイシン、ロイシン、パリン、それらの塩、及びそれらの誘導体から なる群より選択される少なくとも 1種と、前記化合物以外のリウマチ治療薬とを有効成 分として含むことを特徴とする医薬組成物。  [1] An effective component comprising at least one selected from the group consisting of ordinine, isoleucine, leucine, parin, salts thereof, and derivatives thereof, and a therapeutic agent for rheumatism other than the above compounds. And a pharmaceutical composition.
[2] 前記リウマチ治療薬が、副腎皮質ステロイド薬 (ステロイド薬）、寛解導入抗リウマチ 薬（DMARDs)、及び非ステロイド系消炎症薬（NSAIDs)からなる群より選択される 少なくとも 1種であることを特徴とする請求項 1記載の医薬組成物。  [2] The therapeutic agent for rheumatism is at least one selected from the group consisting of corticosteroids (steroids), remission-inducing antirheumatic drugs (DMARDs), and nonsteroidal anti-inflammatory drugs (NSAIDs). 2. The pharmaceutical composition according to claim 1, wherein
[3] 前記ステロイド薬がハイド口コルチゾン、コルチゾン、プレドニゾロン、メチルプレドニゾ ロン、トリアムシノロン、パラメタゾン、デキサメタゾン、及びべタメタゾンからなる群より 選択される少なくとも 1種であることを特徴とする請求項 2記載の医薬組成物。  [3] The medicament according to claim 2, wherein the steroid drug is at least one selected from the group consisting of cortisone hydrid, cortisone, prednisolone, methylprednisolone, triamcinolone, paramethasone, dexamethasone, and betamethasone. Composition.
[4] 前記 DMARDsがメトトレキサート、ブシラミン、オーラノフィン、ぺニシラミン、チォリン ゴ酸ナトリウム、ミゾリビン、及び口ベンザリットニナトリウムからなる群より選択される少 なくとも 1種であることを特徴とする請求項 2記載の医薬組成物。  [4] The DMARDs are at least one selected from the group consisting of methotrexate, busilamine, auranofin, penicillamine, sodium thiolingoate, mizoribine, and oral benzaritni sodium. Item 4. The pharmaceutical composition according to Item 2,
[5] 前記 NSAIDsが、アスピリン、インドメタシン、イブプロフェン、メフエナム酸、及びピロ キシカムからなる群より選択される少なくとも 1種であることを特徴とする請求項 2記載 の医薬組成物。  [5] The pharmaceutical composition according to claim 2, wherein the NSAIDs are at least one selected from the group consisting of aspirin, indomethacin, ibuprofen, mefenamic acid, and piroxicam.
[6] 炎症性疾患治療剤であることを特徴とする請求項 1一 5の何れか一項に記載の医 薬組成物。  [6] The pharmaceutical composition according to any one of claims 15 to 15, which is a therapeutic agent for an inflammatory disease.
[7] リウマチ治療剤であることを特徴とする請求項 1一 5の何れか一項に記載の医薬組 成物。  [7] The pharmaceutical composition according to any one of claims 15 to 15, which is a therapeutic agent for rheumatism.
[8] 経口投与の場合、オル二チン、イソロイシン、ロイシン、及びパリンの合計投与量が 1日当り lmg 60gであることを特徴とする請求項 1一 7の何れか一項に記載の医薬 組成物。  [8] The pharmaceutical composition according to any one of claims 17 to 17, wherein in the case of oral administration, the total dose of ordinine, isoleucine, leucine and palin is lmg 60g per day. .
[9] 前記化合物と前記リウマチ治療薬の比率が、質量比で 1 : 1一 2000 : 1であることを 特徴とする請求項 1一 8の何れか一項に記載の医薬組成物。  [9] The pharmaceutical composition according to any one of claims 118, wherein the ratio of the compound to the therapeutic agent for rheumatism is 1: 1 to 2000: 1 by mass ratio.
[10] オル二チン、イソロイシン、ロイシン、ノくリン、それらの塩、及びそれらの誘導体から なる群より選択される少なくとも 1種の製剤と、前記化合物以外のリウマチ治療薬の製 剤とを含む複数薬剤であって、それらを同時に、逐次的に、又は時間を置いて別々 に投与することを特徴とするリウマチ治療剤。 [10] Includes at least one preparation selected from the group consisting of orditin, isoleucine, leucine, noculin, a salt thereof, and a derivative thereof, and a preparation of a therapeutic agent for rheumatism other than the above compound Multiple drugs, which can be separated simultaneously, sequentially or at intervals A therapeutic agent for rheumatism, which is administered to a patient.
[11] 前記リウマチ治療薬が、副腎皮質ステロイド薬 (ステロイド薬)、寛解導入抗リウマチ 薬（DMARDs)、及び非ステロイド系消炎症薬 (NSAIDs)からなる群より選択される 少なくとも 1種であることを特徴とする請求項 10に記載のリウマチ治療剤。  [11] The therapeutic agent for rheumatism is at least one selected from the group consisting of corticosteroids (steroids), remission-inducing antirheumatic drugs (DMARDs), and nonsteroidal anti-inflammatory drugs (NSAIDs). 11. The therapeutic agent for rheumatism according to claim 10, wherein:
[12] 前記化合物と前記リウマチ治療薬の比率が、質量比で 1 : 1一 2000 : 1であることを 特徴とする請求項 10又は 11に記載のリウマチ治療剤。  12. The therapeutic agent for rheumatism according to claim 10, wherein the ratio of the compound to the therapeutic agent for rheumatism is 1: 1 to 2000: 1 by mass ratio.
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007018278A1 (en) * 2005-08-05 2007-02-15 Ajinomoto Co., Inc. Inhibitor for the onset and progress of liver cancer
WO2008072663A1 (en) 2006-12-12 2008-06-19 Ajinomoto Co., Inc. Composition for amelioration/prevention of adverse side effect in steroid therapy
WO2013118773A1 (en) 2012-02-06 2013-08-15 味の素株式会社 Prophylactic or therapeutic agent for idiopathic inflammatory myopathies

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101687899B (en) * 2007-07-02 2012-11-28 旭化成医疗株式会社 Therapeutic agent for ulcerative colitis comprising mizoribine
JP5985985B2 (en) * 2009-08-03 2016-09-06 エミスフィアー テクノロジーズ インコーポレイテッドＥｍｉｓｐｈｅｒｅ Ｔｅｃｈｎｏｌｏｇｉｅｓ，Ｉｎｃ． Rapid-acting naproxen composition with reduced gastrointestinal effects

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283940A (en) * 1976-01-01 1977-07-13 Kaken Pharmaceut Co Ltd Immuno-inhibitor
JPS5740409A (en) * 1980-08-22 1982-03-06 Mitsui Toatsu Chem Inc Remedy for disease caused by extraordinary propagation of collagen
JPH07285859A (en) * 1994-02-24 1995-10-31 Otsuka Pharmaceut Factory Inc Agent capable of augmenting analgesic action
JPH09508891A (en) * 1993-11-17 1997-09-09 デューク ユニバーシティ メディカル センター Use of nitric oxide synthase inhibitors in the treatment of autoimmune diseases
JPH11510182A (en) * 1995-08-03 1999-09-07 シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ Use of basic amino acids and derivatives to reduce ceramide levels
WO2002000611A2 (en) * 2000-06-29 2002-01-03 Institut National De La Sante Et De La Recherche Medicale (Inserm) Fmoc-l-leucine and derivatives thereof as ppar-gamma agonists
WO2002060431A1 (en) * 2001-01-30 2002-08-08 Ajinomoto Co., Inc. Remedies/preventives for inflammatory diseases
US20020119952A1 (en) * 1998-09-09 2002-08-29 Petrus Edward J. Composition and method of treating arthritis

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5283940A (en) * 1976-01-01 1977-07-13 Kaken Pharmaceut Co Ltd Immuno-inhibitor
JPS5740409A (en) * 1980-08-22 1982-03-06 Mitsui Toatsu Chem Inc Remedy for disease caused by extraordinary propagation of collagen
JPH09508891A (en) * 1993-11-17 1997-09-09 デューク ユニバーシティ メディカル センター Use of nitric oxide synthase inhibitors in the treatment of autoimmune diseases
JPH07285859A (en) * 1994-02-24 1995-10-31 Otsuka Pharmaceut Factory Inc Agent capable of augmenting analgesic action
JPH11510182A (en) * 1995-08-03 1999-09-07 シグマ−タウ・インドゥストリエ・ファルマチェウチケ・リウニテ・ソシエタ・ペル・アチオニ Use of basic amino acids and derivatives to reduce ceramide levels
US20020119952A1 (en) * 1998-09-09 2002-08-29 Petrus Edward J. Composition and method of treating arthritis
WO2002000611A2 (en) * 2000-06-29 2002-01-03 Institut National De La Sante Et De La Recherche Medicale (Inserm) Fmoc-l-leucine and derivatives thereof as ppar-gamma agonists
WO2002060431A1 (en) * 2001-01-30 2002-08-08 Ajinomoto Co., Inc. Remedies/preventives for inflammatory diseases

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KOBAYASHI S. ET AL: "Antirheumatic Drag no Heiyo Ryoho.", JAPANESE JOURNAL OF CLINICAL MEDICINE, vol. 60, no. 12, 1 December 2002 (2002-12-01), pages 2351 - 2356, XP002990278 *
VAN WEST D. ET AL: "Neuroendocrine and Immune Aspects of Fibromyalgia.", BIODRUGS, vol. 15, no. 8, 2001, pages 521 - 531, XP002987110 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007018278A1 (en) * 2005-08-05 2007-02-15 Ajinomoto Co., Inc. Inhibitor for the onset and progress of liver cancer
JP5067160B2 (en) * 2005-08-05 2012-11-07 味の素株式会社 Liver cancer development / proliferation inhibitor
JP2012214485A (en) * 2005-08-05 2012-11-08 Ajinomoto Co Inc Inhibitor for onset and progress of liver cancer
WO2008072663A1 (en) 2006-12-12 2008-06-19 Ajinomoto Co., Inc. Composition for amelioration/prevention of adverse side effect in steroid therapy
CN103120655A (en) * 2006-12-12 2013-05-29 味之素株式会社 Composition for amelioration/prevention of adverse side effect in steroid therapy
EP2606882A1 (en) 2006-12-12 2013-06-26 Ajinomoto Co., Inc. Composition for amelioration/prevention of adverse side effect in steroid therapy
JP5293189B2 (en) * 2006-12-12 2013-09-18 味の素株式会社 Composition for improving / suppressing side effects in steroid therapy
JP2013216671A (en) * 2006-12-12 2013-10-24 Ajinomoto Co Inc Composition for amelioration/prevention of adverse side effect in steroid therapy
JP2015166352A (en) * 2006-12-12 2015-09-24 味の素株式会社 Composition for amelioration/suppression of adverse side effects in steroid therapy
CN103120655B (en) * 2006-12-12 2016-06-01 味之素株式会社 For improving/prevention of steroid treat in the composition of adverse side effect
WO2013118773A1 (en) 2012-02-06 2013-08-15 味の素株式会社 Prophylactic or therapeutic agent for idiopathic inflammatory myopathies
JPWO2013118773A1 (en) * 2012-02-06 2015-05-11 味の素株式会社 Preventive or therapeutic agent for idiopathic inflammatory myopathy

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