WO2011111143A1 - Medicament for rheumatoid arthritis - Google Patents

Medicament for rheumatoid arthritis Download PDF

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WO2011111143A1
WO2011111143A1 PCT/JP2010/007262 JP2010007262W WO2011111143A1 WO 2011111143 A1 WO2011111143 A1 WO 2011111143A1 JP 2010007262 W JP2010007262 W JP 2010007262W WO 2011111143 A1 WO2011111143 A1 WO 2011111143A1
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rheumatoid arthritis
mtx
bed
day
das28
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PCT/JP2010/007262
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French (fr)
Japanese (ja)
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秀人 中村
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Nakamura Hideto
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to a rheumatoid arthritis drug.
  • the “morning stiffness” is a joint pain of the extremities that appears in the early morning and is the most characteristic symptom of RA that has been known for a long time. Further, it is known that “morning stiffness” is an RA-specific circadian rhythm that does not appear during the day but appears early in the morning. This “morning stiffness” is known to involve various inflammatory cytokines such as IL-6 and TNF- ⁇ . In recent years, inflammatory cytokines have a circadian rhythm, and this circadian rhythm has been reported to show a peak in the early morning corresponding to “morning stiffness” appearing in RA patients (Non-patent Document 1). ).
  • MTX methotrexate
  • Non-patent Document 2 In order to suppress inflammatory cytokines that peak in the early morning, considering the circadian rhythms of inflammatory cytokines and daily living behavior of humans, MTX was changed from an existing administration method to a time treatment that is taken only after dinner. Case reports have also been made that rheumatic symptoms can be improved (Non-patent Document 2).
  • Non-Patent Document 2 the pharmacological effect is insufficient even in the time treatment in which MTX is taken only after dinner. The reason is the difference between the half-life of MTX and the circadian rhythm of inflammatory cytokines. The half-life of MTX is 2 to 4 hours. Even if MTX is taken only after dinner, the maximum allowable amount of MTX is administered for inflammatory cytokines that increase from midnight to early morning However, it did not show a sufficient medicinal effect and did not lead to a significant improvement. Therefore, an object of the present invention is to provide a rheumatoid arthritis drug that is effective in ameliorating and suppressing RA symptoms and effectively suppressing it.
  • the rheumatoid arthritis drug of the present invention has been made based on such findings, and as described in claim 1, is a rheumatoid arthritis drug containing MTX as an active ingredient, and is administered to a rheumatoid arthritis patient before going to bed. It is used so that it may be used.
  • the rheumatoid arthritis drug according to claim 2 is the rheumatoid arthritis drug according to claim 1, characterized in that the administration is at night.
  • the rheumatoid arthritis drug according to claim 3 is the rheumatoid arthritis drug according to claim 2, wherein the administration is from 9:00 pm to 3:00 am.
  • the rheumatoid arthritis drug containing MTX of the present invention is administered before bedtime according to the circadian rhythm of inflammatory cytokines, thereby maintaining RA safety without changing the dose and the number of administration, In particular, joint pain can be reduced. In addition, a delayed effect of RA severity and clinical remission can be obtained. In addition, excessive administration of MTX can be prevented, and the burden on the patient's body and treatment costs can be reduced.
  • DAS Disease Activity Score
  • the rheumatoid arthritis drug of the present invention is a drug containing MTX as an active ingredient, and is used as a tablet, capsule or the like.
  • the rheumatoid arthritis drug of the present invention is used so that it is administered before going to bed. Specifically, for example, it may be administered once a day before going to bed, administered before going to bed on the first day, before going to bed on the second day, before going to bed on the third day, and for the remaining 4 days. This is repeated every week.
  • the rheumatoid arthritis drug of the present invention is administered from 9 pm to 3 am before bedtime, and more preferably from 1 am to 3 am.
  • Inflammatory cytokines have a circadian rhythm that increases from midnight (2 am) to early morning (5 am). By taking MTX during this time period, the concentration of MTX in the blood is increased during this time period. This is because if it can be maintained, an increase in inflammatory cytokines can be suppressed, and morning stiffness can be suppressed.
  • the effective dose of MTX is preferably 4 to 20 mg per week.
  • MTX is administered at 4 mg / week.
  • 6 mg / week or more for patients who do not achieve a sufficient effect, 6 mg / week or more, and a maximum of 8 mg / week is administered.
  • MTX is administered at 7.5 to 20 mg / week for RA patients.
  • the effective dose of MTX refers to a dose at which MTX is effective in patients with rheumatoid arthritis.
  • the effect of MTX is judged by the fact that administration of MTX alleviates symptoms such as joint pain and swelling in individual patients.
  • MTX has already been administered as a treatment for RA in RA patients over 20 years old who have been admitted to the medical corporation White Cross Society Sasebo Central Hospital.
  • the subjects were 17 patients with a DAS28 of 3.2 or more showing disease activity of RA and currently not using biologics.
  • the breakdown of the 17 subjects is 5 males and 12 females, the average duration of RA is 11.8 years (2 years (minimum) -33 years (maximum)), and the average age is 61.0. He was 42 years old (minimum)-78 years old (maximum).
  • DAS28 0.56 ⁇ (T28) 1/2 + 0.28 ⁇ (S28) 1/2 + 0.36 ⁇ ln (CRP + 1) + 0.014 ⁇ GH + 0.96 T28 and S28 palpate 28 joints such as hands, elbows, and shoulders, T28 is the number of tender joints (the number of joints that are painful when pressed), and S28 is the number of swollen joints (swelling Number of joints) ”.
  • C-reactive protein is a protein that measures the degree of inflammation by blood sampling. If inflammation or tissue destruction occurs in the body, it is a protein that appears in blood. The stronger the inflammation, the higher the value.
  • GH is a self-assessment of the general condition performed by a patient. On a 100 mm scale called VAS (Visual analog scale), 0 is “very good (no symptoms)”, 100 is “very bad” ", It is the value that the patient indicates. The value calculated by the above formula was evaluated in four stages: high disease activity (high disease activity), moderate disease activity (moderate disease activity), low disease activity (low disease activity), and clinical remission.
  • the therapeutic effect is good (good response), moderate (moderate response), and no response (invariant). It was evaluated in three stages.
  • the value (X) of the disease activity evaluation by DAS28 is “high disease activity” when X> 5.1, “moderate disease activity” when 3.2 ⁇ X ⁇ 5.1, and X ⁇ 3. 2 means “low disease activity” and X ⁇ 2.6 means “clinical remission”.
  • Table 1 since the value (X) of DAS28 was higher at the start of chronotherapy than that of 2 months before the start of chronotherapy, RA symptoms worsened. In DAS28 at the start of chronotherapy, the average value was 3 .83 (3.25 (minimum) -5.30 (maximum)), moderately active disease, and slightly elevated rheumatic symptoms.
  • the average value of DAS28 decreased from one month after chronotherapy, and the average value of DAS28 three months after the start of chronotherapy was 3.31, indicating that although the disease was moderately active, the symptoms of RA were reduced. confirmed.
  • Table 1 and FIG. 1 in the time treatment in which MTX is administered before going to bed, the therapeutic effect appears from one month after the start of the time treatment, and the average value of DAS28 is the first month compared with that before the start of the time treatment. 0.462 at the second month, 0.506 at the second month, and 0.521 at the third month.
  • Table 2 shows the results of the effectiveness evaluation of MTX according to the EULAR improvement criteria.
  • the criteria in Table 2 are the values of the difference in DAS28 (Y) after changing the MTX administration time (after 3 months) relative to DAS28 before changing the MTX administration time (at the start of chronotherapy). This means that the effect of chronotherapy with MTX is “moderate response” when 0.6> Y, and “invariant” when Y ⁇ 0.6, that is, no improvement was observed. It was confirmed that 7 of 17 cases (41.2%) improved to show a moderate response, and of these 4 cases (23.5%) reached clinical remission in DAS28.

Abstract

Disclosed is a medicament for rheumatoid arthritis, which is effective for alleviation and suppression of the symptoms of rheumatoid arthritis. The medicament for rheumatoid arthritis efficiently suppresses the symptoms of rheumatoid arthritis. Specifically disclosed is a medicament for rheumatoid arthritis, which contains methotrexate as an active ingredient and is characterized by having the methotrexate administered at bedtime.

Description

関節リウマチ薬Rheumatoid arthritis
　本発明は、関節リウマチ薬に関するものである。 The present invention relates to a rheumatoid arthritis drug.
　リウマチ性疾患の代表である関節リウマチ（ｒｈｅｕｍａｔｏｉｄ　ａｒｔｈｒｉｔｉｓ;以下、「ＲＡ」という）は、慢性多発性関節炎を主症状とする全身性結合組織疾患で、自己免疫疾患の一種である。ＲＡは、３０～６０歳の女性に好発し、有病者数は本邦では約６０万人と推測されている。ＲＡの病態には関節滑膜における血管新生、炎症性細胞浸潤、滑膜細胞増殖、軟骨・骨破壊などが挙げられる。また、ＲＡにおける関節炎は改善と増悪を繰り返しながら進行し、徐々に軟骨・骨破壊を引き起こし、ＲＡ患者の日常労作の阻害や生活の質（ＱＯＬ）の低下を招く。 Rheumatoid arthritis (hereinafter referred to as “RA”), which is a representative of rheumatic diseases, is a systemic connective tissue disease whose main symptom is chronic polyarthritis, and is a kind of autoimmune disease. RA is common among women aged 30 to 60 years, and the number of affected people is estimated to be about 600,000 in Japan. RA pathologies include angiogenesis in the synovium, inflammatory cell infiltration, synovial cell proliferation, cartilage / bone destruction, and the like. In addition, arthritis in RA progresses with repeated improvements and exacerbations, gradually causing cartilage and bone destruction, leading to inhibition of daily work and deterioration of quality of life (QOL) of RA patients.
　特に「朝のこわばり」という症状は、早朝に現れる四肢の関節痛のことであり、古くから知られているＲＡの最も特徴的な症状である。また、「朝のこわばり」は日中に現れず、早朝に現れるＲＡ固有の概日リズムであることが知られている。
　この「朝のこわばり」には、ＩＬ－６やＴＮＦ－αなどのさまざまな炎症性サイトカインが関与していることが知られている。また近年、炎症性サイトカインには概日リズムが存在し、この概日リズムはＲＡ患者に現れる「朝のこわばり」に対応するように早朝にピークを示すことが報告されている(非特許文献１)。 In particular, the “morning stiffness” is a joint pain of the extremities that appears in the early morning and is the most characteristic symptom of RA that has been known for a long time. Further, it is known that “morning stiffness” is an RA-specific circadian rhythm that does not appear during the day but appears early in the morning.
This “morning stiffness” is known to involve various inflammatory cytokines such as IL-6 and TNF-α. In recent years, inflammatory cytokines have a circadian rhythm, and this circadian rhythm has been reported to show a peak in the early morning corresponding to “morning stiffness” appearing in RA patients (Non-patent Document 1). ).
　現在、ヒトのＲＡ治療薬における第一選択薬は、メトトレキサート（ｍｅｔｈｏｔｒｅｘａｔｅ；以下、「ＭＴＸ」という）を含有する薬剤である。ＭＴＸは、生物学的製剤と比較し薬剤費が安く、世界的にアンカードラッグとして最も使用されている抗リウマチ薬である。本邦のＭＴＸの投与方法は、１週間単位で１日目の朝食後・夕食後、２日目の朝食後の計３回投与することが基準となっている。 Currently, the first-line drug in human RA treatment is a drug containing methotrexate (hereinafter referred to as “MTX”). MTX is an anti-rheumatic drug that is cheaper than biologics and is most commonly used as an anchor drug worldwide. In Japan, MTX is administered on a weekly basis, 3 times after breakfast and dinner on the first day, and after breakfast on the second day.
　そこで、早朝にピークを迎える炎症性サイトカインを抑えるために、炎症性サイトカインの概日リズムとヒトの日常生活行動を考慮して、ＭＴＸを既存の投与方法から夕食後のみに服用する時間治療に変更することで、リウマチ症状を改善できるという症例報告もなされている（非特許文献２）。 Therefore, in order to suppress inflammatory cytokines that peak in the early morning, considering the circadian rhythms of inflammatory cytokines and daily living behavior of humans, MTX was changed from an existing administration method to a time treatment that is taken only after dinner. Case reports have also been made that rheumatic symptoms can be improved (Non-patent Document 2).
　しかしながら、非特許文献２に示されるように、夕食後のみにＭＴＸを服用する時間治療においても、その薬理効果は不十分であった。その理由は、ＭＴＸの半減期と炎症性サイトカインの概日リズムとの乖離にある。ＭＴＸの半減期は２～４時間とされており、夕食後のみにＭＴＸを服用したとしても、深夜から早朝に向けて増加する炎症性サイトカイン等に対しては最大許容量のＭＴＸを投与した場合でも十分な薬効を示せず、顕著な効果改善には至らなかった。従って、本発明は、ＲＡの症状緩和及び抑制に有効であり、かつ効率的に抑えるための関節リウマチ薬を提供することを課題とする。 However, as shown in Non-Patent Document 2, the pharmacological effect is insufficient even in the time treatment in which MTX is taken only after dinner. The reason is the difference between the half-life of MTX and the circadian rhythm of inflammatory cytokines. The half-life of MTX is 2 to 4 hours. Even if MTX is taken only after dinner, the maximum allowable amount of MTX is administered for inflammatory cytokines that increase from midnight to early morning However, it did not show a sufficient medicinal effect and did not lead to a significant improvement. Therefore, an object of the present invention is to provide a rheumatoid arthritis drug that is effective in ameliorating and suppressing RA symptoms and effectively suppressing it.
　本発明者は、かかる問題点を解決するべく鋭意研究の結果、抗リウマチ薬であるＭＴＸの投与量や投与回数を変更することなく、投与時刻を種々検討した結果、生体リズムに合わせてＭＴＸを投与する投与タイミングを見出し、ＭＴＸの薬理効果を安全かつ効率的に高めることができることを確認し、本発明を完成するに至った。
　本発明の関節リウマチ薬は、かかる知見に基づきなされたもので、請求項１に記載の通り、ＭＴＸを有効成分として含有する関節リウマチ薬であって、関節リウマチ患者に対して就寝前に投与されるように用いられることを特徴とする。
　また、請求項２に記載の関節リウマチ薬は、請求項１記載の関節リウマチ薬において、前記投与が夜であることを特徴とする。
　また、請求項３に記載の関節リウマチ薬は、請求項２記載の関節リウマチ薬において、前記投与が午後９時～午前３時であることを特徴とする。 As a result of diligent research to solve such problems, the present inventor has conducted various examinations on the administration time without changing the dose and frequency of administration of MTX, which is an anti-rheumatic drug. The administration timing was determined, and it was confirmed that the pharmacological effect of MTX could be increased safely and efficiently, and the present invention was completed.
The rheumatoid arthritis drug of the present invention has been made based on such findings, and as described in claim 1, is a rheumatoid arthritis drug containing MTX as an active ingredient, and is administered to a rheumatoid arthritis patient before going to bed. It is used so that it may be used.
The rheumatoid arthritis drug according to claim 2 is the rheumatoid arthritis drug according to claim 1, characterized in that the administration is at night.
The rheumatoid arthritis drug according to claim 3 is the rheumatoid arthritis drug according to claim 2, wherein the administration is from 9:00 pm to 3:00 am.
　本発明のＭＴＸを含有する関節リウマチ薬は、炎症性サイトカインの概日リズムにあわせて就寝前に投与することによって、投与量及び投与回数を変更することなく、安全性を維持しつつＲＡ症状、特に関節痛を軽減することができる。また、ＲＡの重症化の遅延効果及び臨床的寛解を得ることができる。また、ＭＴＸの過剰な投与を防止し、患者の身体への負担や治療費の削減ができる。 The rheumatoid arthritis drug containing MTX of the present invention is administered before bedtime according to the circadian rhythm of inflammatory cytokines, thereby maintaining RA safety without changing the dose and the number of administration, In particular, joint pain can be reduced. In addition, a delayed effect of RA severity and clinical remission can be obtained. In addition, excessive administration of MTX can be prevented, and the burden on the patient's body and treatment costs can be reduced.
ＭＴＸを就寝前に３ヶ月間投与した場合のＤｉｓｅａｓｅ　Ａｃｔｉｖｉｔｙ　Ｓｃｏｒｅ　（ＤＡＳ）２８の変化を表すグラフGraph showing change in Disease Activity Score (DAS) 28 when MTX is administered for 3 months before going to bed
　本発明における関節リウマチ患者とは、リウマチ専門医によって関節リウマチと診断された患者であって、ＭＴＸを治療薬として利用する患者のことをいい、いずれの関節リウマチ患者も含む。 The rheumatoid arthritis patient in the present invention refers to a patient diagnosed with rheumatoid arthritis by a rheumatologist and uses MTX as a therapeutic agent, and includes any rheumatoid arthritis patient.
　本発明の関節リウマチ薬は、ＭＴＸを有効成分として含有する薬剤であり、錠剤、カプセル剤などとして用いられる。 The rheumatoid arthritis drug of the present invention is a drug containing MTX as an active ingredient, and is used as a tablet, capsule or the like.
　本発明の関節リウマチ薬は、就寝前に投与されるように用いる。具体的には、例えば、１日１回の就寝前の投与でよく、１日目の就寝前、２日目の就寝前、３日目の就寝前に投与し、残りの４日間は休薬し、これを１週間毎に繰り返すものである。 The rheumatoid arthritis drug of the present invention is used so that it is administered before going to bed. Specifically, for example, it may be administered once a day before going to bed, administered before going to bed on the first day, before going to bed on the second day, before going to bed on the third day, and for the remaining 4 days. This is repeated every week.
　本発明の関節リウマチ薬は、就寝前、午後９時から午前３時に投与され、さらに好ましいのは、午前１時から午前３時に投与されることである。炎症性サイトカインは、深夜（午前２時）から早朝（午前５時）にかけて増加する概日リズムを有しており、この時間帯にＭＴＸを服用することで血中のＭＴＸ濃度をこの時間帯に保つようにできれば、炎症性サイトカインの増加を抑えることができ、朝のこわばりを抑えることができるからである。 The rheumatoid arthritis drug of the present invention is administered from 9 pm to 3 am before bedtime, and more preferably from 1 am to 3 am. Inflammatory cytokines have a circadian rhythm that increases from midnight (2 am) to early morning (5 am). By taking MTX during this time period, the concentration of MTX in the blood is increased during this time period. This is because if it can be maintained, an increase in inflammatory cytokines can be suppressed, and morning stiffness can be suppressed.
　本発明における、ＭＴＸの有効投与量として、１週間あたりが４～２０ｍｇとすることが好ましい。一般的な日本国内のＲＡ治療において、ＭＴＸは４ｍｇ／週の投与が行われる。しかし、十分な効果が得られない患者については、６ｍｇ／週以上、最大８ｍｇ／週の投与が行われる。なお、海外ではＲＡ患者に対し、ＭＴＸは７．５～２０ｍｇ／週投与されている。 In the present invention, the effective dose of MTX is preferably 4 to 20 mg per week. In general Japanese RA treatment, MTX is administered at 4 mg / week. However, for patients who do not achieve a sufficient effect, 6 mg / week or more, and a maximum of 8 mg / week is administered. Overseas, MTX is administered at 7.5 to 20 mg / week for RA patients.
　前記ＭＴＸの有効投与量とは、関節リウマチ患者個人において、ＭＴＸが効果を示す用量のことをいう。ＭＴＸの効果とは、ＭＴＸの投与によって、患者個人における関節の疼痛、腫脹等の症状が緩和されたことで判断される。 The effective dose of MTX refers to a dose at which MTX is effective in patients with rheumatoid arthritis. The effect of MTX is judged by the fact that administration of MTX alleviates symptoms such as joint pain and swelling in individual patients.
（対象）
　平成２１年７月以前より、医療法人白十字会佐世保中央病院に外来にて通院している年齢２０歳以上のＲＡ患者で、すでにＲＡに対する治療としてＭＴＸを投与され、投与による改善が認められず、ＲＡの疾患活動性を示すＤＡＳ２８が３．２以上、生物学的製剤を現在使用していない患者１７名を被験者とした。１７名の被験者の内訳は、男性５例、女性１２例であり、ＲＡの罹患期間は平均１１．８年（２年（最小）－３３年（最大））であり、平均年齢は６１．０歳（４２歳（最小）－７８歳（最大）)であった。 (Target)
Since July 2009, MTX has already been administered as a treatment for RA in RA patients over 20 years old who have been admitted to the medical corporation White Cross Society Sasebo Central Hospital. The subjects were 17 patients with a DAS28 of 3.2 or more showing disease activity of RA and currently not using biologics. The breakdown of the 17 subjects is 5 males and 12 females, the average duration of RA is 11.8 years (2 years (minimum) -33 years (maximum)), and the average age is 61.0. He was 42 years old (minimum)-78 years old (maximum).
（投与方法）
　被験者が投与されていた既存のＭＴＸの投与量及び投与回数を基準として設定し、ＭＴＸの１週間における総投与量及び投与回数は変更せず、投与時間を１日１回就寝前（午後９時から午前１時の間）のみに変更した。投与期間は、投与時間を１日１回就寝前とする時間治療実施から３ヶ月間とした。なお、本実施例におけるＭＴＸの１週間における投与量は、４ｍｇが４例、６ｍｇが８例、８ｍｇが５例であり、投与量が４ｍｇの場合、時間治療開始前では、１日目朝食後２ｍｇ、夕食後２ｍｇの投与を、時間治療後では１日目就寝前２ｍｇ、２日目就寝前２ｍｇに変更した。
　投与量が６ｍｇの場合、時間治療開始前では、１日目朝食後２ｍｇ、夕食後２ｍｇ、２日目朝食後２ｍｇの投与を、時間治療後では１日目就寝前２ｍｇ、２日目就寝前、２ｍｇ、３日目就寝前２ｍｇに変更した。
　投与量が８ｍｇの場合、時間治療開始前では、１日目朝食後４ｍｇ、夕食後２ｍｇ、２日目朝食後２ｍｇの投与を、時間治療後では１日目就寝前４ｍｇ、２日目就寝前２ｍｇ、３日目就寝前２ｍｇに変更した。 (Method of administration)
Established based on the existing dose and number of doses of MTX that were administered by the subject, and did not change the total dose and number of doses of MTX for one week, and once a day before going to bed (9:00 pm From 1 am to 1 am). The administration period was 3 months after the time treatment was performed once a day before going to bed. In addition, 4 mg is 4 cases, 6 mg is 8 cases, and 8 mg is 5 cases in this example, and when the dose is 4 mg, before the start of time treatment, The administration of 2 mg and 2 mg after dinner was changed to 2 mg before going to bed on the first day and 2 mg before going to bed on the second day after time treatment.
When the dose is 6 mg, 2 mg after breakfast on the first day, 2 mg after dinner on the second day, 2 mg after breakfast on the first day before the start of the time treatment, 2 mg before going to bed on the first day and 2 days before going to bed after the time treatment 2 mg, changed to 2 mg before going to bed on the 3rd day.
When the dose is 8 mg, 4 mg after breakfast on the first day, 2 mg after dinner on the second day, 2 mg after breakfast on the first day before the start of the time treatment, 4 mg before going to bed on the first day and 2 days before going to bed after the time treatment The dose was changed to 2 mg before going to bed on the third day.
（評価方法）
　試験期間は、時間治療実施から３ヶ月間とし、外来来院ごとに毎月診断及び採血を行った。
　主要評価項目の有効性にはＤＡＳ２８による疾患活動性評価及びＥＵＬＡＲ（Ｅｕｒｏｐｅａｎ　Ｌｅａｇｕｅ　Ａｇａｉｎｓｔ　Ｒｈｅｕｍａｔｉｓｍ；欧州リウマチ学会）改善基準を用いて確認した。
　ＤＡＳ２８は、下記式により算出した。
　ＤＡＳ２８＝０．５６×（Ｔ２８）１／２＋０．２８×（Ｓ２８）１／２＋０．３６×ｌｎ（ＣＲＰ＋１）＋０．０１４×ＧＨ＋０．９６
　Ｔ２８及びＳ２８は、手、肘、肩など２８ヵ所の関節を触診し、Ｔ２８は「圧痛関節数（おさえたときに痛みのある関節の数）」であり、Ｓ２８は「腫脹関節数（腫れている関節の数）」である。
　Ｃ反応性タンパク（ＣＲＰ）は、採血によって炎症の程度を測定するもので、体内で炎症や組織の破壊が起きると、血液中にあらわれるタンパク質であり、炎症が強いほど、数値が高くなる。
　ＧＨは、患者が行う全身状態の自己評価のことであり、ＶＡＳ（Ｖｉｓｕａｌ　ａｎａｌｏｇ　ｓｃａｌｅ）という１００ｍｍのスケール上で、０を「体調が大変よい（症状なし）」、１００を「体調が非常に悪い」とした場合、どのあたりになるか患者が示した値である。
　前記式によって算出された値は、ｈｉｇｈ　ｄｉｓｅａｓｅ　ａｃｔｉｖｉｔｙ（高疾患活動性）、ｍｏｄｅｒａｔｅ　ｄｉｓｅａｓｅ　ａｃｔｉｖｉｔｙ（中等度疾患活動性）、ｌｏｗ　ｄｉｓｅａｓｅ　ａｃｔｉｖｉｔｙ（低疾患活動性）及び臨床的寛解の４段階で評価した。
　また、ＥＵＬＡＲ改善基準においては、投与時間を変更する前のＤＡＳ２８に対する投与時間変更後のＤＡＳ２８の差を用いて、治療効果をｇｏｏｄ（反応良好）、ｍｏｄｅｒａｔｅ（中等度反応）及びｎｏ　ｒｅｓｐｏｎｓｅ（不変）の３段階で評価した。 (Evaluation methods)
The test period was 3 months from the time treatment, and monthly diagnosis and blood sampling were performed at each outpatient visit.
Efficacy of the primary endpoint was confirmed using DAS28 disease activity assessment and EULAR (European League Against Rheumatism) improvement criteria.
DAS28 was calculated by the following formula.
DAS28 = 0.56 × (T28) 1/2 + 0.28 × (S28) 1/2 + 0.36 × ln (CRP + 1) + 0.014 × GH + 0.96
T28 and S28 palpate 28 joints such as hands, elbows, and shoulders, T28 is the number of tender joints (the number of joints that are painful when pressed), and S28 is the number of swollen joints (swelling Number of joints) ”.
C-reactive protein (CRP) is a protein that measures the degree of inflammation by blood sampling. If inflammation or tissue destruction occurs in the body, it is a protein that appears in blood. The stronger the inflammation, the higher the value.
GH is a self-assessment of the general condition performed by a patient. On a 100 mm scale called VAS (Visual analog scale), 0 is “very good (no symptoms)”, 100 is “very bad” ", It is the value that the patient indicates.
The value calculated by the above formula was evaluated in four stages: high disease activity (high disease activity), moderate disease activity (moderate disease activity), low disease activity (low disease activity), and clinical remission.
In addition, in the EULAR improvement criteria, using the difference of DAS28 after changing the administration time with respect to DAS28 before changing the administration time, the therapeutic effect is good (good response), moderate (moderate response), and no response (invariant). It was evaluated in three stages.
　ＤＡＳ２８による疾患活動性評価の結果を表１及び図１に示した。１７人のＲＡ患者から得られたデータは平均±標準偏差で表し、統計解析は群内の比較には反復分散分析を行い、多重比較検定にはＦｉｓｈｅｒのＰＬＳＤを行った。有意水準は５％とした。 The results of disease activity evaluation by DAS28 are shown in Table 1 and FIG. Data obtained from 17 RA patients were expressed as mean ± standard deviation, statistical analysis was repeated variance analysis for comparison within groups, and Fisher's PLSD was performed for multiple comparison tests. The significance level was 5%.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　ＤＡＳ２８による疾患活動性評価の値（Ｘ）は、Ｘ＞５．１は「高疾患活動性」を、３．２≦Ｘ≦５．１は「中等度疾患活動性」を、Ｘ＜３．２では「低疾患活動性」を、Ｘ＜２．６では「臨床的寛解」であることを意味する。
　表１において、時間治療開始時には時間治療開始２ヶ月前と比べＤＡＳ２８の値（Ｘ）が高くなっていることからＲＡの症状は悪化しており、時間治療開始時のＤＡＳ２８において、平均値は３．８３（３．２５（最小）－５．３０（最大））であり、中等度疾患活動性で、やや高いリウマチ症状が見られていた。時間治療１ヶ月後からＤＡＳ２８の平均値の値は下がり、時間治療開始３ヶ月後のＤＡＳ２８の平均値は３．３１となり、中等度疾患活動性であるものの、ＲＡの症状が軽くなったことが確認された。
　また、表１及び図１に示すように、ＭＴＸを就寝前に投与する時間治療では、時間治療開始後１ヶ月から治療効果が現れ、ＤＡＳ２８の平均値は時間治療開始前と比較し１ヶ月目で０．４６２、２ヶ月目で０．５０６、３ヶ月目で０．５２１とそれぞれ有意に減少した。上記式１に示すＤＡＳ２８に使用するすべての項目で減少傾向が示され、特に腫脹関節数（Ｓ２８）が顕著に減少し、ＲＡ症状が低減されたことが確認された。また、ＤＡＳ２８は時間治療開始１ヶ月目から有意に低下し、この抑制効果は３ヶ月間継続することが確認された。以上より、ＭＴＸの時間治療では、投与量の増量や投薬回数の変えることなく、ＭＴＸの投薬時刻を変更することで、従来の投与方法と比較してより高い治療効果が得られることが明らかとなった。 The value (X) of the disease activity evaluation by DAS28 is “high disease activity” when X> 5.1, “moderate disease activity” when 3.2 ≦ X ≦ 5.1, and X <3. 2 means “low disease activity” and X <2.6 means “clinical remission”.
In Table 1, since the value (X) of DAS28 was higher at the start of chronotherapy than that of 2 months before the start of chronotherapy, RA symptoms worsened. In DAS28 at the start of chronotherapy, the average value was 3 .83 (3.25 (minimum) -5.30 (maximum)), moderately active disease, and slightly elevated rheumatic symptoms. The average value of DAS28 decreased from one month after chronotherapy, and the average value of DAS28 three months after the start of chronotherapy was 3.31, indicating that although the disease was moderately active, the symptoms of RA were reduced. confirmed.
In addition, as shown in Table 1 and FIG. 1, in the time treatment in which MTX is administered before going to bed, the therapeutic effect appears from one month after the start of the time treatment, and the average value of DAS28 is the first month compared with that before the start of the time treatment. 0.462 at the second month, 0.506 at the second month, and 0.521 at the third month. A decrease tendency was shown in all items used for DAS28 shown in the above-mentioned formula 1, and it was confirmed that the number of swollen joints (S28) was significantly reduced, and RA symptoms were reduced. In addition, DAS28 significantly decreased from the first month of chronotherapy, and it was confirmed that this inhibitory effect continued for 3 months. From the above, it is clear that in MTX chronotherapy, a higher therapeutic effect can be obtained by changing the MTX dosing time without increasing the dose or changing the dosing frequency. became.
　ＥＵＬＡＲ改善基準によるＭＴＸの有効性評価の結果を表２に示した。 Table 2 shows the results of the effectiveness evaluation of MTX according to the EULAR improvement criteria.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表２中の基準とは、ＭＴＸ投与時間を変更する前（時間治療開始時）のＤＡＳ２８に対するＭＴＸ投与時間変更後（３ヶ月後）のＤＡＳ２８の差の値（Ｙ）において、１７名の患者のＭＴＸによる時間治療の効果が、０．６＞Ｙで「中等度反応」であることを、Ｙ＜０．６で「不変」、即ち、改善が見られなかったことを意味する。
　１７例中７例（４１．２％）で中等度反応を示すまでに改善し、このうち４例（２３．５％）ではＤＡＳ２８における臨床的寛解に到達したことが確認された。 The criteria in Table 2 are the values of the difference in DAS28 (Y) after changing the MTX administration time (after 3 months) relative to DAS28 before changing the MTX administration time (at the start of chronotherapy). This means that the effect of chronotherapy with MTX is “moderate response” when 0.6> Y, and “invariant” when Y <0.6, that is, no improvement was observed.
It was confirmed that 7 of 17 cases (41.2%) improved to show a moderate response, and of these 4 cases (23.5%) reached clinical remission in DAS28.
　３ヶ月間の本発明による時間治療において１７名の患者には副作用は認められなかった。 In the chronotherapy according to the present invention for 3 months, no side effects were observed in 17 patients.
　本発明は、就寝前に投与することにより、関節リウマチの症状を顕著に抑えることができる関節リウマチ薬として産業上利用できる。 The present invention can be industrially used as a rheumatoid arthritis drug capable of remarkably suppressing the symptoms of rheumatoid arthritis by being administered before going to bed.

Claims (3)

  1. 　メトトレキサートを有効成分として含有する関節リウマチ薬であって、関節リウマチ患者に対して、就寝前に投与されるように用いられることを特徴とする関節リウマチ薬。 Rheumatoid arthritis drug containing methotrexate as an active ingredient, which is used to be administered to a rheumatoid arthritis patient before going to bed.
  2. 　前記投与が夜であることを特徴とする請求項１に記載の関節リウマチ薬。 The rheumatoid arthritis drug according to claim 1, wherein the administration is at night.
  3. 　前記投与が午後９時～午前３時であることを特徴とする請求項２に記載の関節リウマチ薬。 The rheumatoid arthritis drug according to claim 2, wherein the administration is from 9:00 pm to 3:00 am.
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Cited By (10)

* Cited by examiner, † Cited by third party
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WO2016201069A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc Low-density enzyme-containing particles
WO2016201040A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc. Water-triggered enzyme suspension
WO2016201044A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc Osmotic burst encapsulates
WO2018183662A1 (en) 2017-03-31 2018-10-04 Danisco Us Inc Delayed release enzyme formulations for bleach-containing detergents
WO2019006077A1 (en) 2017-06-30 2019-01-03 Danisco Us Inc Low-agglomeration, enzyme-containing particles
WO2019125683A1 (en) 2017-12-21 2019-06-27 Danisco Us Inc Enzyme-containing, hot-melt granules comprising a thermotolerant desiccant
WO2019156670A1 (en) 2018-02-08 2019-08-15 Danisco Us Inc. Thermally-resistant wax matrix particles for enzyme encapsulation
WO2020047215A1 (en) 2018-08-30 2020-03-05 Danisco Us Inc Enzyme-containing granules
CN113795250A (en) * 2019-05-10 2021-12-14 西奈克制药有限公司 Combination therapy for arthritic disorders
WO2023039270A2 (en) 2021-09-13 2023-03-16 Danisco Us Inc. Bioactive-containing granules

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