WO2011111143A1 - 関節リウマチ薬 - Google Patents

関節リウマチ薬 Download PDF

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Publication number
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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Prior art keywords
rheumatoid arthritis
mtx
bed
day
das28
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PCT/JP2010/007262
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English (en)
French (fr)
Japanese (ja)
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秀人 中村
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Individual
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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.

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Immunology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP2010/007262 2010-03-12 2010-12-15 関節リウマチ薬 Ceased WO2011111143A1 (ja)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2010056428A JP2011190199A (ja) 2010-03-12 2010-03-12 関節リウマチ薬
JP2010-056428 2010-03-12

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WO2011111143A1 true WO2011111143A1 (ja) 2011-09-15

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016201044A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc Osmotic burst encapsulates
WO2016201040A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc. Water-triggered enzyme suspension
WO2016201069A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc Low-density enzyme-containing particles
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 PARTICLES CONTAINING LOW AGGLOMERATION ENZYME
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 (zh) * 2019-05-10 2021-12-14 西奈克制药有限公司 关节炎疾病的联合治疗
WO2023039270A2 (en) 2021-09-13 2023-03-16 Danisco Us Inc. Bioactive-containing granules
US12239631B2 (en) 2021-06-21 2025-03-04 Synact Pharma Aps Polymorphs of phenyl pyrrole aminoguandium salts

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
HIDETO FUJI: "Ko Rheumatism-yaku no Jikan Chiryo eno Tenbo", JOURNAL OF CHRONOBIOLOGY, vol. 15, no. 2, 2009, pages 33 - 39 *
HIDETO FUJI: "Ko Rheumatism-yaku no Jikan Yakubutsu Ryoho o Mezashite", SHUKAN YAKUJI SHINPO, vol. 2610, 1 January 2010 (2010-01-01), pages 6 - 12 *
TO,H. ET AL., THE JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 61, no. 10, 2009, pages 1333 - 8 *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016201044A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc Osmotic burst encapsulates
WO2016201040A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc. Water-triggered enzyme suspension
WO2016201069A1 (en) 2015-06-09 2016-12-15 Danisco Us Inc Low-density enzyme-containing particles
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 PARTICLES CONTAINING LOW AGGLOMERATION ENZYME
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 (zh) * 2019-05-10 2021-12-14 西奈克制药有限公司 关节炎疾病的联合治疗
CN113795250B (zh) * 2019-05-10 2024-10-15 西奈克制药有限公司 关节炎疾病的联合治疗
US12303489B2 (en) 2019-05-10 2025-05-20 Synact Pharma Aps Combination treatment of arthritic disease
US12239631B2 (en) 2021-06-21 2025-03-04 Synact Pharma Aps Polymorphs of phenyl pyrrole aminoguandium salts
WO2023039270A2 (en) 2021-09-13 2023-03-16 Danisco Us Inc. Bioactive-containing granules

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