Development and Clinical Use of Beclomethasone dipropionate Preparations for the Purpose of Treatments of Ulcerative Colitis Patients

用于治疗溃疡性结肠炎患者的二丙酸倍氯米松制剂的开发和临床应用

• 批准号: 09672319
• 负责人: AOYAMA Takao
• 金额: $ 1.98万
• 依托单位: University of Tokyo
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 1997
• 资助国家: 日本
• 起止时间: 1997 至 1998
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09672319/
• 关键词: beclomcthasone dipropionate; cnema; ulcerativecolitis; suppository; rat; Corticosteroid; 2,4,6-trinitrobenzensulfonic acid; Becluomettiascne clipropionote; ulceratiue cclitis palients; Cuppesitory; 2,4,6-Trinitrobeuzeuswtonic acid; Bechromethaz

(1) Beclomethasone dipropionate (BDP), with a strong anti-inflammatory action and low systemic side effects, was prepared and a pharmaceutical study of this enema was performed for the clinical application of ulcerative colitis patients. Enemas were prepared by adding BDP ethanol to an aqueous solution of 1 % methylcellose. The mean residual concentration of BDP in these enemas (n=6), preserved in dark under refrigeration at 4 ﾟC declined to 93.4% in one week and 85.6% in four weeks, when compared to the concentration decided immediately after preparation. Although the residual concentration of BDP enemas, preserved in light at 40 ﾟC, declined to 93.9% in one week and remained almost constant thereafter, crystallization of BDP was observed the first day after preparation. The stability of BDP in enemas was improved by adding methyl p-hydroxybenzoate to these solutions. Theses BDP enemas were administered to three patients with ulcerative colitis. Improvements were seen in all three sub … More jects, in terms of both clinical symptoms and blood data (values related to inflammatory : white blood cells and C-reactive protein). Also the disappearance of side effects were confirmed after administration of BDP enemas in two of the subjects who had developed side effects such as moon face arid edema with predonisolone enemas. It has been suggested that BDP enemas are efficacious in the treatment of ulcerative colitis.(2) The effects of BDP enemas to ulcerative colitis were investigated by administrating BDP enemas to Fischer male rats with inflammatory bowel disease induced by 2, 4, 6-trinitrobenzensulfonic acid (TNB). BDP enemas were administrated to rats one time a day at a dose of 20 or 50 mug of BDP during 4 or 11 days from 3 days after TNB treatment. After BDP dosing, the rate of rats occurring diarrhea and melena was decreased in comparison with BDP free rats with time, and their symptoms of all rats were improved the day 4 at the dose of 50 mug of BDP.A dose dependent recovery in the wet tissue weights and scores of damage, and the mycloperoxidase (MPO) activity in the tissue were found at the early days (the day 4). However, their measurements the day 11 at the each dose of BDP were not different from control significantly, as colon damages of control were recovered naturally with time. The clinical usefulness of BDP enemas was supported by elucidating the dose dependent effect at the early days in the model rats with inflammatory bowel disease induced by TNB. Less

(1)制备了抗炎作用强、全身副作用小的二丙酸倍氯米松(BDP)灌肠剂，并对其进行了药学研究，为溃疡性结肠炎的临床应用奠定了基础。将BDP乙醇加入1%甲基纤维素水溶液中制备灌肠剂。在4ﾟC冷藏条件下黑暗保存的6例灌肠中，与制备后即刻测定的浓度相比，1周内平均残留浓度下降至93.4%，4周后下降至85.6%。在40ﾟC光照下保存的灌肠液的残留浓度在一周内下降到93.9%，此后几乎保持不变，但在制备后的第一天就观察到了结晶。在灌肠液中加入对羟基苯甲酸甲酯，可提高BDP在灌肠中的稳定性。这些BDP灌肠用于3例溃疡性结肠炎患者。在所有三个子…中均有改善在临床症状和血液数据(与炎症相关的数值：白细胞和C反应蛋白)方面，受试者更多。此外，在两名出现副作用的受试者中，服用BDP灌肠后，副作用也得到证实，如月亮脸和强的松龙灌肠引起的浮肿。用BDP灌肠治疗2，4，6-三硝基苯磺酸(TNB)诱导的大鼠炎症性肠病模型，观察BDP灌肠对溃疡性结肠炎的治疗作用。从TNB给药后3d开始连续灌肠4d或11d，每天给药1次，剂量分别为20或50µg。给予BDP后，大鼠腹泻、黑便发生率随时间延长而降低，给药后第4天，所有大鼠的症状均有所改善，湿组织重量、损伤评分和组织中肌过氧化物酶(MPO)活性均出现剂量依赖性恢复。然而，在第11天，各剂量BDP的测量结果与对照组没有显著差异，因为对照组的结肠损伤随着时间的推移而自然恢复。通过阐明BDP灌肠在TNB诱导的炎症性肠病模型大鼠早期的剂量依赖效应，支持了BDP灌肠的临床应用。较少

项目成果

嶋田修治,青山隆夫 他: "ジプロピオン酸ベクロメタゾン注腸液の炎症性腸疾患モデルラットを用いた結腸障害に対する効果の検討" 薬学雑誌. 118(6). 216-225 (1998)

Shuji Shimada、Takao Aoyama 等人：“使用炎症性肠病模型大鼠评估二丙酸倍氯米松灌肠溶液对结肠疾病的影响”，Pharmaceutical Journal 118(6) (1998)。

Shuji Shimada, Takao Aoyama, et al.: "Therapeutic Effects of Beclomethasone Dipropionate Enemas on Colon Damage of Inflammatory Bowel Disease Model Rats" YAKUGAKU ZASSHI. 118 (6). 216-225 (1998)

Shuji Shimada、Takao Aoyama 等：“二丙酸倍氯米松灌肠对炎症性肠病模型大鼠结肠损伤的治疗作用”YAKUGAKU ZASSSHI。

嶋田 修治、青山 隆夫、他: "ジプロビオン酸ベクロメタゾン注腸液の炎症性腸疾患モデルラットを用いた結腸障害に対する効果の検討" 薬学雑誌. (in press). (1998)

Shuji Shimada、Takao Aoyama 等人：“使用炎症性肠病模型大鼠评估倍氯米松二丙酸灌肠溶液对结肠疾病的影响”（正在出版）。

Shuji Shimada, Takao Aoyama, et al.: "Pharmaceutical Study of Beclomethasone Dipropionate Enemas and their Application to Ulcerative Colitis Patients" Jpn.J.Hosp.Pharm.24 (5). 449-456 (1998)

Shuji Shimada、Takao Aoyama 等人：“二丙酸倍氯米松灌肠剂的药物研究及其在溃疡性结肠炎患者中的应用”Jpn.J.Hosp.Pharm.24 (5)。

嶋田修治,青山隆夫他: "ジプロピオン酸ベクロメタゾン注腸液の炎症性腸疾患モデルラットで用いた結腸障害に対する効果の検討" 薬学雑誌. 118(6). 216-225 (1998)

Shuji Shimada、Takao Aoyama 等人：“二丙酸倍氯米松灌肠液对炎症性肠病模型大鼠结肠疾病的影响的评估”Pharmaceutical Journal 118(6) (1998)。