Strategic application of self-micellizing solid dispersion technology to respirable powder formulation of tranilast for improved therapeutic potential

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• 作者：Hiroki Suzuki^a ; Yoshiki Kojo^a ; Keisuke Yakushiji^a ; Kayo Yuminoki^b ; Naofumi Hashimoto^b ; Satomi Onoue^a ; ^{onoue@u-shizuoka-ken.ac.jp" class="auth_mail" title="E-mail the corresponding author}
• 关键词：ANOVA ; analysis of variance ; AUC ; area under the curve of blood concentration versus time curve ; BALF ; bronchoalveolar lavage fluid ; COPD ; chronic obstructive pulmonary disease ; DMEM ; Dulbecco&rsquo ; s modified eagle medium ; ESI-MS ; electrospray ionization mass spectrometry ; LDH ; lactate dehydrogenase ; MPO ; myeloperoxidase ; OCT ; optimal cutting temperature ; OVA ; ovalbumin ; PBS ; phosphate-buffered saline ; PXRD ; powder X-ray diffraction ; RP ; respirable powder ; SEM ; scanning electron microscopy ; SMS
• 刊名：International Journal of Pharmaceutics
• 出版年：2016
• 出版时间：29 February 2016
• 年：2016
• 卷：499
• 期：1-2
• 页码：255-262
• 全文大小：1566 K

文摘

The present study aimed to develop an inhalable self-micellizing solid dispersion of tranilast (SMSD/TL) using poly[MPC-co-BMA] to improve the therapeutic potential and safety.

Methods

The safety of poly[MPC-co-BMA] in lungs was assessed using rat lung epithelium-derived L2 cells. SMSD/TL and respirable powder of SMSD/TL (SMSD/TL-RP) were prepared using a wet milling system and jet mill, respectively. The physicochemical properties of TL formulations were characterized in terms of dissolution, morphology, and particle size. Pharmacological and pharmacokinetic studies were also conducted on inhaled SMSD/TL-RP.

Results

The lactate dehydrogenase level from L2 cells treated with poly[MPC-co-BMA] was lower than that with polysorbate 80, a positive control. SMSD/TL showed enhanced dissolution behavior of TL. The jet milled SMSD/TL particles easily separated from the lactose carrier, and the particle size was suitable for inhalation. Compared with RP of TL, inhaled SMSD/TL-RP (100 μg-TL/rat) could more strongly suppress the inflammatory responses in antigen-sensitized rats. The TL level in plasma after intratracheal administration of SMSD/TL-RP at a pharmacological effective dose (100 μg-TL/rat) was ca. 4.2-fold lower than that after oral administration of TL solution at a clinical dose (1.67 mg/kg).

Conclusion

SMSD/TL-RP might be an attractive dosage form to improve the anti-inflammatory effects and safety of TL.