Enhanced anti-tumor activity and alleviated hepatotoxicity of clotrimazole-loaded suppository using poloxamer-propylene glycol gel.
To develop a novel clotrimazole-loaded poloxamer-based suppository with enhanced anti-tumor activity and alleviated hepatotoxicity, the melting point of various formulations composed of P 188 and propylene glycol were investigated. The dissolution and anti-tumor activity of clotrimazole delivered by the poloxamer-based suppository was performed. Furthermore, the hepatotoxicity of clotrimazole was carried out after its rectal administration compared to oral administration in mice. The poloxamer mixtures composed of P 188 and propylene glycol were homogeneous phases. P 188 greatly affected the melting point of poloxamer mixtures. In particular, the poloxamer mixture [P 188/propylene glycol (70%/30%)] with the melting point of about 32 degrees C was a solid form at room temperature and instantly melted at physiological temperature. The ratio of P 188/propylene glycol greatly affected the dissolution rates of clotrimazole from poloxamer-based suppository. Dissolution mechanism analysis showed the dissolution rate of clotrimazole from poloxamer-based suppositories was independent of the time. The clotrimazole-loaded suppository with P 188 and propylene glycol could not irritate or damage the rectal tissues of rats and gave the improved anti-tumor activity in a dose-dependent manner at mouse. Furthermore, its rectal administration decreased the hepatotoxicity compared to oral administration. Thus, the poloxamer-based solid suppository system with clotrimazole/P 188/propylene glycol was an effective rectal dosage form for the treatment of tumors with alleviated adverse effects.
Yong
Chul Soon
CS
College of Pharmacy, Yeungnam University, 214-1, Dae-Dong, Gyongsan 712-749, South Korea.
Xuan
Jing Ji
JJ
Paek
Seung-Hwan
SH
Oh
Yu-Kyoung
YK
Woo
Jong-Soo
JS
Lee
Mann Hyung
MH
Kim
Jung-Ae
JA
Choi
Han-Gon
HG
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D003022:Clotrimazole / Q000008:administration & dosage* / Q000633:toxicity; D005782:Gels; D008099:Liver / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D020442:Poloxamer / Q000008:administration & dosage; D019946:Propylene Glycol / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D013488:Suppositories
D000970:Antineoplastic Agents; D005782:Gels; D013488:Suppositories; D020442:Poloxamer; D019946:Propylene Glycol; D003022:Clotrimazole