Toxicity studies of cremophor-free paclitaxel solid dispersion formulated by a supercritical antisolvent process.
To evaluate the acute toxicity of a paclitaxel solid dispersion formulation, single dose studies in ICR mice were carried out for injectable excipients, paclitaxel solid dispersion powder, and Taxol. In the dose range of excipients used for preparing paclitaxel solid dispersion, each excipient was clinically safe, and the LD(50) for exicipients was higher than 2,000 mg/kg for both males and females. In this study, there were no remarkable clinical signs or deaths related to paclitaxel solid dispersion even at doses up to 160 mg/kg of paclitaxel. But Taxol resulted in clinical signs when it contained more than 30 mg/mL paclitaxel. The LD(50) for paclitaxel solid dispersion was above 160 mg/kg and the LD(50) for Taxol was 31.3 mg/kg, more than 5 times lower than that of paclitaxel solid dispersion. However, paclitaxel solid dispersion could not be administered i.v. at a dose exceeding 160 mg/kg, because of high viscosity. To evaluate the nephrotoxicity of paclitaxel solid dispersion, plasma level of creatinine and kidney weight were measured and compared to Taxol. At the doses administered, paclitaxel solid dispersion did not change creatinine clearance, while Taxol killed all animals at doses >15 mg/kg. To investigate membrane damage when paclitaxel formulations were injected, hemolytic activity was determined for different concentrations. Paclitaxel solid dispersion showed about 10% hemolytic activity, whereas Taxol showed about 40% hemolytic activity when it contained 2 mg of paclitaxel. Comparisons with the LD(50) value, nephrotoxicity, and hemolytic activity of Taxol suggested that Cremophor-free paclitaxel solid dispersion as an injectable formulation is a promising approach to increasing the safety and clinical efficacy of paclitaxel for treatment of cancer.
Park
Jae-Hyun
JH
College of Pharmacy, Sungkyunkwan University, Suwon, 440-746, Korea.
Chi
Sang-Cheol
SC
Lee
Won Seok
WS
Lee
Won Mo
WM
Koo
Yoon Bon
YB
Yong
Chul Soon
CS
Choi
Han Gon
HG
Woo
Jong Soo
JS
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D025924:Chromatography, Supercritical Fluid; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005079:Excipients / Q000737:chemistry / Q000633:toxicity*; D005260:Female; D005990:Glycerol / Q000633:toxicity; D006461:Hemolysis / Q000187:drug effects; D007275:Injections, Intravenous; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009929:Organ Size / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D011092:Polyethylene Glycols / Q000633:toxicity; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D013678:Technology, Pharmaceutical / Q000379:methods*
D000972:Antineoplastic Agents, Phytogenic; D005079:Excipients; D011208:Powders; C022131:cremophor; D011092:Polyethylene Glycols; D003404:Creatinine; D017239:Paclitaxel; D005990:Glycerol