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- 주제어 : Paclitaxel solid dispersion (검색결과 6 건)
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박재현,지상철,용철순,최한곤,우종수,이원석,이원모,구윤본 대한약학회 2009 Archives of Pharmacal Research Vol.32 No.1
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 LD50 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 LD50 for paclitaxel solid dispersion was above 160 mg/kg and the LD50 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 LD50 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.
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초임계유체를 이용한 파클리탁셀고체분산체의 제조 및 평가
우종수,박재현,지상철 한국약제학회 2008 Journal of Pharmaceutical Investigation Vol.38 No.4
Paclitaxel is a taxane diterpene amide, which was first extracted from the stem bark of the western yew, Taxus brevifolia. This natural product has proven to be useful in the treatment of a variety of human neoplastic disorders, including ovarian cancer, breast and lung cancer. Paclitaxel is a highly hydrophobic drug that is poorly soluble in water. It is mainly given by intravenous administration. Therefore, The pharmaceutical formulation of paclitaxel (TaxolR; Bristol-Myers Squibb) contains 50% CremophorR EL and 50% dehydrated ethanol. However the ethanol/Cremophor EL vehicle required to solubilize paclitaxel in TaxolR has a pharmacological and pharmaceutical problems. To overcome these problems, new formulations for paclitaxel that do not require solubilization by CremophorR EL are currently being developed. Therefore this study utilized a supercritical fluid antisolvent (SAS) process for cremophor-free formulation. To select hydrophilic polymers that require solubilization for paclitaxel, we evaluated polymers and the ratio of paclitaxel/polymers. HP-β-CD was used as a hydrophilic polymer in the preparation of the paclitaxel solid dispersion. Although solubility of paclitaxel by polymers was increased, physical stability of solution after paclitaxel/polymer powder soluble in saline was unstable. To overcome this problem, we investigated the use of surfactants. At 1/20/40 of paclitaxel/hydrophilic polymer/surfactant weight ratio, about 10 mg/mL of paclitaxel can be solubilized in this system. Compared with the solubility of paclitaxel in water (1 μg/mL), the paclitaxel solid dispersion prepared by SAS process increased the solubility of paclitaxel by near 10,000 folds. The physicochemical properties was also evaluated. The particle size distribution, melting point and amophorization and shape of the powder particles were fully characterized by particle size distribution analyzer, DSC, SEM and XRD. In summary, through the SAS process, uniform nano-scale paclitaxel solid dispersion powders were obtained with excellent results compared with TaxolR for the physicochemical properties, solubility and pharmacokinetic behavior.
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Choi, Jin-Seok,Cho, Nam Hyuk,Kim, Dong-Hyun,Park, Jeong-Sook Elsevier 2019 Materials Science and Engineering C Vol.100 No.-
<P><B>Abstract</B></P> <P>The purpose of this study was to develop paclitaxel (PTX) formulations with solid dispersion (SD) and micelles (M) in order to improve solubility and oral absorption in rats. In addition, the enhanced anti-cancer effects of PTX formulations were compared in various breast cancer cell lines. The SD formulations with various copolymers were prepared using a solvent evaporation method, and micelles with Soluplus® mixed with <SMALL>D</SMALL>-α-tocopheryl polyethylene glycol-1000-succinate (TPGS) were prepared using a film hydration method. The physical properties of SD and M formulations were evaluated. The dissolution (%) of SD4 and SD9 formulations, and the solubility of M2 were significantly higher than those of PTX. The SD formulations and micelles were also stable for 3 and 1 month, respectively. The anti-cancer effects of SD4, SD9, and M2 significantly increased in breast cancer cells, whereas the blank formulations were not toxic to normal cells. The SD4, SD9 and M formulations improved the permeability of Cou-6 compared to Cou-6 solution in Madin-Darby canine kidney cells (MDCK line). The SD formulations and micelles had enhanced bioavailability (BA) compared to that of PTX, showing relative BA values of 667.3% (SD4), 359.6% (SD9), and 365.4% (M2). This study demonstrates the technologies to increase the anti-cancer effects and BA of PTX, <I>via</I> SD and micelle formulations, and, to our knowledge, is the first comparison of the two formulations.</P> <P><B>Highlights</B></P> <P> <UL> <LI> The SD and M formulations were successfully prepared using a solvent evaporation and a film hydration method, respectively. </LI> <LI> Improving the solubility and oral bioavailability in rats of PTX in SD and M compared to those of PTX. </LI> <LI> Improving the anti-cancer effects of PTX in SD and M formulations compared to that of PTX in various cancer cell lines. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>
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Shanmugam, Srinivasan,Park, Jae-Hyun,Chi, Sang-Cheol,Yong, Chul Soon,Choi, Han-Gon,Woo, Jong Soo Informa Healthcare 2011 Drug development and industrial pharmacy Vol.37 No.6
<P><I>Aim:</I> To investigate the physicochemical stability, pharmacokinetics (PK), and biodistribution of paclitaxel (PTX) from paclitaxel solid dispersion (PSD) prepared by supercritical antisolvent (SAS) process.</P><P><I>Methods:</I> Physicochemical stability was performed in accelerated (40°째C 70 ??±짹 ??5% RH) and stress (60°째C) storage conditions for a period of 6 months and 4 weeks, respectively. PK and biodistribution studies were performed in rats following i.v. administration of PTX equivalent to 6 and 12 ??mg/kg formulations.</P><P><I>Results:</I> Physical stability of PSD showed excellent stability with no recrystallization of the amorphous form. Chemical stability of PSD in terms of % PTX remaining was 98.2 ??±짹 ??0.6% at 6 months and 97.9 ??±짹 ??0.3% at 4 weeks of accelerated and stress conditions, respectively. The PK study showed a nonlinear increase in AUC with increasing dose, that is, 100% increase in dose (from 6 to 12 ??mg/kg) resulted in 405.90% increase in AUC. Unlike PK study, the organ distribution study of PTX from PSD showed linear relationship with dose escalation. The order of organ distribution of PTX from highest to lowest for both PSD and Taxol<SUP>®짰</SUP> was liver>kidney>lung>brain.</P><P><I>Conclusions:</I> This study demonstrated excellent physicochemical stability with insight information on the PK and biodistribution of PTX from PSD prepared by SAS process.</P>
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