Pharmacologic Effects of Oxaliplatin Instability in Chloride-Containing Carrier Fluids on the Hyperthermic Intraperitoneal Chemotherapy to Treat Colorectal Cancer In Vitro and In Vivo.

BACKGROUND: Oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) involves mixing oxaliplatin with 5% dextrose solution (5DW) to prevent the structural degradation of oxaliplatin in chloride-containing fluids. This study evaluated oxaliplatin degradation in carrier fluids containing different chloride ion concentrations to determine a carrier fluid that is optimal for use in oxaliplatin-based HIPEC. METHODS: Five types of carrier fluids (normal saline, half saline, 5DW, Dianeal PD-2 peritoneal dialysis solution, and non-chloride Dianeal solution) were compared. An in vitro study was performed that monitored an oxaliplatin concentration of 1 ml (2 mg/ml) oxaliplatin mixed in 24 ml of each carrier fluid during 3 days to evaluate the rate of oxaliplatin degradation in each carrier fluid. An in vivo study, which subjected Sprague-Dawley rats to HIPEC for 60 min, also was performed. The efficacy of each carrier fluid for preserving oxaliplatin was evaluated using area under the curve (AUC) ratios between peritoneal fluid and plasma. RESULTS: The degradation rate of oxaliplatin in non-chloride fluids was significantly lower than in chloride-containing fluids. However, the rate was less than 10 to 15% at 30 min. The in vivo study indicated that oxaliplatin concentrations in peritoneal fluids did not differ significantly, whereas those in plasma did differ. The AUC ratios of both normal saline and Dianeal were higher than those of 5DW and non-Cl- Dianeal solutions. CONCLUSIONS: Chloride-containing fluids, such as normal saline or Dianeal, which display high absorption rates of oxaliplatin and acceptable degradation rates, may be more beneficial for use in oxaliplatin-based HIPEC than 5DW.

Pharmacokinetic Profile and Anti-Adhesive Effect of Oxaliplatin-PLGA Microparticle-Loaded Hydrogels in Rats for Colorectal Cancer Treatment.

Colorectal cancer (CRC) is one of the most malignant and fatal cancers worldwide. Although cytoreductive surgery combined with chemotherapy is considered a promising therapy, peritoneal adhesion causes further complications after surgery. In this study, oxaliplatin-loaded Poly-(d,l-lactide-co-glycolide) (PLGA) microparticles were prepared using a double emulsion method and loaded into hyaluronic acid (HA)- and carboxymethyl cellulose sodium (CMCNa)-based cross-linked (HC) hydrogels. From characterization and evaluation study PLGA microparticles showed smaller particle size with higher entrapment efficiency, approximately 1100.4 ± 257.7 nm and 77.9 ± 2.8%, respectively. In addition, microparticle-loaded hydrogels showed more sustained drug release compared to the unloaded microparticles. Moreover, in an in vivo pharmacokinetic study after intraperitoneal administration in rats, a significant improvement in the bioavailability and the mean residence time of the microparticle-loaded hydrogels was observed. In HC21 hydrogels, AUC0-48h, Cmax, and Tmax were 16012.12 ± 188.75 ng·h/mL, 528.75 ± 144.50 ng/mL, and 1.5 h, respectively. Furthermore, experimental observation revealed that the hydrogel samples effectively protected injured tissues from peritoneal adhesion. Therefore, the results of the current pharmacokinetic study together with our previous report of the in vivo anti-adhesion efficacy of HC hydrogels demonstrated that the PLGA microparticle-loaded hydrogels offer novel therapeutic strategy for CRC treatment.

Pharmacologic Properties of the Carrier Solutions for Hyperthermic Intraperitoneal Chemotherapy: Comparative Analyses Between Water and Lipid Carrier Solutions in the Rat Model.

BACKGROUND: Carrier solutions play an important role in the distribution, plasma absorption, chemical stability, and solubility of anticancer agents during hyperthermic intraperitoneal chemotherapy (HIPEC). In the current study, lipophilic properties of carrier solutions were evaluated to determine whether they improved anticancer drug absorption rates using mitomycin-C (MMC) or oxaliplatin HIPEC as compared to hydrophilic carrier solutions. METHODS: Sprague-Dawley rats were divided into two groups: MMC and oxaliplatin treatment groups. Each group was then further subdivided by carrier solution: Dianeal® PD-2 peritoneal dialysis solution, 5% dextrose solution and 20% lipid solution (Lipision®). HIPEC was performed over 60 min at 41-42 °C using the anticancer drugs MMC (35 mg/m2) or oxaliplatin (460 mg/m2). The plasma area under the curve (AUC; AUCplasma), peritoneal AUC (AUCperitoneum), and peritoneal/plasma AUC ratios were compared among HIPEC carrier solutions. RESULTS: Plasma drug concentrations were significantly different among carrier solutions, varying by time. In contrast, peritoneal drug concentrations did not change with carrier solution. In the MMC group, the peritoneal/plasma AUC ratio of a lipid solution was three times higher than Dianeal® (p < 0.001). In the oxaliplatin group, the peritoneal/plasma AUC ratio was significantly different between carrier solutions (p = 0.046). Although the oxaliplatin AUCperitoneum did not vary (p = 0.941), the AUCplasma of a lipid solution was lower than that of 5% dextrose solution (p = 0.039). CONCLUSIONS: The lipid carrier solution increases the peritoneal/plasma AUC ratio and decreases plasma absorption rates. However, further study is required before clinical uses, considering its pharmacologic properties and possible risks after HIPEC.

Solubilization of the poorly water soluble drug, telmisartan, using supercritical anti-solvent (SAS) process.

Telmisartan is a biopharmaceutical classification system (BCS) class II drug that has extremely low water solubility but is freely soluble in highly alkalized solutions. Few organic solvents can dissolve telmisartan. This solubility problem is the main obstacle achieving the desired bioavailability. Because of its unique characteristics, the supercritical anti-solvent (SAS) process was used to BCS class II drug in a variety of ways including micronization, amorphization and solid dispersion. Solid dispersions were prepared using hydroxypropylmethylcellulose/polyvinylpyrrolidone (HPMC/PVP) at 1:0.5, 1:1, and 1:2 weight ratios of drug to polymer, and pure telmisartan was also treated using the SAS process. Processed samples were characterized for morphology, particle size, crystallinity, solubility, dissolution rate and polymorphic stability. After the SAS process, all samples were converted to the amorphous form and were confirmed to be hundreds nm in size. Solubility and dissolution rate were increased compared to the raw material. Solubility tended to increase with increases in the amount of polymer used. However, unlike the solubility results, the dissolution rate decreased with increases in polymer concentration due to gel layer formation of the polymer. Processed pure telmisartan showed the best drug release even though it had lower solubility compared to other solid dispersions; however, because there were no stabilizers in processed pure telmisartan, it recrystallized after 1 month under severe conditions, while the other solid dispersion samples remained amorphous form. We conclude that after controlling the formulation of solid dispersion, the SAS process could be a promising approach for improving the solubility and dissolution rate of telmisartan.