Development of novel dual-reverse thermosensitive hydrogel system

Abstract

Abstract-1 The purpose of this study was to develop novel solid lipid nanoparticles (SLNs)-loaded dual-reverse thermosensitive hydrogel (DRTH) for rectal and intramuscular administration of flurbiprofen with improved bioavailability and reduced toxicity. The flurbiprofen-loaded solid lipid nanoparticles (SLNs) were prepared by hot homogenization technique, after optimizing the amounts of lipid mixture (tricaprin and triethanolamine in 8:2 weight ratio), drug and surfactant. The flurbiprofen-loaded thermosensitive SLN composed of drug, lipid mixture and surfactant at a weight ratio of 10/15/1.3 was a solid at room temperature, and changed to liquid form at physiological temperature. This SLN gave the mean particle size of about 190 nm and entrapment efficiency of around 90%. The SLN-loaded DRTHs were prepared by adding this flurbiprofen-loaded thermosensitive SLN in various poloxamer solutions. Their rheological characterization, release and stability study were performed while morphological and pharmacokinetic study were carried out after its rectal and intramuscular administration to rats compared with flurbiprofen suspension and hydrogel. Poloxamer 188 and SLN decreased the gelation temperature and gelation time, but increased the viscosity at 25 °C, gel strength and mucoadhesive force of DRTHs. Poloxamer 188 decreased the drug release, but SLN increased. In particular, the DRTH with the gelation temperature of about 35 °C existed as liquid at room temperature, but gelled at 30-36oC, leading to opposite reversible property of SLN. Thus, it was easily administered, rectally and intramuscularly which gels rapidly inside the body. This DRTH gave a significantly increased drug release as compared to the flurbiprofen suspension, but decreased as compared to flurbiprofen hydrogel. This DRTH administered rectally and intramuscularly in rats gave significantly higher plasma concentration and AUC values compared to the flurbiprofen suspension and lower initial plasma concentration and Cmax value compared to the flurbiprofen hydrogel, even if there was no significant difference between them. The DRTH administered intramuscularly in rats show sustained plasma concentration at a higher value for 60 hr. Particularly, it improved about 7.5 fold bioavailability compared to the drug. No damage in rectal mucosa or muscle was observed after the application of DRTH. Flurbiprofen hydrogel hardly irritated the rectal mucous membrane, but caused severe damage to the muscle. Furthermore, this DRTH was physically and chemically stable over a period of 4 months. Thus, this DRTH system with improved bioavailability, reduced toxicity and excellent stability would be recommended as an alternative for the flurbiprofen-based rectal and intramuscular pharmaceutical products.

Abstract-II The purpose of this study was to fabricate irinotecan-loaded dual reverse thermosensitive hydrogel (DRTH) for rectal and intramuscular administration with reduced burst effect, minimized toxicity and improved antitumor efficacy. Irinotecan-loaded thermosensitive SLNs were prepared by microemulsion method and DRTH by cold method. Physicochemical characteristics, release pattern and stability of DRTH were determined. The optimized formulation was evaluated for pharmacokinetic, morphology and anti-tumor efficacy, compared with control, solution and hydrogel, after rectal and intramuscular administration. DRTH gave thermosensitive behavior, as the SLNs were solid and hydrogel was liquid at room temperature, respectively, and oppositely changed to liquid and gel at physiological temperature. In release study, unlike DRTH, the irinotecan solution and hydrogel gave initial burst release. The AUC of the intravenously administered solution was significantly higher than the AUC of rectally administered DRTH and hydrogel. However, the AUC value of DRTH was higher than that of hydrogel, even if there was no significant difference. The Tmax of hydrogel was significantly different from the Tmax of the DRTH, suggesting that the initial burst release was reduced in the DRTH. Moreover, after intramuscular administration, all the formulations showed sustained property of plasma concentration; however solution sustained the maximum plasma concentration only for 24 h, followed by hydrogel which showed a sustained property till 48 h. But, the DRTH gave sustained property for 60 h resulting a decreased release and less side effects of the drug. The DRTH and hydrogel gave significantly lower plasma concentration compared to solution. However, the plasma concentration of hydrogel and DRTH were not significantly different from one another. No damage in rectal mucosa was observed after the application of DRTH and hydrogel however, severe inflammation was observed in case of hydrogel after intramuscular administration. DRTH showed significantly increased antitumor efficacy as compared to hydrogel and solution in terms of its tumor volume control and weight change analysis. Moreover, the increased level of Caspac-3 and poly (ADP-ribose) polymerase (PARP) and decreased level of platelet/endothelial cell adhesion molecule 1 (PECAMI1, CD31) and Ki-67 in tumor cells suggested that tumor cells underwent apoptosis and that angiogenesis was inhibited with in tumor. Furthermore, the DRTH was stable for a period of 6 months. It can be concluded that the DRTH was successfully developed with particles in nano size, excellent dual reverse thermosensitive effect, decreased burst effect, minimized toxicity and improved antitumor efficacy.