Tolmetin Sodium Fast Dissolving Tablets for Rheumatoid Arthritis Treatment: Preparation and Optimization Using Box-Behnken Design and Response Surface Methodology.

Tolmetin sodium (TLM) is a non-steroidal anti-inflammatory drug (NSAIDs). TLM is used to treat inflammation, skeletal muscle injuries, and discomfort associated with bone disorders. Because of the delayed absorption from the gastro intestinal tract (GIT), the currently available TLM dosage forms have a rather protracted start to the effect, according to pharmacokinetic studies. The aim of this study was to create a combination for TLM fast dissolving tablets (TLM-FDT) that would boost the drug's bioavailability by increasing pre-gastric absorption. The TLM-FDTs were developed using a Box-Behnken experimental design with varied doses of crospovidone (CP), croscarmellose sodium (CCS) as super-disintegrants, and camphor as a sublimating agent. In addition, the current study used response surface approach to explore the influence of various formulation and process factors on tablet qualities in order to verify an optimized TLM-FDTs formulation. The optimized TLM-FDTs formula was subsequently evaluated for its in vivo anti-inflammatory activity. TLM-FDTs have good friability, disintegration time, drug release, and wetting time, as well as fast disintegration and dissolution behavior. Significant increase in drug bioavailability and reliable anti-inflammatory efficacy were also observed, as evidenced by considerable reductions in paw thickness in rats following carrageenan-induced rat paw edema. For optimizing and analyzing the effect of super-disintegrants and sublimating agents in the TLM-FDTs formula, the three-factor, three-level full factorial design is a suitable tool. TLM-FDTs are a possible drug delivery system for enhancing TLM bioavailability and could be used to treat rheumatoid arthritis.

In Vitro and In Vivo Co-delivery of siRNA and Doxorubicin by Folate-PEG-Appended Dendrimer/Glucuronylglucosyl-ß-Cyclodextrin Conjugate.

We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-ß-cyclodextrin (Fol-PEG-GUG-ß-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-ß-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-ß-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-ß-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-ß-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-ß-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-ß-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.

Preparation and evaluation of polyamidoamine dendrimer conjugate with glucuronylglucosyl-ß-cyclodextrin (G3) as a novel carrier for siRNA.

Abstract In this study, we newly synthesized the polyamidoamine STARBURST dendrimer (dendrimer, generation 3: G3) conjugates with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-ß-cyclodextrin [GUG-ß-CDE (G3)] having the various degrees of substitution (DS) of GUG-ß-cyclodextrin of 1.6, 3.0, 3.7, 5.0 and 8.6, and evaluated them as a siRNA transfer carrier. GUG-ß-CDEs (G3) formed the positively charged and nano-order complexes with siRNA. Of the siRNA complexes with five GUG-ß-CDEs (G3), the complex with GUG-ß-CDE (G3, DS 3.7) showed the highest RNAi effect and cellular uptake with negligible cytotoxicity in KB cells at a charge ratio of 20. In addition, the RNAi effect and cellular uptake of the complex with GUG-ß-CDE (G3, DS 3.7) were higher than those of α-CDE (G3, DS 2.4) and comparable to those of Lipofectamine™ 2000. Furthermore, the complex with GUG-ß-CDE (G3, DS 3.7) possessed the endosomal escaping ability, the releasing property of siRNA in the cytoplasm and serum resistance. These results suggest that GUG-ß-CDE (G3, DS 3.7) has the potential as a novel siRNA carrier.