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Sorafenib, a potent anticancer drug, has low absorption in the gastrointestinal tract due to its poor aqueous solubility. The main purpose of this investigation was to design sorafenib nanoparticle using a newly developed technique, nanoparticulation using fat and supercritical fluid (NUFS™) to improve the absorption of sorafenib. The quality by design (QbD) tool was adopted to define the optimal formulation variables: hydroxypropyl methyl cellulose (HPMC), polyvinyl pyrrolidone K30 (PVP), and poloxamer. The studied response variables were particle size of nanoparticle, dissolution (5, 60, and 180 min), drug concentration time profile of nanoparticle formulations, and maximum drug concentration. The result of particle size revealed that an increase in concentration of poloxamer and HPMC decreased the particle size of nanoparticles (p 0.05). Likewise, the concentration of drug release at different time point (5, 60, and 180 min) showed HPMC and poloxamer had positive effects on drug dissolution while PVP had negative effects on it. The design space was built in accordance with the particle size of nanoparticle (target 500 nm) and dissolution of sorafenib (target 7 µm/mL), following failure probability analysis using Monte Carlo simulations. In vivo pharmacokinetics studies in beagle dogs demonstrated that optimized formulation of sorafenib (F3 and F4 tablets) exhibited higher blood drug profiles indicating better absorption compared to the reference tablet (Nexavar

// Si Yeol Song 1, 3 , Kyu-pyo Kim 2 , Seong-Yun Jeong 3, 4 , Jin Park 3, 4 , Jaesook Park 3, 4 , Joohee Jung 5 , Hye Kyung Chung 6 , Sa-Won Lee 7 , Min Hyo Seo 7 , Jung-shin Lee 2, 3 , Kyung Hae Jung 2 , Eun Kyung Choi 1, 3 1 Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 2 Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 3 Institute for Innovative Cancer Research, Asan Medical Center, Seoul, Korea 4 Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea 5 College of Pharmacy, Duksung Women’s University, Seoul, Korea 6 Korea Institute of Radiological and Medical Sciences, National Project to Establish Platform to Develop The New Concept Therapy, Seoul, Korea 7 Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, Korea Correspondence to: Eun Kyung Choi, email: ekchoi@amc.seoul.kr Kyung Hae Jung, email: khjung@amc.seoul.kr Keywords: PNP-DTX, phase I, MTD, efficacy, pancreas Received: March 27, 2016 Accepted: September 25, 2016 Published: October 14, 2016 ABSTRACT We assessed the efficacy of the polymeric nanoparticle containing docetaxel (PNP-DTX) in preclinical mouse models and determined the maximum tolerated dose (MTD) through clinical study. Subcutaneous and orthotopic mouse models were dedicated. Tumor growth delay in orthotopic model and quantification of in vivo imaging in orthotopic model were evaluated. Phase I clinical study was a single-center, prospective, open-label trial in advanced solid tumors. PNP-DTX was injected intravenously and the starting dose was 20 mg/m 2 escalated to 35 mg/m 2 , 45 mg/m 2 , 60 mg/m 2 and 75 mg/m 2 . Pharmacokinetics, tumor response, toxicities were evaluated. Preclinical result revealed the more potent cytotoxic effect of PNP-DTX than docetaxel (DTX). However, there was no difference between PNP-DTX and DTX in subcutaneous model. Tubulin polymerization assay showed that PNP-DTX preserved original mode of action of DTX. For phase I clinical trial, 18 patients were analyzed. The dose of 75 mg/m 2 was tentatively determined as the MTD and the most common toxicity was grade 4 neutropenia not lasting over 7days. The C max of 60 mg/m 2 PNP-DTX and AUC last of 45 mg/m 2 PNP-DTX were measured to be comparable to those of 75 mg/m 2 DTX. Partial remission (PR) was achieved in 4 (22%) patients. The potency of PNP-DTX was revealed especially in orthotopic mouse model. The MTD of PNP-DTX could not be confirmed, but 75 mg/m 2 was tentatively determined. The PNP-DTX of 45 mg/m 2 had the same pharmacokinetic profile with that of 75 mg/m 2 DTX.

Nanoxel-PM™, docetaxel-loaded methoxy-poly(ethylene glycol)-block-poly(d,l-lactide) (mPEG-PDLLA) micellar formulation was prepared in an effort to develop alternative, less toxic and efficacious Tween 80-free docetaxel formulation, and its pharmacokinetics, efficacy, and toxicity were evaluated in comparison with Taxotere® in preclinical studies. The mean diameter of the Nanoxel-PM™ was 10-50 nm and the polydispersity of samples exhibited a narrow size distribution and monodisperse unimodal pattern. Pharmacokinetic study in mice, rats and beagle dogs revealed that Nanoxel-PM™ exhibited similar pharmacokinetic profiles (C(max), AUC, t(1/2), CL, V(ss)) to Taxotere, and the relative mean AUC(t) and C(max) of Nanoxel-PM™ to Taxotere® were within 80-120%. Furthermore, excretion study in rats demonstrated that there was no statistically significant difference in the amount excreted in feces or urine as an unmetabolized docetaxel between Nanoxel-PM™ and Taxotere®. Its pharmacokinetic bioequivalence resulted in comparable anti-tumor efficacy to Taxotere® in human lung cancer xenografts H-460 in nude mice as well as in lung, ovary and breast cancer cell lines. Several animal toxicity studies on Nanoxel-PM™ compared with Taxotere® were carried out. In single dose rat and dog model and repeated dose mouse model, both Nanoxel-PM™ and Taxotere® exhibited similar toxic effects on hematology and body weight gain. On the other hand, vehicle related hypersensitivity reactions and fluid retentions were not observed when Nanoxel-PM™ was administered, unlike Taxotere®, in the beagle dog study. Based on these results, it is expected that Nanoxel-PM™ can reduce side effects of hypersensitivity reactions and fluid retention while retaining antitumor efficacy in cancer patients. Currently, Nanoxel-PM™ is under evaluation for bioequivalence with Taxotere® in a multi-center, open-label, randomized, crossover study.

For the development of in-situ gelling and mucoadhesive acetaminophen liquid suppository prepared with poloxamers (P 407, P 188) and sodium alginate, the physicochemical characteristics of liquid suppositories [acetaminophen/P 407/P 188/sodium alginate (5/15/19/0–1.0%)] were evaluated. Furthermore, a pharmacokinetic study of acetaminophen from liquid and conventional solid suppositories in human subjects was carried out. The results showed that acetaminophen liquid suppository [acetaminophen/P 407/P 188/sodium alginate (5/15/19/0.6%)] with optimal gelation temperature, gel strength and bioadhesive force had a similar release pattern to conventional suppository. The area under the drug concentration–time curve (AUC), mean residence time (MRT), biological half-life (t1/2) and apparent elimination rate constant (Kel) of acetaminophen from liquid suppository were not significantly different from those from conventional suppository. However, liquid suppository gave significantly faster the time to reach the maximum plasma concentration (Tmax) and higher the maximum plasma concentration of drug (Cmax) of acetaminophen than conventional suppository (p

The purpose of this work was to develop a solid dispersion system containing cyclosporin A (CsA) in order to improve the bioavailability of poorly water-soluble CsA. Solid dispersion systems that are spherical in shape (CsA-microspheres) were prepared with varying ratios of CsA/sodium lauryl sulfate/dextrin using a spray-drying technique. The effects of sodium lauryl sulfate (SLS) and dextrin on the dissolution of CsA dispersed in SLS-dextrin based solid microspheres were investigated. The bioavailability of CsA-microspheres was compared with CsA powder alone and commercial Sandimmun in dogs. SLS significantly enhanced the dissolution of CsA from microspheres, while dextrin did not affect this. The CsA-microspheres at the CsA/SLS/dextrin ratio of 1/3/1, which gave the highest dissolution rate of CsA among the formula treated, was selected as an optimal formula for oral delivery. This formula gave significantly higher blood levels, area under the drug concentration-time curve (AUC) and maximum blood concentration of drug (Cmax) of CsA in dogs compared with the CsA powder alone. The AUC, Cmax and time to reach maximum blood concentration (Tmax) of CsA with CsA-microspheres was not significantly different from those after oral administration of Sandimmun, suggesting the similar bioavailability to Sandimmun in dogs. Our study demonstrates that the CsA-microspheres prepared with SLS and dextrin, with improved bioavailability of CsA, would be useful to deliver a poorly water-soluble CsA and could be applicable to other poorly water-soluble drugs.