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Min Soo Kim,1,* Dong Woo Yeom,1,* Sung Rae Kim,1 Ho Yub Yoon,1 Chang Hyun Kim,1 Ho Yong Son,1 Jin Han Kim,1 Sangkil Lee,2 Young Wook Choi1 1College of Pharmacy, Chung-Ang University, Seoul, 2College of Pharmacy, Keimyung University, Daegu, South Korea *These authors contributed equally to this work Abstract: A double layer-coated colon-specific drug delivery system (DL-CDDS) was developed, which consisted of chitosan (CTN) based polymeric subcoating of the core tablet containing citric acid for microclimate acidification, followed by an enteric coating. The polymeric composition ratio of Eudragit E100 and ethyl cellulose and amount of subcoating were optimized using a two-level factorial design method. Drug-release characteristics in terms of dissolution efficiency and controlled-release duration were evaluated in various dissolution media, such as simulated colonic fluid in the presence or absence of CTNase. Microflora activation and a stepwise mechanism for drug release were postulated. Consequently, the optimized DL-CDDS showed drug release in a controlled manner by inhibiting drug release in the stomach and intestine, but releasing the drug gradually in the colon (approximately 40% at 10 hours and 92% at 24 hours in CTNase-supplemented simulated colonic fluid), indicating its feasibility as a novel platform for CDD. Keywords: chitosan, colon-specific delivery, acidification, microflora, factorial design, controlled release

To improve the dissolution behavior of telmisartan (TMS), a poorly water-soluble angiotensin II receptor blocker, TMS-phospholipid complex (TPC) was prepared by solvent evaporation method and characterized by differential scanning calorimetry and powder X-ray diffractometry. The crystalline structure of TMS was transited into an amorphous state by TPC formation. The equilibrium solubility of TPC (1.3–6.1 mg/mL) in various vehicles was about 100 times higher than that of TMS (0.009–0.058 mg/mL). TPC-loaded self-microemulsifying drug delivery system (SMEDDS) formulation was optimized using the D-optimal mixture design with the composition of 14% Capryol 90 (oil; X1), 59.9% tween 80 (surfactant; X2), and 26.1% tetraglycol (cosurfactant; X3) as independent variables, which resulted in a droplet size of 22.17 nm (Y1), TMS solubilization of 4.06 mg/mL (Y2), and 99.4% drug release in 15 min (Y3) as response factors. The desirability function value was 0.854, indicating the reliability and accuracy of optimization; in addition, good agreement was found between the model prediction and experimental values of Y1, Y2, and Y3. Dissolution of raw TMS was poor and pH-dependent, where it had extremely low dissolution (< 1% for 2 h) in water, pH 4, and pH 6.8 media; however, it showed fast and high dissolution (> 90% in 5 min) in pH 1.2 medium. In contrast, the dissolution of the optimized TPC-loaded SMEDDS was pH-independent and reached over 90% within 5 min in all the media tested. Thus, we suggested that phospholipid complex formation and SMEDDS formulation using the experimental design method might be a promising approach to enhance the dissolution of poorly soluble drugs.

Dong Woo Yeom,1,* Bo Ram Chae,2,* Ho Yong Son,1 Jin Han Kim,1 Jun Soo Chae,1 Seh Hyon Song,2 Dongho Oh,2 Young Wook Choi1 1College of Pharmacy, Chung-Ang University, Seoul, 2Daewon Pharm. Co., Ltd, Seoul, Republic of Korea *These authors contributed equally to this work Abstract: A novel, supersaturable self-microemulsifying drug delivery system (S-SMEDDS) was successfully formulated to enhance the dissolution and oral absorption of valsartan (VST), a poorly water-soluble drug, while reducing the total quantity for administration. Poloxamer 407 is a selectable, supersaturating agent for VST-containing SMEDDS composed of 10% Capmul® MCM, 45% Tween® 20, and 45% Transcutol® P. The amounts of SMEDDS and Poloxamer 407 were chosen as formulation variables for a 3-level factorial design. Further optimization was established by weighting different levels of importance on response variables for dissolution and total quantity, resulting in an optimal S-SMEDDS in large quantity (S-SMEDDS_LQ; 352 mg in total) and S-SMEDDS in reduced quantity (S-SMEDDS_RQ; 144.6 mg in total). Good agreement was observed between predicted and experimental values for response variables. Consequently, compared with VST powder or suspension and SMEDDS, both S-SMEDDS_LQ and S-SMEDDS_RQ showed excellent in vitro dissolution and in vivo oral bioavailability in rats. The magnitude of dissolution and absorption-enhancing capacities using quantity-based comparisons was in the order S-SMEDDS_RQ > S-SMEDDS_LQ > SMEDDS > VST powder or suspension. Thus, we concluded that, in terms of developing an effective SMEDDS preparation with minimal total quantity, S-SMEDDS_RQ is a promising candidate. Keywords: valsartan, SMEDDS, supersaturation, factorial design, optimization, bio­availability&nbsp

This paper addresses the problem in Web page ranking of effectively combining link and content information with efficiency high enough to be applicable to real-world search engines. Unlike previous surfer models, our approach is based on the viewpoint of a Web page author. Based on this viewpoint, we formulate the concept of contribution score, which indicates the amount to which a term in each page is utilized by other pages. To improve efficiency without loss of effectiveness, we exploit the expectations of both a Web page author and a Web search engine user on retrieval results, and restrict candidate terms that can contribute to other pages to a set of keywords of each page. In this paper, we propose three contribution-based models: C-Rank, PC-Rank and HC-Rank. Experimental results show that C-Rank provides the best precision among the models and is very effective for topic distillation tasks on the .GOV collection in TREC. Most importantly, the proposed models are efficient enough to be applicable to real-world search engines.

To improve the dissolution and oral bioavailability (BA) of atorvastatin calcium (ATV), we previously introduced an optimized self-microemulsifying drug delivery system (SMEDDS) using Capmul(®) MCM (oil), Tween(®) 20 (surfactant), and tetraglycol (cosurfactant). In this study, various solid carriers were employed to develop a solidified SMEDDS (S-SMEDDS): mannitol (M) and lactose (L) as water-soluble carriers, and Sylysia(®) 350 (S) and Aerosil(®) 200 (A) as water-insoluble carriers. Maximum solidifying capacities (SCmax) of water-insoluble carriers were significantly greater than those of water-soluble carriers were. The resultant powders were free flowing with an angle of repose

This paper proposes an approach to web page ranking that effectively combines link and content information with efficiency high enough to be applicable to real-world search engines. Experimental results show that the proposed approach gives better precision than existing models. Most importantly, it is fairly efficient enough to be applicable to real-world search engines.

Purpose: To determine the impact of stereotactic radiosurgery (SRS) on the clinical course, hormonal status, and follow-up CT/MRI scan of pituitary macroadenomas. Methods and Materials: From July 1988 to March 1996, 24 pituitary macroadenomas had been treated using 6 MV linear accelerator based SRS. They consisted of 11 (45.8%) prolactinomas, 2 (8.3%) growth hormone (GH)-secreting tumors, 1 (4.2%) Cushing’s disease, 8 (33.3%) nonsecreting (nonfunctioning: NF) tumors, and 2 (8.3%) mixed prolactin-growth hormone (PRL-GH)-secreting tumors (M:F = 12:12; aged 21–61 years). Postoperative irradiation was performed in all cases except for the instance of Cushing’s disease. The prescribed dose to tumor center varied from 10 to 27 Gy (mean 21.1 Gy) using a collimator size of 0.5 to 2.5 cm. The follow-up duration ranged from 13 to 89 months (mean 49.2 months). Results from these patients were compared to our results using conventional radiation. Results: Visual acuity and field defect were improved or became normal in 19 (79.2%) cases. Four (16.7%) remained unchanged after the treatment. One (4.1%) progressed 6 years after SRS and subsequently had repeat surgery with conventional boost irradiation. Of the 13 (46.4%) prolactinomas, including two mixed PRL-GH secreting tumors, 11 (84.1%) revealed normal hormonal levels within 1 year after SRS. In contrast, it took 2 years to become normal after conventional radiation therapy. In four GH-secreting tumors including two mixed PRL-GH secreting tumors, SRS and conventional methods showed similar responses. On follow-up imagings of the 21 patients, the mass was completely resolved in 4 (16.7%), including 3 PRLs and one NF, decreased in 11 (45.8%), and unchanged in 5 (16.7%) with central necrosis or cysts. One (4.2%) progressed and was reoperated 6 years after treatment. The complications related to SRS were comparable to those from conventional method. Conclusion: Radiosurgery can be used effectively in patients with pituitary adenoma. In this study, a more rapid hormonal and clinical response was achieved with radiosurgery than with conventional pituitary irradiation treatment.

We propose a robust H/sub /spl infin// controller for semi-active suspension system in this paper. For the improvement of riding performance, a robust H/sub /spl infin// controller is designed to satisfy robust stability and the suppression of the road disturbance using an H/sub /spl infin// controller design method. The performance of the designed controller under variable road conditions are evaluated by computer simulation and the simulation results show the usefulness and applicability of the proposed robust H/sub /spl infin// controller.