The search for pyruvate kinase-R activators; from a HTS screening hit via an impurity to the discovery of a lead series.

Pyruvate kinase (PK) is an essential component of cellular metabolism, converting ADP and phosphoenolpyruvate (PEP) to pyruvate in the final step of glycolysis. Of the four unique isoforms of pyruvate kinase, R (PKR) is expressed exclusively in red blood cells and is a tetrameric enzyme that depends on fructose-1,6-bisphosphate (FBP) for activation. PKR deficiency leads to hemolysis of red blood cells resulting in anemia. Activation of PKR in both sickle cell disease and beta-thalassemia patients could lead to improved red blood cell fitness and survival. The discovery of a novel series of substituted urea PKR activators, via the serendipitous identification and diligent characterization of a minor impurity in an High Throughput Screening (HTS) hit will be discussed.

Dynamic visualization of ultraviolet dose on skin with sunscreen applied using minimum erythema dose.

BACKGROUND: Visualizing the ultraviolet (UV) dose on skin serve as an intuitive approach to ensure appropriate sunscreen usage and reduce the risk of erythema. UV dose is determined by a number of external factors, such as properties of sunscreens, weather, and type of outdoor activity. We propose a framework for visualizing UV doses that considers various external factors. MATERIALS AND METHODS: First, the skin of a three-dimensional human model was represented using triangular meshes, and various static postures and dynamic motions were simulated to express outdoor activities. Then, we evaluated the persistency and insufficiency properties of sunscreen, which are time dependent and directly affect the effectiveness of the sunscreen skin protection factor (SPF) during UV exposure. Finally, to calculate the UV dose in real time, we tracked the trajectory of the sun and motion of the skin while considering the time-dependent properties of sunscreen. RESULTS: An S/W system was implemented based on the proposed framework to visualize the distribution of UV doses through dynamic color changes in exposed skin areas. The color types include true colors, which represent the minimum erythema dose (MED), and pseudo colors representing states before 1 MED is reached. We devised various examples to discuss the usability of the proposed framework. CONCLUSION: The system conveniently displays the MED according to an individual's skin phototype. When the properties of a wide range of commercial sunscreens are added to the system database, it is expected that the rate of appropriate sunscreen usage by customers will increase.

Layering sunscreen with facial makeup enhances its sun protection factor under real-use conditions.

BACKGROUND: The proper application of sunscreen is important to ensure protection of the skin against ultraviolet (UV) damage. Sunscreens are used in various ways in real world situations, which alters their UV protection efficacy. In this study, we simulated typical consumer use of sunscreen, which is often sequentially covered with facial makeup, in a laboratory study. METHODS: We compared the sun protection factors (SPF) of sunscreen and makeup products after consecutive layering of the products. RESULTS: The SPF of each sunscreen and makeup product was dramatically lower than stated on the label upon application of a typical amount used by a consumer, which is lower than recommended. For high-SPF products, the drop in effective protection was proportionally greater than those for the low-SPF products upon application of lower doses. However, layering sunscreen and makeup products greatly increased the effective SPF compared with that achieved by single application of each product, even when the amount of each product used was below the recommended level. CONCLUSION: Layering sunscreen with makeup may compensate for insufficient sunscreen application in real-life conditions by providing an additional source of UV protection and improving the homogeneity of coverage. Our results suggest that recommending consecutive application of sunscreen and makeup products may be a practical and useful approach to improving UV protection that would not require additional steps in the facial care routines of many individuals.

Evaluation of anisotropic properties of striae distensae with regard to skin surface texture and viscoelasticity.

BACKGROUND: Striae distensae (SD) are skin lesions of parallel streaks, which mostly occur during rapid tissue expansion. Considering the etiological mechanism of SD, including dermal network ruptures and alignment to mechanical stretch, structural directionality or anisotropy could be expected. Non-invasive objective methods for measuring the anisotropy of SD have not been suggested yet. Therefore, we evaluated the anisotropic properties of SD with regard to skin surface texture and viscoelasticity, to verify them as new objective evaluation parameters of SD. METHODS: Thirty-two healthy subjects with SD on their body participated. Anisotropy of skin surface texture and biomechanical properties of SD-involved skin and adjacent normal skin was assessed and compared. RESULTS: Analysis of skin surface texture, based on the ×60 magnified images, revealed that SD have more disordered patterns compared to the regular honeycomb patterns seen in the normal surrounding skin. SD have bigger sizes of each blob than normal skin. The overall anisotropy of skin texture was significantly higher in SD. Skin biomechanical parameters, measured using Cutiscan® , indicated the less deformable, less recovered, and less viscoelastic properties of SD. When comparing viscoelastic properties over 360°, SD were more anisotropic than the adjacent normal skin as well. CONCLUSION: We observed that SD were significantly more anisotropic than adjacent normal skin with regard to skin surface texture and viscoelasticity. Therefore, anisotropy could be an objective evaluation parameter to represent the distinctive features of SD. It can be applied for evaluation of the SD severity and clinical efficacy of various treatments.

Structures of full-length plasma kallikrein bound to highly specific inhibitors describe a new mode of targeted inhibition.

Plasma kallikrein (pKal) is a serine protease responsible for cleaving high-molecular-weight kininogen to produce the pro-inflammatory peptide, bradykinin. Unregulated pKal activity can lead to hereditary angioedema (HAE) following excess bradykinin release. HAE attacks can lead to a compromised airway that can be life threatening. As there are limited agents for prophylaxis of HAE attacks, there is a high unmet need for a therapeutic agent for regulating pKal with a high degree of specificity. Here we present crystal structures of both full-length and the protease domain of pKal, bound to two very distinct classes of small-molecule inhibitors: compound 1, and BCX4161. Both inhibitors demonstrate low nM inhibitory potency for pKal and varying specificity for related serine proteases. Compound 1 utilizes a surprising mode of interaction and upon binding results in a rearrangement of the binding pocket. Co-crystal structures of pKal describes why this class of small-molecule inhibitor is potent. Lack of conservation in surrounding residues explains the ∼10,000-fold specificity over structurally similar proteases, as shown by in vitro protease inhibition data. Structural information, combined with biochemical and enzymatic analyses, provides a novel scaffold for the design of targeted oral small molecule inhibitors of pKal for treatment of HAE and other diseases resulting from unregulated plasma kallikrein activity.

Preparation and Characterization of Celecoxib Nanosuspension Using Bead Milling.

The aim of this study is to develop nanosuspension for improved dissolution of poorly water-soluble celecoxib. We first prepared coarse suspension of celecoxib with Tween 80 and hydroxypropyl methylcellulose as stabilizers, and then fabricated nanosuspension using the bead milling technique. Depending on milling time, the physical properties of nanosuspension were evaluated by photon correlation spectroscopy (e.g., particle size and distribution) and scanning electron microscopy (SEM) (e.g., morphology). As results, the mean size of crystalline celecoxib particles was highly reduced (368.1±14.5 nm) as milling process proceeded comparing to celecoxib powder (6.5±1.0 µm). Morphology of milled celecoxib particles has changed considerably from bar-shape or plate-shape to needle-shape due to a high energy caused by milling. In the dissolution test, the celecoxib nanosuspension showed an improved dissolution profile at pH 1.2 compared to celecoxib powder (less than 1%). In contrast, 53.4% of celecoxib in nanosuspension was dissolved up to 30 minutes, demonstrating improved dissolution of celecoxib. Taken together, bead-milled nanosuspension could be an effective strategy that can improve the dissolution and bioavailability.

Effects of poloxamer 407-induced hyperlipidemia on hepatic multidrug resistance protein 2 (Mrp2/Abcc2) and the pharmacokinetics of mycophenolic acid in rats.

Hepatic multidrug resistance-associated protein 2 (Mrp2) is responsible for the majority of the biliary elimination of endogenous and exogenous substances, therefore it is important to evaluate possible functional changes in Mrp2 activity under conditions of hyperlipidemia (HL). Thus, the present study assessed the protein expression and transporting activity of hepatic Mrp2 based on the in vivo biliary excretion of phenolsulfonphthalein (PSP) as a model anionic substrate for Mrp2 in poloxamer 407-induced hyperlipidemic rats (HL rats) and compared these values with those for control rats. The pharmacokinetics of mycophenolic acid (MPA) and mycophenolic acid-7-O-glucuronide (MPAG) were evaluated after the intravenous (5 mg/kg) and oral (10 mg/kg) administration of MPA to control and HL rats. In HL rats, the protein expression of hepatic Mrp2 and its biliary transporting activity exhibited significant reductions (by 24.3% and 24.6%, respectively) in the absence of a change in bile flow rate. Unexpectedly, HL and control rats showed comparable biliary excretion rates of MPAG due to the counter effects of the reduced expression and activity of Mrp2 and a 484% increase in the free fraction of MPAG in HL rats. The estimated biliary clearance value of free MPAG in HL rats was considerably slower (by 77.1%) than that in control rats. Although significant pharmacokinetic changes in total MPA and MPAG levels were not observed in HL rats, there was a marked increase in free MPA and MPAG levels. Clinically relevant pharmacokinetic changes in subjects with HL that are related to MRP2 could not be ruled out. Copyright © 2016 John Wiley & Sons, Ltd.

Clinical outcomes of early gastric cancer with lymphovascular invasion or positive vertical resection margin after endoscopic submucosal dissection.

BACKGROUND: In early gastric cancer (EGC) cases with lymphovascular invasion or positive vertical margins after endoscopic submucosal dissection (ESD), additional radical gastrectomy is performed on principle. However, an additional surgery is often difficult to consider if the surgical approach itself is challenging or the patient refuses surgery. In such cases, only close surveillance is performed without additional surgical procedures. This study aimed to examine the difference in clinical prognosis of EGC cases with lymphovascular invasion or positive vertical margins after ESD either with or without surgery. METHODS: We retrospectively studied 83 patients with lymphovascular invasion or positive vertical margins after ESD from July 2005 to November 2013. RESULTS: Of the 83 patients, 45 (54.2%) underwent radical additional gastrectomy (surgical group) and 38 (45.8%) were under close surveillance without surgical or endoscopic treatments (close surveillance group.) The cancer-free survival period was 78.3 ± 3.4 months in the surgical group and 64.5 ± 4.6 months in the close surveillance group. The recurrence rates did not significantly differ between the 2 groups, at 7.9% in the surgical group and 6.7% in the non-surgical group. CONCLUSIONS: Close surveillance may be suggested as an option for EGC patients for whom a surgical approach is difficult, who exhibit a positive vertical margin after ESD, and who have no lymphovascular or deep submucosa invasion after ESD.

Pharmacokinetics of tolbutamide and its metabolite 4-hydroxy tolbutamide in poloxamer 407-induced hyperlipidemic rats.

Under hyperlipidemic conditions, there are likely to be alterations in the pharmacokinetics of CYP2C11 substrates following decreased expression of CYP2C11, which is homologous to human CYP2C9. The pharmacokinetics of tolbutamide (TB) and its metabolite 4-hydroxy tolbutamide (4-OHTB) were evaluated as a CYP2C11 probe after intravenous and oral administration of 10 mg/kg tolbutamide to poloxamer 407-induced hyperlipidemic rats (HL rats). Changes in the expression and metabolic activity of hepatic CYP2C11 and the plasma protein binding of tolbutamide in HL rats were also evaluated. The total area under the plasma concentration-time curve (AUC) of tolbutamide in HL rats after intravenous administration was comparable to that in controls due to their comparable non-renal clearance (CLNR ). The free fractions of tolbutamide in plasma were comparable between the control and HL rats. The 4-hydroxylated metabolite formation ratio (AUC4-OHTB /AUCTB ) in HL rats was significantly smaller than that in the control rats as a result of the reduced expression of hepatic CYP2C11 (by 15.0%) and decreased hepatic CLint (by 28.8%) for metabolism of tolbutamide to 4-OHTB via CYP2C11. Similar pharmacokinetic changes were observed in HL rats after oral administration of tolbutamide. These findings have potential therapeutic implications, assuming that the HL rat model qualitatively reflects similar changes in patients with hyperlipidemia. Since other sulfonylureas in clinical use are substrates of CYP2C9, their hepatic CLint changes have the potential to cause clinically relevant pharmacokinetic changes in a hyperlipidemic state.

Physiologically Based Pharmacokinetic (PBPK) Modeling to Predict CYP3A-Mediated Drug Interaction between Saxagliptin and Nicardipine: Bridging Rat-to-Human Extrapolation.

The aim of this study was to predict the cytochrome P450 3A (CYP3A)-mediated drug-drug interactions (DDIs) between saxagliptin and nicardipine using a physiologically based pharmacokinetic (PBPK) model. Initially, in silico and in vitro parameters were gathered from experiments or the literature to construct PBPK models for each drug in rats. These models were integrated to predict the DDIs between saxagliptin, metabolized via CYP3A2, and nicardipine, exhibiting CYP3A inhibitory activity. The rat DDI PBPK model was completed by optimizing parameters using experimental rat plasma concentrations after co-administration of both drugs. Following co-administration in Sprague-Dawley rats, saxagliptin plasma concentration significantly increased, resulting in a 2.60-fold rise in AUC, accurately predicted by the rat PBPK model. Subsequently, the workflow of the rat PBPK model was applied to humans, creating a model capable of predicting DDIs between the two drugs in humans. Simulation from the human PBPK model indicated that nicardipine co-administration in humans resulted in a nearly unchanged AUC of saxagliptin, with an approximate 1.05-fold change, indicating no clinically significant changes and revealing a lack of direct translation of animal interaction results to humans. The animal-to-human PBPK model extrapolation used in this study could enhance the reliability of predicting drug interactions in clinical settings where DDI studies are challenging.

Efficacy of combined osteotomy and ulnar nerve transposition for cubitus valgus with ulnar nerve palsy in adults.

BACKGROUND: Tardy ulnar nerve palsy is a common late complication of traumatic cubitus valgus deformity. Whether both problems can be corrected together, safely and effectively, in a single surgical procedure remains unknown. QUESTIONS/PURPOSES: We therefore reviewed a patient cohort having this combined surgery and compared preoperatively and at a minimum of 24 months postoperatively (1) active elbow ROM; (2) radiographic correction of the cubitus valgus deformity of the preoperative and postoperative humerus-elbow-wrist angles and the medial prominence index; (3) ulnar nerve function through grip strength and static two-point discrimination; and (4) overall upper limb disability by the DASH score. METHODS: Between 2004 and 2009, 13 patients who had traumatic cubitus valgus deformities and tardy ulnar nerve palsy (Dellon's Grade III) were treated with simultaneous supracondylar dome osteotomy and anterior transposition of the ulnar nerve and were reviewed retrospectively. The minimum followup was 24 months (mean, 33 months; range, 24-52 months). RESULTS: The mean preoperative ROM was 16° to 124° and mean postoperative ROM was 10° to 126°. All osteotomies healed uneventfully. The mean postoperative humerus-elbow-wrist angle was 11° and the average correction was 24°. None of the patients had recurrence of the deformity or residual prominence of the medial condyle at the last followup. The mean grip strength and static two-point discrimination improved from 20 kg of force and 6.9 mm to 27 kg of force and 4.0 mm (p=0.002 and p=0.004, respectively). Subjective ulnar nerve symptoms improved in all but one patient. The mean DASH score improved from 29 points to 16 points (p=0.001). CONCLUSION: A combined supracondylar dome osteotomy and anterior transposition of the ulnar nerve is effective in correcting posttraumatic cubitus valgus deformity and its associated ulnar nerve palsy. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

[(18)F]T807, a novel tau positron emission tomography imaging agent for Alzheimer's disease.

OBJECTIVE: We wished to develop a highly selective positron emission tomography (PET) imaging agent targeting PHF-tau in human Alzheimer's disease (AD) brains. METHODS: To screen potential tau binders, human AD brain sections were used as a source of native paired helical filament (PHF)-tau and Aß rather than synthetic tau aggregates or Aß fibrils generated in vitro to measure the affinity and selectivity of [(18)F]T807 to tau and Aß. Brain uptake and biodistribution of [(18)F]T807 in mice were also tested. RESULTS: In vitro autoradiography results show that [(18)F]T807 exhibits strong binding to PHF-tau-positive human brain sections. A dissociation constant (Kd) of [(18)F]T807 (14.6 nM) was measured using brain sections from the frontal lobe of AD patients. A comparison of autoradiography and double immunohistochemical staining of PHF-tau and Aß on adjacent sections demonstrated that [(18)F]T807 binding colocalized with immunoreactive PHF-tau pathology, but did not highlight Aß plaques. In vivo studies in mice demonstrated that [(18)F]T807 was able to cross the blood-brain barrier and washed out quickly. CONCLUSIONS: [(18)F]T807 demonstrates high affinity and selectivity to PHF-tau as well as favorable in vivo properties, making this a promising candidate as an imaging agent for AD.

A long term study of the difference in efficacy and effect rate of various concentrations of retinol (1500-6600 IU) in middle aged women.

Retinol is widely used for topical application for antiaging. However, the efficacy and effect rate of different concentrations of retinol have been rarely analyzed. Therefore, in this study, the efficacy and rate of effect of retinol concentrations from 1500 to 6600 IU, on various skin parameters, have been compared. Seventy-two Korean women aged 40-59 years participated in this study. Retinol was used by them for 24 weeks; the effects were measured at 0, 2, 4, 8, 12, and 24 weeks. The measurement parameters for aging were crow's feet, forehead wrinkles, nasolabial fold, dermal density, and elasticity and that for skin color were skin brightness, yellowness, redness, and standard deviation of skin brightness. The texture of the skin was measured by measuring the skin roughness and pores, and the skin barrier function was evaluated through hydration, sebum, and desquamation. Low concentration retinol (1500-2500 IU) had a significantly higher effect in skin color, brightness, and elasticity and faster improvement rate in skin brightness and elasticity compared to that for high concentration (3300-6600 IU). High concentration of retinol had a significantly higher effect in wrinkles, dermal density and pores and faster improvement rate for wrinkles, skin texture, pores, and desquamation compared to that for low concentration. This study evaluated the changes caused by different concentration of retinol over a long period of time. The results of this study have great implications as the optimal concentration of retinol can be prescribed for an accurate period for the desired results without side effects.

Skin biophysical properties including impaired skin barrier function determine ultraviolet sensitivity.

BACKGROUND: The levels of burning susceptibility to ultraviolet (UV) radiations are affected by various factors, including Fitzpatrick skin types, skin color, sex, and ethnicity. However, studies on the relationship between skin biophysical properties and erythemal responses to UV radiations are rare. OBJECTIVE: This study aimed to investigate biophysical properties of the skin that determined individual skin sensitivity to UV radiation. METHODS: As an indicator of skin sensitivity to UV radiation, Korean women were subjected to minimal erythema dose (MED) testing. The skin biophysical properties, such as skin hydration, transepidermal water loss (TEWL), were measured. MED were also evaluated in further variations in the skin, including barrier disruption. RESULTS: A significant negative correlation was observed between TEWL and MED. With an increase in TEWL, that represents reduced skin barrier function, skin UV sensitivity also increased. Artificial alteration of skin conditions also changed erythemal response to UV radiation. When the skin barrier was disrupted, MED significantly decreased, indicating increased skin UV sensitivity. It is hypothesized that the altered penetration of UV radiation into the stratum corneum under the respective skin conditions caused different erythema reactions. CONCLUSION: For the first time in a clinical study, the skin biophysical properties, including skin barrier function, were found to have significant effects on skin sensitivity to UV radiation. This finding could help predict individual susceptibility to UV damage. Therefore, skincare products that improve skin conditions associated with UV sensitivity, as well as sunscreen are important for protection against the hazards of UV radiation.

Structure-activity relationship (SAR) of the α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists.

This letter describes the structure-activity relationship (SAR) of the 'right-wing' α-amino acid residue of potent tetrahydroisoquinoline (THIQ)-derived LFA-1/ICAM-1 antagonists. Novel (S)-substituted heteroaryl-bearing α-amino acids have been identified as replacements of the 'right-wing' (S)-2,3-diaminopropanoic acid (DAP) moiety. Improvement of potency in the Hut-78 assay in the presence of 10% human serum has also been achieved.

Comparison of Pharmacokinetics and Anti-Pulmonary Fibrosis-Related Effects of Sulforaphane and Sulforaphane N-acetylcysteine.

Sulforaphane (SFN), belonging to the isothiocyanate family, has received attention owing to its beneficial activities, including chemopreventive and antifibrotic effects. As sulforaphane N-acetylcysteine (SFN-NAC), a major sulforaphane metabolite, has presented similar pharmacological activities to those of SFN, it is crucial to simultaneously analyze the pharmacokinetics and activities of SFN and SFN-NAC, to comprehensively elucidate the efficacy of SFN-containing products. Accordingly, the anti-pulmonary fibrotic effects of SFN and SFN-NAC were assessed, with simultaneous evaluation of permeability, metabolic stability, and in vivo pharmacokinetics. Both SFN and SFN-NAC decreased the levels of transforming growth factor-ß1-induced fibronectin, alpha-smooth muscle actin, and collagen, which are major mediators of fibrosis, in MRC-5 fibroblast cells. Regarding pharmacokinetics, SFN and SFN-NAC were metabolically unstable, especially in the plasma. SFN-NAC degraded considerably faster than SFN in plasma, with SFN being formed from SFN-NAC. In rats, SFN and SFN-NAC showed a similar clearance when administered intravenously; however, SFN showed markedly superior absorption when administered orally. Although the plasma SFN-NAC concentration was low owing to poor absorption following oral administration, SFN-NAC was converted to SFN in vivo, as in plasma. Collectively, these data suggest that SFN-NAC could benefit a prodrug formulation strategy, possibly avoiding the gastrointestinal side effects of SFN, and with improved SFN-NAC absorption.

Discovery of tetrahydroisoquinoline (THIQ) derivatives as potent and orally bioavailable LFA-1/ICAM-1 antagonists.

This letter describes the discovery of a novel series of tetrahydroisoquinoline (THIQ)-derived small molecules that potently inhibit both human T-cell migration and super-antigen induced T-cell activation through disruption of the binding of integrin LFA-1 to its receptor, ICAM-1. In addition to excellent in vitro potency, 6q shows good pharmacokinetic properties and its ethyl ester (6t) demonstrates good oral bioavailability in both mouse and rat. Either intravenous administration of 6q or oral administration of its ethyl ester (6t) produced a significant reduction of neutrophil migration in a thioglycollate-induced murine peritonitis model.

Development of 20(S)-Protopanaxadiol-Loaded SNEDDS Preconcentrate Using Comprehensive Phase Diagram for the Enhanced Dissolution and Oral Bioavailability.

In this study, we aimed to develop a 20(S)-protopanaxadiol (PPD)-loaded self-nanoemulsifying drug delivery system (SNEDDS) preconcentrate (PSP) using comprehensive ternary phase diagrams for enhanced solubility, physical stability, dissolution, and bioavailability. Capmul MCM C8 and Capryol 90 were selected as the oil phase owing to the high solubility of PPD in these vehicles (>15%, w/w). Novel comprehensive ternary phase diagrams composed of selected oil, surfactant, and PPD were constructed, and the solubility of PPD and particle size of vehicle was indicated on them for the effective determination of PSP. PSPs were confirmed via particle size distribution, physical stability, and scanning electron microscope (SEM) with the dispersion of water. The optimized PSP (CAPRYOL90/Kolliphor EL/PPD = 54/36/10, weight%) obtained from the six possible comprehensive ternary phase diagrams showed a uniform nanoemulsion with the particle size of 125.07 ± 12.56 nm without any PPD precipitation. The PSP showed a dissolution rate of 94.69 ± 2.51% in 60 min at pH 1.2, whereas raw PPD showed negligible dissolution. In oral pharmacokinetic studies, the PSP group showed significantly higher Cmax and AUCinf values (by 1.94- and 1.81-fold, respectively) than the raw PPD group (p < 0.05). In conclusion, the PSP formulation with outstanding solubilization, dissolution, and in-vivo oral bioavailability could be suggested using effective and comprehensive ternary phase diagrams.

Preparation and Characterization of Tenofovir Disoproxil-Loaded Enteric Microparticle.

Tenofovir disoproxil (TD) has narrow absorption site mostly in upper intestinal tract where tenofovir rapidly decomposes. The aim of this work was to prepare and evaluate tenofovir disoproxil-loaded enteric microparticles (TDEMs) for the enhanced duodenal delivery. TDEMs were composed of TD, eudragit L-100 (EL) and ethyl cellulose (EC) as release-controlling polymers. For the physicochemical characterization, TDEMs were evaluated in terms of encapsulation efficiency (EE%), scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FT-IR). The dissolution test was also performed while continuously changing the medium pH. The EE% of TD in TDEMs was good and more than 90%. The EC and EL formed a physically mixed structure and maintained their respective properties in TDEMs as confirmed by SEM image and FT-IR analysis. Combination of EL and EC gave higher enteric properties to TDEMs than the single use of EL or EC. The optimized TDEM (TD/EL/EC = 0.2/1/1, w/w/w ratio) yielded mean dissolution rate less than 10% in 1 h at pH 1.2, but completed dissolution with a dissolution more than 85% within 1 h at pH 6.5. Thus, the suggested TDEM would be promising enteric microparticles for the intensive delivery of TD to the duodenum.

Optimization of Hydroxypropyl Methylcellulose and Dextrin in Development of Dried Nanosuspension for Poorly Water-Soluble Drug.

The purpose of this study is to identify the effects of a stabilizer and matrix former in the development of a celecoxib dried nanosuspension (DNS) for high dissolution rate and drug loading. Tween 80 and Hydroxypropyl Methylcellulose (HPMC) were used as stabilizers in the bead-milling process and dextrin was used as the matrix former in the spray-drying. Various nanosuspensions (NS) were prepared by varying the ratio of HPMC and dextrin, and the physicochemical properties of each formulation were evaluated for particle size, morphology, drug loading, crystallinity, redispersibility, physical stability and dissolution rate. HPMC efficiently stabilized the NS system and reduced the particle size of NS. The mean particle size of the NS with 0.5% HPMC (w/v) was the smallest (248 nm) of all formulations. Dextrin has been shown to inhibit the increase of particle size efficiently, which is known to occur frequently when NS is being solidified. As the dextrin increased in DNS, the dissolution rates of reconstituted NS were significantly improved. However, it was confirmed that more than the necessary amount of dextrin in DNS reduced the dissolution and drug loading. The dissolution of celecoxib in DNS prepared at the ratio (drug:dextrin, 1:2.5) was almost the highest. The dissolution of optimal formulation was 95.8% at 120 min, which was 2.0-fold higher than that of NS dried without dextrin. In conclusion, these results suggest that the formulation based on Tween 80, HPMC and dextrin may be an effective option for DNS to enhance its in vitro dissolution and in vivo oral absorption.