[Show abstract][Hide abstract] ABSTRACT: In the present study, solid dispersion nanoparticles with a hydrophilic polymer and surfactant were developed using the supercritical antisolvent (SAS) process to improve the dissolution and oral absorption of megestrol acetate. The physicochemical properties of the megestrol acetate solid dispersion nanoparticles were characterized using scanning electron microscopy, differential scanning calorimetry, powder X-ray diffraction, and a particle-size analyzer. The dissolution and oral bioavailability of the nanoparticles were also evaluated in rats. The mean particle size of all solid dispersion nanoparticles that were prepared was <500 nm. Powder X-ray diffraction and differential scanning calorimetry measurements showed that megestrol acetate was present in an amorphous or molecular dispersion state within the solid dispersion nanoparticles. Hydroxypropylmethyl cellulose (HPMC) solid dispersion nanoparticles significantly increased the maximum dissolution when compared with polyvinylpyrrolidone K30 solid dispersion nanoparticles. The extent and rate of dissolution of megestrol acetate increased after the addition of a surfactant into the HPMC solid dispersion nanoparticles. The most effective surfactant was Ryoto sugar ester L1695, followed by D-α-tocopheryl polyethylene glycol 1000 succinate. In this study, the solid dispersion nanoparticles with a drug:HPMC:Ryoto sugar ester L1695 ratio of 1:2:1 showed >95% rapid dissolution within 30 minutes, in addition to good oral bioavailability, with approximately 4.0- and 5.5-fold higher area under the curve (0-24 hours) and maximum concentration, respectively, than raw megestrol acetate powder. These results suggest that the preparation of megestrol acetate solid dispersion nanoparticles using the supercritical antisolvent process is a promising approach to improve the dissolution and absorption properties of megestrol acetate.
Drug Design, Development and Therapy 09/2015; 9:4269-77. DOI:10.2147/DDDT.S90706 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study was carried out to develop an oral formulation of pranlukast hemihydrate with improved dissolution and oral bioavailability using a surface-modified microparticle. Based on solubility measurements, surface-modified pranlukast hemihydrate microparticles were manufactured using the spray-drying method with hydroxypropylmethyl cellulose, sucrose laurate, and water and without the use of an organic solvent. The hydrophilicity of the surface-modified pranlukast hemihydrate microparticle increased, leading to enhanced dissolution and oral bioavailability of pranlukast hemihydrate without a change in crystallinity. The surface-modified microparticles with an hydroxypropylmethyl cellulose/sucrose laurate ratio of 1:2 showed rapid dissolution of up to 85% within 30 minutes in dissolution medium (pH 6.8) and oral bioavailability higher than that of the commercial product, with approximately 2.5-fold and 3.9-fold increases in area under the curve (AUC0→12 h) and peak plasma concentration, respectively. Therefore, the surface-modified microparticle is an effective oral drug delivery system for the poorly water-soluble therapeutic pranlukast hemihydrate.
Drug Design, Development and Therapy 06/2015; 9:3257-3266. DOI:10.2147/DDDT.S87738 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, a gelatin microparticle-containing self-microemulsifying formulation (SMF) was developed using a spray-drying method to enhance the oral delivery of the poorly water-soluble therapeutic dutasteride. The effect of the amount of gelatin and the type and amount of hydrophilic additives, namely, Gelucire(®) 44/14, poloxamer 407, sodium lauryl sulfate, Soluplus(®), Solutol™ HS15, and D-α-tocopheryl polyethylene glycol 1000 succinate, on the droplet size, dissolution, and oral absorption of dutasteride from the SMF was investigated. Upon dispersion of the gelatin microparticle-containing SMF in water after spray-drying, the mean droplet size of the aqueous dispersion was in the range of 110-137 nm. The in vitro dissolution and recrystallization results showed that gelatin could be used as a solid carrier and recrystallization inhibitor for the SMF of dutasteride. Furthermore, combination of the gelatin microparticle-containing SMF and Soluplus enhanced the dissolution properties and oral absorption of dutasteride. The results of our study suggest that the gelatin microparticle-containing SMF in combination with Soluplus could be useful to enhance the oral absorption of dutasteride.
Drug Design, Development and Therapy 06/2015; 9:3231-3238. DOI:10.2147/DDDT.S86458 · 3.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study aimed to investigate the effect of Eudragit® E/HCl (E-SD) on the degradation of sirolimus in simulated gastric fluid (pH 1.2) and to develop a new oral formulation of sirolimus using E-SD solid dispersions to enhance oral bioavailability. Sirolimus-loaded solid dispersions were fabricated by a spray drying process. A kinetic solubility test demonstrated that the sirolimus/E-SD/TPGS (1/8/1) solid dispersion had a maximum solubility of 196.7 μg/mL within 0.5 h that gradually decreased to 173.4 μg/mL after 12 h. According to the dissolution study, the most suitable formulation was the sirolimus/E-SD/TPGS (1/8/1) solid dispersion in simulated gastric fluid (pH 1.2), owing to enhanced stability and degree of supersaturation of E-SD and TPGS. Furthermore, pharmacokinetic studies in rats indicated that compared to the physical mixture and sirolimus/HPMC/TPGS (1/8/1) solid dispersion, the sirolimus/E-SD/TPGS (1/8/1) solid dispersion significantly improved oral absorption of sirolimus. E-SD significantly inhibited the degradation of sirolimus in a dose-dependent manner. E-SD also significantly inhibited the precipitation of sirolimus compared to hydroxypropylmethyl cellulose (HPMC). Therefore, the results from the present study suggest that the sirolimus-loaded E-SD/TPGS solid dispersion has great potential in clinical applications.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to prepare a dutasteride-loaded solid-supersaturatable self-microemulsifying drug delivery system (SMEDDS) using hydrophilic additives with high oral bioavailability, and to determine if there was a correlation between the in vitro dissolution data and the in vivo pharmacokinetic parameters of this delivery system in rats. A dutasteride-loaded solid-supersaturatable SMEDDS was generated by adsorption of liquid SMEDDS onto Aerosil 200 colloidal silica using a spray drying process. The dissolution and oral absorption of dutasteride from solid SMEDDS significantly increased after the addition of hydroxypropylmethyl cellulose (HPMC) or Soluplus. Solid SMEDDS/Aerosil 200/Soluplus microparticles had higher oral bioavailability with 6.8- and 5.0-fold higher peak plasma concentration (Cmax) and area under the concentration-time curve (AUC) values, respectively, than that of the equivalent physical mixture. A linear correlation between in vitro dissolution efficiency and in vivo pharmacokinetic parameters was demonstrated for both AUC and Cmax values. Therefore, the preparation of a solid-supersaturatable SMEDDS with HPMC or Soluplus could be a promising formulation strategy to develop novel solid dosage forms of dutasteride.
International Journal of Molecular Sciences 05/2015; 16(5):10821-10833. DOI:10.3390/ijms160510821 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Etanercept was approved by the Food and Drug Administration (FDA) in 2010 as a biologic agent for the treatment of rheumatoid arthritis (RA). The aim of the study was to investigate the pharmacokinetic properties of etanercept after intravenous and subcutaneous injection in rats. The plasma concentration of etanercept was determined using an enzyme-linked immunosorbent assay (ELISA). Intravenous and subcutaneous administration of 2 mg/kg of etanercept to rats showed that etanercept was slowly absorbed (time to reach the peak drug concentration [T
max] = 1.60 days, bioavailability [F] = 47.18 %) and slowly eliminated (half-life [t
1/2], 2.33 days after intravenous administration and 3.31 days after subcutaneous administration). The area under the curve values on day 13 (AUC13day) were 121.25 ± 14.37 and 48.56 ± 6.78 μg day/mL after intravenous and subcutaneous administration, respectively. A two-compartment model with Michaelis–Menten elimination kinetics (V
max = 94.28 µg/day; K
m = 10.88 µg/mL) was used to describe the pharmacokinetic profile of etanercept. Our results describe the pharmacokinetic profile of etanercept, and these results could be used for the development of etanercept biosimilars.
European Journal of Drug Metabolism and Pharmacokinetics 03/2015; DOI:10.1007/s13318-015-0270-9 · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to develop celecoxib-polyvinylpyrrolidone (PVP) solid dispersion nanoparticles with and without surfactant using the supercritical antisolvent (SAS) process. The effect of different surfactants such as gelucire 44/14, poloxamer 188, poloxamer 407, Ryoto sugar ester L1695, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) on nanoparticle formation and dissolution as well as oral absorption of celecoxib-PVP K30 solid dispersion nanoparticles was investigated. Spherical celecoxib solid dispersion nanoparticles less than 300 nm in size were successfully developed using the SAS process. Analysis by differential scanning calorimetry and powder X-ray diffraction showed that celecoxib existed in the amorphous form within the solid dispersion nanoparticles fabricated using the SAS process. The celecoxib-PVP-TPGS solid dispersion nanoparticles significantly enhanced in vitro dissolution and oral absorption of celecoxib relative to that of the unprocessed form. The area under the concentration-time curve (AUC0→24 h) and peak plasma concentration (Cmax) increased 4.6 and 5.7 times, respectively, with the celecoxib-PVP-TPGS formulation. In addition, in vitro dissolution efficiency was well correlated with in vivo pharmacokinetic parameters. The present study demonstrated that formulation of celecoxib-PVP-TPGS solid dispersion nanoparticles using the SAS process is a highly effective strategy for enhancing the bioavailability of poorly water-soluble celecoxib.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to fabricate valsartan composite nanoparticles by using the supercritical antisolvent (SAS) process, and to evaluate the correlation between in vitro dissolution and in vivo pharmacokinetic parameters for the poorly water-soluble drug valsartan. Spherical composite nanoparticles with a mean size smaller than 400 nm, which contained valsartan, were successfully fabricated by using the SAS process. X-ray diffraction and thermal analyses indicated that valsartan was present in an amorphous form within the composite nanoparticles. The in vitro dissolution and oral bioavailability of valsartan were dramatically enhanced by the composite nanoparticles. Valsartan-hydroxypropyl methylcellulose-poloxamer 407 nanoparticles exhibited faster drug release (up to 90% within 10 minutes under all dissolution conditions) and higher oral bioavailability than the raw material, with an approximately 7.2-fold higher maximum plasma concentration. In addition, there was a positive linear correlation between the pharmacokinetic parameters and the in vitro dissolution efficiency. Therefore, the preparation of composite nanoparticles with valsartan-hydroxypropyl methylcellulose and poloxamer 407 by using the SAS process could be an effective formulation strategy for the development of a new dosage form of valsartan with high oral bioavailability.
International Journal of Nanomedicine 11/2014; 9:5167-76. DOI:10.2147/IJN.S71891 · 4.38 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to develop lercanidipine-hydroxypropylmethyl cellulose (HPMC) nanoparticles with high oral bioavailability. The lercanidipine-HPMC nanoparticles with/without surfactants were manufactured using a supercritical antisolvent (SAS) process. Gelucire 44/14, poloxamer 407, and d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) were evaluated as surfactants. Spherical lercanidipine-HPMC nanoparticles with a mean particle size less than 400nm were successfully prepared using a SAS process. The dissolution and oral bioavailability of lercanidipine was significantly increased by addition of surfactants. Especially lercanidipine-HPMC nanoparticles with TPGS showed a 2.47-fold higher oral bioavailability than raw material. Furthermore, the dissolution efficiency was strongly correlated to the in vivo Cmax and AUC0→24h. Therefore, the preparation of HPMC nanoparticles with TPGS using a SAS process is a highly effective formulation strategy for enhanced oral bioavailability of lercanidipine.
International Journal of Biological Macromolecules 08/2014; 72. DOI:10.1016/j.ijbiomac.2014.08.017 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to investigate the effect of Soluplus® on the solubility of atorvastatin calcium and to develop a solid dispersion formulation that can improve the oral bioavailability of atorvastatin calcium. We demonstrated that Soluplus® increases the aqueous solubility of atorvastatin calcium. Several solid dispersion formulations of atorvastatin calcium with Soluplus® were prepared at various drug : carrier ratios by spray drying. Physicochemical analysis demonstrated that atorvastatin calcium is amorphous in each solid dispersion, and the 2 : 8 drug : carrier ratio provided the highest degree of sustained atorvastatin supersaturation. Pharmacokinetic analysis in rats revealed that the 2 : 8 dispersion significantly improved the oral bioavailability of atorvastatin. This study demonstrates that spray-dried Soluplus® solid dispersions can be an effective method for achieving higher atorvastatin plasma levels.
[Show abstract][Hide abstract] ABSTRACT: 1. JHL45, a novel immune modulator against atopic dermatitis (AD), was synthesized from decursin isolated from Angelica gigas. The goal is to evaluate the lead compound using quantitative modeling approaches to novel anti-AD drug development. 2. We tested the anti-inflammatory effect of JHL45 by in vitro screening, characterized its in vitro pharmacokinetic (PK) properties. The dose-dependent efficacy of JHL45 was developed using a pharmacokinetics/pharmacodynamics/disease progression (PK/PD/DIS) model in NC/Nga mice. 3. JHL45 has drug-like properties and pharmacological effects when administered orally to treat atopic dermatitis. The developed PK/PD/DIS model described well the rapid metabolism of JHL45, double-peak phenomenon in the PK of decursinol and inhibition of IgE generation by compounds in NC/Nga mice. Also, a quantitative model was developed and used to elucidate the complex interactions between serum IgE concentration and atopic dermatitis symptoms. 4. Our findings indicate that JHL45 has good physicochemical properties and powerful pharmacological effects when administered orally for treatment of AD in rodents.
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to develop a novel valsartan-loaded spray-dried emulsion based on hydroxypropylmethyl cellulose (HPMC) with enhanced oral absorption. The valsartan-loaded redispersible dry emulsion was prepared by using a high-pressure homogenization and spray-drying process with water, Capryol 90, HPMC, and different surfactants, based on the results of the solubility study. The spray-dried emulsions formed small and homogeneous emulsions with a mean droplet emulsion size ranging from 133.5 to 152.5nm at the dispersion state in water. The valsartan-loaded redispersible dry emulsion with HPMC/poloxamer 407 showed enhanced pH-independent valsartan release, resulting in a dramatically enhanced oral bioavailability of valsartan compared to the raw material and commercial product. Therefore, a formulation strategy using the redispersible dry emulsion with HPMC/poloxamer 407 is very effective for the development of a new dosage form containing valsartan.
International Journal of Biological Macromolecules 05/2014; 69. DOI:10.1016/j.ijbiomac.2014.05.059 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim:
The objective of the present study was to develop population pharmacokinetic models for olmesartan medoxomil and hydrochlorothiazide and to investigate the influence of demographic factors on these population pharmacokinetics.
Plasma concentrations of olmesartan medoxomil and hydrochlorothiazide were measured in 41 healthy volunteers enrolled in our bioequivalence study by LC-MS/MS following oral administration of an olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) fixed-dose combination tablet. This data and covariates were subjected to nonlinear mixed-effect modeling analysis using the NONMEM software. Evaluation featured a visual predicted check and bootstrapping.
The distributions of olmesartan medoxomil and hydrochlorothiazide were best fitted using a two-compartment model with no lag time and first-order elimination. When analyzing hydrochlorothiazide kinetics, we found that TCHO and CL/F were correlated, while. HB and Ka influenced olmesartan medoxomil modeling. All evaluations indicated that the pharmacokinetic profiles of olmesartan medoxomil and hydrochlorothiazide were adequately described using our PPK model.
This study indicates that demographic factors influence the inter-individual variability in the disposition of the combination drug, and it might be more useful to apply it to the PK of olmesartan medoxomil/hydrochlorothiazide (20/12.5 mg) FDC tablets administered to patients with hypertension. *These two authors contributed equally to this work.
International journal of clinical pharmacology and therapeutics 05/2014; 52(8). DOI:10.5414/CP202046 · 1.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The objective of this study was to investigate the effect of particle size on the dissolution and oral absorption of pranlukast microsuspensions and nanosuspensions stabilized by hydroxypropylmethyl cellulose. Four pranlukast suspensions with different mean particle sizes (0.16, 0.89, 3.13, and 18.21μm) were prepared by various top-down processes such as jet milling, high pressure homogenization, and bead milling. The dissolution rate and oral absorption of pranlukast suspensions were significantly affected by the particle size. The in vivo pharmacokinetic parameters of pranlukast suspensions were increased with decreasing mean particle size of suspensions. Especially, the AUC0→24h and Cmax values of pranlukast nanosuspension with a particle size of 0.16μm were approximately 3.5- and 6.3-fold greater, respectively, than that of pranlukast microsuspension with a particle size of 18.21μm. Therefore, the preliminary results from our study suggest that a pranlukast nanosuspension with a mean particle size of about 0.16μm may have significant potential for clinical application.
International journal of biological macromolecules 03/2014; 67. DOI:10.1016/j.ijbiomac.2014.03.006 · 2.86 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Angelica gigas Nakai and its components are known to have neuroprotective, antiplatelet, and anticancer activities. The present study evaluated the in vitro and in vivo biopharmaceutical characterization of Angelica gigas component substances, including decursin (the main substance), decursinol angelate (decursin isomer), JH714 (ether form of decursin) and epoxide decursin (epoxide form of decursin). Decursin, decursinol angelate and JH714 exhibited acceptable metabolic stability (>50%) in liver microsomes from human and higher bound fraction (>90%) in human plasma operating ultrafiltration. Decursin and decursinol angelate in CYP1A2 and CYP2C19 indicated less than 50% CYP activity, suggesting inhibition of the CYP isoforms using Vivid® CYP screening kit. JH714 only showed an apparent permeability coefficient of 1.5, suggesting good brain/plasma ratio at 0.5, 1, 3, and 5 h. In contrast, Cbrain/Cplasma was 1.5% of the dose remained in GI tract after 8 h, and the excretion rate in urine was
Drug Development and Industrial Pharmacy 09/2013; 39(10). DOI:10.3109/03639045.2012.717296 · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract The study of pharmacokinetics of alendronate has been hampered by difficulties in accurately and reproducibly determining their concentrations in serum and urine. Thus, pharmacokinetic characteristics of alendronate have been described in many reports based on urinary excretion data; and plasma pharmacokinetics and the simultaneous pharmacokinetic models of alendronate in plasma and urine are not available. The aims of this study were to measure alendronate concentration in plasma and excretion in urine concurrently and to develop compartmental pharmacokinetic model using urine data. In open-label, single-dose pharmacokinetic study, 10 healthy male volunteers received oral dose of alendronate (70 mg tablet). Blood and urine alendronate concentrations were determined using validated high-performance liquid chromatography method. Non-compartmental analysis was performed using WinNonlin program (Pharsight Inc., Apex, NC). A one-compartment pharmacokinetic model was applied to describe pharmacokinetics of alendronate. A peak plasma alendronate concentration of 33.10 ± 14.32 ng/mL was attained after 1.00 ± 0.16 h. The cumulative amount of alendronate excreted in urine and peak excretion rate were 731.28 ± 654.57 μg and 314.68 ± 395.43 μg/h, respectively. The model, which included first-order absorption rate for oral dosing, showed good fit to alendronate data obtained from plasma and urine. The absorption rate constant was 2.68 ± 0.95 h(-1). The elimination rate constants Kurine and Knon-ur were 0.005 ± 0.004 h(-1) and 0.42 ± 0.08 h(-1), respectively. The pharmacokinetics of alendronate in plasma and urine of healthy men can be predicted using one-compartment model, and thus the behavior of drug in plasma can be estimated from urinary excretion data.
Drug Development and Industrial Pharmacy 07/2013; 40(10). DOI:10.3109/03639045.2013.819880 · 2.10 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Doxifluridine (5'-deoxy-5-fluorouridine, 5'-dFUR) is a fluoropyrimidine derivative that is activated preferentially in malignant cells by thymidine phosphorylase to form 5-fluorouracil (5-FU). The purpose of this study was to investigate the pharmacokinetic properties of doxifluridine and its two major metabolites, 5-FU, and 5-fluorouridine (5-FUrd), in beagle dogs following a single oral administration of 200 mg doxifluridine capsule (Furtulon(®)). After the administration of 200 mg of Furtulon to 23 beagle dogs, the plasma concentrations of doxifluridine, 5-FU, and 5-FUrd were measured simultaneously, using LC-MS/MS. The parent-metabolite compartment model with first-order absorption and Michaelis-Menten kinetics described the pharmacokinetics of doxifluridine, 5-FU, and 5-FUrd. Michaelis-Menten kinetics sufficiently explained the generation and elimination processes of 5-FU and 5-FUrd. The studies described here are the first to evaluate the relationship between pharmacokinetics of doxifluridine and its metabolites in dogs, and these findings will help in understanding the toxicity mechanism of doxifluridine.
European Journal of Drug Metabolism and Pharmacokinetics 04/2013; 38(4). DOI:10.1007/s13318-013-0130-4 · 1.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract 1. The objectives of this study were to develop a pharmacokinetic model for sarpogrelate and its metabolite M-1 and to identify the effect of food on sarpogrelate and M-1 pharmacokinetics in beagle dogs. 2. A single 100 mg oral dose of sarpogrelate was administered to fasted and fed beagle dogs and the plasma concentrations of sarpogrelate and M-1 were measured simultaneously by liquid chromatography tandem mass spectrometry. The resultant data were analyzed by modeling approaches using ADAPT5. 3. The plasma concentration time course of sarpogrelate and M-1 were described using a parent-metabolite compartment model with first-order absorption and elimination. The systemic exposure of sarpogrelate and its metabolite after the administration of a single 100 mg oral dose was significantly decreased under the fed condition compared to that under the fasting condition. Modeling approaches have sufficiently explained the food effect of sarpogrelate, i.e. an increased Vc and decreased Ka, in fed dogs. The food effect of sarpogrelate was due to its pH-dependent dissolution. 4. These findings suggest that food intake affects both the rate and extent of absorption of sarpogrelate, and that the pharmacological effect of sarpogrelate can differ significantly according to food intake.