In-hwan Baek

Fabrication and evaluation of valsartan-polymer- surfactant composite nanoparticles by using the supercritical antisolvent process

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.

Formulation, Characterization, and in Vivo Evaluation of Celecoxib-PVP Solid Dispersion Nanoparticles Using Supercritical Antisolvent Process

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.

Pharmacokinetic/pharmacodynamic modeling of the cardiovascular effects of beta blockers in humans

Pharmacokinetic-pharmacodynamic (PK/PD) analysis is useful study in clinical pharmacology, also PK/PD modeling is major tools for PK/PD analysis. In this study, we sought to characterize the relationship between the cardiovascular effects and plasma concentrations of the beta blocker drugs carvedilol and atenolol using PK/PD modeling in healthy humans. One group received oral doses of atenolol (50 mg) and the other group received oral doses of carvedilol (25 mg). Subsequently, blood samples were taken, and the effects of the drugs on blood pressure were determined. Plasma concentrations of drugs were measured by HPLC, and PK/PD modeling performed by applied biophase model, plasma drug concentrations were linked to the observed systolic blood pressure (SBP) and diastolic blood pressure (DBP) via an effect compartment. The model parameters were estimated using the ADAPT II program. In PK/PD analysis, it was observed the time delay between plasma concentration and effect and the time delay between SBP and DBP. The two time delays were properly explained by PD parameter “Keo” in applied biophase model. As conclusion, the biophase PK/PD model described the relationship between the plasma concentrations of the drugs and the cardiovascular effects, including the time delay between systolic blood pressure and diastolic blood pressure.

Preparation and in Vivo Evaluation of a Dutasteride-Loaded Solid-Supersaturatable Self-Microemulsifying Drug Delivery System

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.

Effect of decursin on the pharmacokinetics of theophylline and its metabolites in rats

ETHNOPHARMACOLOGICAL RELEVANCE Decursin is used as a traditional Asian medicine to treat various womens diseases. AIM OF THE STUDY Herb-drug interaction has become a serious problem since herbal medicine is extensively used in the modern world. This study investigates effects of decursin, on the pharmacokinetics of theophylline, a typical substrate of cytochrome P450 1A2 enzyme, in rats. MATERIALS AND METHODS After decursin pretreatment for 3 days, on the fourth day rats were administered decursin and theophylline concomitantly. The blood theophylline and its major metabolites (1-methylxanthine (1-MX), 3-methylxanthine (3-MX), 1-methyluric acid (1-MU), and 1,3-dimethyluric acid (1,3-DMU)) levels were monitored with LC-MS/MS. RESULTS The results indicated that the clearance, elimination rate constant (K(el)) of theophylline was significantly decreased and area under concentration-time curve (AUC), C(max), half-life was increased in decursin (25mg/kg) pretreatment when theophylline (10mg/kg) was given. In the presence of decursin, the pharmacokinetic parameters of three metabolites (1-MX, 1,3-DMU, and 1-MU) were affected and the differences were statistically significant about AUC(24)(h) parameter. CONCLUSION Our results suggest that patients who want to use CYP1A2-metabolized drugs such as caffeine and theophylline should be advised of the potential herb-drug interaction, to reduce therapeutic failure or increased toxicity of conventional drug therapy.

Influence of Dissolved Oxygen Concentration on the Pharmacokinetics of Alcohol in Humans

BACKGROUND Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation. We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5% v/v). METHODS Blood alcohol concentrations (BACs) were determined by converting breath alcohol concentrations. Breath samples were collected every 30 min when the BAC was higher than 0.015%, 20 min at BAC < or =0.015%, 10 min at BAC < or =0.010%, and 5 min at BAC < or =0.006%. RESULTS The high dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p < 0.05). In analyzing pharmacokinetic parameters, AUC(inf) and K(el) of the high oxygen groups were lower than in the normal oxygen group, while C(max) and T(max) were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC(inf) and t(1/2) was expected to be reduced in the high oxygen group compared to the normal oxygen group. CONCLUSIONS In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol. Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol-related side effects and accidents.

Effects of smoking on the pharmacokinetics and pharmacodynamics of a nicotine patch

The effect of smoking on the pharmacokinetics and pharmacodynamics of a nicotine transdermal delivery system, administered as a single dose or multiple doses, was examined in smokers (n=12) and nonsmokers (n=12). The study was a two‐period, parallel trial. In the first period, a single dose of the Nicotinell TTS 20 patch was administered, followed by a 1‐week washout period. Then, in the second period, multiple doses of the Nicotinell TTS 20 patch were administered over 4 days. Regarding the pharmacokinetics of nicotine, the AUC36h and AUCτ of smokers were about 20% and 40% greater, respectively, than those of nonsmokers. Significant differences in heart rate were observed between smokers and nonsmokers at 10, 12, 16 and 24 h, and significant differences in systolic blood pressure were seen between smokers and nonsmokers at 12, 30 and 36 h in the single‐dose study. With multiple doses, significant differences in systolic and diastolic blood pressures were detected between smokers and nonsmokers only at 72.5 and 82 h. Here, it is demonstrated for the first time that the pharmacokinetic and hemodynamic effects of a nicotine patch are significantly different between smokers and nonsmokers. Copyright

Development of megestrol acetate solid dispersion nanoparticles for enhanced oral delivery by using a supercritical antisolvent process.

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.

Comparison of average, scaled average, and population bioequivalence methods for assessment of highly variable drugs: An experience with doxifluridine in beagle dogs

Several strategies for overcoming the challenge of establishing bioequivalence (BE) for highly variable drugs (HVDs; drugs having within-subject variability >0.3) have been considered in recent years. Within-subject variability of the area under the curve (AUC(4h)) and peak concentration (C(max)) of doxifluridine in the minimal group (n=24) were 0.444 and 0.491, respectively, meeting the criteria for an HVD. For the large group (n=60), within-subject variability of the AUC(4h) and C(max) were 0.431 and 0.493, respectively. The 90% confidence interval for the AUC(4h) and C(max) of the ratio of the test drug to the reference drug exceeded the acceptable BE limits (0.80-1.25) of the ABE (average bioequivalence), in both the minimal and large groups. However, the 90% CI fell within the extended BE limits (0.61-1.64) of the SABE (scaled average bioequivalence), calculated using within-subject variability. The 95% CI of the AUC(4h) and C(max) of the ratio of test to reference drug were within the extended BE limit (<1.73) of the PBE (population bioequivalence), calculated using total variance. Our results suggest that the SABE method may be useful for evaluating the BE of HVDs and for meeting the need for international guidelines for BE.

Simultaneous analysis of naltrexone and its major metabolite, 6-β-naltrexol, in human plasma using liquid chromatography–tandem mass spectrometry: Application to a parent-metabolite kinetic model in humans

We developed a method for simultaneously determining naltrexone, an opioid antagonist, and its major metabolite (6-beta-naltrexol) in plasma using LC/MS/MS. Three compounds, and naloxone as an internal standard, were extracted from plasma using a mixture of methyl-tertiary-butyl ether. After drying the organic layer, the residue was reconstituted in a mobile phase (0.1% formic acid-acetonitrile:0.1% formic acid buffer, 95:5, v/v) and injected onto a reversed-phase C(18) column. The isocratic mobile phase was eluted at 0.2ml/min. The ion transitions monitored in multiple reaction-monitoring modes were m/z 342-->324, 344-->326, and 328-->310 for naltrexone, 6-beta-naltrexol, and naloxone, respectively. The coefficient of variation of the assay precision was less than 11.520%, and the accuracy exceeded 93.465%. The limit of quantification was 2ng/ml for naltrexone and 7.2ng/ml for 6-beta-naltrexol. And the limit of detection was 0.1ng/ml for naltrexone and 0.36ng/ml for 6-beta-naltrexol. This method was used to measure the plasma concentration of naltrexone and 6-beta-naltrexol in healthy subjects after a single oral 50mg dose of naltrexone. This analytical method is a simple, sensitive, and accurate way of determining the pharmacokinetic profiles of naltrexone and its metabolites. The pharmacokinetic parameters were analyzed using both non-compartmental analysis performed for each subject according to standard methods and compartmental analysis with a parent-metabolite pharmacokinetic model that was fitted to the data, simultaneously, using the program ADAPT II. The tested parent-metabolite pharmacokinetic model successfully described the relationship between the plasma concentration of naltrexone and one of its major metabolites, 6-beta-naltrexol.