Hyun-Il Kim

Novel amides and esters prodrugs of olmesartan: Synthesis, bioconversion, and pharmacokinetic evaluation

Synthesis of novel amides and esters prodrugs of olmesartan is described. Their in vitro stability in rat plasma was tested. The results showed that the ester derivative IIa with n-octyl substituted dioxolone moiety was rapidly converted into olmesartan within 30 min. The pharmacokinetic parameters of IIa were studied and compared with those of olmesartan medoxomil. Compound IIa is proposed to be a promising prodrug of olmesartan.

Pharmacokinetic Comparison Study of a Combination Containing 500 mg of Naproxen and 20 mg of Esomeprazole: A Randomized, Single-dose, 2-way Crossover, Open-label Study in Healthy Korean Men

PURPOSE Nonsteroidal anti-inflammatory drugs have been used for analgesic, anti-inflammatory, and antithrombotic effects, but they carry a risk of major gastrointestinal damage. This risk can be greatly reduced by the coadministration of inhibitors of gastric acid secretion, such as proton pump inhibitors. This study was performed for the subsequent marketing of a combination drug that contained 500 mg of naproxen and 20 mg of esomeprazole in Korea. We evaluated the comparative bioavailability and tolerability of the test and reference formulations in healthy men. METHODS A total of 60 healthy men were enrolled in this single-dose, randomized, open-label, 2-period, 2-sequence, crossover study. During each period, men received a combination of 500 mg of naproxen and 20 mg of esomeprazole for test or reference, and between each period, there was a 1-week washout period. Blood samples were obtained 21 times throughout each period before dosing and 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 10, 12, 24, 48, and 72 hours after oral administration. Plasma concentrations were determined using LC-MS/MS. The pharmacokinetic parameters, including Cmax, AUC0-t, AUC0-∞, and Tmax, were measured, and all treatment-emergent adverse events and their associations with the study medications were recorded throughout the entire study. FINDINGS A total of 59 men completed the study. No significant differences were found in the prevalence of AEs between the 2 formulations. In addition, there were no serious or unexpected AEs during the study. Both formulations had very similar Cmax, AUC, and t½ values, but the Tmax of naproxen appeared earlier in the test formulation than in the reference formulation and that of esomeprazole appeared later in the test formulation than in the reference formulation. IMPLICATIONS This study suggests that the test and reference formulations of a combination of 500 mg of naproxen and 20 mg of esomeprazole are bioequivalent in the extent of absorption and peak concentration. We anticipate that the test formulation will treat those who need relief from pain and inflammation and will decrease the risk of developing gastric ulcers. cris.nih.go.kr identifier: KCT0001117.

Design, synthesis, bioconversion, and pharmacokinetics evaluation of new ester prodrugs of olmesartan

Synthesis of new ester prodrugs of olmesartan is described. Their in vitro stabilities in simulated gastric juice, rat plasma, and rat liver microsomes were tested. And the pharmacokinetic parameters for olmesartan after their oral administration were also estimated and compared with those in case of olmesartan medoxomil. Compounds 13 and 14 demonstrated high stability in simulated gastric juice and were rapidly metabolized to olmesartan in rat liver microsomes and rat plasma in vitro. In addition, C(max) and AUC(last) parameters were significantly increased in case of compounds 13 and 14 compared with olmesartan medoxomil. These results indicate that compounds 13 and 14 with cyclohexylcarboxyethyl and adamantylcarboxymethyl promoieties, respectively, are promising prodrugs of olmesartan with markedly increased oral bioavailability.

Controlled Release of Tamsulosin from Enteric Coated Sustained-Release Matrices with Aqueous Microchannels

Tamsulosin has been frequently used for the treatment of benign prostatic hyperplasia. To avoid dose-dependent side effects of tamsulosin upon oral administration, the development of sustained-release delivery system is required, that can maintain therapeutic drug levels for a longer period of time. The aim of this study was therefore to formulate sustained-release tamsulosin matrix tablets and assess their formulation variables. We designed enteric coated sustained-release tamsulosin matrices to fulfill above statement. Aqueous microchannels in the enteric film need to be formed in order to obtain tamsulosin release even in an acidic environment such as gastric region. In the sustained-release tamsulosin matrix, low viscosity hydroxypropylmethylcellulose was used as a rate controller. Povidone K30 was also added to the matrices to facilitate water uptake so that a decrease in the release rate of tamsulosin as time elapses was prevented, possibly leading to pseudo zero-order release of the drug. The matrices were enteric-coated with hydroxypropylmethylcellulose phthalate (HPMCP), along with povidone K30 as an aqueous microchannel former. With the aqueous microchannels formed within the enteric film, tamsulosin could be released in an acidic condition. The release of tamsulosin decreased with increasing thickness of HPMCP membrane while the release rates of tamsulosin from those having different HPMCP thickness in pH 7.2 aqueous media were not considerably different, indicating that the enteric film was promptly dissolved at pH 7.2. These results clearly suggest that the sustained-release oral delivery system for tamsulosin could be designed with satisfying drug release profile approved by the KFDA.

Acid Inhibitory Effect of a Combination of Omeprazole and Sodium Bicarbonate (CDFR0209) Compared With Delayed‐Release Omeprazole 40 mg Alone in Healthy Adult Male Subjects

CDFR0209, a combination of an immediate‐release formulation of omeprazole 40 mg and sodium bicarbonate 1100 mg, has been developed to treat acid‐related disorders. We compared the acid inhibitory effects of CDFR0209 and delayed‐release omeprazole (omeprazole‐DR, Losec 40 mg) after repeated dosing in Helicobacter pylori–negative healthy adult male subjects. In this 2‐period crossover study, 30 subjects were randomized to CDFR0209 or omeprazole‐DR daily for 7 days. An ambulatory continuous 24‐hour intragastric pH recording was performed at baseline and on days 1 and 7 of each administration period. Integrated gastric acidity was calculated from time‐weighted average hydrogen ion concentrations at each hour of the 24‐hour record. An analysis of variance model was used to test the pharmacodynamic equivalence of CDFR0209 and omeprazole‐DR, using the natural logarithmic transformation of the percent decrease from baseline in integrated gastric acidity for the 24‐hour interval after the seventh dose of each omeprazole formulation. The geometric least‐squares mean ratios (CDFR0209/omeprazole‐DR) of the percent decrease from baseline in integrated gastric acidity was 0.98 (90%CI, 0.93–1.07). Both CDFR0209 and omeprazole‐DR are equally effective in decreasing integrated gastric acidity at steady state.