Average Bioequivalence of Clarithromycin Immediate Released Tablet Formulations in Healthy Male Volunteers

Abstract

The objective of this study was to assess average bioequivalence of two immediate released tablet formulations of 500-mg clarithromycin tablets in 24 healthy Thai male volunteers. In a randomized, single dose, fasting state, two-period, crossover study design with a 1-week washout period, each subject received a 500-mg clarithromycin tablet. Plasma samples were collected over a 24-hour period after oral administration and were analyzed by using a validated method using high performance liquid chromatography with electrochemical detection. Pharmacokinetic parameters were determined by using noncompartmental analysis. The time to reach the maximal concentration (t_max, h), the peak concentration (C_max, ng/mL), and the area under the curve (AUC_{0 ? ∞}, ng.h/mL) of the Reference and Test formulations were 2.0 ± 0.8 vs. 2.2 ± 0.9, 2793 ± 1338 vs. 2642 ± 1344, and 17912 ± 7360 vs. 17660 ± 7992, respectively. Relative bioavailability was 0.99. The 90% confidence interval of C_max and AUC_{0 ? ∞} were 82.6–112.1% and 84.7–112.0%. Bioequivalence between the Test and Reference formulation can be concluded.     

Development and uniform evaluation of ropinirole osmotic pump tablets with REQUIP XL both in vitro and in beagle dogs

REQUIP XL, prolonged release formulation of ropinirole hydrochloride (RH) in market, could release ropinirole constantly and showed satisfactory therapeutic effect and good compliance. REQUIP XL was composed of more than 10 kinds of excipients and prepared by Geomatrix technology, which was complex and laborious. The purpose of this study was to obtain a dosage form of RH with similar in vitro release profile and bioequivalence in vivo compared to REQUIP XL. Osmotic pump tablet combined with fast release phase was selected as the delivery system of RH and similar release curves were obtained in different media. The tablets were also administered to beagle dogs and the pharmacokinetic parameters were calculated using a non-compartmental model. C_max, t_max, mean residence time (MRT), and area under the curve from 0 to 24?h (AUC_0–24) were 3.97?±?0.53?ng/mL, 3.58?±?0.49?h, 8.29?±?0.93?h, and 35.20?±?8.11?ng/mL???h for ropinirole osmotic pump tablets (ROPT) and 4.15?±?1.07?ng/mL, 2.92?±?0.49?h, 7.84?±?1.09?h, and 34.34?±?10.06?ng/mL???h for REQUIP XL. The log-transformed mean C_max and AUC_0–24 of ROPT were about 92.15% and 102.49% relative to that of REQUIP XL, respectively. The 90% confidence intervals of C_max and AUC_0–24 for ROPT were 75.69–115.31% and 88.89–122.30%, respectively. So it could be concluded that ROPT was uniform with REQUIP XL both in vitro and in beagles and the release profiles of Geomatrix technology may be obtained by osmotic pump combined with fast release technology.     

Evaluation of Bioequivalence of Two Formulations Containing 100 Milligrams of Aceclofenac

ABSTRACT

The bioequivalence of two oral formulations containing aceclofenac 100 mg was determined in 24 healthy Indian male volunteers. The study was designed as a single dose, fasting, two-period two-sequence crossover study with a washout period of 1 week. The content of aceclofenac in plasma was determined by a validated HPLC method with UV detection. The preparations were compared using the parameters area under the plasma concentration–time curve (AUC_0–t), area under the plasma concentration–time curve from zero to infinity (AUC_0–∞), peak plasma concentration (C_max), and time to reach peak plasma concentration (t_max). No statistically significant difference was observed between the logarithmic transformed AUC_0–∞ and C_max values of the two preparations. The 90% confidence interval for the ratio of the logarithmic transformed AUC_0–t, AUC_0–∞, and C_max were within the bioequivalence limit of 0.80–1.25.     

Improved dissolution rate and bioavailability of fenofibrate pellets prepared by wet-milled-drug layering

Objective: The objective of this study is to investigate the wet-milled-drug layering process which could significantly improve the dissolution rate and oral bioavailability of fenofibrate pellets.

Methods: Fenofibrate was milled with HPMC-E5 to prepare a uniform suspension in the micrometer and nanometer range, and this suspension was then layered on to sugar spheres to form the pellets (F1, F2).

Results: The particle size was significantly reduced (from 1000 µm to 1–10 µm and 400?nm) but the fenofibrate in suspension retained its crystallinity from the results of DSC and PXRD investigations. The dissolution rate of F1-F2 and Antara® capsules was 55.47 %, 61.27 % and 58.43 %, respectively, in 0.01?mol/L SDS solution over 60?min. In addition, F1, F2, and Antara® capsules were given orally to 6 beagle dogs to determine the bioavailability. The C_max of F1, F2 (8.21?±?2.55 and 9.33?±?2.37 μg/mL)and the AUC_(0?t) of F1, F2 (152.46?±?78.89 and 172.17?±?67.58 μg/mL·h)were higher than those of Antara® (6.02?±?3.34 μg/mL and 89.82?±?46.46 μg/mL·h) and, F1, F2 reached their C_max earlier than Antara® (F1: 2.0?±?1.1?h; F2: 1.8?±?1.2?h; Antara®: 6.0?±?8.9?h).

Conclusion: These results show that the wet-milled-drug layering technique is a powerful method to improve the dissolution rate and the bioavailability of fenofibrate.     

Preparation,characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA–SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA–PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA–PEG6000 (1:3) SD and NA–suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA–PEG6000 (1:3) SD (C_max?=?0.645?±?0.262?µg/ml, AUC_0–t?=?0.471?±?0.084?µg/ml?h) were higher than that of NA–suspension (C_max?=?0.328?±?0.183?µg/ml, AUC_0–t =?0.361?±?0.093?µg/ml?h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.     

Comparative Bioavailability Study of a Generic Naltrexone Tablet Preparation

The bioavailability of a generic preparation of naltrexone (Narpan) was compared with the innovator product, Trexan. Twelve healthy volunteers participated in the study, conducted according to a completely randomized, two-way crossover design. The preparations were compared using the parameters area under the plasma concentration–time curve AUC_0–∞, peak plasma concentration C_max, and time to reach peak plasma concentration T_max. No statistically significant difference was observed between the logarithmic transformed AUC_0–∞ and the logarithmically transformed C_max values of the two preparations. Also, no statistically significant difference was observed between the untransformed T_max values. In addition, the 90% confidence interval for the ratio of the logarithmic transformed AUC_0–∞ values of Narpan over those of Trexan was found to lie between 0.87 and 1.01, while that of the logarithmic transformed C_max values was between 0.94 and 1.23, both being within the bioequivalence limit of 0.80–1.25. The numerical values of the elimination half-life (t_1/2) obtained with the two preparations were also not significantly different and were comparable to those reported in the literature.     

Pharmacokinetics and pharmacodynamics of FSK0808 and Gran after single intravenous drip administration or single subcutaneous administration: comparative study in healthy Japanese adult male subjects

FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran®. We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran® by a randomized crossover study of single intravenous dose (200?µg/m²) and single subcutaneous dose (400?µg/m²) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration – time curve by 48 hours after administration (AUC_0–48) in a single intravenous drip (IVD) study, and AUC_0–48 and maximum blood concentration (C_max) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34⁺ cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC_0–48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for C_max and AUC_0–48 were within the range of log(0.8)–log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)–log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar.     

Pharmacokinetic properties and bioequivalence of candesartan cilexetil in Korean healthy volunteers

Candesartan is a long-acting and selective nonpeptide AT₁ subtype angiotensin II receptor antagonist. The aim of this study was to compare the pharmacokinetics and to evaluate the bioequivalence of two candesartan cilexetil 16?mg formulations. Forty healthy volunteers were randomly assigned into two groups. After a single dose of 16?mg candesartan cilexetil oral administration, blood samples were collected at specific time intervals from 0–36?h. The plasma concentrations of candesartan cilexetil were determined by LC-MS/MS. The pharmacokinetic parameters such as AUC_last, AUC_inf and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data. The mean for AUC_last in the reference and the test drug were 1530.1?±?434.6 and 1315.7?±?368.6 ng·h/mL. The mean for AUC_inf in the reference and the test drug were 1670.0?±?454.5 and 1441.2?±?397.8 ng·h/mL. The mean value for C_max in the reference and the test drug was 142.6?±?41.0 and 134.9?±?41.4?ng/mL. The 90% confidence intervals for the AUC_last, AUC_inf and C_max were in the range of log 0.81–log 0.91, log 0.81–log 0.91 and log 0.88–log1.01, respectively. No adverse events were reported by subjects or found on analysis of vital signs or laboratory tests. This single dose study found that the test and reference products met the regulatory criteria for bioequivalence in these health volunteers. Both formulations were safe and well tolerated in 16?mg of candesartan cilexetil hydrochloride.     

Pharmacokinetic properties and bioequivalence of orally inhaled salbutamol in healthy Chinese volunteers

Context: Salbutamol is a short-acting β₂-adrenergic receptor agonist that has been used for many years for relief of bronchospasm. However, studies on the pharmacokinetic profile of orally inhaled salbutamol doses used in clinical practice have not yet been reported in Chinese subjects.

Objective: The aim of this study was to compare the pharmacokinetics and evaluate the bioequivalence of two orally inhaled salbutamol formulations.

Materials and methods: A single-dose randomized fasting two-period, two-treatment and two-sequence crossover open-label bioequivalence study was conducted in 24 healthy Chinese adult male volunteers, with a 1-week washout period between treatments. Plasma concentrations of salbutamol were determined using liquid chromatography coupled to tandem mass spectrometry. Pharmacokinetic parameters, including AUC_0–0.33?h, AUC_0–24?h and C_max were calculated and the 90% confidence intervals of the ratio (test/reference) pharmacokinetic parameters were obtained by analysis of variance on logarithmically transformed data.

Results: The mean (SD) pharmacokinetic parameters of the reference drug were AUC_0–0.33?h, 227.2 (89.9) pg·h/ml; AUC_0–24?h, 2551.9 (1008.0) pg·h/ml; C_max, 801.3 (307.3) pg/ml and t_1/2, 5.14(1.36) h. Those of the test drug were AUC_0–0.33?h, 244.0 (104.4) pg·h/ml; AUC_0–24?h, 2664.4 (1081.8) pg·h/ml; C_max, 873.7 (374.4) pg/ml, t_1/2, 5.29 (1.23) h. The median value for T_max was 0.25?h for both formulations. The 90% confidence intervals for the AUC_0–0.33?h, AUC_0–24?h and C_max were in the range of 0.892–1.208, 0.876–1.195 and 0.911–1.203, respectively.

Conclusion: This single-dose study found that the test and reference products met the regulatory criteria for bioequivalence of China in healthy Chinese volunteers.     

Preparation of fenofibrate immediate-release tablets involving wet grinding for improved bioavailability

Objective: The purpose of this study was to investigate the dissolution and oral bioavailability of an immediate-release tablet involving wet grinding of a poorly water-soluble drug, fenofibrate. Methods: The milled suspension was prepared using a Basket Dispersing Mill in the presence of a hydrophilic polymer solution and then granulated with common excipients, and compressed into an immediate-release tablet with blank microcrystalline cellulose granules. Results: Compared with unmilled tablets (56% within 30 minutes), the dissolution of wet-milled tablets (about 98% in 30 minutes) was markedly enhanced. No significant decrease in the dissolution rate (96% in 30 minutes) of the wet-milled tablet was observed after 3 months under 40°C and 75% relative humidity storage. In addition, the oral bioavailability of the wet-milled tablets (test) and Lipanthyl® supra-bioavailability tablets (reference) was determined in beagle dogs after a single dose (160 mg fenofibrate) in a randomized crossover, own-control study. The results suggested that both the area under the plasma concentration–time curve (AUC_(0?t) = 46.83 ± 11.09 μg/mL h) and the mean peak concentration of the test (C_max = 4.63 ± 1.71 μg/mL) were higher than the reference (AUC_(0?t) = 35.12 ± 10.97 μg/mL h, C_max = 2.11 ± 0.08 μg/mL). The relative bioavailability of the wet-milled tablet was approximately 1.3-fold higher. Furthermore, the apparent rate of absorption of fenofibrate from the wet-milled tablet (T_max = 2.63 hours) was faster than that from Lipanthyl® (T_max = 3.75 hours). Conclusion: These results indicated that the dissolution and the bioavailability of fenofibrate were significantly enhanced by wet-grinding process. So, this shows that wet grinding is a powerful technique to improve the bioavailability for poorly water-soluble drugs, especially for Biopharmaceutics Classification System Class II compounds.     

Preparation,Characterization, and Bioavailability of Ursodeoxycholic Acid–Phospholipid Complex In Vivo

The aim of this study was to prepare ursodeoxycholic acid–phospholipid complex (UDCA-PLC) to enhance oral bioavailability of UDCA, and the physicochemical properties of the complex were studied. Compared with those of UDCA tablet after oral administration in rats, the main pharmacokinetic characteristics and bioavailability of UDCA-PLC orally administered were evaluated. Tetrahydrofuran was used as a reaction medium, UDCA and phospholipids were resolved into the medium, and UDCA-PLC was formed after the organic solvent was evaporated off under vacuum condition. The physicochemical properties of the complex were evaluated using scanning electron microscopy (SEM), transmission electron microscopy (TEM), differential scanning calorimetry (DSC), X-ray diffraction, particle size distribution analysis, and n-octanol/water partition coefficient (P) study. The blood concentrations of UDCA-PLC and UDCA tablet at different time points after oral administration in rats were assayed by high-performance liquid chromatography (HPLC) after derivatization. The pharmacokinetic parameters were computed by software program 3p87. The X-ray diffraction and DSC studies showed that UDCA and phospholipids in the UDCA-PLC were combined by noncovalent bond, not forming a new compound, and n-octanol/water partition coefficient (P) of UDCA-PLC was effectively enhanced. The mean serum concentration–time curves of UDCA after oral administration of UDCA-PLC and UDCA tablet in rats were both in accordance with open two-compartment model. Pharmacokinetic parameters of UDCA tablet and the PLC in rats were T_max 1.9144 and 1.5610 h, C_max 0.0576 and 0.1346 μg/mL, and AUC_0–∞ 4.736 and 11.437 μg h/mL, respectively. The bioavailability of UDCA in rats was significantly different (p < .05) compared with those of UDCA tablet after administration. The UDCA-PLC would be more prospective formulation in future.     

Bioequivalence Evaluation of Two Formulations of Doxazosin Tablet in Healthy Thai Male Volunteers

ABSTRACT

The bioequivalence of two doxazosin 2 mg tablets was determined in 24 healthy Thai male volunteers after one single dose in a randomized cross-over study with a one week washout period. The study was conducted at Faculty of Pharmaceutical Sciences and Health Sciences Research Institute, Naresuan University, Phitsanulok, Thailand. Reference (Cardura®, Heinrich Mack Nachf. GmbH & Co. GK, Illertissen, Germany) and test (Dozozin-2®, Umeda Co., Ltd., Bangkok Thailand) were administered to volunteers after overnight fasting. Blood samples were collected at specified time intervals and plasma was separated. The validated HPLC method with fluorescence detection was used for quantification of doxazosin in plasma samples. The pharmacokinetic parameters, T_max, C_max, AUC_t, AUC_∞, T_1/2, λ_z, Cl and V_d, were determined from plasma concentration time profile of both formulations by using non-compartment analysis. The calculated pharmacokinetic parameters were compared statistically to evaluate bioequivalence between the two brands. The analysis of variance (ANOVA) using log-transformed C_max, AUC_t, and AUC_∞ did not show any significant difference between two formulations. The point estimates and 90% confidence intervals for C_max, AUC_t and AUC_∞ were within the acceptance range (0.80–1.25), satisfying the bioequivalence criteria of the Thailand Food and Drug Administration Guidelines. These results indicate that Dozozin-2® is bioequivalent to Cardura® and, thus, may be prescribed interchangeably.     

Garenoxacin pharmacokinetics in patients undergoing maintenance hemodialysis

Introduction: Studies on the pharmacokinetics of the antibiotic garenoxacin (GRNX) in patients with renal insufficiency are lacking. In this study, we attempted to ascertain the appropriate dose of GRNX in patients undergoing maintenance hemodialysis (MH) based on pharmacokinetic parameters and clinical outcomes. Methods: Six male patients with infections who were undergoing MH received 200 mg GRNX once daily. Blood samples were taken before and at 1, 2, 4, 6, 12, and 24 hours after GRNX administration. Plasma GRNX concentrations were measured using high‐performance liquid chromatography. Findings: The mean maximum plasma concentration (C_max) was 3.00 ± 1.12 µg/mL, time to maximum plasma concentration (T_max) was 3.0 ± 2.0 hours, and area under the curve for 24 hours (AUC_0–24) was 40.7 ± 16.7 µg·h/mL. The half‐life (T_1/2) of GRNX could not be calculated because plasma concentrations remained high 24 hours after administration. C_max was strongly associated with the GRNX dose per kilogram body weight (r = 0.85, P = 0.03). Clinically, fever resolved within 3 days of GRNX administration and C‐reactive protein levels returned to normal 14 days after administration. One patient experienced temporary increases in serum transaminase levels. Discussion: MH patients receiving 200 mg GRNX once daily for infection showed a reduced C_max but similar AUC_0–24 compared with healthy individuals. While this study evaluated the effect of GRNX treatment, further research is needed to assess the accumulation of GRNX and the impact of continuous administration on its pharmacokinetics, as well as to prevent the development of resistant mutants.     

Sustained-release of Cyclosporin A pellets: preparation,in vitro release,pharmacokinetic studies and in vitro–in vivo correlation in beagle dogs

The aim of this study was to develop Cyclosporin A (CsA) sustained-release pellets which could maintain CsA blood concentration within the therapeutic window throughout dosing interval and to investigate the in vitro–in vivo correlation (IVIVC) in beagle dogs. The CsA sustained-release pellets (CsA pellets) were prepared by a double coating method and characterized in vitro as well as in vivo. Consequently, the CsA pellets obtained were spherical in shape, with a desirable drug loading (7.18?±?0.17?g/100?g), good stability and showed a sustained-release effect. The C_max, T_max and AUC_0–24 of CsA pellets from the in vivo pharmacokinetics evaluation was 268.22?±?15.99?ng/ml, 6?±?0?h and 3205.00?±?149.55?ng·h/ml, respectively. Compared with Neoral®, CsA pellets significantly prolonged the duration of action, reduced the peak blood concentration and could maintain a relatively high concentration level till 24?h. The relative bioavailability of CsA pellets was 125.68?±?5.37% that of Neoral®. Moreover, there was a good correlation between the in vitro dissolution and in vivo absorption of the pellets. In conclusion, CsA pellets which could ensure a constant systemic blood concentration within the therapeutic window for 24?h were prepared successfully. Meanwhile, this formulation possessed a good IVIVC.     

Pharmacokinetic and Bioequivalent Study of a Generic Metoprolol Tablet Preparation

Abstract

A study was conducted to compare the in vivo bioavailability of a generic metoprolol tablet preparation (Metoprolol®) with that of the innovator product, Betaloc®. Both preparations have a labeled dose of 100 mg metoprolol tartrate. Twelve healthy adult male volunteers participated in the study, which was conducted according to a standard two-way crossover design with a washout period of I week. The bioavailability was compared using the total area under the plasma level versus time curve (AUC₀-∞_oo), peak plasma concentration (C_max), and time to reach peak plasma concentration (T_max). No statistically significant difference was observed between the logarithmically transformed AUC₀-_oo values or the logarithmically transformed C_max values of the two preparations. However, a statistically significant difference was observed between the T_max values, but may not be therapeutically significant or important. Moreover, the 90% confidence interval (CI) for the ratio of the logarithmically transformed AUC₀-_oo values of Metoprolol over those of Betaloc was calculated to be between 0.94 and 1.02, while that of C_max was between 0.98 and 1.01, both of which are within the acceptable limit of 0.80-1.25. From the data obtained, it was also observed that a high proportion of our volunteers of Asian origin appeared to be poor metabolizers of metoprolol, which was consistent with what had been observed in our previous study of another preparation of metoprolol.     

Comparative Bioavailability Study of Two Controlled-Release Pentoxifylline Tablet Preparations

The bioavailability of a generic preparation of pentoxifylline sustained-release (SR) tablet was evaluated in comparison with a proprietary product (Trental 400®). For the study, 12 healthy male volunteers participated; the study was conducted according to a randomized, two-way crossover design. The bioavailability was compared using the parameters total area under the plasma level-time curve AUC_0?∞, peak plasma concentration C_max, and time to reach peak plasma concentration T_max. No statistically significant difference was observed between the values of the two products in all three parameters. The 90% confidence interval for the ratio of the logarithmic transformed AUC_0?∞ values of the generic pentoxifylline over those of Trental 400 was found to lie between 0.83 and 1.00, while that of the parameter C_max was between 0.91 and 1.29. In addition, elimination half-life t_1/2 and apparent volume of distribution V_d were calculated. There was no statistically significant difference between the t_1/2V_d values obtained from the data of the two preparations.     

Production of an Extremly Low Dose Procaterol HCl Preparation by Fluidized-Bed Coating Method: In Vitro and In Vivo Evaluation

Abstract

A convenient and reliable method to prepare procaterol HCl oral dosage form at an extremely low dosage (25 µg/cap) is presented in this paper. Procaterol HCl was mixed with the film-forming agent hydroxypropyl methylcellulose in an aqueous solution, which was then spray-coated on sugar spheres (Nu-pareil PG 20/25) to produce procaterol HCl pellets. The IR spectra of coated and noncoated pellets indicated that procaterol HCl was coated on the sugar spheres successfully with a weight increment less than 1%. Most of the coated pellets were able to pass through an 18-mesh screen with no agglomeration. The average weights of coated pellets filled inside of capsules were monitored during the filling process. A simple liquid chromatographic method was developed and validated for the assay and uniformity test of procaterol HCl in different dosage forms. The results of assay and content uniformity test for both in-house product and a commercial product, i.e., Meptin®-mini tablet, were satisfied. The data of f₂ function and ANOVA analysis for the dissolution profiles of both procaterol HCl products suggested that they are pharmaceutical equivalent.

In an in vivo study (n = 24), a single dose of 75 µg procaterol HCl was administrated to each volunteer and the plasma concentration of procaterol was determined by a LC/MS/MS method, developed by the same authors. There were no significant differences (p > 0.05) in the data of AUC_0→16h, AUC_0→∞, C_max, and MRT for both preparations. It is confirmed that the pellets capsule produced in this study is bioequivalent with Meptin®-mini tablet.     

Development and pharmacokinetic evaluation of alginate-pectin polymeric rafts forming tablets using box behnken design

Abstract

Raft is an emerging drug delivery system, which is suitable for controlled release drug delivery and targeting. The present study aimed to evaluate the physico-chemical properties of raft, in vitro release of pantoprazole sodium sesquihydrate and conduct bioavailability studies. Box behnken design was used with three independent and dependent variables. Independent variables were sodium alginate (X₁), pectin (X₂) and hydroxypropyl methyl cellulose K100M (X₃) while dependent variables were percentage drug release at 2 (Y₂), 4 (Y₄) and 8?h (Y₈). The developed rafts were evaluated by their physical and chemical properties. Fourier transform infrared spectroscopy and differential scanning calorimetry were used to study the chemical interaction and thermal behaviour of drug with polymers. Alginate and pectin contents of R9 formulation were 99.28% and 97.29%, respectively, and acid neutralization capacity was 8.0. R9 formulation showed longer duration of neutralization and nature of raft was absorbent. The raft of R9 formulation showed 98.94% release of PSS at 8?h in simulated gastric fluid. Fourier transform infrared spectroscopy showed no chemical interaction and differential scanning calorimetry indicated endothermic peaks at 250?°C for pantoprazole sodium sesquihydrate. t_max for the test and reference formulations were 8?±?2.345?h and 8?±?2.305?h, respectively. C_max of test and reference formulations were 46.026?±?0.567?µg/mL and 43.026?±?0.567?µg/mL, respectively. AUC_(0-t) of the test and reference formulations were 472.115?±?3.467?µg?×?h/mL and 456.105?±?2.017?µg?×?h/mL, respectively. Raft forming system successfully delivered the drug in controlled manner and improved the bioavailability of drugs.     

Comparative Study on the Bioequivalence of Two Formulations of Pioglitazone Tablet in Healthy Thai Male Volunteers

The bioequivalence study of two 30 mg pioglitazone formulations was determined in healthy Thai male volunteers after a single dose administration in a randomized cross-over study with a 1-week washout period. Due to the high variability of the rate and extent of absorption of pioglitazone, an add-on subject study was required to assess bioequivalence. Reference product (Actos®, Takeda Chemical Industries, Ltd., Osaka, Japan) and test product (Glubosil®, Silom Medical Co. Ltd., Bangkok, Thailand) were given to 35 volunteers after overnight fasting. Blood samples were collected at specified time intervals. Plasma was analyzed for pioglitazone concentration using a validated HPLC method. Pharmacokinetic parameters were compared between test and reference products from plasma concentration-time profile by using non-compartment analysis. The statistical comparison of C_max and AUC_0?t, AUC_t?∞ clearly indicated that no significant difference in two products of pioglitazone tablets in add-on subject study. The 90% confidence intervals for the mean ratio (test/reference) of C_max and AUC_0?t, AUC_t?∞ were within the Thailand Food and Drug Administration acceptance range. Based on the pharmacokinetic and statistical results of this study, we can conclude that Glubosil® is bioequivalent to Actos®, and that two products can be considered interchangeable in medical practice.     

Comparison of pharmacokinetics in beagle dogs of nimesulide bilayer tablets with dispersible tablets

The purpose of this study was to compare the in vitro release and the in vivo pharmacokinetics of bilayer tablets with the conventional dispersible tablets of nimesulide. The tablets were administered to beagle dogs and the plasma levels of nimesulide were determined by high-performance liquid chromatography-MS/MS. The pharmacokinetic parameters were calculated using a noncompartmental model. The bilayer tablets showed a biphasic in vitro release pattern with initial burst release and sustained release following the quasi-Fickian diffusion-based release mechanism. The C_max, t_max, mean residence time (MRT), and area under the curve from 0 to 36 h were 10.8 ± 4.2 μg/mL, 2.3 ± 1.0 h, 6.7 ± 2.1 h, 81.5 ± 26.7 μg·h/mL for the bilayer tablets and 14.8 ± 5.8 μg/mL, 2.7 ± 0.8 h, 5.6 ± 0.9 h, 95.4 ± 44.2 μg·h/mL for the dispersible tablets. Compared with the dispersible tablets, the bilayer tablets have lower C_max, similar t_max, and longer MRT. The aforementioned pharmacokinetic parameters, especially the MRT demonstrated to be valuable for evaluating the biphasic characteristics. This study provides a promising in vivo evaluation method for the bilayer tablets with biphasic release pattern.