Pilot study of relative bioavailability of two oral formulations of ketoprofen 25 mg in healthy subjects. A fast-dissolving lyophilized tablet as compared to immediate release tablet

The pharmacokinetics of ketoprofen from a fast-dissolving lyophilized tablet (LT), which need not be swallowed, as compared to an immediate release (IR) tablet as reference after single oral dose (25 mg) administration was determined in six healthy subjects aged between 25-40 years using a randomized crossover design. In this study, the rate and extent of absorption of ketoprofen were found to be very different after administration of the LT and the IR tablet. The rate of absorption of ketoprofen from LT was significantly faster than that of IR tablet and had significantly higher Cmax (by about 50%) and earlier tmax (by 15 min), whereas the extent of absorption expressed by AUC was about 68% higher as compared to the IR tablet. The relative bioavailability (frel) of the LT compared with the IR tablet was 168%. The difference between the two formulations for half-life and MRT were statistically significant (p<0.05). The tolerance of the two tested formulations was excellent. Ketoprofen LT remained physically and chemically stable for 12 months at 25 degrees C and 60% relative humidity.     

Formulation of a Fast-Dissolving Ketoprofen Tablet Using Freeze-Drying in Blisters Technique

ABSTRACT

The aim of this work was to develop a ketoprofen tablet which dissolve-rapidly in the mouth, therefore, needing not be swallowed. The solubility and dissolution rate of poorly water-soluble ketoprofen was improved by preparing a lyophilized tablet (LT) of ketoprofen using freeze-drying technique. The LT was prepared by dispersing the drug in an aqueous solution of highly water-soluble carrier materials consisting of gelatin, glycine, and sorbitol. The mixture was dosed into the pockets of blister packs and then was subjected to freezing and lyophilization. The saturation solubility and dissolution characteristics of ketoprofen from the LT were investigated and compared to the plain drug and the physical mixture (PM). Results obtained showed that the increase in solubility of ketoprofen from LT matrix, nearly three times greater than the solubility of the plain drug, was due to supersaturation generated by amorphous form of the drug. Results obtained from dissolution studies showed that LT of ketoprofen significantly improved the dissolution rate of the drug compared with the PM and the plain drug. More than 95% of ketoprofen in LT dissolved within 5 min compared to only 45% of ketoprofen plain drug dissolved during 60 min. Initial dissolution rate of ketoprofen in LT was almost tenfold higher than that of ketoprofen powder alone. Crystalline state evaluation of ketoprofen in LT was conducted through differential scanning calorimetry (DCS) and x-ray powder diffraction (XRPD) to denote eventual transformation to amorphous state during the process. Scanning electron microscopic (SEM) analysis was performed and results suggest reduction in ketoprofen particle size.     

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.     

Formulation Design of an HPMC-Based Sustained Release Tablet for Pyridostigmine Bromide as a Highly Hygroscopic Model Drug and its In Vivo/In Vitro Dissolution Properties

Pyridostigmine bromide (PB), a highly hygroscopic drug was selected as the model drug. A sustained-release (SR) tablet prepared by direct compression of wet-extruded and spheronized core pellets with HPMC excipients and exhibited a zero-order sustained release (SR) profile. The 2³ full factorial design was utilized to search an optimal SR tablet formulation. This optimal formulation was followed zero-order mechanism and had specific release rate at different time intervals (released % of 1, 6, and 12 hr were 15.84, 58.56, and 93.10%). The results of moisture absorption by Karl Fischer meter showed the optimum SR tablet could improve the hygroscopic defect of the pure drug (PB). In the in vivo study, the results of the bioavailability data showed the T_max was prolonged (from 0.65 ± 0.082 hr to 4.83 ± 1.60 hr) and AUC_0–t (from 734.88 ± 230.68 ng/ml.hr to 1153.34 ± 488.08 ng/ml.hr) and was increased respectively for optimum PB-SR tablets when compared with commercial immediate release (IR) tablets. Furthermore, the percentages of in vitro dissolution and in vivo absorption in the rabbits have good correlation. We believe that PB-SR tablets designed in our study would improve defects of PB, decrease the frequency of administration and enhance the retention period of drug efficacy in vivo for personnel exposed to contamination situations in war or terrorist attacks in the future.     

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.     

Development of Sustained-Release Tablets Containing Sodium Valproate: In Vitro and In Vivo Correlation

ABSTRACT

We have developed a 200 mg and 400 mg sustained-release sodium valproate tablet that allows effective blood concentration of the active drug with once-a-day dosing. The controlled dissolution or sustained release of the drug was attained by a membrane-controlled system. A single-coating system did not adequately control the dissolution rate, and therefore double-coated tablets were prepared and a human pharmacokinetic study was conducted. With the 200 mg VPA-Na tablets, the nonfasting C_max was only 20% higher than the fasting C_max. An in vitro dissolution test was conducted to predict the effects of food on drug dissolution after administration of this tablet. A relatively good correlation was observed between the absorption profiles and the dissolution profiles of the drug.     

Topical Oleo-Hydrogel Preparation of Ketoprofen with Enhanced Skin Permeability

In an attempt to improve the skin penetration of ketoprofen, various transdermal formulations were prepared, and their in vitro skin permeability and in vivo percutaneous absorption were evaluated. In vitro permeation studies were performed using a modified Franz cell diffusion system in which permeation parameters such as cumulative amount at 8 hr Q_8hr, steady-state flux J_ss, or lag time t_L were determined. In the in vivo percutaneous absorption study using the hairless mouse, maximum concentration C_max and area under the curve at 24 hr AUC_24h were measured. The optimal transdermal formulation (oleo-hydrogel formulation) of ketoprofen showed a Q_8hr value of 227.20 μg/cm², a J_ss value of 29.61 μg/cm²/hr, and a t_L value of 0.46 hr. The Q_8hr and J_ss values were about 10-fold (p <. 01) higher than those (Q_8hr = 19.61 μg/cm²; J_ss = 2.66 μg/cm²/hr) from the K-gel and about 3.5-fold (p <. 01) than those (Q_8hr = 60.00 μg/cm²; J_ss = 7.99 μg/cm²/hr) of the K-plaster. In the in vivo percutaneous absorption, the C_max (6.82 μg/ml) and AUC_24h (55.74 μg·hr/ml) values of the optimal formulation were significantly (p <. 01) higher than those of K-gel and K-plaster. The relative bioavailability of the oleo-hydrogel following transdermal administration in reference to oral administration was about 37%, and the C_max value (4.73 μg/cm²) in the hypodermis following topical administration was much higher than those from the conventional products (C_max of K-gel and K-plaster were 0.92 ± 0.19 μg/cm² and 1.27 ± 0.37 μg/cm², respectively). These data demonstrate that the oleo-hydrogel formulation of ketoprofen was more beneficial than conventional products (K-gel and K-plaster) in enhancing transdermal permeation and skin absorption of ketoprofen. Furthermore, there was a good correlation between in vitro permeation parameters and in vivo percutaneous absorption parameters.     

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.     

Effect of Sodium Lauryl Sulphate and TweenR80 on the Therapeutic Efficacy of Glibenclamide Tablet Formulations in Terms of BSL Lowering in Rabbits and Diabetic Human Volunteers

Abstract

Glibenclamide has limited gastrointestinal absorption. Therefore, different concentrations of sodium lauryl sulphate and tween^R80 were included into the tablet formulations to increase the absorption of the drug and hence, to enhance the BSL lowering in rabbits and human volunteers suffering from maturity onset diabetes mellitus. It was found that the surfactants had enhanced both the rate and extent of BSL lowering in rabbits as well as in diabetic patients in higher concentrations present in the tablet formulations.     

Film-Coated Enteric Tablet Formulation of Ketorolac Tromethamine

Abstract

A great majority of polymers used for pharmaceutical film-coating purposes have been derivatives of cellulose or methacrylate copolymers (Eudragit series) in most recent studies. The type and frequency of the ester substituents in the chemical structure of these polymers determines their water permeability and pH-solubility characteristics; therefore, different members of the series may be employed for taste-masking or as enteric-coating agents or dissolution rate-controlling membranes in sustained-release dosage forms. Ketorolac tromethamine (KT) is a non-steroidal drug with potent analgesic and anti-inflammatory activity and is absorbed rapidly (T_max < 1.0 hr) with an efficiency of > 87% following oral and intramuscular administration. The most frequent adverse effects occurring with KT are gastrointestinal disturbances such as peptic ulceration and gastrointestinal bleeding. For this reason, enteric-coated film tablets of KT were prepared in this study by the spray technique. Eudragit S-100 and L-100 were selected as coating materials. Polyethylene glycol (PEG) 4000 was used as a plastifying agent. Core tablets of KT were prepared by the direct compression technique. Tablet specifications were determined and evaluated statistically.     

Prediction of in vivo plasma concentration–time profile from in vitro release data of designed formulations of milnacipran using numerical convolution method

The aim of this study was to predict the in vivo plasma drug level of milnacipran (MIL) from in vitro dissolution data of immediate release (IR 50?mg and IR 100?mg) and matrix based controlled release (CR 100?mg) formulations. Plasma drug concentrations of these formulations were predicted by numerical convolution method. The convolution method uses in vitro dissolution data to derive plasma drug levels using reported pharmacokinetic (PK) parameters of a test product. The bioavailability parameters (C_max and AUC) predicted from convolution method were found to be 106.90?ng/mL, 1138.96?ng/mL?h for IR 50?mg and 209.80?ng/mL, 2280.61?ng/mL?h for IR 100?mg which are similar to those reported in the literature. The calculated PK parameters were validated with percentage predication error (% PE). The % PE values for C_max and AUC were found to be 7.04 and ?7.35 for IR 50?mg and 11.10 and ?8.21 for IR 100?mg formulations. The C_max, T_max, and AUC for CR 100?mg were found to be 120?ng/mL, 10?h and 2112.60?ng/mL?h, respectively. Predicted plasma profile of designed CR formulation compared with IR formulations which indicated that CR formulation can prolong the plasma concentration of MIL for 24?h. Thus, this convolution method is very useful for designing and selection of formulation before animal and human studies.     

The development of carbamazepine-succinic acid cocrystal tablet formulations with improved in vitro and in vivo performance

Abstract

The use of soluble cocrystal for delivering drugs with low solubility, although a potentially effective approach, often suffers the problem of rapid disproportionation during dissolution, which negates the solubility advantages offered by the cocrystal. This necessitates their robust stabilization in order for successful use in a tablet dosage form. The cocrystal between carbamezepine and succinic acid (CBZ-SUC) exhibits a higher aqueous solubility than its dihydrate, which is the stable form of CBZ in water. Using this model system, we demonstrate an efficient and material-sparing tablet formulation screening approach enabled by intrinsic dissolution rate measurements. Three tablet formulations capable of stabilizing the cocrystal both under accelerated condition of 40?°C and 75% RH and during dissolution were developed using three different polymers, Soluplus® (F₁), Kollidon VA/64 (F₂) and Hydroxypropyl methyl cellulose acetate succinate (F₃). When compared to a marketed product, Epitol® 200?mg tablets (F₀), drug release after 60?min from formulations F₁ (～82%), F₂ (～95%) and F₃ (～95%) was all higher than that from Epitol® (79%) in a modified simulated intestinal fluid. Studies in albino rabbits show correspondingly better bioavailability of F₁–F₃ than Epitol.     

Enhanced oral bioavailability of lurasidone by self-nanoemulsifying drug delivery system in fasted state

Objective: The purpose of this work was to develop a new formulation to enhance the bioavailability and reduce the food effect of lurasidone using self-nanoemulsifying drug delivery systems (SNEDDSs).

Methods: The formulation of lurasidone-SNEDDS was selected by the solubility and pseudo-ternary phase diagram studies. The prepared lurasidone-SNEDDS formulations were characterized for self-emulsification time, effect of pH and robustness to dilution, droplet size analysis, zeta potential and in vitro drug release. Lurasidone-SNEDDSs were administered to beagle dogs in fed and fasted state and their pharmacokinetics were compared to commercial available tablet as a control.

Results: The result showed lurasidone-SNEDDS was successfully prepared using Capmul MCM, Tween 80 and glycerol as oil phase, surfactant and co-surfactant, respectively. In vitro drug release studies indicated that the lurasidone-SNEDDS showed improved drug release profiles and the release behavior was not affected by the medium pH with total drug release of over 90% within 5?min. Pharmacokinetic study showed that the AUC_(0–∞) and C_max for lurasidone-SNEDDS are similar in the fasted and fed state, indicating essentially there is no food effect on the drug absorption.

Conclusion: It was concluded that enhanced bioavailability and no food effect of lurasidone had been achieved by using SNEDDS.     

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.     

Gastrointestinal Transit and Concomitant Absorption of Verapamil from a Single-Unit Sustained-Release Tablet

Abstract

A radiographic procedure is described for determining the position of a single-unit sustained-release tablet and the concomitant drug serum level. The results confirmed that, under fasting conditions, an essential part of the absorption of the model drug, verapamil, takes place in the colon. Food affected not only the gastrointestinal transit of the tablet but also the absorption rate of verapamil. With food the commencement of absorption was clearly more rapid than under fasting conditions. This is because the tablet is retained for a longer time by the food in the upper parts of the gastrointestinal tract, which favour drug absorption. It is concluded that absorption of verapamil from the colon is also effective and can be utilized in sustained release formulations. The ratio of AUC values of verapamil to those of norverapamil was markedly higher under fasting conditions, indicating enhanced bioavailability of verapamil from formulations which release most of the drug into the colon.     

Relative Bioavailability and Pharmacokinetic Parameters Following Adminstration of Single Oral Dose (2×150 mg) of Chloroquine Tablet in Healthy Subjects

Abstract

The bioavailability ot Chloroquine phosphate (150 mg base) film coated tablet (manufactured by Pars - Darou Co. Iran) was compared with that ot the Resochin tablet (Bayer, Germany) in seven healthy male and female volunteers. Blood samples were collected up to 14 days utter oral dosing of 300 nig and chloroquine serum concentrations were determined by means ot High Performance Liquid Chromatography (HPLC). From the analysis ot serum samples the following pharmacokinetic parameters were obtained: the absorption rate of test tablet and that of reference were 0.25 h^?1 and 0.34 h^?1 respectively; maximum serum concentration of both tablets was nearly equal, 81.6±25 and 83.4±27 ng/ml (for test and reference tablets respectively); time to reaching C_max (t_max) was also very similar, 4±1.6 for test and 4±1.0 h for reference; the area under the serum concentration-time curve [AUC(O -)] of 6976 ng.ml^?1.h±1967 for test and 6446 ng.ml^?1.h ± 2460 for reference tablets were found using trapezoidal rule. By evaluating of the r=(T/R)×100 for each parameters, the test tablet was found to be bioequivalent to Resochin at p = 0.05.     

Clinical pharmacokinetic study for the effect of glimepiride matrix tablets developed by quality by design concept

Objective: Implementation of a new pharmaceutical technique to improve aqueous solubility and thus dissolution, enhancement of drug permeation, and finally formulation of a controlled release tablet loaded with glimepiride (GLMP).

Significance: Improve GLMP bioavailability and pharmacokinetics in type II diabetic patients.

Methods: Different polymers were used to enhance aqueous GLMP solubility of which a saturated polymeric drug solution was prepared and physically adsorbed onto silica. An experimental design was employed to optimize the formulation parameters affecting the preparation of GLMP matrix tablets. A compatibility study was conducted to study components interactions. Scanning electron microscope (SEM) was performed before and after the tablets were placed in the dissolution medium. An in vivo study in human volunteers was performed with the optimized GLMP tablets, which were compared to pure and marketed drug products.

Results: Enhancement of GLMP aqueous solubility, using the polymeric drug solution technique, by more than 6–7 times when compared with the binary system. All the studied formulation factors significantly affected the studied variables. No significant interaction was detected among components. SEM illustrated the surface and inner tablet structure, and confirmed the drug release which was attributed to diffusion mechanism. The volunteer group administered the optimized GLMP tablet exhibited higher drug plasma concentration (147.4?ng/mL), longer time to reach maximum plasma concentration (4?h) and longer t_1/2 (7.236?h) compared to other groups.

Conclusions: Matrix tablet loaded with a physically modified drug form could represent a key solution for drugs with inconsistent dissolution and absorption profiles.     

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.     

Optimization of Direct Compression Tablet Formulations for Use in Tropical Countries

Abstract

With the aid of a combined mixture- and factorial- design, 2 standard tablet formulations were selected suitable for use in tropical countries. The formulations were based on native ingredients or ingredients that are available worldwide. The selection of the standard formulations was based on both the initial tablet properties of the formulations one day after preparation as well as the physical stability after storage under tropical conditions.

The selected formulations were evaluated by adding model drugs (diazepam, 2 mg per tablet or hydrochlorthiazide, 100 mg per tablet) and measuring tablet properties, not only one day after preparation, but also after storage under tropical conditions. Both selected tablet formulations were suitable standard formulations for tablets prepared by direct compression for use in tropical countries.     

Formulation of a fast-dissolving ketoprofen tablet using freeze-drying in blisters technique

The aim of this work was to develop a ketoprofen tablet which dissolve-rapidly in the mouth, therefore, needing not be swallowed. The solubility and dissolution rate of poorly water-soluble ketoprofen was improved by preparing a lyophilized tablet (LT) of ketoprofen using freeze-drying technique. The LT was prepared by dispersing the drug in an aqueous solution of highly water-soluble carrier materials consisting of gelatin, glycine, and sorbitol. The mixture was dosed into the pockets of blister packs and then was subjected to freezing and lyophilization. The saturation solubility and dissolution characteristics of ketoprofen from the LT were investigated and compared to the plain drug and the physical mixture (PM). Results obtained showed that the increase in solubility of ketoprofen from LT matrix, nearly three times greater than the solubility of the plain drug, was due to supersaturation generated by amorphous form of the drug. Results obtained from dissolution studies showed that LT of ketoprofen significantly improved the dissolution rate of the drug compared with the PM and the plain drug. More than 95% of ketoprofen in LT dissolved within 5 min compared to only 45% of ketoprofen plain drug dissolved during 60 min. Initial dissolution rate of ketoprofen in LT was almost tenfold higher than that of ketoprofen powder alone. Crystalline state evaluation of ketoprofen in LT was conducted through differential scanning calorimetry (DCS) and x-ray powder diffraction (XRPD) to denote eventual transformation to amorphous state during the process. Scanning electron microscopic (SEM) analysis was performed and results suggest reduction in ketoprofen particle size.