Bioequivalence of two lansoprazole delayed release capsules 30 mg in healthy male volunteers under fasting, fed and fasting-applesauce conditions: a partial replicate crossover study design to estimate the pharmacokinetics of highly variable drugs.

An open-label, 2-treatment, 3-sequence, 3-period, single-dose, partial replicate crossover studies under fasting (n=48), fed (n=60) and fasting-applesauce (n=48) (sprinkled on one table spoonful of applesauce) modalities were conducted in healthy adult male volunteers to evaluate bioequivalence between 2 formulations of lansoprazole delayed release capsules 30 mg. In all the 3 studies, as per randomization, either test or reference formulations were administered in a crossover manner with a required washout period of at least 7 days. Blood samples were collected adequately (0-24 h) to determine lansoprazole plasma concentrations using a validated LC-MS/MS analytical method. To characterize the pharmacokinetic parameters (Cmax, AUC0-t, AUC0-∞, Tmax, Kel and T1/2) of lansoprazole, non-compartmental analysis and ANOVA was applied on ln-transformed values. The bioequivalence was tested based on within-subject variability of the reference formulation. In fasting and fed studies (within-subject variability>30%) bioequivalence was evaluated with scaled average bioequivalence, hence for the pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞, the 95% upper confidence bound for (µT-µR)2-θσ2 WR was ≤0, and the point estimates (test-to-reference ratio) were within the regulatory acceptance limit 80.00-125.00%. In fasting-applesauce study (within-subject variability<30%) bioequivalence was evaluated with average bioequivalence, the 90% CI of ln-transformed data of Cmax, AUC0-t and AUC0-∞ were within the regulatory acceptance limit 80.00-125.00%. Based on these aforesaid statistical inferences, it was concluded that the test formulation is bioequivalent to reference formulation.

Bioequivalence of fixed dose combination of atorvastatin 10 mg and aspirin 150 mg capsules: a randomized, open-label, single-dose, two-way crossover study in healthy human subjects.

The present study evaluated the bioavailability and bioequivalence of fixed dose combination test formulation (atorvastatin 10 mg and aspirin 150 mg capsule) against marketed reference formulations (Lipitor® tablets 10 mg and Nu-Seals tablets 75 mg). This study was an open label, balanced, randomized, 2-treatment, 2-period, 2-sequence, single dose, crossover trial in 80 healthy adult human volunteers under fasting conditions. Plasma concentrations of atorvastatin, aspirin and salicylic acid were quantified using LC-MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental model and mean pharmacokinetic parameters were comparable between test and reference formulations. The mean pharmacokinetic parameters (AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞) for atorvastatin test and reference formulations were (52.69 ng.h/mL, 55.64 ng.h/mL, 9.45 ng/mL, 0.18 1/h and 0.17 1/h) and (52.20 ng.h/mL, 55.38 ng.h/mL, 10.25 ng/mL, 0.20 1/h and 0.19 1/h) respectively; and for aspirin were (1 378.62 ng.h/mL, 1 383.90 ng.h/mL, 1 022.18 ng/mL, 0.75 1/h and 0.75 1/h) and (1 314.17 ng.h/mL, 1 314.50 ng.h/mL, 985.90 ng/mL, 0.75 1/h and 0.75 1/h) respectively. Where as for salicylic acid, above parameters were (42 357.57 ng.h/mL, 44 139.47 ng.h/mL, 9 820.15 ng/mL, 0.24 1/h and 0.23 1/h) and (40 217.08 ng.h/mL, 42 032.44 ng.h/mL, 9 569.18 ng/mL, 0.24 1/h and 0.24 1/h) respectively for test and reference formulations. The 90% confidence intervals of atorvastatin and salicylic acid for AUC0-t, AUC0-∞, Cmax, Cmax /AUC0-t and Cmax/AUC0-∞ parameters were found to be within the acceptable regulatory bioequivalence limits. In conclusion, the new fixed dose combination test formulation was bioequivalent to the reference formulations under fasting conditions.

Bioequivalence study of two subcutaneous formulations of dalteparin: randomized, single-dose, two-sequence, two-period, cross-over study in healthy volunteers.

OBJECTIVE: This study assessed relative bioavailability of a new subcutaneous formulation, test (T) (dalteparin sodium 95000 IU/3.8 mL) with the branded product (R) in healthy subjects to meet the regulatory requirements of bioequivalence in the US. METHODS: This was an open label, randomized, single dose, two-sequence, two-period cross-over study under fasting conditions. A total of 88 healthy adult volunteers were randomized to either of the treatment arms (T or R) separated by a washout period of 7 days. Pharmacodynamic surrogates, namely anti-Xa and anti-IIa activity, heparin clotting assay (heptest), and activated partial thromboplastin time (aPTT) were used as a tool to establish bioequivalence between these two formulations. Blood samples were collected up to 36 h post-dose to characterize the primary pharmacokinetic parameters A max, AUC0- t , and AUC0-∞ for anti-Xa and anti-IIa and heptest; parameters (Δt )max and AU(Δt ) for aPTT. RESULTS: For anti-Xa activity, the means (SD) of A max (IU/mL) were 1.34 (0.25) [range = 0.59-2.03] and 1.39 (0.35) [range = 0.65-2.69]; AUC0- t (IU•h/mL) values were 11.4 (2.76) [range = 2.89-19.5] and 12.1 (2.87) [range = 2.52-21.30]; AUC0 - ∞ (IU•h/mL) values were 13.1 (3.59) [range = 3.15-28.2] and 14.5 (4.97) [range = 2.79-36.1] for test and branded formulations, respectively. For anti-IIa activity, the means (SD) of A max (IU/mL) were 0.34 (0.12) [range = 0.14-0.72] and 0.34 (0.13) [range = 0.11-0.84]; AUC0- t (IU•h/mL) values were 2.05 (0.72) [range = 0.61-4.69] and 2.11 (0.76) [range = 0.84-4.80]; AUC0 - ∞ (IU•h/mL) values were 2.47 (0.80) [range = 0.76-6.29] and 2.61 (0.86) [range = 1.31-5.36], for test and branded formulations, respectively. The 90% CI for all the primary pharmacokinetic parameters of all the pharmacodynamic surrogates tested met the regulatory bioequivalence criterion of 80.00-125.00%. CONCLUSION: The test product met the US regulatory criteria of bioequivalence relative to the branded product in this single dose bioequivalence study. Study limitations include open-label single dose design.

Pharmacokinetics and tissue distribution of piperine lipid nanospheres.

The purpose of this study was to estimate the pharmacokinetic parameters and tissue distribution of positively charged stearylamine (LN-P-SA) and pegylated lipid nanospheres (LN-P-PEG) of piperine in BALB/c mice. Lipid nanospheres of piperine (LN-P), LN-P-PEG and LN-P-SA were prepared by homogenization followed by ultrasonication. The pharmacokinetics and tissue distribution of different lipid nanosphere formulations (piperine, LN-P, LN-P-PEG and LN-P-SA) were studied in male BALB/c mice. The pharmacokinetic parameters of LN-P-PEG and LN-P-SA were: AUC(0-24): 372.1 +/- 71.6 and 162.2 +/- 36.4 microg h(-1) ml(-1), clearance 13 +/- 2.5 and 32 +/- 7.5 ml h(-1), Cmax: 24.7 +/- 1.5 and 22.3 +/- 1.0 microg ml(-1), Vd: 0.45 +/- 0.02 and 0.66 +/- 0.06 l Kg(-1)). Pharmacokinetics of piperine in lipid nanospheres showed a biexponential decline with significantly high AUC, a lower rate of clearance and a smaller volume of distribution than piperine.

Pharmacokinetics and tissue distribution of etoposide delivered in parenteral emulsion.

Etoposide was incorporated in an injectable parenteral emulsion, in an attempt to alter its pharmacokinetics and improve anticancer activity. Parenteral emulsion of etoposide (EPE), which remained stable over 6 months' storage, was prepared (under optimal experimental conditions) using soybean oil and phosphatidylcholine as emulsifier. The particle size distribution and zeta potential were measured using photon correlation spectroscopy. The pharmacokinetics and tissue distribution of EPE and commercial etoposide injectable solution (ETP) were studied in Swiss albino mice. The antitumor activity was performed on BDF1 mice bearing Lewis lung carcinoma. The particle size distribution with polydispersity indices, zeta potential, entrapment efficacy, and assay of EPE were found to be 218.7 +/- 4.7 (0.14 +/- 0.0) nm, -53.5 +/- 0.2 mV, 75 +/- 2.1%, and 0.85 +/- 0.1 mg/mL, respectively. The EPE was stable for >6 months and drug leaching was 5.8 +/- 1.5%. The pharmacokinetics and tissue distribution of EPE was significantly different than that of ETP. The EPE showed high AUC(0-alpha), MRT (mean residence time), and lower clearance than that of ETP. It was found that etoposide concentration was higher in liver, spleen, and lung after ETP administration when compared with EPE; however, in heart and brain, etoposide was more after EPE than that of ETP. The EPE showed lower reticuloendothelial system (liver and spleen) tissue uptake. The anticancer activity of EPE was higher in Lewis lung carcinoma-bearing mice. On the fifteenth day of transplantation, the percentage of tumor growth suppression rate was 63.23% in EPE-treated mice and 33.78% in ETP-treated mice.

Formulation and evaluation of oil-in-water emulsions of piperine in visceral leishmaniasis.

Present studies are aimed to find out the utility of oil-in-water emulsions also known as lipid nanospheres (LN) or fat emulsions for delivering piperine for the treatment of visceral leishmaniasis. Lipid nanosphere formulations of piperine were prepared using soybean oil, egg lecithin, cholesterol, stearylamine and phosphatidylethanolamine distearylmethoxypolyethyleneglycol (DSPE-PEG) by homogenization followed by ultrasonication of oil and aqueous phases. Antileishmanial activity of all the formulations was assessed in BALB/c mice infected with Leishmania donovani AG83 for 60 days. A single dose (5 mg/kg) of piperine, or lipid nanospheres of piperine (LN-P), or lipid nanosphere of piperine with stearylamine (LN-P-SA) or pegylated lipid nanospheres of piperine (LN-P-PEG) was injected intravenously. Mice were sacrificed after 15 days of treatment with piperine or formulations and Leishman Donovan Unit (LDU) is counted. Toxicity of formulations and pure piperine was assessed in normal mice. The size distribution of formulations ranged from 200 to 885 nm. Piperine reduced the parasite burden in liver and spleen by 38% and 31% after 15 days post infection respectively. LN-P reduced the parasite burden in liver and spleen by 63% and 52% after 15 days post infection, respectively. LN-P-PEG reduced the parasite burden in liver and spleen by 78% and 75% after 15 days post infection, respectively. LN-P-SA reduced the parasite burden in liver and spleen by 90% and 85% after 15 days post infection, respectively. LN-P, LN-P-PEG, LN-P-SA treated mice did not show any significant changes in the serum levels of SGOT, ALP, creatinine and urea compared to normal mice. Stable and sterile formulations of lipid nanospheres of piperine were developed. A single dose of 5 mg/kg of lipid nanospheres of piperine could significantly reduce the liver and splenic parasite burden.

Pharmacokinetics and tissue distribution of piperine in animals after i.v. bolus administration.

A reverse phase HPLC method to determine piperine, a pungent constituent of black pepper, in rabbit serum and various tissues of the rat was developed. A pharmacokinetic study was performed in rabbits and tissue distribution studies were carried out in rats. High reproducibility was achieved in quantitative analysis over the concentration range of 0.2-20 micrograms/ml serum. After bolus intravenous administration of piperine at a dose of 10 mg/kg, the serum concentration--time curve fitted the two-compartment open model. The tissue distribution pattern of piperine in rats also supports the two-compartment open model.