Pharmacokinetic study of liposome-encapsulated and plain mepivacaine formulations injected intra-orally in volunteers.

OBJECTIVES: The pharmacokinetics of commercial and liposome-encapsulated mepivacaine (MVC) injected intra-orally in healthy volunteers was studied. METHODS: In this double blind, randomized cross-over study, 15 volunteers received, at four different sessions, 1.8 ml of the following formulations: 2% MVC with 1 : 100 000 epinephrine (MVC(2%EPI) ), 3% MVC (MVC(3%) ), 2% and 3% liposome-encapsulated MVC (MVC(2%LUV) and MVC(3%LUV) ). Blood samples were collected pre dose (0 min) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360 min after injections. Liquid chromatography-tandem mass spectrometry was used to quantify plasma MVC concentrations. RESULTS: Pharmacokinetic analysis showed that the maximum plasma concentration (Cmax) and the areas under the curves (AUC(0-360) and AUC(0-∞)) after MVC(2%LUV) and MVC(2%EPI) injections were smaller (P < 0.05) than the equivalent figures for MVC(3%) and MVC(3%LUV). The time to maximum plasma concentration (Tmax) and the half-life of elimination (t½beta) obtained after the treatment with MVC(2%LUV), MVC(2%EPI), MVC(3%) and MVC(3%LUV) presented no statistically significant differences (P > 0.05). Cmax, AUC(0-360) and AUC(0-∞) after injection of the 2% formulations (MVC(2%LUV) and MVC(2%EPI) ) did not exhibit statistically significant differences (P > 0.05). The pharmacokinetics of MVC(2%LUV) were comparable to the pharmacokinetics of MVC(2%EPI). CONCLUSION: The liposomal formulation of 2% MVC exhibits similar systemic absorption to the local anesthetic with vasoconstrictor.

Evaluation of pantoprazole formulations in different dissolution apparatus using biorelevant medium.

PURPOSE: The study was developed to compare the in vitro dissolution profiles of pantoprazole (CAS 102625-70-7) formulations in both The United States Pharmacopeia (USP) apparatus 2 and 3 by applying biorelevant medium. Moreover, an in vitro-in vivo relationship was proposed considering in vivo data from a previously published study. METHODS: In vitro dissolution profiles were evaluated in biorelevant medium in USP apparatus 2 and 3 and the dissolution curves were either compared by the similarity factor (f2) or a model-independent approach. The fraction of drug dissolved in vitro in apparatus 2 was compared with the fraction of drug absorbed in vivo, which was obtained from a retrospective in vivo study. An in vitro-in vivo relationship analysis was then applied to elucidate the overall absorption characteristics of formulations. RESULTS: The dissolution profiles of formulations demonstrated similar disposition in biorelevant medium in both USP apparatus 2 and 3. The dissolution profiles were described by f2 model in apparatus 2 and Weibull's function in apparatus 3. The vitro-in vivo relationship analysis showed that the formulations exhibited permeability rate-limiting absorption. CONCLUSION: Biorelevant medium in both USP apparatus 2 and 3 may be used as a tool to predict in vivo disposition of formulations of pantoprazole. Furthermore, it can be argued that biowaiver can be granted for enteric coated formulations of pantoprazole on the basis of in vitro dissolution profile.

Pharmacokinetic and local toxicity studies of liposome-encapsulated and plain mepivacaine solutions in rats.

The pharmacokinetics and the local toxicity of commercial and liposome-encapsulated mepivacaine formulations injected intra-orally in rats were studied. Animals were divided in groups (n = 4-6) and treated with 0.1 mL of the formulations: 2% mepivacaine with 1:100,000 epinephrine (MVC(2%EPI)), 3% mepivacaine (MVC(3%)), and 2% liposome-encapsulated mepivacaine (MVC(LUV)). The results showed that the 2% liposome-encapsulated mepivacaine reduced C(max), prolonged AUC(0-infinity) and t(1/2) compared with 3% plain and 2% vasoconstritor-associated mepivacaine, after intraoral injection. In addition, it was also observed that liposomal mepivacaine might protect the tissue against local inflammation evoked by plain or vasoconstrictors-associated mepivacaine, giving supporting evidence for its safety and possible clinical use in dentistry.

Bioequivalence of two enteric coated formulations of pantoprazole in healthy volunteers under fasting and fed conditions.

PURPOSE: To compare the bioavailability of two pantoprazole (CAS 102625-70-7) formulations (40 mg pantoprazole enteric coated tablets) under fasted and fed conditions as well as to evaluate the dissolution profile in biorelevant media. METHODS: The subjects received either 40 mg of the reference or of test formulation in fasting (n = 28) and fed (n=70) condition. The studies were conducted according to a single dose and randomized crossover design. Blood samples were collected up to 12 h after drug administration in fasting condition and up to 48 h in fed condition. Plasma concentrations of pantoprazole were determined by LC-MS/MS. Pharmacokinetic parameters were calculated from the observed plasma concentration-time profiles. Bioequivalence between the formulations in fasting and fed condition was assessed considering 90% confidence intervals for the ratio of means for lnCmax and lnAUC(0-t) within 0.8-1.25. Dissolution profiles were evaluated in biorelevant media [Fasting State Simulating Intestinal Fluid (FaSSIF) and Fed State Simulating Intestinal Fluid (FeSSIF)]. The sameness of the dissolution curves was assessed by f2 values between 50 and 100. RESULTS: Under fasting condition the 90% confidence interval for the ratio of means for the lnCmax, (0.94-1.03) and lnAUC(0-t) (0.89-0.99) was within the guideline range of bioequivalence (0.80-1.25). However, the data for lnCmax (0.51-0.76) and lnAUC(0-t) (0.68-0.90) under fed condition were not within the bioequivalence range. The postprandial study demonstrated a high intra-subject variability and in some subjects pantoprazole could not be detected for up to 24 h, although the dissolution profile of reference and test formulations presented a similar disposition in FaSSIF and FeSSIF as confirmed by the values of f2 higher than 50. CONCLUSION: The results demonstrated that the test formulation was bioequivalent to the reference in fasting condition but not in postprandial state. The dissolution profile in FaSSIF indicates that this biorelevant medium was more adequate to discriminate the in vivo disposition of pantoprazole than FeSSIF. Furthermore, the fed condition study had shown a pronounced influence of food in the absorption of pantoprazole after single oral dose administration.