Preclinical Evaluation of Ropivacaine in 2 Liposomal Modified Systems.

BACKGROUND: Our research group has recently developed liposomes with ionic gradient and in a combined manner as donor and acceptor vesicles containing ropivacaine (RVC; at 2% or 0.75%). Looking for applications of such novel formulations for postoperative pain control, we evaluated the duration of anesthesia, pharmacokinetics, and tissue reaction evoked by these new RVC formulations. METHODS: The formulations used in this study were large multivesicular vesicle (LMVV) containing sodium acetate buffer at pH 5.5 or in a combined manner with LMVV as donor and large unilamellar vesicles (LUVs) as acceptor vesicles with an external pH of 7.4. Wistar rats were divided into 6 groups (n = 6) and received sciatic nerve block (0.4 mL) with 6 formulations of RVC (LMVVRVC0.75%, LMVV/LUVRVC0.75%, LMVVRVC2%, LMVV/LUVRVC2%, RVC 0.75%, and RVC 2%). To verify the anesthetic effect, the animals were submitted to the pain pressure test and the motor block was also monitored. Histopathology of the tissues surrounding the sciatic nerve region was also assessed 2 and 7 days after treatment. Rats (n = 6) were submitted to a hind paw incision, and mechanical hypersensitivity was measured via the withdrawal response using von Frey filaments after injection of the 6 formulations. Finally, New Zealand white rabbits (n = 6) received sciatic nerve block (3 mL) with 1 of the 6 formulations of RVC. Blood samples were collected predose (0 minutes) and at 15, 30, 45, 60, 90, 120, 180, 240, 300, 360, 420, 480, and 540 minutes after injection. RVC plasma levels were determined using a triple-stage quadrupole mass spectrometer. RESULTS: Duration and intensity of the sensory block were longer with all liposomal formulations, when compared to the plain RVC solution (P < .05). Histopathological evaluation showed greater toxicity for the positive control (lidocaine 10%), when compared to all formulations (P < .05). After the hind paw incision, all animals presented postincisional hypersensitivity and liposomal formulations showed longer analgesia (P < .05). LMVVRVC0.75% presented higher time to reach maximum concentration and mean residence time than the remaining formulations with RVC 0.75% (P < .05), so LMVV was able to reduce systemic exposure of RVC due to slow release from this liposomal system. CONCLUSIONS: All new liposomal formulations containing 0.75% RVC were able to change the pharmacokinetics and enhance anesthesia duration due to slow release of RVC from liposomes without inducing significant toxic effects to local tissues.

Bupivacaine in alginate and chitosan nanoparticles: an in vivo evaluation of efficacy, pharmacokinetics, and local toxicity.

OBJECTIVE: This study reports a preclinical evaluation of an alginate/chitosan nanoparticle formulation containing NovaBupi®, a racemic bupivacaine (BVC) containing 25% dextrobupivacaine and 75% levobupivacaine. METHODS: New Zealand White rabbits (n=6) received intraoral or intrathecal injections of BVC 0.5% or BVC 0.5%-loaded alginate-chitosan nanoparticles (BVCALG). BVC plasma levels and pharmacokinetic parameters were determined in blood samples of these rabbits. An infraorbital nerve blockade was performed in male Wistar rats (n=7) with the same formulations and the vehicle (NPALG). Histological evaluation of local toxicity after 6 hours and 24 hours of the treatments was performed in rats' (n=6) oral tissues. RESULTS: No statistically significant difference was observed between plasma concentrations and pharmacokinetic parameters (p>0.05) after intraoral injections. However, after intrathecal injection BVCALG changed approximately three times the values of volume of distribution and area under the curve (AUC0-t; p<0.05). The total analgesic effect of BVC after infraorbital nerve blockade was improved by 1.4-fold (p<0.001) with BVCALG. BVC and BVCALG did not induce significant local inflammatory reaction. CONCLUSION: The encapsulation of BVC prolongs the local anesthetic effect after infraorbital nerve blockade and altered the pharmacokinetics after intrathecal injection.

Pharmacokinetics and Pharmacodynamics Evaluation of Tramadol in Thermoreversible Gels.

We evaluated pharmacokinetics (PK) and pharmacodynamics (PD) induced by new formulations of tramadol (TR) in thermoreversible gels. The poloxamer- (PL-) tramadol systems were prepared by direct dispersion of the drug in solutions with PL 407 and PL 188. The evaluated formulations were as follows: F1: TR 2% in aqueous solution and F2: PL 407 (20%) + PL 188 (10%) + TR 2%; F3: PL 407 (25%) + PL 188 (5%) + TR 2%; F4: PL 407 (20%) + TR 2%. New Zealand White rabbits were divided into four groups (n = 6) and treated by subcutaneous route with F1, F2, F3, or F4 (10 µg·kg-1). PK evaluation used TR and M1 plasma levels. PD evaluation was performed with the measurement of both pupils' diameters. F2 showed higher TR plasma concentration after 180 minutes and presented lower M1 concentrations at almost all evaluated periods. Areas under the curve (ASC0-480 and ASC0-∞ ) and clearance of F2 presented differences compared to F1. F2 presented significant correlation (Pearson correlation) between the enhancement of TR and M1 concentrations and the decrease of pupil size (miosis). Thus, F2 was effective in altering pharmacokinetics and pharmacodynamics effects of TR.

Estudo de bioequivalência entre duas formulações de topiramato comprimidos revestidos de 100 mg, em voluntários sadios após administração de dose única / Study of bioequivalence between two formulations of topiramate 100 mg coated tablets, in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de topiramato 100 mg comprimidos revestidos (Aché Laboratórios Farmacêuticos S/A - formulação teste e Topamax® por Janssen Cilag Farmacêutica Ltda.) em 28 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de 14 dias. As amostras de plasma de 23 dos 28 voluntários inicialmente incluídos foram obtidas ao longo de um intervalo de 120 horas. As concentrações de topiramato foram determinadas através de um equipamento LC-MS-MS, utilizando prednisona como padrão interno. A partir dos dados obtidos se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t, ASC0-¥ e Cmax. A razão das médias geométricas de Topiramato/Topamax® 100 mg foi de 100,97% para ASC0-t, 101,38% para ASC0-¥ e 96,94% para Cmax; os intervalos de confiança de 90% foram de 107,02% - 107,40%, 104,45% - 110,42% e 90,98% - 103,29%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80% a 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que comprimido revestido de topiramato 100 mg foi bioequivalente ao comprimido de Topamax® de 100 mg e, desta forma, o produto teste pode ser considerado intercambiável na prática médica...

Estudo comparativo da atividade antiinflamatória, ulcerogênica e citotóxica do S-ibuprofeno e ibuprofeno racêmico / Comparative study of anti-inflammatory, ulcerogenic and cytotoxic activities of racemate and S-ibuprofen

Ibuprofen is widely commercialized in racemic form. Although metabolic chiral inversion occurs through the conversion of R(-)-ibuprofen to S(+)-ibuprofen and the latter enantiomer is considered the active form, clinical trials involving the administration of a racemate to S-enantiomer dosage ratio of 1:0.5 have demonstrated that S(+)-ibuprofen is as efficacious as the racemic formulation. Moreover, the R(-)-enantiomer has been implicated in adverse gastrointestinal effects found with the racemic form, but the mechanisms involved in this process are not yet fully understood. The aim of the present study was to evaluate the anti-inflammatory activity of a racemate to S(+)-ibuprofen dosage ratio of 1:0.5 using the carrageenan air pouch model of inflammation and determine both ulcerogenic activity and the chiral conversion rate in rats. An in vitro study of the cytotoxicity of racemate and S(+)-ibuprofen in gastric cells was also performed. Although the plasma level of S(+)-ibuprofen was raised after racemate administration, no significant difference was found in anti-inflammatory activity, as assessed by exudate formation, PGE2 production and leukocyte migration to the air pouches. Fewer gastric lesions were found after S(+)-ibuprofen administration, despite the low gastric PGE2 content. In the in vitro study, the racemic compound proved more cytotoxic than S(+)-ibuprofen. The present findings suggest that the S-enantiomer of ibuprofen could be considered a therapeutic alternative to minimize gastrointestinal side effects, since the chiral inversion of R(-)-ibuprofen to S(+)-ibuprofen did not result in an improved anti-inflammatory response.

O Ibuprofeno é normalmente comercializado na forma racêmica. Embora ocorra inversão quiral convertendo a forma R(-)- em S(+)-ibuprofeno e, a última seja considerada a forma ativa, a administração da proporção 1:0,5 (racemato: S-enantiômero) demonstrou que o S(+)-ibuprofeno é mais eficaz que a formulação racêmica. Adicionalmente, o R(-)-enantiômero está envolvido nos efeitos adversos gastrintestinais descritos para a formulação racêmica, embora os mecanismos não sejam complemente compreendidos. O objetivo deste estudo foi avaliar a atividade antiinflamatória da proporção 1:0,5 (racemato:S-ibuprofeno) utilizando o modelo experimental de bolsa de ar, a atividade ulcerogênica e a taxa de conversão quiral em ratos. Também estudamos in vitro, a citotoxicidade provocada pelo racemato e S(+)-ibuprofeno em células gástricas. Embora os níveis plasmáticos de S(+)-ibuprofeno tenham aumentado após a administração do racemato, a atividade antiinflamatória avaliada pela formação de exsudato, produção de PGE2 e migração de leucócitos para a bolsa de ar não foram diferentes. As lesões gástricas foram reduzidas após a administração de S(+)-ibuprofeno, apesar da inibição de PGE2 gástrica. In vitro, o composto racêmico foi mais citotóxico que o S(+)-ibuprofeno. Nossos resultados sugerem que o S-enantiômero do ibuprofeno pode ser considerado uma alternativa terapêutica visando a redução dos efeitos colaterais gastrintestinais, visto que a inversão quiral do R(-)- para o S(+)-ibuprofeno não resultou em melhora do efeito antiinflamatório observado.

Estudo de biodisponibilidade relativa entre duas formulações orais de cloridrato de ranitidina, em voluntários sadios após administração de dose única / Relative bioavailability study of two oral ranitidine hydrochloride formulations in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a biodisponibilidade relativa de duas formulações orais de cloridrato de ranitidina, sendo a formulação teste cloridrato de ranitidina suspensão oral de 40 mg/ml (Aché Laboratórios Farmacêuticos S/A) e a formulação referência Antak® xarope de 150 mg/10 ml produzida por Glaxo Smith Kline Brasil Ltda. em 36 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de quatro dias. As amostras de plasma de 34 dos 36 voluntários inicialmente incluídos foram obtidas ao longo de um intervalo de 12 horas. As concentrações de ranitidina foram determinadas através de um equipamento LC-MS-MS, utilizando cimetidina como padrão interno. A partir dos dados obtidos, calcularam-se os seguintes parâmetros farmacocinéticos: ASC0-t , ASC0-¥ e Cmax. A razão das médias geométricas de Ranitidina/Antak® foi de 99,75% para ASC0-t, 100,24% para ASC0-¥ e 98,87% para Cmax; os intervalos de confiança de 90% foram de 93,91%-105,95%, 94,47%-106,37% e 88,79%-110,09%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax, e ASC0-t estiveram dentro da faixa de 80% a 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que a solução oral de cloridrato de ranitidina 40 mg/ml foi bioequivalente a de Antak® 150 mg/10 ml e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica...

Estudo de bioequivalência entre duas formulações de rivastigmina cápsulas de 6 mg, em voluntários sadios após administração de dose única / Study of bioequivalence between two formulations of rivastigmine 6 mg capsules, in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de rivastigmina 6 mg cápsulas (Aché Laboratórios Farmacêuticos S/A, formulação teste, e Exelon® por Novartis Biociências S/A - formulação referência, Brasil) em 56 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de 7 dias. As amostras de plasma de 46 dos 56 voluntários inicialmente incluídos foram obtidas ao longo de um intervalo de 12 horas. As concentrações de rivastigmina foram determinadas através de um equipamento LC-MS-MS, utilizando zolpidem como padrão interno. A partir dos dados obtidos calcularam-se os seguintes parâmetros farmacocinéticos: ASC0-t , ASC0-¥ e Cmax. A razão das médias geométricas de Rivastigmina/Exelon® 6 mg foi de 100,97% para ASC0-t, 101,38% para ASC0-¥ e 89,01% para Cmax; os intervalos de confiança de 90% foram de 93,20% - 109,39%, 93,65% - 109,75% e 81,10% - 97,70%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80% - 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que a cápsula de rivastigmina 6 mg foi bioequivalente ao comprimido de Exelon® de 6 mg e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica.

Estudo de bioequivalência entre duas formulações de dicloridrato de pramipexol comprimido de 0,25 mg, em voluntários sadios após administração de dose única / Bioequivalence study between two formulations of pramipexole dihydrochloride 0,25 mg tablets in health volunteers after single dose administration

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de dicloridrato de pramipexol 0,25 mg comprimidos (Aché Laboratórios Farmacêuticos S/A (formulação teste)) e Sifrolâ (Boehringer Ingelheim do Brasil Química e Farmacêutica Ltda. (formulação referência)) em 24 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de 14 dias. As amostras de plasma foram obtidas ao longo de um intervalo de 36 horas. As concentrações de dicloridrato de pramipexol foram determinadas através de um equipamento LC-MS-MS, utilizando pramipexol D5 como padrão interno. A partir dos dados obtidos se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t , ASC0-¥ e Cmax. A média geométrica de pramipexol/Sifrolâ 0,25 mg foi de 98,17% para ASC0-t, 96,99% para ASC0-¥ e 96,62% para Cmax; os intervalos de confiança de 90% foram de 93,73 - 102,82%, 93,51% - 100,60% e 89,99 - 103,74%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax, e ASC0-t estiveram dentro da faixa de 80% - 125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que o comprimido de dicloridrato de pramipexol 0,25 mg foi bioequivalente ao comprimido de Sifrolâ de 0,25 mg e, desta forma, o produto teste pode ser considerado intercambiável na prática médica.

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.

Estudo de bioequivalência entre duas formulações de bissulfato de clopidogrel comprimido revestido de 75 mg, em voluntários sadios após administração de dose única / Study of bioequivalence between two formulations of clopidrogel tablets (75mg) in healthy volunteers

O estudo foi realizado para comparar a biodisponibilidade/bioequivalência de duas formulações de clopidogrel 75 mg comprimidos revestidos (Aché Laboratórios Farmacêuticos S/A - formulação teste e (Plavix®) por Sanofi-Aventis Farmacêutica Ltda. - formulação referência, Brasil) em 48 voluntários de ambos os sexos. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de uma semana. As amostras de plasma foram obtidas ao longo de um intervalo de 48 horas. As concentrações do metabólito ativo do clopidogrel, ácido carboxílico SR26334 foram determinadas através de um equipamento LC-MS-MS, utilizando enalapril como padrão interno. A partir dos dados obtidos se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t, ASC0-¥ e Cmax. A média geométrica de clopidogrel/Plavix® 75 mg foi de 96,71% para ASC0-t, 96.64% para ASC0-¥ e 98,29% para Cmax; os intervalos de confiança de 90% foram de 93,42 - 100,12%, 93,48% - 99,90% e 91,02 - 106,15%, respectivamente. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-t estiveram dentro da faixa de 80%-125% proposta pelo FDA e pela ANVISA (Agência Nacional de Vigilância Sanitária do Brasil), conclui-se que o comprimido de clopidogrel de 75 mg foi bioequivalente ao comprimido de Plavix® de 75 mg e, dessa forma, o produto teste pode ser considerado intercambiável na prática médica.

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.

Optimization of enantioselective resolution of racemic ibuprofen by native lipase from Aspergillus niger.

Resolution of (R,S)-ibuprofen (2-(4-isobutylphenyl)propionic acid) enantiomers by esterification reaction with 1-propanol in different organic solvents was studied using native Aspergillus niger lipase. The main variables controlling the process (enzyme concentration and 1-propanol:ibuprofen molar ratio) have been optimized using response surface methodology based on a five-level, two-variable central composite rotatable design, in which the selected objective function was enantioselectivity. This enzyme preparation showed preferentially catalyzes the esterification of R(-)-ibuprofen, and under optimum conditions (7% w/v of enzyme and molar ratio of 2.41:1) the enantiomeric excess of active S(+)-ibuprofen and total conversion values were 79.1 and 48.0%, respectively, and the E-value was 32, after 168 h of reaction in isooctane.