Methylphenidate Multiphasic Release Tablet: Bioequivalence Assessment between Two Formulations Administered under Fasting and Fed Conditions.

Methylphenidate hydrochloride is used to treat children, adolescents, and adults with attention deficit/hyperactivity disorder (ADHD). Multiphasic release formulation has been used to control drug levels, mainly during children's school period. This study aimed to evaluate the bioequivalence between two methylphenidate hydrochloride extended-release tablets to meet regulatory requirements for registration in Brazil. Two independent studies (under fasting and fed conditions) designed as open-label, randomized, single-dose, two-period, two-way crossover trials were conducted in healthy subjects of both genders. Subjects were enrolled and randomly received a single dose of the test formulation methylphenidate hydrochloride 54 mg extended-release tablet (Consiv®, Adium S.A., São Paulo, Brazil) or the reference formulation (Concerta®, Janssen-Cilag Farmacêutica Ltd., São Paulo, Brazil), in each period, with a 7-day washout interval. Serial blood samples were collected up to 24 h post dose and methylphenidate plasma concentrations were obtained using a validated LC-MS/MS method. A total of 96 healthy subjects were enrolled in the fasting study, of which 80 completed the study. For the fed study, 52 healthy subjects were enrolled, and 46 subjects completed it. In both studies, 90% confidence intervals for Cmax, AUC0-t, AUC0-inf, and partial AUCs were within the acceptable limits of 80.00 to 125.00%. Thus, according to regulatory requirements, the test formulation (Consiv®) was considered to be bioequivalent to the reference formulation (Concerta®) in both conditions (fasting and fed) and, therefore, it can be considered interchangeable in clinical practice. Both formulations were safe and well tolerated in single-dose administration.

Development and validation of an LC-ESI-MS/MS method for the simultaneous quantification of naproxen and sumatriptan in human plasma: application to a pharmacokinetic study.

A sensitive and fast liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) method was developed and validated for the simultaneous quantification of naproxen and sumatriptan in human plasma. A simple liquid-liquid extraction procedure, with a mixture of ethyl acetate, methyl tert-butyl ether, and dichloromethane (4:3:3, v/v), was used for the cleanup of plasma. Naratriptan and aceclofenac were employed as internal standards. The analyses were carried out using an ACE C18 column (50 × 4.6 mm i.d.; particle size 5 µm) and a mobile phase consisting of 2 mM aqueous ammonium acetate with 0.025 % formic acid and methanol (38:62, v/v). A triple-quadrupole mass spectrometer equipped with an electrospray source in the positive mode was set up in the selective reaction monitoring mode to detect the ion transitions m/z 231.67 → m/z 185.07, m/z 296.70 → m/z 157.30, m/z 354.80 → m/z 215.00, and m/z 336.80 → m/z 97.94 for naproxen, sumatriptan, aceclofenac, and naratriptan, respectively. The method was validated and proved to be linear, accurate, precise, and selective over the ranges of 2.5-130 µg mL(-1) for naproxen and 1-50 ng mL(-1) for sumatriptan. The validated method was successfully applied to a pharmacokinetic study with simultaneous administration of naproxen sodium and sumatriptan succinate tablet formulations in healthy volunteers.

Comparative study between two recombinant human NPH insulin formulations for the treatment of type 2 diabetes mellitus.

OBJECTIVE: To compare the effects of the neutral protamine Hagedorn (NPH) recombinant human insulin formulations Gansulin and Humulin N® on the glycemic control of patients with type 2 diabetes mellitus (T2DM). SUBJECTS AND METHODS: Prospective, double-blind, randomized, parallel, single-center study of 37 individuals with T2DM treated with NPH insulin formulations. The Tukey-Kramer test for multiple comparisons, the Wilcoxon paired comparison test and the Chi-Square test were used for the statistical analyses. The significance level was set at 5% (p < 0.05). RESULTS: The NPH insulin formulations Humulin and Gansulin similarly reduced the HbA1c levels observed at the end of the study compared with the values obtained at the beginning of the study. In the Humulin group, the initial HbA1c value of 7.91% was reduced to 6.56% (p < 0.001), whereas in the Gansulin group, the reduction was from 8.18% to 6.65% (p < 0.001). At the end of the study, there was no significant difference between the levels of glycated hemoglobin (p = 0.2410), fasting plasma glucose (FG; p = 0.9257) and bedtime plasma glucose (BG; p = 0.3906) between the two insulin formulations. There was no nt difference in the number of hypoglycemic events between the two insulin formulations, and no severe hyp episodes were recorded. CONCLUSION: This study demonstrated similar glycemic control by NPH insulin Gansulin compared with human insulin Humulin N® in patients with T2DM.

Comparative study between two recombinant human NPH insulin formulations for the treatment of type 2 diabetes mellitus

ABSTRACT Objective To compare the effects of the neutral protamine Hagedorn (NPH) recombinant human insulin formulations Gansulin and Humulin N® on the glycemic control of patients with type 2 diabetes mellitus (T2DM). Subjects and methods Prospective, double-blind, randomized, parallel, single-center study of 37 individuals with T2DM treated with NPH insulin formulations. The Tukey-Kramer test for multiple comparisons, the Wilcoxon paired comparison test and the Chi-Square test were used for the statistical analyses. The significance level was set at 5% (p < 0.05). Results The NPH insulin formulations Humulin and Gansulin similarly reduced the HbA1c levels observed at the end of the study compared with the values obtained at the beginning of the study. In the Humulin group, the initial HbA1c value of 7.91% was reduced to 6.56% (p < 0.001), whereas in the Gansulin group, the reduction was from 8.18% to 6.65% (p < 0.001). At the end of the study, there was no significant difference between the levels of glycated hemoglobin (p = 0.2410), fasting plasma glucose (FG; p = 0.9257) and bedtime plasma glucose (BG; p = 0.3906) between the two insulin formulations. There was no nt difference in the number of hypoglycemic events between the two insulin formulations, and no severe hyp episodes were recorded. Conclusion This study demonstrated similar glycemic control by NPH insulin Gansulin compared with human insulin Humulin N® in patients with T2DM.

Estudo de bioequivalência entre duas formulações de pregabalina 150 mg cápsulas em voluntários sadios / Bioequivalence study between two formulations of pregabalin 150 mg capsules in healthy volunteers

A biodisponibilidade de pregabalina em duas formulações diferentes de cápsulas gelatinosas duras de 150 mg foi comparada por meio de um estudo de bioequivalência de dose única, randomizado, aberto, cruzado em dois períodos e com 36 voluntários brasileiros, sadios, do sexo masculino. Amostras de sangue foram coletadas durante um período de 48 horas e o plasma obtido foi mantido congelado até o momento de análise. As concentrações plasmáticas de pregabalina foram determinadas utilizando um método de HPLC-MS/MS validado. A separação cromatográfica foi obtida com fase móvel composta por tampão acetato de amônio 2 mM com 0,025% de ácido fórmico e metanol (3:7 v/v), com fluxo de 1,5 mL/min. A coluna cromatográfica empregada foi ACE 5 C18 (100 x 4,6mm) e o tempo total de corrida foi 2,5 minutos. A detecção por espectrometria de massas foi realizada utilizando-se ionização por electrospray no modo positivo. Os intervalos com 90% de confiança para concentração plasmática máxima (Cmax) e área sob a curva (ASC0-t) foram determinados utilizando os dados após transformação logarítmica. As formulações teste e referência foram consideradas bioequivalentes, uma vez que os intervalos com 90% de confiança para a média geométrica da razão teste/referência ficaram compreendidos na faixa de 80% a 125%, conforme preconizado pelo Food and Drug Administration (FDA) e a Agência Nacional de Vigilância Sanitária (ANVISA). O intervalo com 90% de confiança para as razões das médias geométricas para Cmax foi 99,90% (92,85%-107,49%) e para ASC0-t foi 102,61% (100,69-104,56%). Desta forma, as cápsulas de pregabalina 150 mg testadas (Zodiac Produtos Farmacêuticos S.A.) foram bioequivalentes às cápsulas de Lyrica® 150 mg (Laboratórios Pfizer), de acordo com taxa e extenção de absorção...

An improved LC-MS/MS method for quantitation of indapamide in whole blood: application for a bioequivalence study.

An improved LC-MS/MS method for the quantitation of indapamide in human whole blood was developed and validated. Indapamide-d3 was used as internal standard (IS) and liquid-liquid extraction was employed for sample preparation. LC separation was performed on Synergi Polar RP-column (50 × 4.6 mm i.d.; 4 µm) and mobile phase composed of methanol and 5 mm aqueous ammonium acetate containing 1 mm formic acid (60:40), at flow rate of 1 mL/min. The run time was 3.0 min and the injection volume was 20 µL. Mass spectrometric detection was performed using electrospray ion source in negative ionization mode, using the transitions m/z 364.0 → m/z 188.9 and m/z 367.0 → m/z 188.9 for indapamide and IS, respectively. Calibration curve was constructed over the range 0.25-50 ng/mL. The method was precise and accurate, and provided recovery rates >80% for indapamide and IS. The method was applied to determine blood concentrations of indapamide in a bioequivalence study with two sustained release tablet formulations. The 90% confidence interval for the geometric mean ratios for maximum concentration was 95.78% and for the area under the concentration-time curve it was 97.91%. The tested indapamide tablets (Eurofarma Laboratórios S.A.) were bioequivalent to Natrilix®, according to the rate and extent of absorption.

Comparação da bioequivalência entre duas formulações de pregabalina 150 mg cápsula gelatinosa dura em voluntários sadios após a administração de dose única / Comparison of the bioequivalence between two formulations of pregabalin 150 mg capsules in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a bioequivalência de duas formulações de pregabalina, Dorene cápsula gelatinosa dura de 150 mg (pregabalina do Aché Laboratórios Farmacêuticos S/A, formulação teste) e Lyrica® (pregabalina da Pfizer Manufacturing Deutschland Gmbh, Brasil, formulação referência), em 32 voluntários sadios do sexo masculino. O estudo foi realizado através de um desenho aberto, randomizado, dois tratamentos (referência e teste), duas sequências (RT e TR), cruzado em dois períodos com tempo de washout de dez dias. As amostras de plasma foram obtidas ao longo de um intervalo de 48 horas. As concentrações de pregabalina foram determinadas através de um equipamento UPLC/MS/MS, utilizando gabapentina como padrão interno. A partir dos dados de concentração plasmática obtidos individualmente, calcularam-se os seguintes parâmetros farmacocinéticos: ASC0-t, Cmax e Tmax. As médias para ASC0-48 para as formulações teste e referência foram 26127,511 ng.h/mL e 26174,410 ng.h/mL, para Cmax foram 4367,727 ng/mL e 4238,842 ng/mL e para Tmax foram 0,903 h e 1,016 h, respectivamente. As razões das médias geométricas foram de 100,04 % para ASC0-48, e 104,42 % para Cmax. Os intervalos com 90% de confiança foram 97,79 - 102,33% para ASC0-48, e 97,39 - 111,95% para Cmax. Uma vez que os intervalos de confiança de 90% para Cmax e ASC0-48 estiveram dentro da faixa de 80% a 125% proposta pelo Food and Drug Administration (FDA) e pela ANVISA (Agência Nacional de Vigilância Sanitária) conclui-se que cápsula gelatinosa dura de pregabalina de 150 mg (Dorene) é bioequivalente à cápsula gelatinosa dura de Lyrica® de 150 mg e, desta forma, o produto teste pode ser considerado intercambiável na prática médica...

Estudo de bioequivalência entre duas formulações de ciprofibrato 100 mg comprimidos em voluntários sadios após administração de dose única / Bioequivalence study between two formulations of ciprofibrate 100 mg tablets in healthy volunteers after single dose administration

A comparação da biodisponibilidade de duas formulações de ciprofibrato 100 mg comprimidos (ciprofibrato 100 mg - Aché Laboratórios Farmacêuticos S/A, formulação teste, e Oroxadin® 100 mg - Sanofi-Aventis Farmacêutica Ltda., formulação referência) foi realizada por meio de um estudo de bioequivalência em 52 voluntários sadios. O estudo foi realizado através de um delineamento aberto, randomizado, em dose única, cruzado em dois períodos e com tempo de washout de nove semanas. As amostras de plasma foram obtidas durante um intervalo de tempo de 72 horas. As concentrações plasmáticas de ciprofibrato foram determinadas por cromatografia líquida de alta eficiência com detecção por espectrometria de massas (CLAE-MS/MS), com ionização por electrospray em modo positivo. Os parâmetros farmacocinéticos área sob a curva (ASC0-72), concentração plasmática máxima (Cmax) e tempo máximo (Tmax) foram obtidos a partir da curva de concentração plasmática do ciprofibrato versus tempo. As razões das médias geométricas com intervalo de confiança 90% após transformação logarítmica foram 89,43% (85,09% - 93,99%) para Cmax e 97,23% (94,73% - 99,79%) para ASC0-72. As formulações teste e referência são consideradas bioequivalentes se os intervalos com 90% de confiança para a média geométrica da razão teste/referência ficarem compreendidos na faixa de 80% a 125%. Dessa forma os comprimidos de ciprofibrato 100 mg testados (Aché Laboratórios Farmacêuticos S/A) foram bioequivalentes aos comprimidos de Oroxadin® 100 mg, de acordo com taxa e extenção de absorção.

Comparação da bioequivalência entre duas formulações de levodopa 200 mg + benserazida 50 mg comprimidos em voluntários sadios após a administração de dose única / Comparison of the bioequivalence between two formulations of Levodopa 200 mg + Benserazide 50 mg tablets in healthy volunteers after a single dose administration

O estudo foi realizado para comparar a bioequivalência de duas formulações de levodopa 200 mg + benserazida 50 mg (equivalente a 57 mg de cloridrato de benserazida) sob a forma de comprimidos (levodopa + cloridrato de benserazida do Aché Laboratórios Farmacêuticos S/A, formulação teste e Prolopa® de Produtos Roche Químicos e Farmacêuticos S/A, formulação referência) em 36 voluntários sadios. O estudo foi realizado através de um desenho aberto, randomizado, cruzado em dois períodos com tempo de washout de quatro semanas. As amostras de plasma foram obtidas ao longo de um intervalo de 96 horas. As concentrações de levodopa e do metabólito 3-O-metildopa foram determinadas através de um equipamento HPLC/MS/MS, utilizando carbidopa como padrão interno. A partir dos dados de concentração plasmática obtidos individualmente se calcularam os seguintes parâmetros farmacocinéticos: ASC0-t, Cmáx e Tmáx...

Determination of triamcinolone in human plasma by a sensitive HPLC-ESI-MS/MS method: application for a pharmacokinetic study using nasal spray formulation.

A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method for the quantitation of triamcinolone in human plasma after nasal spray application was developed and validated. Betamethasone was used as internal standard (IS). The analytes were extracted by a liquid-liquid procedure and separated on a Zorbax Eclipse XDB C(18) column with a mobile phase composed of 2 mM aqueous ammonium acetate pH 3.2 and acetonitrile (55:45). Selected reaction monitoring was performed using the transitions m/z 435 → 415 and m/z 393 → 373 to quantify triamcinolone acetonide and betamethasone, respectively. Calibration curve was constructed over the range of 20-2000 pg/ml for triamcinolone acetonide. The lower limit of quantitation was 20 pg/ml. The mean RSD values were 4.6% and 5.7% for the intra-run and inter-run precision, respectively. The mean accuracy value was 98.5% and a recovery rate corresponding to 97.5% was achieved. No matrix effect was detected in the samples. The validated method was successfully applied to determine the plasma concentrations of triamcinolone acetonide in healthy volunteers, in a pharmacokinetic study with nasal spray formulation.

Liquid chromatography-tandem mass spectrometry for the simultaneous quantitation of artemether and lumefantrine in human plasma: application for a pharmacokinetic study.

A liquid chromatography-electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS) method for the simultaneous quantitation of artemether and lumefantrine in human plasma was developed and validated. Artesunate was used as an internal standard (IS). The analytes were extracted by a protein precipitation procedure and separated on a reversed-phase Zorbax SB-Ciano column with a mobile phase composed of methanol and 10mM aqueous ammonium acetate containing 0.2% (v/v) acetic acid and 0.1% (v/v) formic acid. Multiple reaction monitoring was performed using the transitions m/z 316 → m/z 267, m/z 530 → m/z 348 and m/z 402 → m/z 267 to quantify artemether, lumefantrine and artesunate, respectively. Calibration curves were constructed over the range of 10-1000 ng/mL for artemether and 10-18,000 ng/mL for lumefantrine. The lower limit of quantitation was 10 ng/mL for both drugs. The mean R.S.D. values for the intra-run precision were 2.6% and 3.0% and for the inter-run precision were 3.6% and 4.6% for artemether and lumefantrine, respectively. The mean accuracy values were 102.0% and 101.2% for artemether and lumefantrine, respectively. No matrix effect was detected in the samples. The validated method was successfully applied to determine the plasma concentrations of artemether and lumefantrine in healthy volunteers, in a one-dose pharmacokinetic study, over the course of 11 days.