Comparison between 200 mg generic celecoxib hard capsules and Celebra®: bioequivalence study in healthy male and female subjects under fasting conditions after a single dose / Comparação entre celecoxibe genérico de 200 mg em cápsulas duras e Celebra®: estudo de bioequivalência em indivíduos saudáveis do sexo masculino e feminino, em jejum, após uma dose única

ABSTRACT BACKGROUND AND OBJECTIVES: The objective of this study was to assess the bioequivalence between two 200 mg celecoxib hard capsule formulations administered to healthy male and female participants under fasting conditions with the aim of providing an alternative pharmaceutical product to the reference drug, Celebra®. METHODS: A randomized, open label, single dose, 2x2 crossover trial was conducted with 60 adult healthy subjects under fasting conditions comparing single doses of two celecoxib hard capsules formulation. Pharmacokinetic parameters were calculated following the determination of drugs concentrations in human plasma using a validated liquid chromatography with a tandem mass spectrometer detector method (LC-MS/MS). RESULTS: Statistical analysis provided geometric mean of test/reference ratio, confidence intervals, intra-subject variation coefficient and power of the test to the pharmacokinetic parameters Cmax, AUC0-t, and AUC0-∞. Confidence intervals for the geometric mean (90% CI) of the test/reference drugs for celecoxib were 98.26 to 122.75% for Cmax, 100.27% to 110.78% for AUC0-t, and 96.87% to 110.29% for AUC0-∞. The power of the test found was 95.09% for Cmax, 100.00% for AUC0-t, and 99.99% for AUC0-∞. CONCLUSION: The formulations met the Brazilian standards for interchangeability, as the confidence intervals for Cmax and AUC0-t ratios are within the range of 80% to 125%, thus meeting the requirements of the legislation during market registration. The researched product was approved by the regulatory authorities and became a commercially competitive option to the reference product for the Brazilian population.

RESUMO JUSTIFICATIVA E OBJETIVOS: O objetivo deste estudo foi avaliar a bioequivalência entre duas formulações de cápsulas duras de celecoxibe de 200 mg administradas a participantes saudáveis do sexo masculino e feminino em condições de jejum com o objetivo de fornecer um produto farmacêutico alternativo ao fármaco de referência, Celebra®. MÉTODOS: Estudo randomizado, aberto, de dose única e cruzado 2x2. Foi conduzido com 60 indivíduos adultos saudáveis em condições de jejum, comparando doses únicas de duas formulações de cápsulas duras de celecoxibe. Os parâmetros farmacocinéticos foram calculados após a determinação das concentrações dos fármacos no plasma humano usando uma cromatografia líquida validada com um método detector de espectrômetro de massa em tandem (LC-MS/MS). RESULTADOS: A análise estatística forneceu a média geométrica da razão teste/referência, os intervalos de confiança, o coeficiente de variação intra-sujeito e o poder do teste para os parâmetros farmacocinéticos Cmáx, AUC0-t e AUC0-∞. Os intervalos de confiança para a média geométrica (IC 90%) dos fármacos teste/referência para o celecoxibe foram 98,26 a 122,75% para Cmáx, 100,27% a 110,78% para AUC0-t e 96,87% a 110,29% para AUC0-∞. O poder do teste encontrado foi de 95,09% para Cmáx, 100,00% para AUC0-t e 99,99% para AUC0-∞. CONCLUSÃO: As formulações atenderam aos padrões brasileiros de intercambialidade, pois os intervalos de confiança para as razões Cmáx e AUC0-t estão dentro da faixa de 80% a 125%, atendendo, assim, às exigências da legislação para o registro no mercado. O produto pesquisado foi aprovado pelas autoridades regulatórias e tornou-se uma opção comercialmente competitiva ao produto de referência para a população brasileira.

Data verification and sensitivity analysis of statistical analysis in bioequivalence studies / 药学实践杂志

Objective To sort out the key points, problems and countermeasures of data verification through data verification of statistical analysis in 18 bioequivalence studies, and provide reference for improving the statistical analysis reports of related research. Methods SAS and WinNonlin software was used to illustrate that whether the random number tables, main pharmacokinetic parameters and bioequivalence data could reproduce the corresponding results in the original statistical analysis reports. Results Among the 18 studies, sensitivity analysis was supplemented or re-performed for 5 studies due to sampling time deviation of individual subjects or adjustment of sensitivity data sets, resulting in differences in pharmacokinetic parameters from the original statistical analysis report, but same for the bioequivalence evaluation. Other verified data was consistent with the original statistical analysis reports. Conclusions The verification of statistical analysis data of bioequivalence studies is extremely important, and the problems found in this paper should be fully considered when writing such statistical analysis reports.

Study on the bioequivalence of Palbociclib capsules in human / 中国药房

OBJECTIVE To evaluate the bioequivalence of a single oral administration of two palbociclib preparations in healthy subjects under fasting and fed conditions. METHODS Twenty-four healthy subjects （fasting test） and twenty healthy subjects （fed test） were enrolled and divided into two groups. A single-center， open-label， single-dose， two-formulation， two- period， two-sequence and crossover trial was designed. The subjects in the two groups were given the test preparation （domestic Palbociclib capsules） or the reference preparation （original Palbociclib capsules） orally under fasting or fed conditions respectively followed by a 14-day washout period. The blood samples were collected at different time points before and after treatment. After pretreatment， the mass concentration of palbociclib in vivo was determined by high-performance liquid chromatography-tandem mass spectrometry with palbociclib-d8 as the internal standard. SAS V9.4 software was used to calculate the pharmacokinetic parameters and evaluate the bioequivalence. RESULTS Under fasting condition， the cmax of the test preparation and the reference preparation were （71.4±18.1） and （73.8±19.0） ng/mL； AUC0－t were （1 754±412） and （1 793±448） h·ng/mL； AUC0－∞ were （1 851±456） and （1 887±478） h·ng/mL， respectively. Under fed condition， the cmax of the test preparation and the reference preparation were （78.4±18.3） and （81.9±21.7） ng/mL； AUC0－t were （1 905±375） and （1 932±318） h·ng/mL； AUC0－∞ were （2 027±411） and （2 050±342） h·ng/mL， respectively. The 90%CI of the geometric mean ratio of the above parameters was within the acceptable range （80.00%-125.00%）. Under fasting and fed conditions， there were 20 and 16 adverse events in 9 and 8 subjects， respectively， but no serious adverse event was observed. CONCLUSIONS Under the fasting and fed conditions， the test preparation and the reference preparation of Pibociclib capsules are bioequivalent and have comparable safety.

A unique formulation of sodium bicarbonate buffered pantoprazole powder for oral suspension: perspectives from an active controlled cross-over bioequivalence study

Background:The aim was determining bioequivalence between pantoprazole buffered powder for oral suspension and pantoprazole enteric coated tablets under fasting conditions in healthy volunteers.Methods:In randomized cross-over study, participants were administered a single oral dose of pantoprazole powder as suspension 40 mg (sodium bicarbonate as buffer) or one enteric coated tablet of pantoprazole 40 mg, with240�ml of water as per the randomization schedule in each study period. Blood samples were collected at pre-dose and at 0.33, 0.67, 1, 1.33, 1.67, 2, 2.33, 2.67, 3, 3.33, 3.67, 4, 4.5, 5, 5.5, 6, 7, 8, 9, 10, 12, 14, 16and 24hours post-dose. Plasmaconcentration of pantoprazole was determined with LC-MS and various pharmacokinetic parameters like Cmax, AUC0-t, AUC0-inf were compared between test and reference groups.Results:Amongst 41 subjects, Cmax(3752.4�84.6 vs. 3521.7�99.5 ng/ml)was achieved higher in less Tmaxtime (1 (0.28) vs. 2.3 (0.83) hrs)with test drug as compared to reference drug. The ratios of geometric least square mean and its 90% confidence interval on log transformed Cmax, AUC0-t and AUC0-inffor pantoprazole fall within the acceptance criteria of 80% to 125%. No adverse events were observed.Conclusions:Pantoprazole powder for oral suspension 40 mg (sodium bicarbonate as buffer) was well tolerated and bioequivalent with pantoprazole enteric coated tablets IP 40 mg in terms of rate and extent of absorption under fasting conditions. At same time, the shift in AUC to the left with reduction in Tmaxwith the new formulation is suggestive of faster rate of absorption.

Elaboration of guideline for monitoring in relative bioavailability / pharmaceutical bioequivalence study by the sponsor / Elaboração de diretriz para monitoramento em biodisponibilidade relativa / estudo de bioequivalência farmacêutica pelo patrocinador / Elaboración de la directriz para el seguimiento en la biodisponibilidad relativa / estudio de bioequivalencia farmacéutica por parte del promotor

For registration of generic and similar drugs, it is necessary to carry out pharmaceutical equivalence (PE) tests and pharmaceutical bioequivalence (PB). To carry out these tests, duly qualified research centers are contracted, which need to be monitored by the sponsor who is legally responsible for the activities. To this end, it is the recommendation of the Document of the Americas, periodic monitoring to verify compliance with quality requirements, Standard Operating Procedures, Good Clinical Practices (GCP), Good Laboratory Practices (GLP), of the applicable regulatory framework, as well as of compliance with the study protocol. Thus, monitoring is a methodical and documented process to evaluate the degree of adhesion of the center to the planned design for the evaluation of the formulations. To this end, the implementation of a standardized and easily completed guideline is a very important tool to guarantee a consistent evaluation and maintain the organizational memory of the evaluated items by monitors designated by the sponsor, contributing to the constant improvement of the contracted centers and supporting traceability of the studies. This work provided a systemic view of the evidence process related mainly to pharmaceutical bioequivalence, with the monitoring guideline summarizing the items of greatest relevance to be verified.

Para registro de medicamentos genéricos e similares, é necessária a realização de testes de equivalência farmacêutica (EF) e bioequivalência farmacêutica (BF). Para a realização desses testes, são contratados centros de pesquisa devidamente habilitados, que precisam ser monitorados pelo patrocinador legalmente responsável pelas atividades. Há também a recomendação do Documento das Américas de realizar monitoramentos periódicos para verificar o cumprimento dos requisitos de qualidade, Procedimentos Operacionais Padrão, Boas Práticas Clínicas (BPC), Boas Práticas de Laboratório (BPL), de marco regulatório aplicável, bem como de cumprimento do protocolo do estudo. Assim, o monitoramento é um processo metódico e documentado para avaliar o grau de adesão do centro ao desenho planejado para a avaliação das formulações. Para tanto, a implantação de uma diretriz padronizada e de fácil preenchimento é uma ferramenta muito importante para garantir uma avaliação consistente e manter a memória organizacional dos itens avaliados por monitores designados pelo patrocinador, contribuindo para a melhoria constante dos centros contratados e apoiando rastreabilidade dos estudos. Este artigo forneceu uma visão sistêmica do processo de evidência relacionado principalmente à bioequivalência farmacêutica, com a diretriz de monitoramento resumindo os itens de maior relevância a serem verificados.

Para el registro de medicamentos genéricos y similares, es necesario realizar pruebas de equivalencia farmacéutica (EP) y de bioequivalencia farmacéutica (PB). Para llevar a cabo estas pruebas se contratan centros de investigación debidamente cualificados, que deben ser supervisados por el promotor, que es el responsable legal de las actividades. Para ello, es la recomendación del Documento de las Américas, el monitoreo periódico para verificar el cumplimiento de los requisitos de calidad, los Procedimientos Operativos Estándar, las Buenas Prácticas Clínicas (BPC), las Buenas Prácticas de Laboratorio (BPL), del marco regulatorio aplicable, así como del cumplimiento del protocolo del estudio. Así, la monitorización es un proceso metódico y documentado para evaluar el grado de adhesión del centro al diseño previsto para la evaluación de las formulaciones. Para ello, la implantación de una pauta estandarizada y de fácil cumplimentación es una herramienta muy importante para garantizar una evaluación consistente y mantener la memoria organizativa de los elementos evaluados por parte de los monitores designados por el promotor, contribuyendo a la mejora constante de los centros contratados y apoyando la trazabilidad de los estudios. Este trabajo proporcionó una visión sistémica del proceso de evidencia relacionado principalmente con la bioequivalencia farmacéutica, con la pauta de monitoreo que resume los ítems de mayor relevancia a ser verificados.

Exploring the knowledge and perception towards generic medicines among undergraduate medical and nursing students – A questionnaire-based comparative study

Background: Healthcare providers are still hesitant in prescribing generic medicines due to several misconceptions about bioequivalence, efficacy, quality, and safety of generic medicines as compared to their branded counterparts. Proper teaching and training help in positive changes in perception as well as the prescribing and dispensing practices of healthcare providers. Aim and Objectives: The aims of this study were to study the knowledge and perception about the generic medicine among 2nd year MBBS and nursing students and to find out the differences between the student’s responses. Materials and Methods: An observational cross-sectional study was conducted involving 83 2nd year MBBS students and 60 2nd year nursing students in Bundelkhand Medical College, Sagar (M.P.), India. Assessment of knowledge and perception about generic medicines using the normal 5-point Likert scale and calculation using the independent-samples Mann–Whitney U-Test and P < 0.05 was considered statistically significant for differences observed among the two groups. Results: Only 33% of MBBS students and 17% of nursing students were select correct answer for bioequivalence limits. Almost 82% of MBBS and 53% of nursing students were agreed toward generic medicines are less expensive than brand name medicines (P = 0.00). Only 45% of MBBS students and 15% of nursing students were disagreed toward generic medicines are of inferior quality to branded drugs (P = 0.001). About 37% of MBBS students and 20% of nursing students were disagreed toward generic medicines are less effective and less safe than brand name medicines (P = 0.01) and only 12% of MBBS students and 7% of nursing students were disagreed toward brand name medicine which are required to meet higher safety standards than generic medicines (P = 0.09). Conclusion: In our study, we found that significant knowledge gap with regard to the regulatory bioequivalence limits for generic medicines and misconceptions about generic drugs is also quite prevalent. Educational interventions are most important tool to improve knowledge and change in perceptions among healthcare students about generic medicines and eventually promote practice of prescribing cost-effective generic drugs.

Avaliação da bioequivalência entre duas formulações de rivaroxabana ­ 20 mg comprimido revestido ­ administradas em jejum e pós-prandial em voluntários sadios / Evaluation of bioequivalence between two rivaroxaban formulations ­ coated tablet 20 mg ­ administered under fasting and fed conditions in healthy volunteers

Objetivo: O objetivo deste trabalho foi avaliar a bioequivalência entre duas formulações de rivaroxabana 20 mg comprimido revestido, sendo a formulação teste produzida por Sanofi Medley, Brasil e a formulação referência (Xarelto®) comercializada por Bayer S/A. Métodos: Os estudos foram conduzidos em voluntários sadios de ambos os sexos e as formulações foram administradas em dose única, sob o estado de jejum e pós-prandial. Cada estudo foi conduzido de maneira independente, sendo ambos do tipo aberto, randomizado e com intervalo (washout) de sete dias entre os períodos. O estudo em jejum foi realizado em quatro períodos, com 48 voluntários, enquanto o pós-prandial foi realizado em dois períodos, com 36 voluntários. Resultados: Na administração em jejum, a razão entre a média geométrica da formulação teste e referência (T/R) de Cmáx foi de 100,77%, com intervalo de confiança de 90% (IC 90%) de 94,24% a 107,76%. Para ASC0-t, a razão T/R foi de 100,65%, com IC 90% de 96,13% a 105,39%. Na administração pós-prandial, a razão T/R de Cmáx foi de 110,63%, com IC 90% de 102,39% a 119,54%. Para ASC0-t, a razão T/R foi de 104,65%, com IC 90% de 98,44% a 109,12%. Conclusões: As formulações teste e referência foram consideradas estatisticamente bioequivalentes em ambas as condições de administração, de acordo com os critérios exigidos pela Agência Nacional de Vigilância Sanitária (Anvisa). A formulação teste foi registrada na Anvisa e disponibilizada para comercialização, contribuindo, assim, para a ampliação da disponibilidade do tratamento para doenças tromboembólicas e para a redução de custos ao paciente e ao Sistema Único de Saúde.

Objective: The objective of the present study was to evaluate the bioequivalence between two formulations of rivaroxaban 20 mg coated tablet, the test formulation being manufactured by Sanofi Medley, Brazil and the reference formulation (Xarelto® ) commercialized by Bayer S/A. Methods: The studies were conducted in healthy volunteers of both sexes and the formulations were administered in a single dose, under fasting and fed conditions. Each study was conducted independently, both being open-label, randomized and with a seven-day interval (washout) between periods. The fasting study was carried out in four periods, with 48 volunteers, while the fed study was carried out in two periods, with 36 volunteers. Results: In the fasting administration, the ratio between.

Study on postprandial bioequivalence of Diacerein capsules in healthy volunteers / 中国药房

OBJECTIVE To evaluate the postprandial bioequivalence of two kinds of Diacerein capsules in healthy volunteers with oral administration . METHODS A total of 24 adult healthy subjects were included and randomly divided into two groups ， with 12 subjects in each group . A randomized ，open，double-cycle cross -over trial design was adopted . Both groups took 50 mg of the test preparation （domestic Diacerein capsules ）or the reference preparation （Ambridine®）respectively at 30 min after eating the standard meal in the morning of the first day of each cycle of the trial . The cleaning period was one week . Blood samples were collected at different time points before and after taking the medicine and the protein was precipitated with methanol for sample pretreatment. The concentration of active metabolite rhein was determined by LC -MS/MS using emodin as internal standard . The pharmacokinetic parameters were calculated with DAS 3.2.9 software，and the bioequivalence of test and reference preparation were evaluated. RESULTS After the subjects took the test preparation and the reference preparation after meal ， the main pharmacokinetic parameters of rhein were as follows ：cmax were（3 517±1 121）and（3 225±755）ng/mL；AUC0－24h were （25 764±6 134）and（24 316±5 856）ng·h/mL；AUC0－∞ were（26 679±6 409）and（25 170±6 415）ng·h/mL；tmaxwere 3.50 （0.67，12.00）and 4.00（1.50，7.00）h；t1/2 were（4.26±1.12）and（4.19±1.05）h，respectively. The 90% confidence intervals of the geometric mean ratios of cmax，AUC0－24h and AUC 0－∞ were 100.8%-113.9%，103.1%-109.4% and 103.2%-109.9%，respectively. CONCLUSIONS The test preparation and reference preparation are bioequivalent in the postprandial state of healthy subjects .

Population bioequivalence statistical method based on earth mover′s distance for evaluation of particle size distribution consistency of ophthalmic emulsion / 中国药科大学学报

@#Population bioequivalence (PBE) is a statistical approach recommended by FDA to evaluate the consistency of particle size distribution of numerous nanoparticle products.However, when particle size distribution (PSD) profile exhibits multiple peaks or other complex distributions, the traditional descriptors D50 and SPAN are no longer suitable to describe PSD.Earth mover''s distance (EMD) is a new statistical metric for assessing the difference between distributions.In this study, we used EMD to measure the discrepancy between PSD and then PBE was applied to perform statistical test to establish equivalence.Our results showed that the proposed method can effectively reject an unequivalent product and pass an equivalent product, thus indicating its helpfulness in guiding the optimization of formulation and preparation process.

Bioequivalence and safety evaluation of domestic Nadroparin calcium injection in Chinese healthy volunteers / 中国药房

OBJECTIVE To evaluate the bioequivalence and safety of two k inds of Nadroparin calcium injection in healthy Chinese volunteers by subcutaneous injection. METHODS According to the block randomization method ，24 Chinese healthy adult volunteers were included and divided into TR （test preparation-reference preparation ）group and RT （reference preparation-test preparation）group at a ratio of 1∶1. A randomized ，open-labelled，single-dose and two-cycle crossover study was designed ，the fasting subjects of two groups were given test or reference preparation 6 150 AⅩaIU subcutaneously on the first day of each cycle and exchanged in the second cycle ，and the wash-out period was 7 days. The blood samples were collected at different time points before and after administration. The activity of anti-coagulant factor Ⅹa（Anti-Ⅹa）and Anti- Ⅱa in human plasma were determined by chromogenic substrate method ，and the pharmacodynamic parameters were calculated according to the non-atrioventricular model and the bioequivalence was evaluated. The occurrence of adverse events （AEs）was recorded. RESULTS After administration ，the main pharmacodynamic parameters for Anti- Ⅹa activity of test preparation and reference preparation were as follows ：t1/2 were（4.87±1.06） and（4.03±1.00）h，tmax were 4.50（2.00，8.00）and 5.50（2.50，8.00）h，Anti-Ⅹamax were（0.66±0.12）and（0.56±0.11）IU/mL；main pharmacodynamic parameters of Anti- Ⅱa activity of two preparations were as follows ：t1/2 were（3.64±1.60）and（5.74±7.23）h，tmax were 4.00（2.50，8.00）and 4.00（2.00，8.00）h，Anti-Ⅱamax were both （0.10±0.03）IU/mL. The values of 90％confidence interval of geometric mean ratio of Anti- Ⅹamax，AUEC0－t and AUEC 0－∞ were 110.98％-123.50％，112.11％-121.24％and 111.57％-120.00％， respectively. During experiment ，14 subjects reported 19 cases of mild AEs ，among which hematoma ，purpura and maculopapular rash may be related to drugs ；no serious AEs were observed. CONCLUSIONS The domestic Nadroparin calcium injection is bioequivalent to the reference preparation ，and both of them show good safety.

Pharmacokinetics and bioequivalence study of efavirenz tablets in healthy Chinese subjects under fasting administration / 药学学报

A randomized, open, fasting, single dose, two sequence, two cycle and double cross administration trial design was adopted. Took the test or reference efavirenz tablets of 200 mg orally in a single time. The plasma concentration of efavirenz in healthy subjects was determined by LC-MS/MS. WinNonLin8.1 software was used to calculate the main pharmacokinetic parameters of efavirenz and to evaluate the bioequivalence. The main pharmacokinetic parameters within 72 h: tmax were 2.574 ± 0.871 and 2.808 ± 0.912 h; Cmax were 1 586.732 ± 424.538 and 1 549.518 ± 366.086 ng·mL-1; AUC0-72 h were 28 464.672 ± 5 682.518 and 27 828.826 ± 5 082.487 h·ng·mL-1; t1/2 were 63.524 ± 26.037 and 58.748 ± 20.950 h; λz were 0.013 ± 0.006 and 0.013 ± 0.005 h-1. The main bioequivalence indicators were as follows: The 90% confidence interval of Cmax was 95.62%-107.15%, and the geometric mean ratio was 101.22%; The 90% confidence interval of AUC0-72 h was 100.43%-104.38%, and the geometric mean ratio was 102.38%. The results showed that the main pharmacokinetic parameters of the test drug and the reference drug were similar, and the two preparations had bioequivalence. This human bioequivalence clinical study was approved by the drug clinical trials ethics committee of the Second Hospital of Anhui Medical University (ethics approval No.: YW2021-110).

Mupirocin ointments: In vitro x In vivo bioequivalence evaluation

Abstract Bioequivalence (BE) assessment of topical drug products is a long-standing challenge. Agencies such as the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have published several drafts in recent years suggesting different approaches as alternative to evaluate the BE. A proposed Topical Classification System (TCS) has even been discussed. Given the above, the objective of this research was to use in vitro and in vivo BE approaches to evaluate Brazilian marketed mupirocin (MPC) ointments, previously classified as TCS class The in vitro permeation test (IVPT) was performed by applying formulations to pig skin by Franz cells. The in vivo methodology was dermatopharmacokinetic (DPK). These approaches (in vivo tape stripping and IVPT) demonstrated capability of distinguishing among different formulations, thus making them useful methodologies for BE evaluation.

In vitro evaluation of saxagliptin and metformin hydrochloride sustained-release tablets / 中国药科大学学报

@#In order to evaluate the consistency of the release behavior between the self-made saxagliptin and metformin hydrochloride sustained-release tablets and the reference preparations in vitro, the similarity of the dissolution curves between the self-made preparations and the reference preparations in four dissolution mediums: HCl (pH 1.0), acetate buffer saline (pH 4.5), phosphate buffer saline (pH 6.8) and pure water, and the gel morphology and strength of the self-made preparations and the reference preparations in the HCl (pH 1.0) solution medium were compared.Results showed that in four dissolution mediums, the dissolution rates of saxagliptin in the self-made preparations and the reference preparations at 15 min were greater than 85%, and the ?2 similarity factors of metformin hydrochloride were 89, 83, 80, 86, all greater than 50, so the dissolution of the self-made preparations was consistent with those of the reference preparations.The volume expansion rate, water absorption rate and erosion rate were consistent with those of the reference preparations, and the gel strength of the self-made preparations was the same as that of the reference preparations.The in vitro release behaviors of the self-made preparations and the reference preparations are consistent, which provide a good guarantee for bioequivalence.

Development of a fast and sensitive method for direct analysis of insulin aspart in human plasma / 药学学报

A fast and sensitive UPLC-MS/MS method was established for the direct quantification of insulin aspart in human plasma. The plasma samples were extracted by solid phase extraction (SPE), an ESI ion source was used and operated in the positive ion mode with multiple reaction monitoring (MRM). Bovine insulin was chosen as internal standard and the chromatographic separation of insulin aspart was performed on Waters ACQUITY UPLC CSH C18 column (50 mm×2.1 mm, 1.7 μm). A mixture of acetic acid aqueous solution and acetonitrile with acetic acid at a flow rate of 0.6 mL·min-1 in gradient elution mode was employed as mobile phase. We found that the method was validated over the range of 0.200-10.0 ng·mL-1 for insulin aspart and showed excellent linearity. The intra-and inter-assay accuracy and precision were below 14.5% and the recovery was 36.7%-41.7% over the three concentration levels evaluated. The UPLC-MS/MS method was selective, accurate, sensitive and robust, and the method was successfully applied in supporting the pharmacokinetic research of two insulin aspart injections (Test Product and NovoRapid®) in heathy male subjects. This clinical trial was approved according to the Ethics Committee of West China Hospital, Sichuan University (2017 Clinical Trial (Western Medicine) Approval (148)).

The analysis of unconventional research projects and common problems in the in vitro consistency evaluation of oral solid generic drugs / 药学学报

Based on the "requirements on the submitted documents for consistency evaluation of generic oral solid dosage forms of chemical drugs" and relevant guidance, this article summarized and formulated the decision tree of in vitro consistency evaluation of oral solid generic drugs, discussed the differences and common problems of in vitro evaluation research projects under different conditions, selective analyzed the technical requirements and concern problems of unconventional research projects, and proposed corresponding recommendations for concern problems, in order to provide more references for the follow-up study on consistency evaluation of oral solid generic drugs.

Bioequivalence Study Comparing Meloxicam 15mg Tablet of Pascual Laboratories, Inc. with Meloxicam (Mobic®) 15mg Tablet of Boehringer Ingelheim in Healthy Male Filipino Subjects under Fasting Conditions

@#<p style="text-align: justify;"><strong>Objective.</strong> Proof of bioequivalence is important for the interchangeability of pharmaceutically equivalent drug products. This study aimed to compare the rate and extent of absorption of meloxicam 15 mg tablet of Pascual Laboratories, Inc. (Test) with meloxicam 15 mg tablet (Mobic) of Boehringer Ingelheim (Reference) in healthy Filipino men. In addition, the study also determined the safety and tolerability of single doses of the said medications, under the same conditions.</p><p style="text-align: justify;"><strong>Methods.</strong> This was a randomized, open label, blind-endpoint analysis, truncated, crossover study with single drug doses administered in the fasting condition in each of the two treatment periods, separated by a two-week washout period. Pharmacokinetic blood sampling was performed up to 72 h post-dose. Plasma samples were analyzed using a validated liquid chromatography with tandem mass spectrometry technology. The primary endpoints were: area under plasma-concentration-time curve from time zero to the last observed concentration at time 72 h (AUC0-72) and maximum plasma concentration (Cmax) for meloxicam.</p><p style="text-align: justify;"><strong>Results.</strong> Eighteen men (mean age 21.5 years; mean body mass index 22.9 kg/m2) completed the study. When administered one meloxicam 15 mg tablet, the ratios of the geometric means of the primary endpoints AUC0-72 and Cmax, were within the established bioequivalence limits of 80% to 125% compared with Mobic 15 mg tablet: 104.07% (90% Confidence Interval [CI]: 100.26, 108.03), and 103.34% (90% CI: 96.22, 110.97), respectively. No adverse event was reported.</p><p style="text-align: justify;"><strong>Conclusion.</strong> Meloxicam 15 mg tablet of Pascual Laboratories, Inc. and the innovator Mobic 15 mg tablet are bioequivalent. Single doses of both products were safe and well tolerated.</p>

Intercambiabilidad de medicamentos en el Perú: panorama actual y perspectivas futuras

Los medicamentos genéricos desempeñan un papel importante en los sistemas de atención de salud, ya que representan una alternativa eficaz más asequible para la población. En el Perú, se estableció un reglamento que regula la intercambiabilidad de medicamentos genéricos (también llamados multifuentes), que define los procedimientos y requisitos a seguir para desarrollar estudios de equivalencia terapéutica in vivo e in vitro, siguiendo el enfoque de aplicación gradual y el criterio de riesgo sanitario. El cumplimiento de este reglamento permitirá un mayor acceso a medicamentos genéricos eficaces, seguros y de calidad. Mientras tanto, se siguen comercializando genéricos en ausencia de estudios de equivalencia terapéutica. Los estudios demuestran que algunos medicamentos fallaron en las comparaciones in vivo e in vitro con el medicamento de referencia. Esta implementación representa un gran desafío para los laboratorios fabricantes y los titulares de registros sanitarios a fin de demostrar la intercambiabilidad de sus productos farmacéuticos con el medicamento de referencia.

Generic drugs play an important role in healthcare systems as they represent an effective and more affordable alternative for the population. In Peru, a regulation of interchangeability of generic drugs (also called multisource drugs) was stablished to define the procedures and requirements for developing in vivo and in vitro therapeutic equivalence studies, following the gradual application approach and sanitary risk criteria. Compliance with the new regulation will allow greater access to effective, safe and quality generic drugs. Meanwhile, drugs continue to be marketed in the absence of therapeutic equivalence studies. Findings show that some drugs failed in in vivo and in vitro comparisons with the reference product. This regulation represents a great challenge for manufacturers and holders of sanitary registrations in order to demonstrate the interchangeability of their pharmaceutical products with the reference product.

Estudio comparativo de la calidad biofarmacéutica de Alprazolam 0, 5 mg comercializadas en el mercado peruano / Comparative study of the biopharmaceutical quality of Alprazolam 0. 5 mg commercialized in the Peruvian market

El Alprazolam pertenece a las benzodiazepinas. Sus efectos se atribuyen a que actúa sobre receptores de membrana específicos, lo cual facilita la acción inhibitoria presináptica y postsináptica del ácido γ-aminobutírico (GABA), especialmente en la formación reticular ascendente. Se utiliza para el tratamiento de los estados de ansiedad, crisis de angustia, ataques de pánico y estrés intenso. Este estudio se realizó para analizar los parámetros comparativos de control de calidad in vitro mediante la evaluación de la variación de peso, friabilidad, dureza, tiempo de desintegración, perfil y eficiencia de disolución entre el medicamento innovador (Xanax®) y multifuentes que son comercializados en el mercado peruano. Para realizarlo, se seleccionaron tabletas de Alprazolam 0,5 mg multifuente de diferentes laboratorios comparándolos con el medicamento innovador y se evaluaron las características fisicoquímicas y biofarmacéuticas. Los ensayos farmacopeicos se evaluaron según lo establecido en la USP 42. Los resultados de las pruebas fisicoquímicas indicaron que las muestras analizadas no tenían diferencia significativa y estaban dentro de lo establecido en la farmacopea, así mismo el perfil y eficiencia de disolución permitieron establecer que el comportamiento biofarmacéutico de las mismas era muy similar para ambos tipos de molécula. Se estableció que las tabletas multifuentes de Alprazolam 0,5 mg de esta investigación son bioequivalentes con el innovador, por lo que permite proponer a la comunidad científica la determinación de la equivalencia biofarmacéutica como elemento de apoyo en la toma de decisiones de compra en el servicio farmacéutico

Alprazolam belongs to benzodiazepines. Its effects are attributed to the fact that it acts on specific membrane receptors, which facilitates the presynaptic and postsynaptic inhibitory action of γ-aminobutyric acid (GABA), especially in the ascending reticular formation. It is used to treat anxiety states, panic attacks, and intense stress. This study was carried out to analyze comparative parameters of in vitro quality control by evaluating the variation in weight, friability, hardness, disintegration time, profile and dissolution efficiency between the innovative drug (Xanax®) and multi-sources tablets that are marketed in the Peruvian market. To perform this, Alprazolam 0.5 mg multi-source tablets were selected from different laboratories comparing them with the innovative medicine and the physicochemical and biopharmaceutical characteristics were evaluated. Pharmacopoeial trials were evaluated as established in USP 42. The results of physicochemical tests indicated that analyzed samples did not have a significant difference and were within the established in the pharmacopoeia, as well as the profile and dissolution efficiency allowed to establish that their biopharmaceutical behavior was very similar for both types of molecules. It was established that Alprazolam 0.5 mg multi-source tablets from this research are bioequivalent with innovator, which makes it possible to propose to scientific community determination of biopharmaceutical equivalency as a support element in decision-making process for purchasing services pharmacist

Drug Release and Pharmacokinetics Behavior of a Simple Ethylcellulose Coating Pulsatile Tablet of Time-controlled Explosive System

Background The time rhythm of human body is associated with the occurrence and development of manydiseases. Kinds of diseases of particular onset biorhythm provided the room for the development ofchronopharmacological drug delivery systems.Aim In this work, the drug release and pharmacokinetics behavior of metoprolol tartrate (MT) pulsatile tabletdeveloped in our lab was investigated to figure out its feasibility of convenient drug taking to exert effectivechronotherapy for cardiovascular diseases like hypertension and angina pectoris.Methods The in vitro release behavior of MT pulsatile tablets was investigated by using basket method. Theappearance and morphology of MT pulsatile tablets during drug release was observed by naked eye and scanning electronic microscope, respectively. In vivo pharmacokinetics performance was studied in NewZealand rabbits.Results The lag time of MT pulsatile tablets was approximately 7 h in vitro, and a fast release was observedthereafter, with more than 90% releasing within 10 min. The pharmacokinetics study in rabbits demonstrateda perfect consistence in the absorption lag time of 7.04 ± 0.29 h in vivo. Compared with the marketedconventional tablet, the MT pulsatile tablet showed a bioequivalence in absorption extent with a relativebioavailability of 110.04%, but not in absorption rate.Conclusion The designed lag time of 7 hours enabled the MT pulsatile tablets to achieve effectivechronotherapy for cardiovascular diseases like hypertension and angina pectoris with a high attack rhythmaround 4:00-6:00 A.M by giving medicine conveniently around 22:00 P.M. the night before.

Evaluation of the bioequivalence of two formulations containing the combination of 400 mg of acetaminophen (paracetamol), 4 mg of phenylephrine and 4 mg of chlorpheniramine in capsules: open-label, three-way crossover study, partially replicated in healthy volunteers of both sexes

This study was carried out in order to compare the relative bioavailability of two different formulations containing 400 mg of acetaminophen + 4 mg of phenylephrine hydrochloride + 4 mg of chlorpheniramine maleate, Test formulation (Cimegripe®) and Reference formulation (Resfenol®) in 84 healthy volunteers of both sexes under fasting conditions. The study was conducted in a single dose, randomized, open-label, crossover 3-way and partially replicated. The tolerability was evaluated by the monitoring of adverse events and vital signs, results of clinical and laboratory tests. Plasma concentrations were quantified by validated bioanalytical methods using the ultra-performance liquid chromatography coupled to tandem mass spectrometry. The Cmax, Tmax, AUC0-t, AUC0-inf, T1/2 and Kel pharmacokinetic parameters were calculated from these obtained concentrations. The 90% confidence intervals were constructed for the ratio reference/test from the geometric average of the Cmax and AUC parameters which were comprised between 80% and 125%. Only the Cmax parameter of the phenylephrine was applied the scaled average bioequivalence due to the intraindividual coefficient of variation > 30% obtained, thus extending the acceptance limits of the interval. It can be concluded that the two formulations were bioequivalent in terms of rate and absorption extent and thus interchangeable