Substandard and falsified antimicrobials in selected east African countries: A systematic review.

BACKGROUND: Globally, millions of people have been affected by fraudulent pharmaceutical products, particularly those in developing countries. Although the problem of falsified and substandard drugs is acknowledged, the extent of the issue is ever-changing, has a dynamic nature, and should be quantified and captured in a recent snapshot. OBJECTIVE: This systematic review seeks to examine the data that can quantify and provide a current snapshot of the prevalence of SF antimicrobials in selected east Africa countries. METHODS: Scientific studies on antimicrobial quality were searched in PubMed, Embase, Scopus, and Google Scholar from 2017 to February 2023. The search strategy focused on scientific articles published in peer-reviewed scientific journals written in English and the studies exclusively done in any of the selected countries of east Africa. The articles were carefully reviewed by two individuals for inclusion independently, first by title followed by abstract and the full-text retrieval. To minimize bias associated with the methodology used for data collection, the quality of the studies was assessed for quality according to the Medicine Quality Assessment Reporting Guidelines (MEDQUARG). The reporting of this systematic review was done following Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA). RESULTS: Fifteen studies that estimated the prevalence of poor-quality antimicrobial medicines in selected four east African countries were included. The overall percentage of samples of antimicrobials that failed at least one quality test was 22.6% (151/669) with each class's prevalence of 17% in antibiotics (73/432), 24% in antimalarial (41/171), and 56% in anthelmintics (37/66). Quality control parameters of API content were the most commonly examined in the included studies, accounting for 14/15 (93%) studies. Fifty (33.1%) of the failing samples failed assay API- content determination, while 26.5% (n = 40) failed the visual inspection and packaging analysis; 19.2% (29) failed dissolution; 14% (n = 21) flawed hardness or friability; 4%(n = 6) failed uniformity, as well as 3.2% (n = 5) failed disintegration test of the quality control parameter. CONCLUSION: It was found that this review was general in these selected east African countries and was a catalyst for combating the menace of poor-quality medications that affect millions of lives.

Compressibility behavior of pioglitazone hydrochloride in mannitol-based formulations: An investigation using compaction simulator and QbD approach.

This study aimed to investigate the compressibility properties of Pioglitazone Hydrochloride (PGZ) oral dispersible tablets using a compaction simulator. The tablets were prepared and formulated by direct compression method with varying particle sizes of PGZ in mannitol-based formulations, containing Ludiflash® and its corresponding physical mixture. All formulations were compressed at different compaction forces (5kN-20kN). Powders were evaluated for their tablet properties, such as hardness, friability, disintegration time and dissolution rate. Results showed that all formulations exhibited good compressibility properties. The compaction force and choice of excipient played a vital role in formulation performance and drug release profile. With the use of Minitab 19™ an optimized formulation was derived and all predicted outputs was seen to be within range after evaluations. In conclusion, the combined use of the compaction simulator and Minitab 19™ were found to be useful tools in predicting the compressibility properties of PGZ and therefore developing a robust oral dispersible tablet. These findings suggest that the compressibility properties of PGZ oral dispersible tablets can be effectively modified by adjusting the critical process parameters (CPP). Hence, providing valuable insights into the compressibility behavior of PGZ oral dispersible tablets and also aiding in the development of optimized tablet formulations.

Critical Tools in Tableting Research: Using Compaction Simulator and Quality by Design (QbD) to Evaluate Lubricants' Effect in Direct Compressible Formulation.

As commonly known, the product development stage is quite complex, requires intensive knowledge, and is time-consuming. The selection of the excipients with the proper functionality and their corresponding levels is critical to drug product performance. The objective of this study was to apply quality by design (QbD) principles for formulation development and to define the desired product quality profile (QTPP) and critical quality attributes (CQA) of a product. QbD is a risk- and science-based holistic approach for upgraded pharmaceutical development. In this study, Ibuprofen DC 85W was used as a model drug, Cellactose® 80 along with MicroceLac® 100 as a filler, and magnesium stearate, stearic acid, and sodium stearyl fumarate as lubricants. By applying different formulation parameters to the filler and lubricants, the QbD approach furthers the understanding of the effect of critical formulation and process parameters on CQAs and the contribution to the overall quality of the drug product. An experimental design study was conducted to determine the changes of the obtained outputs of the formulations, which were evaluated using the Modde Pro 12.1 statistical computer program that enables optimization by modeling complex relationships. The results of the optimum formulation revealed that MicroceLac® 100 was the superior filler, while magnesium stearate at 1% was the optimum lubricant. A design space that indicates the safety operation limits for the process and formulation variables was also created. This study enriches the understanding of the effect of excipients in formulation and assists in enhancing formulation design using experimental design and mathematical modeling methods in the frame of the QbD approach.

Evaluation of Lactose-Based Direct Tableting Agents' Compressibility Behavior Using a Compaction Simulator.

OBJECTIVES: A compaction simulator (CS) is a single-punch instrument that records data during the powder compaction process. The aim of the study was to determine the behavior of lactose-based direct tableting agents (DTAs) by CS. The data recorded were used to evaluate the flowability and compressibility of powders. The focus of the study was on comparing the compressibility of StarLac® [alpha lactose monohydrate (85%) and white maize starch (15%)] and FlowLac®100 (spray-dried alpha lactose monohydrate) in order to make tablets containing poorly flowable paracetamol. MATERIALS AND METHODS: Two lactose-based DTAs were used. Physical characterization of these powders was done by measuring bulk, tapped, and true densities alongside scanning electron microscopy analysis. Flow properties were then calculated by the angle of repose, Hausner ratio, and Carr's compressibility index. Force, in-die thickness, and punch displacement data produced by the CS were captured during in-die compression. Compressibility was calculated using the Heckel equation. RESULTS: The physical characterization test results showed no significant difference between the two DTAs. Hardness results revealed that tablet formulations containing FlowLac® had higher sensitivity to an increase in compression force in comparison with StarLac®. From the Heckel plots generated by the CS during the compression cycle, yield pressure (Py) values were calculated for FlowLac®100 and StarLac®. The Heckel parameter (Py) for FlowLac®100 and StarLac® was calculated as 87.5 MPa and 85.2 MPa, respectively, during the compaction cycle at 5 kN. These data indicated that both powders are compressible and have brittle behavior. CONCLUSION: StarLac® is less brittle, which was shown by its lower sensitivity to compression force. Py values obtained from the Heckel equation described the plasticity of particles, which gives distinct information on the compressibility of both DTAs in real time during the compaction cycle.

Investigation of the Compressibility Characteristics of Paracetamol using "Compaction Simulator".

OBJECTIVES: This study was performed to understand the behavior of poorly compressible paracetamol powder using a compaction simulator (CS), equipment that records data during the compaction process. The aim was to investigate the compressibility of paracetamol tablets using a dry granulation (slugging) process, with different formulation compositions. MATERIALS AND METHODS: Formulations were prepared to observe the effect on compressibility with two different lactose-based fillers, Flowlac®100 and Granulac®70, and a binder, Kollidon® K90. In each combination, a total of four formulations were prepared with paracetamol to filler ratios of 1:1 and 0.8:1. Tablets were produced by single punch (11.28 mm) CS at six different pressures (152, 210, 263, 316, 400, and 452 MPa). During compression, upper punch displacement and force data were produced by the CS equipment. The compressed tablets were tested for hardness, thickness, and weight variation and compared with each other. RESULTS: All formulations reached maximum tensile strength at compaction pressures between 263 and 316 MPa. In the formulations without binder, those containing Granulac®70 had higher tensile strength than those containing Flowlac®100 at both filler ratios. The results obtained indicated that the addition of binder to the formulations (F-45-1, F-45-2, F-50-3, and F-50-4) improved the compressibility of paracetamol. Formulation F-45-2, containing Flowlac®100 and binder, showed better compressibility at 2.9 MPa tensile strength. Data from the CS were used to compare Young's modulus and work of compaction on selected formulations (F-45-1 and F-45-2). CONCLUSION: The proposed lactose-based filler, Flowlac®100, with low pressure can be successfully applied for improving the compressibility of paracetamol. An optimum formulation can be designed with smaller amounts of materials using a compaction simulator.

A Solid Ultra Fine Self-Nanoemulsifying Drug Delivery System (S-SNEDDS) of Deferasirox for Improved Solubility: Optimization, Characterization, and In Vitro Cytotoxicity Studies.

The research work was designed to develop a solid self-nanoemulsifying drug delivery system (S-SNEDDS) of deferasirox (DFX). According to the solubility studies of DFX in different components, Peceol, Kolliphor EL, and Transcutol were selected as excipients. Pseudo-ternary phase diagrams were constructed, and then SNEDDS formation assessment studies and solubility of DFX in selected SNEDDSs formulations were performed. DFX loaded SNEDDS were prepared and characterized. The optimum DFX-SNEDDS formulations were developed. The relative safety of the optimized SNEDDS formulation was examined in a human immortalized myelogenous leukemia cell line, K562 cells, using the MTT cell viability test. Cytotoxicity studies revealed more cell viability (71.44%) of DFX loaded SNEDDS compared to pure DFX (3.99%) at 40 µM. The selected DFX-SNEDDS formulation was converted into S-SNEDDS by adsorbing into porous carriers, in order to study its dissolution behavior. The in vitro drug release studies indicated that DFX release (Q5%) from S-SNEDDS solidified with Neusilin UFL2 was significantly higher (93.6 ± 0.7% within 5 min) compared with the marketed product (81.65 ± 2.10%). The overall results indicated that the S-SNEDDS formulation of DFX could have the potential to enhance the solubility of DFX, which would in turn have the potential to improve its oral bioavailability as a safe novel delivery system.

Bioequivalence studies on bisphosphonates: the example of alendronate.

The study was designed to evaluate the bioequivalence of two formulations of alendronate (CAS 121268-17-5, Osalen 10 mg tablets, in the following referred to as "test" vs. the originator product, in the following referred to as "reference") in 89 healthy male and female volunteers, who were administered four 10 mg alendronate tablets under fasting conditions. The trial was performed according to an open, randomized, cross-over design with a wash-out period of 14 days in one study center. Urine samples were taken up to 36 h post dose, and the concentrations of alendronate were determined by HPLC/Fl method. The mean Ae0-36 were 102.89 +/- 57.52 microg and 96.23 +/- 60.81 microg for the test and reference formulations, respectively, while the mean Rmax were 36.15 +/- 21.07 microg/h and 35.36 +/- 22.88 microg/h, respectively. The test and reference tablets Tmax were 0.592 +/- 0.858 h and 0.583 +/- 0.858 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence interval for the primary target parameters, intra-individual ratios of Ae0-36 and Rmax of alendronate were between 1.01 and 1.17 for Ae0-36 and between 0.96 and 1.11 for Rmax, and thus within the acceptance range for bioequivalence trials. In the light of the present study it can be concluded that alendronate test tablets are bioequivalent to the reference formulation.

Assessment of the bioequivalence of different formulations containing azithromycin (tablets and suspension).

Azithromycin (CAS 11772-70-0) is an orally administered macrolide antimicrobial drug, structurally related to erythromycin, with a similar spectrum of antimicrobial activity. The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of azithromycin (Azro) 500 mg tablets (study 1) and azithromycin (Azro) 200 mg/5 mL suspensions (study 2) with originator products. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in 24 healthy volunteers with a wash-out period from 14 to 21 days. Blood samples were taken up to 96 h post dosing, and concentrations of azithromycin were determined by HPLC method. In the first study, the 90% confidence interval for intra-individual ratios (test vs. reference) of AUC0-t and Cmax of azithromycin were between 0.82 and 1.04 for AUC0-t and 0.81 and 1.11 for Cmax, and thus within the acceptance ranges for bioequivalence trials. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of azithromycin administered as suspension were between 0.89 and 1.22 and 0.91 and 1.23, respectively. These values were also within the acceptance range. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences for azithromycin were between -0.49 - 0.50 in the first and between -0.50 - 0.25 in the second study, respectively. In the light of the results of the studies reported here it can be concluded that azithromycin test formulations, i.e. tablet and suspension are bioequivalent to the respective reference formulations.

Bioequivalence study of atorvastatin tablets.

The study was designed to evaluate the relative bioavailability of two formulations of atorvastatin (CAS 134523-03-8). A bioequivalence study was carried out in 24 healthy male volunteers who received four 10 mg tablets of the test formulation (Kolestor) and the same dose of the originator product. The trial was performed according to an open, crossover design with a wash-out period of 7 days in one study center. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of atorvastatin were determined by HPLC-MS-MS method. The mean Cmax were 16.37 ng/mL and 17.05 ng/mL, while the mean AUC0-t were 103.61 ng x h/mL and 102.55 ng x h/mL for the test and reference formulations, respectively. The mean AUC0-inf were 118.10 ng x h/mL and 117.13 ng x h/mL for the test and reference formulations, respectively. The median tmax was 0.67 h for both the test tablet and the reference product. The mean t(1/2 el) was 11.85 h for the test formulation and 13.28 h for the reference formulation. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence intervals for the primary target parameters, intra-individual ratios of AUC0-t and Cmax of atorvastatin, were between 0.85 and 1.05 (AUC0-t) and between 0.84 and 1.23 (Cmax), respectively, and thus within the acceptance ranges. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences was between -0.17 and 0.17 h. In the light of the present study it can be concluded that the two evaluated atorvastatin formulations, i.e. test formulation of atorvastatin and reference preparation are bioequivalent in terms of the rate and extent of absorption.

Studies on the bioequivalence of second generation cephalosporins: cefaclor capsules and suspension.

The aim of the present studies, performed in two different groups of volunteers, was to prove the bioequivalence of 500 mg cefaclor (CAS 70356-03-5) test and reference capsules (Losefar 500 mg Capsules as test and an originator product as reference; study 1) and cefaclor 250 mg/5 mL test and reference suspensions (Losefar 250 mg/5 mL Granules oral suspension as test and an originator product as reference; study 2). Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 8 h post dosing, and concentrations of cefaclor were determined by HPLC method. In the first study, the 90% confidence intervals for intra-individual ratios of AUC0-t and Cmax of cefaclor were 0.99-1.08 for AUC0-t and 0.82-1.06 for Cmax, and thus within the acceptance ranges for bioequivalence trials. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of cefaclor administered as suspensions were 1.10-1.19 and 1.02-1.21, respectively. These values were also within the acceptance range. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences for cefaclor were between -0.13 - 0.13 in the first and between 0.00 - 0.13 in the second study, respectively. In the light of the results of the studies reported here it can be concluded that cefaclor test formulations, i.e. capsules and suspension are bioequivalent to the respective reference formulations.

Studies on the bioequivalence of different strengths of tablets containing clarithromycin.

The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of clarithromycin (CAS 81103-11-9) tablets (Klaromin, test tablets) containing 250 mg (study 1) or 500 mg (study 2) of the drug with reference tablets of the same strength. Each study was conducted according to an open, randomized, single-dose, two-period crossover design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 24 h in both studies, and concentrations of clarithromycin and its principal active 14-hydroxy metabolite were determined by HPLC method. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.93 and 1.05 (AUC0-t) as well as between 0.90 and 1.18 (Cmax). In the second study, i.e. after administration of clarithromycin 500 mg tablets, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.90 and 1.08 (AUC0-t) as well as between 0.85 and 1.22 (Cmax). All these values were within the acceptance ranges for bioequivalence studies. In both studies, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of 14-hydroxy-clarithromycin were also within the acceptance ranges, although the confidence intervals for these parameters were not planned to be compared with the acceptance ranges. In the light of the results of the studies reported here it can be concluded that the clarithromycin 250 mg and 500 mg test tablets are bioequivalent to the respective reference formulations.

Clarithromycin suspension: bioequivalence studies on two different strengths.

Two studies were performed in different groups of volunteers, with the aim to prove the bioequivalence of test (Klaromin) and reference clarithromycin (CAS 81103-11-9) suspensions containing in 5 mL either 125 mg (study 1) or 250 mg (study 2) of the drug, administered as an oral dose of 10 mL. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 24 h in both studies, and concentrations of clarithromycin and its principal active 14-hydroxy metabolite were determined by HPLC. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of clarithromycin were between 0.84 and 1.03 (AUC0-t) and between 0.89 and 1.03 (Cmax). In the second study, i.e. after administration of clarithromycin suspension 250mg/5mL, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of clarithromycin were between 1.01 and 1.17 (AUC0-inf) and between 1.01 and 1.16 (Cmax). All these values were within the acceptance ranges for bioequivalence studies. In both studies, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of 14-hydroxy-clarithromycin were also within the acceptance ranges. In the light of the results of the studies reported here it can be concluded that the clarithromycin test formulations are bioequivalent to the respective reference formulations, i.e. suspensions containing 125 mg/5 mL and 250 mg/5 mL of the drug.

Bioequivalence study of clopidogrel bisulfate film-coated tablets.

The aim of the present study was to evaluate the bioequivalence of two clopidogrel (CAS 120202-66-6) formulations. The study was performed according to an open, cross-over design in one study center in 36 healthy male and female volunteers, comparing a new generic product (tablets containing clopidogrel bisulfate, 75 mg) with the originator product (reference). In each of the two study periods (separated by a wash-out of 7 days) a single dose of 150 mg (test or reference) was administered. Blood samples were taken up to 48 h post dose, the plasma was separated and the concentrations of clopidogrel were determined by an LC/MS/MS method. AUC0-inf, AUC0-t, Cmax, Tmax and T(1/2 el) were calculated for both formulations. The mean AUC0-inf, AUC0-t and Cmax were 29.94 ng x h/mL, 29.53 ng x h/mL and 7.386 ng/mL, respectively, for the test formulation and 29.24 ng x h/mL, 28.83 ng x h/mL and 7.921 ng/mL, respectively, for the reference formulation. The median Tmax for both formulations was 1.25 h. The point estimators of the ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 101.17%, 101.13% and 90.96%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf and AUC0-t were narrow and symmetrical around 100%, i.e. from 96.38% to 106.21% for AUC0-inf and from 96.20% to 106.30% for AUC0-t, whereas the confidence interval for Cmax was 84.07% to 98.41%. In can be concluded that the two clopidogrel formulations (test formulation of clopidogrel bisulfate and reference formulation) are bioequivalent in terms of the rate and extent of absorption.

Effect of the combination of lisinopril and hydrochlorothiazide on the bioequivalence of tablet formulations.

The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of 20 mg lisinopril tablets (Sinopryl as test and an orignator product as reference formulation; study 1) and lisinopril/hydrochlorothiazide (20 mg/12.5 mg) (CAS 83915-83-7/CAS 58-93-5) combined formulations (Sinoretik as test and an originator product as reference formulation; study 2). Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 72 h in both studies, the plasma was separated. Concentrations of lisinopril and hydrochlorothiazide were determined by HPLC-MS-MS method. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of lisinopril were between 0.85 and 1.12 (AUC0-t) and between 0.87 and 1.17 (Cmax), and thus within the acceptance ranges. In the second study, i.e. after administration of combined lisinopril/hydrochlorothiazide formulations, the 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of lisinopril were between 0.83 and 1.22 (AUC0-inf) and between 0.80 and 1.25 (Cmax). The 90% confidence interval for intra-individual ratios of AUC0-inf and Cmax of hydrochlorothiazide were between 0.92 and 1.04 (AUC0-inf) and between 0.88 and 1.08 (Cmax). All the above values were within the acceptance ranges for bioequivalence studies. In the light of the present studies it can be concluded that Hsinopril as well as lisinopril/hydrochlorothiazide test formulations are bioequivalent to the respective reference formulations.

Combination of losartan and hydrochlorothiazide: in vivo bioequivalence.

Two trials were performed in different groups of volunteers with the aim to compare the bioavailability of 50 mg losartan tablets (Sarvas as test and an originator product as reference formulation; study 1) and losartan/hydrochlorothiazide (50 mg/12.5 mg) (CAS 124750-99-8/CAS 58-93-5) combined formulations (Sarvastan as test and an originator product as reference formulation; study 2), respectively. Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in 24 healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 36 h in the first study and up to 48 h in the second study. Concentrations of losartan and its principal active metabolite, i.e. E3174, as well as hydrochlorothiazide were determined by HPLC or LC-MS-MS, respectively. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of losartan were between 0.91 and 1.03 (AUC0-t) as well as between 0.87 and 1.19 (Cmax), and thus within the acceptance ranges. The 90% confidence interval for intra-individual ratios of AUC0-t, and Cmax of E3174 were between 0.90 and 1.13 for AUC0-t, and between 0.97 and 1.14 for Cmax. In the second study, i.e. after administration of combined losartan/hydrochlorothiazide formulations, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of losartan were between 0.90 and 1.04 (AUC0-t) as well as between 0.86 and 1.20 (Cmax). Similarly to the parent compound, no significant differences of bioavailability parameters of E3174 between the two studied formulations were found. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of hydrochlorothiazide were between 0.89 and 0.98 (AUC0-t) as well as between 0.82 and 1.00 (Cmax). In the light of the present studies it can be concluded that the losartan as well as losartan/hydrochlorothiazide test formulations are bioequivalent to the respective reference formulations.

Bioequivalence study of rofecoxib tablets.

The study was designed to evaluate the bioavailability of two rofecoxib (CAS 162011-90-7) tablet formulations. Twenty-four healthy male volunteers were administered a 25 mg tablet of the test formulation (Ecrox) containing rofecoxib or the originator product (reference). The trial was performed according to an open, cross-over design with a wash-out period of 7 days. Blood samples were taken up to 72 h post dose, the plasma was separated and the concentrations of rofecoxib were determined by an HPLC method. The mean Cmax were 192.07 ng/mL and 187.35 ng/mL, while the mean AUC0-t were 3613.84 ng x h/mL and 3501.56 ng x h/mL for the test and reference formulations, respectively. The median tmax was 3.75 h for the test tablet and 4.00 h for the reference formulation. The mean t(1/2 el) was 10.66 h and 10.61 h for the test and reference formulation, respectively. Mean MRT values for the test and reference tablets were 15.34 h and 15.33 h, respectively. Mean MRT values for the test and reference tablets were 15.34 h and 15.33 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence interval for the primary target parameters, i.e. intra-individual ratios of AUC0-t and Cmax of rofecoxib were between 0.99 and 1.10 (AUC0-t) as well as between 0.96 and 1.10 (Cmax) and thus within the acceptance ranges. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences was between -0.25 and 0.25 h. In the light of the present study it can be concluded that the two evaluated rofecoxib formulations, i.e. test tablets of rofecoxib and a reference preparation are bioequivalent in terms of the rate and extent of absorption.

In vivo bioequivalence of oral antidiabetic agents: pioglitazone tablets.

The study was designed to evaluate the bioequivalence of two pioglitazone (CAS 112529-15-4) formulations. The trial was performed in 26 healthy male volunteers with the aim of comparing a new generic product (tablets containing 30 mg pioglit-azone hydrochloride, test) with the originator product (reference). The trial was performed according to an open, crossover design in one study centre. In each of the two study periods (separated by a wash-out of 14 days) a single oral dose of 30 mg (test or reference) formulation was administered. Blood samples were taken up to 120 h post dose, the plasma was separated and the concentrations of pioglitazone and its principal active metabolite hydroxypioglitazone were determined by LC-MS-MS method. AUC0-inf, AUC0-t, Cmax, and Tmax were calculated for both formulations. The mean Cmax of pioglitazone ranged between 1.01 microg/mL and 1.05 microg/mL, while the mean AUC0-inf and AUC0-t ranged between 10.89 microg x h/mL and 10.98 microg x h/mL as well as between 10.56 microg x h/mL and 10.62 microg x h/mL for the test and reference formulations, respectively. The median Tmax for the test tablets was 1.50 h and for the reference was 1.75 h. The ratios test/reference formulation for AUC0-inf, AUC0-t and Cmax were 99.70%, 100.13% and 99.17%, respectively. Furthermore, the 90% geometric confidence intervals of the mean ratio of In-transformed AUC0-inf were narrow and symmetrical around 100%, i.e. 90.59% to 109.72%, for AUC0-t, 90.69% to 110.55%, whereas for Cmax they were 87.52% to 112.37%. As in the case of pioglitazone, mean values of the principal bioequivalence parameters of hydroxypioglitazone did not differ significantly after administration of the test and reference formulations. In the light of the present study it can be concluded that the two evaluated pioglitazone formulations, i.e. test formulation of pioglitazone hydrochloride and reference formulation, are bioequivalent in terms of the rate and extent of absorption.

Serotonin reuptake inhibitors: bioequivalence of sertraline capsules.

The study was designed to evaluate the bioavailability of two sertraline (CAS 79617-96-2) formulations. A bioequivalence study was carried out in 24 healthy male volunteers, who were administered 50 mg capsules of the test formulation (Seralin) and the originator product (reference) as a single dose. The trial was performed according to an open, randomized, cross-over design with a washout period of 14-20 days in one study center. Blood samples were taken up to 96 h post dose, the plasma was separated and the concentrations of sertraline were determined by HPLC-MS-MS. The mean Cmax were 9.01 +/- 2.26 ng/mL and 8.24 +/- 2.14 ng/mL, while the mean AUC0-t were 259.09 +/- 105.36 ng x h/mL and 234.36 +/- 95.18 ng x h/mL for the test and reference formulations, respectively. The mean AUC0-inf were 292.66 +/- 128.09 ng x h/mL (test) and 267.23 +/- 116.40 ng x h/ mL (reference). The mean tmax was 5.88 +/- 1.03 h for the test capsules and 6.17 +/- 1.66 h for the reference formula. The mean t1/2el was 26.49 +/- 6.45 h for the test formulation and 26.23 +/- 6.64 h for the reference formulation. Mean MRT values for the test and reference formulations were 28.14 +/- 5.37 h and 27.81 +/- 5.13 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence interval for the primary target parameters, intra-individual ratios of AUC0-t and Cmax of sertraline were between 1.03 and 1.19 (AUC0-t) as well as between 1.02 and 1.17 (Cmax) and thus within the acceptance ranges for bioequivalence trials. Concerning the secondary parameter tmax the 90% confidence interval for the intra-individual differences was between -1.00 and 0.50 h. In the light of the present study it can be concluded that sertraline test capsules are bioequivalent to the reference formulation.

Effect of the formulation on the bioequivalence of sultamicillin: tablets and suspension.

Sultamicillin (CAS 76497-13-7) is a pro-drug of a combination of ampicillin and sulbactam linked as a double ester. The aim of the present studies, performed in two different groups of volunteers, was to compare the bioavailability of 750 mg sultamicillin tablets (Duobaktam 750 mg tablets, study 1) and sultamicillin 250 mg/5mL suspensions (Duobaktam 250 mg/5mL, study 2). Each study was conducted according to an open, randomized, single-dose, two-period cross-over design in 24 healthy volunteers with a wash-out period from 7 to 14 days. Blood samples were taken up to 12 h post dosing, and concentrations of ampicillin and sulbactam were determined by a HPLC-UV method. In the first study, the 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of ampicillin and sulbactam were between 1.01-1.18 and 0.95-1.09 (AUC0-t) as well as between 0.87-1.04 and 0.80-0.96 (Cmax), respectively, and thus within the acceptance ranges. The 90% confidence interval for intra-individual ratios of AUC0-t and Cmax of sultamicillin suspensions (2nd study) were between 0.94-1.16 (ampicillin) and 0.92-1.14 (sulbactam) for AUC0-t and between 0.96-1.23 (ampicillin) and 0.97-1.24 (sulbactam) for Cmax. These values were also within the acceptance range for bioequivalence studies. Concerning the secondary parameter tmax the 90%-confidence interval for the intra-individual differences for both ampicillin and sulbactam were between 0.00-0.50 in the first and between -0.17-0.00 in the second study, respectively. In the light of the present studies it can be concluded that the sultamicillin test formulations, i.e. tablet and suspension are bioequivalent to the respective reference formulations.