Reference Tablets Research Articles

Development of Oral Tablets of Nebivolol with Improved Dissolution Properties, Based on Its Combinations with Cyclodextrins.

New oral tablets of nebivolol have been developed aiming to improve, by cyclodextrin (CD) complexation, its low solubility/dissolution properties-the main reason behind its poor/variable oral bioavailability. Phase-solubility studies, performed using βCD and highly-soluble βCD-derivatives, indicated sulfobutylether-βCD (SBEβCD) as the best solubilizing/complexing agent. Solid drug-SBEβCD systems were prepared by different methods and characterized for solid-state and dissolution properties. The coevaporated product was chosen for tablet development since it provided the highest dissolution rate (100% increase in dissolved drug at 10 min) and almost complete drug amorphization/complexation. The developed tablets reached the goal, allowing us to achieve 100% dissolved drug at 60 min, compared to 66% and 64% obtained, respectively, with a reference tablet without CD and a commercial tablet. However, the percentage dissolved after 10 min from such tablets was only 10% higher than the reference. This was ascribed to the potential binding/compacting abilities of SBEβCD, reflected in the greater hardness and longer disintegration times of the new tablets than the reference (7.64 vs. 1.06 min). A capsule formulation with the same composition of nebivolol-SBEβCD tablets showed about a 90% increase in dissolved drug after 5 min compared to the reference tablet, and reached 100% dissolved drug after only 20 min.

Assessment of body mass-related covariates for rifampicin pharmacokinetics in healthy Caucasian volunteers

PurposeCurrently, body weight-based dosing of rifampicin is recommended. But lately, fat-free mass (FFM) was reported to be superior to body weight (BW). The present evaluation aimed to assess the influence of body mass-related covariates on rifampicin’s pharmacokinetics (PK) parameters in more detail using non-linear mixed effects modeling (NLMEM).MethodsTwenty-four healthy Caucasian volunteers were enrolled in a bioequivalence study, each receiving a test and a reference tablet of 600 mg of rifampicin separated by a wash-out period of at least 9 days. Monolix version 2023R1 was used for NLMEM. Monte Carlo simulations (MCS) were performed to visualize the relationship of body size descriptors to the exposure to rifampicin.ResultsA one-compartment model with nonlinear (Michaelis–Menten) elimination and zero-order absorption kinetics with a lag time best described the data. The covariate model including fat-free mass (FFM) on volume of distribution (V/F) and on maximum elimination rate (Vmax/F) lowered the objective function value (OFV) by 56.4. The second-best covariate model of sex on V/F and Vmax/F and BW on V/F reduced the OFV by 51.2. The decrease in unexplained inter-individual variability on Vmax/F in both covariate models was similar. For a given dose, MCS showed lower exposure to rifampicin with higher FFM and accordingly in males compared to females with the same BW and body height.ConclusionOur results indicate that beyond BW, body composition as reflected by FFM could also be relevant for optimized dosing of rifampicin. This assumption needs to be studied further in patients treated with rifampicin.

Bioavailability Study of Experimental Push–pull Osmotic Pump Tablet of Nifedipine in Dogs

This study aimed to assess the bioavailability of experimental extended-release nifedipine tablets of push-pull osmotic pump type composed of a semipermeable membrane-coated bilayer core tablet containing PEO N10 and PEO 303 in drug layer and push layer, respectively on dogs. A test on dogs was performed using a two-way randomized crossover design with a single oral dose, fasting condition. Plasma samples were obtained at intervals and analyzed for nifedipine by UPLC-MS/MS after liquid-liquid extraction using glibenclamide as the internal standard. The pharmacokinetic parameters were calculated and the bioavailability of nifedipine extended-release tablets was evaluated by comparing the pharmacokinetic parameters between the prepared extended-release tablets of 30 mg NIF and the reference tablets of Adalat LA 30 mg. It was found that the prepared push-pull osmotic pump tablets of 30 mg nifedipine were equivalent in bioavailability to Adalat LA reference tablets of 30 mg nifedipine in experimental dogs according to the regulations of US-FDA and Vietnamese pharmacopeia 5th edition. The main pharmacokinetic parameters of nifedipine test and reference tablets after a single oral administration were as follows: Cmax 26.95 ± 7.82 (ng.mL-1) and 27.20 ± 6.99 (ng.mL-1), Tmax 12.33 ± 3.44 hours and 11.50 ± 3.33 hours, AUC0-96 728.96 ± 328.87 (ng.h.mL-1) and 702.48 ± 404.48 (ng.h.mL-1), AUC0-∞, 741.05 ± 340.39 (ng.h.mL-1) and 710.71 ± 408.76 (ng.h.mL-1), MRT 21.80 ± 5.25 hours and 22.06 ± 5.20 hours, respectively. The 90% confidence intervals for the ratio of Cmax, AUC0-∞, and MRT values for the test and reference products, using logarithmically transformed data were 90.82% - 108.09%, 91.97% - 118.21%, 90.74% -107.62%, respectively. No statistically significant difference was found for the Tmax value.

Crushing tablets or sprinkling capsules: Implications for clinical strategy and study performance based on BE studies of rivaroxaban and deferasirox.

Administration of oral medicinal products as crushed tablets or open capsules is an important delivery option for patients suffering from dysphagia. To obtain full interchangeability of generics with the original products, demonstration of bioequivalence (BE) between both products administered as crushed tablets/open capsules was required for poorly soluble product by European Medicines Agency (EMA) at the time of development of our rivaroxaban and deferasirox generic products. We present the results of two BE studies with modified administration of these products, which compared relative bioavailability between generic and reference products. In the rivaroxaban study, the test product was administered as a capsule sprinkled on and mixed with applesauce, whereas the reference tablet was crushed and administered with applesauce under fed conditions. In the deferasirox study, both treatments were administered as crushed tablets under fasting conditions. Both studies applied a two-way crossover design and were conducted after a single-dose in healthy volunteers. The 90% confidence interval of the geometric mean ratio area under the analyte concentration versus time curve, from time zero to the time of the last measurable analyte concentration and maximum measured analyte concentration over the sampling period of the test to reference ratio were 103.36-110.37% and 97.98-108.45% for rivaroxaban, respectively, and 96.69-107.29% and 94.19-109.45% for deferasirox, respectively. Thus, the BE criteria (80.00-125.00%) were met in both studies which demonstrated that bioavailability was not affected when the test and reference products were administered in the form of crushed tablet/open capsule. These results support the argument of redundancy of crushed product studies for poorly soluble drugs, which is in line with the currently revised position of the EMA on this topic.

Reduced Plasma Levodopa Fluctuations with More Frequent Administration of a Novel Carbidopa/Levodopa Functionally Scored Tablet.

Levodopa/carbidopa remains the gold standard for treating Parkinsondisease (PD), but chronic pulsatile administration contributes to motor complications. This Phase 1 study used a new immediate-release (IR) formulation of carbidopa/levodopa 25/100mg that is functionally scored for easy and precise splitting to evaluate the effects on levodopa plasma variability when smaller doses are taken more frequently. These functionally scored tablets were shown to be bioequivalent to carbidopa/levodopa 25-/100-mg IR generic reference tablets. Twenty-two healthy volunteers received a whole tablet every 4 hours versus half of the tablet every 2 hours. Plasma levodopa fluctuations were significantly reduced with half-tablets dosed every 2 hours, with a 44% reduction in peaks (P< .0001). While drug exposure did not differ, parameters that underlie motor response variations, including mean peak-to-trough difference and variance, were 51% and 56% less, respectively, with more frequent dosing (both P ≤ .0024). Safety and tolerability of both regimens were similar. In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity.

Investigation of the binding properties of purified Pentadesma butyracea gum: Anatural alternative to a synthetic polymer

Abstract: The focus of most pharmaceutical research in recent times has been the use of natural products like gums as pharmaceutical excipients because they are safer, economical and readily available. This study aimed to investigate the applicability of gum extracted from the exudates from the stem bark of Pentadesma butyracea as a binder in conventional release tablets using acacia gum as a reference polymer. The purified Pentadesma butyracea gum (PBG) was precipitated from the crude gum mucilage using 96% ethanol. Conventional-release paracetamol tablets were formulated using seven (7) different concentrations of the PBG mucilage (0.5 – 6 %w/w) as a binder via wet granulation (PB1 – PB7). The same approach was used for the reference conventional release paracetamol tablets (AC1- AC7). The drug-excipients and excipients-gum compatibility studies were evaluated using the FTIR. The formulated tablets were evaluated using both pharmacopoeia and non-pharmacopoeia tests. Appropriate mathematical models were used to determine the similarity (f2) and the difference (f1) factors of the dissolution profiles of the test and reference formulations. Granules for batches PB1, AC1, PB2, AC2 and AC3 had fair flow properties, whereas the rest had good flow properties. The FTIR studies showed no interactions between the drug and excipients. All formulations passed the pharmacopoeia and non- pharmacopoeia tests except for formulations PB1, PB2, PB3 and AC1 which failed the friability test, PB1 and AC1 which failed the hardness test, and AC7 which also failed the disintegration test. An increase in gum concentration led to a corresponding increase in the mechanical properties of the tablets. A comparative study showed no significant difference in the hardness and tensile strength of the test and reference tablets. All formulations except PB6 were similar to their reference formulations since f1 &gt; 50 and f2 &lt; 15. In conclusion, the PBG exhibited a good binding property comparable to acacia gum.

Preparation and In Vitro Evaluation of Levofloxacin-Loaded Floating Tables Using Various Rate-Controlling Agents.

Floating tablets are a new approach to extending the time a drug is in the stomach to improve therapy outcomes. Floating tablets were formulated with the drug, the polymers hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), and starch, fillers, and lubricants. The tablets were prepared using the direction compression method. The tablets' physical quality control tests were found to be within acceptable limits. The tablets extended drug release up to 12 h and were uniform in their drug contents. The swelling index of the tablets ranged from 60 ± 0.11 to 66 ± 0.14%, and the tablets were less dense than water. The floating lag time (10 ± 0.23 to 16 ± 0.09 s) and total floating time (>12 h) showed good floating behaviors. The kinetic modeling showed that the drug was released from the tablets by pseudo-diffusion, swelling, erosion, or anomalous non-Fickian diffusion. F6 (starch and CMC) showed higher n values (0.994 ± 0.04), exhibiting pseudo-zero-order drug release kinetics compared to those of other tablets. The dissolution data of the test and reference tables were not similar (P > 0.05). In terms of antimicrobial activity, the zones of inhibition of the test F6 tablet powders (5.3 ± 0.08 mm) and the reference tablet powders (5.9 ± 0.13 mm) were found to be significantly similar (P > 0.05). The study concluded that these floating tablets can improve the gastric residence time and therapeutic outcomes.

RESEARCH ON THE PREPARATION OF PARACETAMOL 650 MG PROLONGED-RELEASE TABLETS

Background: Paracetamol is one of the most commonly used active ingredients, even without a doctor's prescription for most people. It has effects on relieving pain and treating fever, especially with an analgesic effect for the elderly who have to suffer from degenerative joint disease. However, the half-life of paracetamol is relatively short, from 1 to 3 hours, so patients need to use it many times a day. The use of large amounts of paracetamol for a long time constantly can cause irreversible liver damage, so the prolonged release dosage form is chosen for the following reasons. Not only does it maintain the therapeutic drug concentration, and help reduce the number of use times but it also limits unwanted side effects. Objectives: the dissolution and the release kinetics of the active ingredient of the reference tablet Tylenol 8 Hour 650 mg were surveyed in order to formulate the paracetamol 650mg prolonged release tablet and there was an in vitro equivalent evaluation between the prepared paracetamol 650mg prolonged release tablet and the reference tablet Tylenol 8 Hour 650 mg. Materials and methods: an active ingredient (paracetamol); excipients are used in double-layer formulations that include an immediate release layer and a sustained release one; an experimental study that used a wet granulation method was conducted on a rotary tablet press. Results: the formulation of paracetamol 650 mg prolonged release tablets with f2, compared with the reference tablets Tylenol 8 Hour 650 mg in all three media with pH of 1.2, 4.5, and 6.8, was greater than 50. Conclusions: the result of the study is one of the most essential bases in order to upgrade to a pilot scale, gradually develop to an industrial scale, test in vivo equivalence, and then bring products with well-made quality and safety to consumers as well as patients.

Proof-of-Concept in Developing a 45% Drug Loaded Amorphous Nanoparticle Formulation

Amorphous solid dispersion (ASD) is an enabling approach utilized to deliver poorly soluble compounds. ASDs can spontaneously generate drug-rich amorphous nanoparticles upon dissolution, which can act as a reservoir for maintaining supersaturation during oral absorption. But, conventional ASDs are often limited in drug loadings to < 20 %. For indications where the dose is high, this can translate into a significant pill burden. The aim of this research was to develop a high drug loading (DL) amorphous nanoparticle (ANP) formulation that can release the drug-rich nanoparticles into solution upon contact with aqueous environment. Nanoparticles were directly engineered using solvent/anti-solvent precipitation. The obtained nanoparticle suspension was then concentrated followed by solidification to a re-dispersible amorphous dosage form using spray drying or lyophilization. The impact of process variables was studied using dynamic light scattering (DLS), scanning electron microscopy (SEM), high performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) and differential scanning calorimetry (DSC). It was observed that spray drying led to a non-re-dispersible formulation. Sucrose and trehalose containing lyocakes resulted in re-dispersible formulations. The trehalose containing lyocakes, in a dog study, gave comparable performance to the reference tablet in the fasted state but lower area under the curve (AUC) in fed state.

Electrochemical Kinetics and Detection of Paracetamol by Stevensite-Modified Carbon Paste Electrode in Biological Fluids and Pharmaceutical Formulations.

Paracetamol (PCT), or acetaminophen, is an important drug used worldwide for various clinical purposes. However, the excessive or indiscriminate use of PCT can provoke liver and kidney dysfunction; hence, it is essential to determine the amount of this target in biological samples. In this work, we develop a quick, simple, and sensitive voltammetric method using chemically modified electrodes to determine PCT in complex matrices, including human serum and commercial solid formulations. We modify the carbon paste electrode with stevensite monoclinic clay mineral (Stv-CPE), using cyclic voltammetry, differential pulse voltammetry, and electrochemical impedance spectroscopy to characterise and detect PCT. The kinetics study provides a better electrochemical characterisation of the electrode behaviour, finding the detection and quantitation limits of 0.2 μM and 0.5 μM under favourable conditions. Further, the best linear working concentration range is 0.6-100 μM for PCT, applying the proposed method to the quantitative determination of PCT content in reference tablet formulations and biological samples for validation.

Development and pharmacokinetic evaluation of Neusilin® US2-based S-SNEDDS tablets for bosentan: Fasted and fed states bioavailability, IVIS® real-time biodistribution, and ex-vivo imaging

The study reported here aimed to develop and optimize the S-SNEDDS tablet of bosentan (BOS) and to investigate its pharmacokinetic and biodistribution properties. The BOS-loaded SNEDDS have been developed and characterized in a previous study. The BOS-loaded SNEDDS formulation was converted to S-SNEDDS using Neusilin® US2. The S-SNEDDS tablets were obtained using the direct compression technique, and in vitro dissolution, in vitro lipolysis, and ex-vivo permeability studies of the tablets were performed. The S-SNEDDS tablet and reference tablet (Tracleer®) were administered to male Wistar rats at 50 mg/kg dose by oral gavage in fasted and fed state conditions. The biodistribution of the S-SNEDDS tablet was investigated in Balb/c mice using fluorescent dye. The tablets were dispersed in distilled water before administration to animals. The relationship between in vitro dissolution data and in vivo plasma concentration was examined. The S-SNEDDS tablets showed 2.47, 7.49, 3.70, and 4.39 increases in the percentages of cumulative dissolution in FaSSIF, FeSSIF, FaSSIF-V2, and FeSSIF-V2, respectively, when compared to the reference, and increased the Cmax and AUC 2.65 and 1.28-fold and 4.73 and 2.37-fold in fasted and fed states, respectively, when compared to the reference. S-SNEDDS tablets also significantly reduced interindividual variability in both fasted and fed states (p < 0.05). The XenoLight™ DiR and VivoTag® 680XL labeled S-SNEDDS tablet formulation increased the real-time biodistribution in the body by factors of 2.4 and 3.4 and organ uptake and total emission increased by factors of 2.8 and 3.1, respectively. The IVIVR has been successfully established for S-SNEDDS tablets (R2 > 0.9). The present study confirms the potential of the S-SNEDDS tablet to enhance the in vitro and in vivo performance of BOS.

Physiologically Based Pharmacokinetic Model Development and Verification for Bioequivalence Testing of Bempedoic Acid Oral Suspension and Reference Tablet Formulation.

The bioequivalence of bempedoic acid oral suspension and commercial immediate release (IR) tablet formulations were assessed using a physiologically based pharmacokinetic (PBPK) model. The mechanistic model, developed from clinical mass balance results and in vitro intrinsic solubility, permeability, and dissolution data, was verified against observed clinical pharmacokinetics (PK) results. Model inputs included a fraction of a dose in solution (0.01%), viscosity (118.8 cps), and median particle diameter (50 µm) for the suspension and particle diameter (36.4 µm) for IR tablets. Dissolution was determined in the relevant media (pH 1.2-6.8) in vitro. Model simulations of bioequivalence predicted oral suspension (test) to IR tablet (reference) geometric mean ratio estimates of 96.9% (90% confidence interval [CI]: 92.6-101) for maximum concentration and 98.2% (90% CI: 87.3-111) for the area under the concentration-time curve. Sensitivity analyses showed gastric transit time had a minor impact on model predictions. Oral suspension biopharmaceutical safe space was defined by extremes of particle size and the percent of bempedoic acid in solution. PBPK model simulations predicted that the rate and extent of bempedoic acid absorption are unlikely to exhibit clinically meaningful differences when dosed as an oral suspension compared with an IR tablet without requiring a clinical bioequivalence study in adults.

Virtual Bioequivalence Assessment of Elagolix Formulations Using Physiologically Based Pharmacokinetic Modeling.

In lieu of large bioequivalence studies and exposing healthy postmenopausal women to additional drug exposure for elagolix coadministered with hormonal add-back therapy, physiologically based pharmacokinetic (PBPK) modeling was used with in vitro dissolution data to test for virtual bioequivalence. For endometriosis, elagolix is approved at doses of 150mg once daily and 200mg twice daily as a tablet. As a combination therapy, two individual tablets, consisting of an elagolix tablet and an estradiol/norethindrone acetate 1/0.5mg (E2/NETA) tablet, were utilized in Phase 3 endometriosis trials. However, the commercial combination drug products consist of a morning capsule (containing an elagolix tablet and E2/NETA tablet as a fixed-dose combination capsule, AM capsule) and an evening capsule (consisting of an elagolix tablet, PM capsule). In vitro dissolution profiles were dissimilar for the tablet and capsule formulations; thus, in vivo bioequivalence studies or a bioequivalence waiver would have been required. To simulate virtual cross-over, bioequivalence trials, in vitro dissolution data was incorporated into a previously verified PBPK model. The updated PBPK model was externally validated using relevant bioequivalence study data. Based on results of the virtual bioequivalence simulations, the commercial drug product capsules met the bioequivalence criteria of 0.80-1.25 when compared to the reference tablets. This was a novel example where PBPK modeling was utilized along with in vitro dissolution data to demonstrate virtual bioequivalence in support of a regulatory bioequivalence waiver.

Design and Evaluation of Solid Lipid Nanoparticle Loaded Transdermal Patch of Nisoldipine: In Vitro, Ex Vivo and In Vivo Evaluation

The objective of the research work is to develop and evaluate the solid lipid nanoparticles (SLNs) loaded matrix type transdermal patch of Nisoldipine (NSD). SLN formulations were developed and evaluated for particle size, zeta potential, polydispersibility index, drug content, entrapment efficiency then optimized formulation was freeze dried and incorporated into a transdermal patch. The physicochemical interaction between Nisoldipine and polymer was examined by DSC (differential scanning calorimetry) and FTIR (Fourier Transform Infrared Spectroscopy). Prepared patches were measured for thickness, uniformity of weight, folding endurance, moisture content, moisture absorption. The in-vitro and ex-vivo permeation of the Nisoldipine of the patches was studied by Franz diffusion cells. In vivo bioavailability study was performed using male wistar rats for optimized formulation N6 and compared with reference tablet (Sular). Dynasan 114 lipid (N-D4, formulation) is found to produce SLNs with low size and high entrapment efficiency. SEM analysis showed non aggregated spherical particles. N6(Formulation) patch containing 8% citral showed 96.5% of drug release and higher flux with 2.17 enhancement ratio (ER). Relative bioavailability of the test formulation with respect to market formulation was considered to be 2.52. The SLN loaded transdermal patches of Nisoldipine were developed successfully. There was considerable increase in bioavailability of the test formulation (N6) when compared to the marketed formulation. The increase may be attributed to avoidance of first pass metabolism of Nisoldipine which occurs through oral administration.

Functional data analysis and nonlinear regression models: an information quality perspective

Data from measurements over time can be analyzed in different ways. In this article, we compare functional data analysis and nonlinear regression models using, among others, eight information quality dimensions. We present two case studies. The first case study introduces functional data analysis and nonlinear regression models in analyzing dissolution profiles of drug tablets where profiles of tablets under test are compared to reference tablets. A second case study involves statistically designed mixture experiments used in optimization tablet formulation. Python and JMP features are used to demonstrate the methods used in the two case studies.

Evaluating the bioequivalence of two pitavastatin calcium formulations based on IVIVC modeling and clinical study.

In vitro-in vivo correlation (IVIVC) allows prediction of the in vivo performance of a pharmaceutical product based on its in vitro drug release profiles and can be used to reduce the number of bioequivalence (BE) studies during product development, and facilitate certain regulatory decisions. Here, we developed an IVIVC model for pitavastatin calcium, a basic Biopharmaceutics Classification System (BCS) II lipid-lowering drug, which was then used to predict the BE outcome of formulations manufactured at two manufacturers. In addition, virtual trials using the IVIVC model using pH4.0 acetate buffer dissolution showed similarity in areas under the curves and maximum plasma concentration (Cmax ) for test and reference tablets under fasting condition. These predicted results were verified in definitive BE study. In conclusion, we demonstrated that for certain BCS II molecules, IVIVC modeling could be used as a priori to predict the BE outcome.

Bioequivalence of two tablet formulations of cefpodoxime proxetil in beagle dogs.

The pharmacokinetic profiles and bioequivalence of two cefpodoxime proxetil tablets were investigated in Beagle dogs. A single-dose, four-way complete replication and crossover design was used in the present study. A total of 28 healthy Beagle dogs (half male and female) with an average body weight of 11.1 kg were randomly allocated to this study. A whole reference or test tablet containing the equivalent of 100 mg of cefpodoxime was administered orally to each dog. Serial plasma samples were collected, and cefpodoxime concentrations were determined by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Then a non-compartmental method was used to calculate the pharmacokinetic parameters of both tablet formulations. The average bioequivalence (ABE) or reference-scaled average bioequivalence (RSABE) methods were used to determine the 90% confidence interval (CI) of AUCINF_obs and Cmax. No significant differences were observed for both parameters between both tablets. The test formulation was bioequivalent to the reference one because the 90% CI ranges of Cmax and AUCINF_obs were all between 80 and 125%.

Pharmacokinetics and Bioequivalence of 2 Safinamide Tablets in Healthy Chinese Volunteers Under Fasting and Fed Conditions.

To assess the bioequivalence of a generic safinamide tablet (test) vs a brand-name safinamide tablet (reference) and effects of food on the pharmacokinetics of safinamide in healthy Chinese subjects, a single-center, single-dose, randomized, open-label, 2-preparation, 2-period study with a 15-day washout period was undertaken. A total of 56 healthy subjects were recruited in this study (fasting, n = 28; fed, n = 28). A single dose of a 100-mg test or reference safinamide tablet was administered to each subject in a randomized sequence. Blood samples were obtained at 5minutes before drug administration and during the 120hours after dosing. The safinamide concentration in plasma was determined by high-performance liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were analyzed with noncompartmental methods. Safety was also monitored. The major pharmacokinetic parameters including maximum plasma drug concentration, area under plasma concentration-time curve (AUC) from zero to time t (AUC0-t ), and AUC from time 0 to infinity (AUC0-∞ ) were similar between the test and reference tablets under fasting and fed conditions. The 90% CIs of the test/reference ratios of log-transformed maximum plasma drug concentration, AUC from zero to time t, and AUC from time 0 to infinity all fell within the equivalence interval (80.0%-125%) whether under fasting condition or fed condition. In conclusion, the 2 formulations of safinamide tablets were bioequivalent and well tolerated under both fasting and fed conditions in healthy Chinese volunteers. High-fat food delayed the absorption of safinamide but did not affect the final bioavailability.

Preparation and Characterization of Controlled-Release Floating Bilayer Tablets of Esomeprazole and Clarithromycin.

Controlled-release effervescent floating bilayer tablets reduce dosage frequency and improve patient compliance with enhanced therapeutic outcomes. Generally, two different tablets of clarithromycin and esomeprazole, respectively, are given for the treatment of Helicobacter pylori infection and it might be worth incorporating both in a single tablet. In the current study, controlled-release floating bilayer tablets of clarithromycin and esomeprazole (F1–F4) were developed with different rates of polymeric materials by a direct compression method. During the formulation, Fourier-transform infrared spectroscopy (FTIR) analysis was performed for possible interactions between drugs and excipients. No interactions between drugs and excipients were noted. Moreover, the bilayer tablets’ thickness, diameter, friability, hardness, weight variation, dissolution, and percent purity were found within the acceptable limits. The floating lag time and total floating time of all formulations were found to be < 25 s and 24 h, respectively. The release of both the clarithromycin and esomeprazole started at the same time from the controlled-release floating bilayer tablets by anomalous non-Fickian diffusion, and the polymeric materials extended the drug release rate up to 24 h. In the case of F1, the results approached ideal zero-order kinetics. The dissolution profiles of the tested and reference tablet formulations were compared, but no significant differences were observed. It can be concluded that such controlled-release effervescent floating bilayer tablets can be efficiently used in clinical practice to reduce dosage frequency and increase patient compliance with continuous drug release for 24 h, which ultimately might enhance therapeutic efficacy.

Design and evaluation of in vivo bioavailability in beagle dogs of bilayer tablet consisting of immediate release nanosuspension and sustained release layers of rebamipide

The purpose of this study was to develop a once-daily, bilayer matrix tablet with immediate (IR) and sustained release (SR) layers of poorly water-soluble and absorption site dependent rebamipide (RBM) to substitute three times a day IR tablet. Owing to the pH-dependent poor water solubility of RBM in low pH condition, salt-caged nanosuspensions (NSPs) consisting of RBM and poloxamer 407 (POX 407) or poloxamer 188 (POX 188) were prepared using an acid-base neutralization method to increase the dissolution rate, which was subsequently applied to the immediate-release (IR) layer. Polyethylene oxide (PEO) with different molecular weights (PEO 100,000 and PEO 5,000,000) and hydroxypropyl methylcellulose 4000 (HPMC 4000) were then investigated as SR agents to incorporate into the SR layer with pure RBM via wet granulation method. The dissolution profile of the optimized bilayer tablet having 50% IR and 50% SR layer of 300 mg RBM showed that the IR layer could rapidly disintegrate in pH 1.2 buffer solution within 2 h, reaching 50% of drug release from the tablet, followed by an extended drug release from the SR layer in pH 6.8 buffer over 24 h. An in vivo pharmacokinetic study was carried out in beagle dogs to compare the optimal formulation (300 mg RBM bilayer tablet) and the commercial tablet (Mucosta® 100 mg) as a reference. Unexpectedly, despite enhanced dissolution rate in a controlled manner, a designed bilayer tablet had no dose- and dosage form dependent in vivo bioavailability in beagle dogs as compared with IR 100 mg RBM reference tablet. It was evident that solubility in low pH condition, gastric residence time and absorption site of RBM should be carefully considered for designing specific SR or gastroretentive dosage form to improve therapeutic outcomes.