Search Results (22)

Objectives: This study explores the development and evaluation of a bilayer sustained-release (SR) tablet formulation of ruxolitinib. As a BCS Class 1 drug, ruxolitinib requires twice-daily dosing due to its short half-life. We designed a bilayer tablet that integrates immediate-release (IR) and SR components in varying ratios to achieve sustained plasma concentrations, which we evaluated using discriminative analysis. Methods: Bilayer tablets combining IR and SR components were prepared in different ratios. In vitro dissolution tests and pharmacokinetic studies were conducted using Beagle dogs, followed by the evaluation of in vivo–in vitro correlation (IVIVC), along with a discriminative pharmacokinetic analysis focused on the SR layer. Results: A discriminative pharmacokinetic and IVIVC analysis was applied to all bilayer tablets, offering clearer insights into the plasma concentration and dissolution profiles. Pharmacokinetic studies showed that test formulation F4, which has a 20:20 IR-to-SR ratio, is expected to provide a similar area under the curve (AUC) while prolonging exposure compared to the reference IR tablet. Conclusions: This study highlights the potential of a bilayer tablet approach, combined with discriminative pharmacokinetic and IVIVC analysis, for creating a sustained-release dosage form of ruxolitinib. Full article

Background/Objectives: Two fibre optic probes were custom designed to perform Raman and near-infrared spectroscopic measurements. Our long-term objective is to develop a non-destructive tool able to collect data in hard-to-access locations for real-time analysis or diagnostic purposes. This study evaluated the quantitative performances of Probe A and Probe B using model pharmaceutical tablets. Methods: Measurements were performed using pharmaceutical tablets containing hydroxyl propylcellulose, titanium dioxide (anatase), lactose monohydrate, and indomethacin (γ form). Material content and thickness of bilayer samples (samples consisting of a top layer and a bottom layer of differing materials) were also assessed using Probe A to evaluate its capabilities to collect sub-surface information. Principal component analysis and partial least squares regression models were using individual and fused data to evaluate the performances of the different probe configurations. Results: Hydroxymethyl cellulose ($R_P^2=0.98$, RMSEP = 2.27% w/w) and lactose monohydrate ($R_P^2=0.97$, RMSEP = 2.96% w/w) content were most effectively estimated by near-infrared spectroscopy data collected using Probe A. Titanium dioxide ($R_P^2=0.99$, RMSEP = 0.21% w/w) content was most effectively estimated using a combination of 785 nm Raman spectroscopy and near-infrared spectroscopy using Probe B. Indomethacin ($R_P^2=0.97$, RMSEP = 1.01% w/w) was best estimated using a low-level fused dataset collected using 0 mm, 2.5 mm, and 5.0 mm lateral offsets of 785 nm spatially offset Raman spectroscopy using Probe A. Conclusions: The different probe configurations were able to reliably collect data and demonstrated robust quantitative performances. These results highlight the advantage of using multiple techniques for analysing different structures. Full article

Parallel artificial membrane permeability analysis (PAMPA) is used to determine the permeability of compounds through concentrated negatively charged phospholipid bilayer barriers. We employed MacroFlux (a scaled-up version of PAMPA) to test the permeation rate of terazosin hydrochloride (TH) tablets and predict in vivo bioequivalence. The dissolution profiles and permeability of one reference formulation, and seven generic TH tablets, were compared. The dissolution profiles of these generic tablets were equivalent to that of the reference drug in four different media. However, the flux and the total permeated amount of some generic TH tablets were below the lower limit of the confidence interval of the original acceptance range in MacroFlux, which implied risk in the bioequivalence test in vivo. We further evaluated potential factors responsible for this discrepancy by µFlux, including active pharmaceutical ingredient (API) permeability and excipient prescriptions. The analysis showed that different properties of API were a main factor leading to biological inequivalence in the MacroFlux assay, while excipient prescriptions did not have an impact on bioequivalence risk. These data indicated that the flux assay may be a helpful as an auxiliary method for predicting bioequivalence of generic drugs and analyze the factors responsible for bioequivalence risk. Full article

This study aimed to evaluate the ejection pressure and the correlation of the findings with the occurrence of internal cracks within bilayer tablets (BLTs) consisting of metformin HCl (MF) and evogliptin tartrate (EG). Then, the mechanism of tablet failure was provided by the finite element method (FEM). The ejection pressure and the difference in diameter depending on MAIN-P were evaluated to understand the correlation between ejection pressure and change in the BLT internal structure. The ejection pressure and the difference in diameter increased as the MAIN-P increased, then steeply decreased from 350 MPa to 375 MPa of MAIN-P, despite there being no pattern in compaction breaking force and porosity. The mechanical integrity at the BLT interface was weakened by internal cracks, reducing ejection pressure. The stress distribution analysis during the compression revealed that crack formation caused by entrapped air located at the center of the BLT interface may not propagate due to concentrated stress, which promotes a tight bond at the edge of the BLT. Furthermore, complete delamination can occur in the ejection process due to localized and intensive shear stresses at the BLT interface. These findings indicate that the mechanisms of internal cracking and delamination were successfully confirmed by FEM simulation. Moreover, measuring ejection pressure before BLT manufacturing can prevent invisible tablet cracks without damaging the tablets. Full article

The objectives of this study were to evaluate the delamination of convex-shaped metformin HCl (MF) and evogliptin tartrate (EG) multi-layer tablets depending on the pre-compression and main compression pressures and simultaneously correlate these results with those of a surface roughness analysis. Free-flowing MF and EG (median diameters of 38.3 and 44.7 μm, respectively) granules prepared using the wet granulation method were pre-compressed and subsequently compressed into bilayer and trilayer tablets using a universal testing machine. The compaction force required to break the tablets increased linearly as the main compression pressure increased (30–150 MPa). Conversely, the interfacial strength and compaction breaking force decreased as the pre-compression pressure increased (10–110 MPa). A surface roughness analysis employing a profilometer revealed that the first layer (MF) roughness drastically decreased from 5.89 to 0.51 μm (Ra, arithmetic average of profile height deviations from the mean line) as the pre-compression pressure increased from 10 to 150 MPa in the bilayer tablet. Accordingly, the decrease in the roughness of the first layer reduced the inter-penetration at the interface, as observed via energy dispersive spectrometer (EDS)-equipped scanning electron microscopy, decreasing the interfacial bonding strength and causing delamination of the MF/EG multi-layer tablets. These findings indicate the significance of roughness control in the actual preparation of multi-layer tablets and the usefulness of profilometer- and EDS-based surface analyses for interpreting the delamination of multi-layer tablets. Full article

Three-dimensional printing by fused deposition modeling (FDM) coupled with hot-melt extrusion (HME) is a point of convergence of research efforts directed toward the development of personalized dosage forms. In addition to the customization in terms of shapes, sizes, or delivered drug doses, the modulation of drug release profiles is crucial to ensure the superior efficacy and safety of modern 3D-printed medications compared to those of conventional ones. Our work aims to solidify the groundwork for the preparation of 3D-printed tablets that ensure the sustained release of diclofenac sodium. Specifically, we achieved the fast release of a diclofenac sodium dose to allow for the prompt onset of its pharmacological effect, further sustaining by the slow release of another dose to maintain the effect over a prolonged timeframe. In this regard, proper formulation and design strategies (a honeycomb structure for the immediate-release layer and a completely filled structure for the sustained-release layer) were applied. Secondarily, the potential of polyvinyl alcohol to function as a multifaceted polymeric matrix for both the immediate and slow-release layers was explored, with the objective of promoting the real-life applicability of the technique by downsizing the number of materials required to obtain versatile pharmaceutical products. The present study is a step forward in the translation of HME-FDM-3DP into a pharmaceutical manufacturing methodology. Full article

Diazepam (DZP) is a long-acting benzodiazepine to treat anxiety or acute alcohol withdrawal. Although this class of drugs should be taken for a short period of time, many patients take them for longer than recommended, which has been linked to an increased risk of dementia and dependence. The present work aimed at using the dual-nozzle system of fused deposition modeling (FDM) 3D printers to prepare tablets with gradual doses of DZP with constant mass and size. Placebo and DZP-loaded filaments were prepared by hot-melt extrusion and used to print the bi-compartmental tablets. Thermal processing allowed the conversion of crystalline DZP to its amorphous counterpart. Tablets with different DZP contents were effectively printed with a mass, thickness and diameter average of 111.6 mg, 3.1 mm, and 6.4 mm, respectively. Microscopic data showed good adhesion between the different layers in the printed tablets. The desired drug contents were successfully achieved and were within the acceptance criteria (European Pharmacopeia). The combination of a placebo and drug-loaded extrudates proved to be beneficial in the production of tablets by FDM for patients in need of drug withdrawal. Full article

Bilayer/multilayer tablets have been introduced to formulate incompatible components for compound preparations, but they are now more commonly used to tailor drug release. This research aimed to formulate a novel gastro-retentive tablet to deliver a combination of a fixed dose of two drugs to eliminate Helicobacter pylori (H. pylori) in the gastrointestinal tract. The bilayer tablets were prepared by means of the direct compression technique. The controlled-release bilayer tablets were prepared using various hydrophilic swellable polymers (sodium alginate, chitosan, and HPMC-K15M) alone and in combination to investigate the percent of swelling behavior and average drug release. The weight of the controlled-release floating layer was 500 mg, whereas the weight of the floating tablets of pantoprazole was 100 mg. To develop the most-effective formulation, the effects of the experimental components on the floating lag time, the total floating time, T 50%, and the amount of drug release were investigated. The drugs’ and excipients’ compatibilities were evaluated using ATR-FTIR and DSC. Pre-compression and post-compression testing were carried out for the prepared tablets, and they were subjected to in vitro characterization studies. The pantoprazole layer of the prepared tablet demonstrated drug release (95%) in 2 h, whereas clarithromycin demonstrated sustained drug release (83%) for up to 24 h (F7). The present study concluded that the combination of sodium alginate, chitosan, and HPMC polymers (1:1:1) resulted in a gastro-retentive and controlled-release drug delivery system of the drug combination. Thus, the formulation of the floating bilayer tablets successfully resulted in a biphasic drug release. Moreover, the formulation (F7) offered the combination of two drugs in a single-tablet formulation containing various polymers (sodium alginate, chitosan, and HPMC polymers) as the best treatment option for local infections such as gastric ulcers. Full article

Compounded medicinal products containing bupropion hydrochloride (BUP·HCl) and naltrexone hydrochloride (NTX·HCl) are available as adjunct therapy for the management of weight in obese/overweight adults. The present work describes the development and validation of a novel RP-HPLC method for a simultaneous quantitation during the dissolution of both drugs from compounded bilayer composition tablets. The method involves a Nucleosil 100-3 C-18 column (4.6 × 150 mm) and a mobile phase of a 70%/30% v/v ACN/KH₂PO₄·H₂O aqueous solution of a 5 mM concentration. The flow rate was set at 1.35 mL/min and the detection was conducted using UV spectrophotometry (λ_max 214 nm). The method was validated according to the ICH guidelines and fulfilled the specifications for the specificity, linearity, accuracy, precision and stability for both the sample and standard solutions. Furthermore, the robustness of the method was evaluated by applying a fractional factorial experimental design and by utilizing both graphical and statistical approaches to identify the HPLC factors that should be strictly controlled during the analysis. The method proved to be suitable for the analysis of the dissolution samples and, consequently, the release of BUP·HCl and NTX·HCl from the formulations. Full article

Thiolation of polymers is one of the most appropriate approaches to impart higher mechanical strength and mucoadhesion. Thiol modification of gum karaya and gum acacia was carried out by esterification with 80% thioglycolic acid. FTIR, DSC and XRD confirmed the completion of thiolation reaction. Anticancer potential of developed thiomer was studied on cervical cancer cell lines (HeLa) and more than 60% of human cervical cell lines (HeLa) were inhibited at concentration of 5 µg/100 µL. Immobilized thiol groups were found to be 0.8511 mmol/g as determined by Ellman’s method. Cytotoxicity studies on L929 fibroblast cell lines indicated thiomers were biocompatible. Bilayered tablets were prepared using Ivabradine hydrochloride as the model drug and synthesized thiolated gums as mucoadhesive polymer. Tablets prepared using thiolated polymers in combination showed more swelling, mucoadhesion and residence time as compared to unmodified gums. Thiol modification controlled the release of the drug for 24 h and enhanced permeation of the drug up to 3 fold through porcine buccal mucosa as compared to tablets with unmodified gums. Thiolated polymer showed increased mucoadhesion and permeation, anticancer potential, controlled release and thus can be utilized as a novel excipient in formulation development. Full article

Since their introduction to pharmacotherapy, proton pump inhibitors (PPIs) have been widely used in the treatment of numerous diseases manifested by excessive secretion of gastric acid. Despite that, there are still unmet needs regarding their availability for patients of all age groups. Their poor stability hinders the development of formulations in which dose can be easily adjusted. The aim of this review is to describe the discovery and development of PPIs, discuss formulation issues, and present the contemporary solutions, possibilities, and challenges in formulation development. The review outlines the physicochemical characteristics of PPIs, connects them with pharmacokinetic and pharmacodynamic properties, and describes the stability of PPIs, including the identification of the most important factors affecting them. Moreover, the possibilities for qualitative and quantitative analysis of PPIs are briefly depicted. This review also characterizes commercial preparations with PPIs available in the US and EU. The major part of the review is focused on the presentation of the state of the art in the development of novel formulations with PPIs covering various approaches employed in this process: nanoparticles, microparticles, minitablets, pellets, bilayer, floating, and mucoadhesive tablets, as well as parenteral, transdermal, and rectal preparations. It also anticipates further possibilities in the development of PPIs dosage forms. It is especially addressed to the researchers developing new formulations containing PPIs, since it covers the most important formulary issues that need to be considered before a decision on the selection of the formula is made. It may help in avoiding unnecessary efforts in this process and choosing the best approach. The review also presents an up-to-date database of publications focused on the pharmaceutical technology of formulations with PPIs. Full article

The objective of this work was to formulate co-loaded bilayer tablets containing ezetimibe (EZB) and atorvastatin (ATC). ATC loaded in the immediate-release (IR) layer is an HMG CoA reductase inhibitor, while EZB, added in the sustained-release (SR) layer, is a lipid-lowering agent. This study was conducted to evaluate the effects of polymer on the formulation and characterization of bilayer tablets, as well as the therapeutic impact of the concurrent use of both drugs having a sequential release pattern. To obtain the optimized results, four different formulations with variable compositions were developed and evaluated for different parameters. The drug release studies were carried out using a type II dissolution apparatus, using phosphate buffer solution (PBS) of 1.2 pH for IR of EZB for an initial 2 h, followed by 24 h studies for ATC in PBS 6.8 pH. The IR layer showed rapid drug release (96%) in 2 h, while 80% of the ATC was released in 24 h from the SR layer. Locally obtained, 6-week-old female albino rats were selected for in vivo studies. Both preventive and curative models were applied to check the effects of the drug combination on the lipid profile, atherosclerosis and physiology of different organs. Studies have shown that the administration of both drugs with different release patterns has a better therapeutic effect (p < 0.05), both in preventing and in curing hyperlipidemia. Conclusively, through the sequential release of ATC and EZB, a better therapeutic response could be obtained. Full article

Hyperlipidemia is still the leading cause of heart disease in patients with hypertension. The purpose of this study is to make rosuvastatin calcium (ROS) and atenolol (AT) bilayer tablets to treat coexisting dyslipidemia and hypertension with a single product. ROS was chosen for the immediate-release layer of the constructed tablets, whereas AT was chosen for the sustained-release layer. The solid dispersion of ROS with sorbitol (1:3 w/w) was utilized in the immediate-release layer while hydroxypropyl methylcellulose (HPMC), ethylcellulose (EC), and sodium bicarbonate were incorporated into the floating sustained-release layer. The concentrations of HPMC and EC were optimized by employing 3² full factorial designs to sustain AT release. The bilayer tablets were prepared by the direct compression method. The immediate-release layer revealed that 92.34 ± 2.27% of ROS was released within 60 min at a pH of 1.2. The second sustained-release layer of the bilayer tablets exhibited delayed release of AT (96.65 ± 3.36% within 12 h) under the same conditions. The release of ROS and AT from the prepared tablets was found to obey the non-Fickian diffusion and mixed models (zero-order, Higuchi and Korsmeyer–Peppas), respectively. Preclinical studies using rabbit models investigated the impact of ROS/AT tablets on lipid profiles and blood pressure. A high-fat diet was used to induce obesity in rabbits. Bilayer ROS/AT tablets had a remarkable effect on decreasing the lipid profiles, slowing weight gain, and lowering blood pressure to normal levels when compared to the control group. Full article

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. Full article

The development of innovative forms of combination drugs is closely related to the invention of the multilayer tablet press, polymers for pharmaceutical applications, the hot-melt extrusion process, and 3D printing in the pharmaceutical industry. However, combining multiple drugs within the same dosage form can bring many physicochemical and pharmacodynamic interactions. More and more new forms of fixed-dose combinations (FDCs) have been developed due to work to overcome the incompatibility of active substances or to obtain different drug release profiles in the same dosage form. This review provides discussions of the application of various innovation formulation technologies of FDC drugs such as bilayer system, multilayer tablet, active film coating, hot-melt extrusion, and 3D printing, taking into account the characteristics of the key ingredients in the FDC formulation and presenting technological problems and challenges related to the development of combination drugs. Moreover, the article summarizes the range of dosage forms that have been made using these technologies over the past 30 years. Full article