Formulation and Development of Novel Sulfasalazine Bilayer Tablets for The Treatment of Arthritis Associated With IBD: In-vitro and In-vivo Investigations.

Sulfasalazine needs frequent daily dosing and the administration of numerous tablets per day pose challenges to patient compliance, contributing to increased adverse effects and difficulties in disease control. These inconveniences result in less effective treatment for arthritis associated with inflammatory bowel disease i.e. ulcerative colitis etc. To improve drug bioavailability, a delayed-release mechanism that releases the drug at the colon is necessary. To develop and optimize colon-targeted controlled release bilayer tablets coated with pH-dependent polymers. The bilayer tablets containing the immediate release part and sustained release part were developed. The tablets were coated with enteric-coated with Eudragit® S-100 and l-100 to achieve release in the colon. Granule properties and tablets were evaluated. The physicochemical parameters of the tablets were evaluated including, stability study, and drug release in 0.1 N HCl (pH 1.2), pH 6.8 phosphate buffer, pH 7.4 phosphate buffer for 2, 1, and up to 24 h respectively. Radiographic imaging and in vivo pharmacokinetic studies were also done in Rabbits. The bilayer tablets containing immediate and sustained release were successfully developed for the colon targeting. The granule properties were found within the acceptable range indicating good flow properties. The physicochemical properties of the tablets were also found acceptable. The tablets did not show release in 0.1 N HCl and 6.8 phosphate buffer but drug release was found under control in the 7.4 pH buffer. Sulfasalazine coated bilayer tablets were found stable and no significant changes were observed in the stability studies. Based on the X-ray studies, the formulated tablet remained discernible in the stomach, small intestine, and colon for a duration of up to 24 h. Finally, by the 32nd hour, the tablet was no longer visible in the X-ray examination, leading to the conclusion of complete drug release. The drug concentration in plasma remained within the therapeutic range for up to 24 h in vivo. These novel formulations present substantial advantages, providing prolonged targeted drug release and reducing systemic adverse effects. The results suggest promising potential for treating arthritis in Inflammatory bowel disease (IBD) patients, offering a solution to current delivery systems.

Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator.

PURPOSE: We investigated whether twice-daily administration of a bilayer tablet formulation of tramadol (35% immediate-release [IR] and 65% sustained-release) is as effective as four-times-daily IR tramadol capsules for managing cancer pain. METHODS: This randomized, double-blind, double-dummy, active-comparator, non-inferiority study enrolled opioid-naïve patients using non-steroidal anti-inflammatory drugs or acetaminophen (paracetamol) to manage cancer pain and self-reported pain (mean value over 3 days ≥ 25 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to either bilayer tablets or IR capsules for 14 days. The starting dose was 100 mg/day and could be escalated to 300 mg/day. The primary endpoint was the change in VAS (averaged over 3 days) for pain at rest from baseline to end of treatment/discontinuation. RESULTS: Overall, 251 patients were randomized. The baseline mean VAS at rest was 47.67 mm (range: 25.6-82.7 mm). In the full analysis set, the adjusted mean change in VAS was - 22.07 and - 19.08 mm in the bilayer tablet (n = 124) and IR capsule (n = 120) groups, respectively. The adjusted mean difference was - 2.99 mm (95% confidence interval [CI] - 7.96 to 1.99 mm). The upper 95% CI was less than the predefined non-inferiority margin of 7.5 mm. Other efficacy outcomes were similar in both groups. Adverse events were reported for 97/126 (77.0%) and 101/125 (80.8%) patients in the bilayer tablet and IR capsule groups, respectively. CONCLUSION: Twice-daily administration of bilayer tramadol tablets was as effective as four-times-daily administration of IR capsules regarding the improvement in pain VAS, with comparable safety outcomes. CLINICAL TRIAL REGISTRATION: JapicCTI-184143/jRCT2080224082 (October 5, 2018).

Controlled release of MT-1207 using a novel gastroretentive bilayer system comprised of hydrophilic and hydrophobic polymers.

In the present study, novel gastroretentive bilayer tablets were developed that are promising for the once-a-day oral delivery of the drug candidate MT-1207. The gastroretentive layer consisted of a combination of hydrophilic and hydrophobic polymers, namely polyethylene oxide and Kollidon® SR. A factorial experiment was conducted, and the results revealed a non-effervescent gastroretentive layer that, unlike most gastroretentive layers reported in the literature, was easy to prepare, and provided immediate tablet buoyancy (mean floating lag time of 1.5 s) that lasted over 24 h in fasted state simulated gastric fluid (FaSSGF) pH 1.6, irrespective of the drug layer, thereby allowing a 24-hour sustained release of MT-1207 from the drug layer of the tablets. Furthermore, during in vitro buoyancy testing of the optimised bilayer tablets in media of different pH values (1.0, 3.0, 6.0), the significant difference (one-way ANOVA, p < 0.001) between the respective total floating times indicated that stomach pH effects on tablet buoyancy are important to be considered during the development of non-effervescent gastroretentive formulations and the choice of dosing regimen. To the best of our knowledge, this has not been reported before, and it should probably be factored in when designing dosing regimens. Finally, a pharmacokinetic study in Beagle dogs indicated a successful in vivo 24-hour sustained release of MT-1207 from the optimised gastroretentive bilayer tablet formulations with the drug plasma concentration remaining above the estimated minimum effective concentration of 1 ng/mL at the 24-hour timepoint and also demonstrated the gastroretentive capabilities of the hydrophilic and hydrophobic polymer combination. The optimised formulations will be forwarded to clinical development.

Dissolution Assay of Bupropion/Naltrexone Hydrochloride Salts of Bilayer Composition Tablets Following the Development and Validation of a Novel HPLC Method.

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 (λmax 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.

Formulation of Modified-Release Bilayer Tablets of Atorvastatin and Ezetimibe: An In-Vitro and In-Vivo Analysis.

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.

Tailoring of Rosuvastatin Calcium and Atenolol Bilayer Tablets for the Management of Hyperlipidemia Associated with Hypertension: A Preclinical Study.

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.

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.

A Bilayer Vaginal Tablet for the Localized Delivery of Disulfiram and 5-Fluorouracil to the Cervix.

This study was performed to develop an adjuvant therapy in the form of a self-administered vaginal tablet regimen for the localized delivery of chemotherapeutic drugs. This therapy will help to reduce relapse by eradicating cancerous cells in the margin of cervical tumors. The vaginal tablet is a very common formulation that is easy to manufacture, easy to place in the vagina, and has a low cost of manufacture, making them ideal for use in developing countries. A combination of disulfiram and 5-fluorouracil, which are both off-patent drugs and provide different modes of action, were evaluated. The tablets developed were evaluated for weight variation, thickness, hardness, friability, swelling index, differential scanning calorimetry (DSC), particle morphology, in vitro drug release, and cytotoxicity on Ca-Ski cells. Both layers were designed to release both drugs concurrently for a synergistic effect. The polymer-polymer interaction between the layers was able to reduce the loss of formulation due to chitosan. While the bilayer tablet had satisfactory performance in the physicochemical tests, in vitro cell culture with Ca-Ski also showed a synergistic effect using a combination of drugs at a low dose. However, the formulation only had 24-h dose release before degradation. Further drug combinations should be evaluated in subsequent studies.

Development of novel bilayer gastroretentive tablets based on hydrophobic polymers.

This study aimed to develop a bilayer gastroretentive (GR) tablet containing an insoluble drug and ascertain the potential of using hydrophobic polymers in GR matrix systems. Highly porous tablets were prepared using a camphor-based sublimation technique. After the screening of several commonly used polymers, two types of GR layers, a conventional hydrophilic GR layer and a hydrophobic GR layer, were designed. The optimal drug layer comprising Metolose® 90SH-100SR and dicalcium phosphate provided not only a gradual matrix erosion but also high strength after hydration. Regarding the GR layers, the hydrophobic layer based on Kollidon® SR was superior to the hydrophilic layer made of PEO 7 M in terms of wet strength, implying a higher resistance to mechanical stresses upon water absorption. Also, the excellent tableting properties of Kollidon® SR and the effects of curing in improving its matrix hardness resulted in porous tablets with better mechanical strength. Moreover, good flowability and low cohesion of Kollidon® SR formulation were advantageous in direct compression. In conclusion, novel bilayer GR tablets were successfully developed, indicating the potential for widening the application of GR systems to insoluble drugs. The results also suggested numerous advantages of incorporating Kollidon® SR into the production of GR tablets.

Evaluation of manufacturing process parameters causing multilayer tablets delamination.

The aim of this study was to evaluate the influence of tableting process parameters, i.e. turret rotation speed, pre-compaction and main compaction pressures, and their interactions on layer adhesion of bilayer tablets. The elastic recovery after compaction was used as estimation for the elasticity of the material. Three potential pharmaceutical formulations were evaluated as combinations of immediate (microcrystalline cellulose, lactose, calcium phosphate, pregelatinized starch) and controlled drug release excipients (ethyl cellulose, hydroxypropyl methylcellulose, polyvinyl acetate/polyvinylpyrrolidone). A 3-levels 3-factors central composite Design of Experiment was performed on each formulation, with layer adhesion selected as response. A custom-made shear test was used to determine the tablet tendency to delaminate. Main compaction and turret rotation speed were the most important parameters to be optimized during tablet manufacturing. Main compaction was the principal parameter leading to delamination in case of formulations with plastic materials, particularly at high pressures where the difference in elasticity of excipients had a major impact and was followed by turret rotation speed. The rotation speed did not have an effect on layer adhesion in the case of formulations with brittle excipients.

Mass-customization of oral tablets via the combination of 3D printing and injection molding.

The new frontier of medicine is the personalization of treatment to match a patient's individual needs. Fused-filament fabrication (FFF) offers a platform for the personalization of drug dosage forms, but one of its chief shortcomings compared to other tablet production methods such as dry compression and wet granulation is relatively low throughput. Conversely, injection molding (IM) is a manufacturing technique for the high-volume production of parts, but in which individual part customization is both expensive and slow requiring the modification of expensive mold tooling. Mass-customization is the manufacture of custom products that match the needs of individual consumers but which are produced at the low unit cost associated with high-volume production. We successfully integrated for the first time FFF with IM in a multi-step manufacturing process for the production of custom bilayer tablets loaded with two active pharmaceutical ingredients used in the treatment of cardiovascular disease. The FFF layer was loaded with the diuretic hydrochlorothiazide, while the IM layer was loaded with lovastatin. Infill percentage was varied for the FFF layer as a means to modify drug release. The IM injection pressure was evaluated for its effect on drug release and layer-layer adhesion. The bilayer tablets obtained offered different combinations of drug release profiles, which were governed by a combination of factors, including surface area to volume ratio; IM injection volume penetration into the FFF layer; FFF infill percentage; layer tortuosity and porosity. These different parameters could be utilized to modify the individual release of both drugs from the bilayer tablet. Thus for the first time, we have demonstrated a viable method for the mass-customization of oral tablets which could hasten the rollout of personalized medicine.

Prediction of dissolution profiles by non-destructive NIR spectroscopy in bilayer tablets.

This study describes how near infrared (NIR) spectroscopy can be used to predict the dissolution of bilayer tablets as a non-destructive approach. Tablets in this study consist of two active pharmaceutical ingredients (APIs) physically separated in layers and manufactured under three levels of hardness. NIR spectra were individually acquired for both layers in diffuse reflectance mode. Reference dissolution profile values were obtained using dissolution apparatus & HPLC. A multivariate partial least squares (PLS) calibration model was developed for each API relating its dissolution profile to spectral data. This calibration model was used to predict dissolution profiles of an independent test set and results of the prediction were compared using model free approaches i.e. dissimilarity (f1) & similarity (f2) factors to assure similarity in dissolution performance.

Discrete particle modeling and micromechanical characterization of bilayer tablet compaction.

A mechanistic particle scale model is proposed for bilayer tablet compaction. Making bilayer tablets involves the application of first layer compaction pressure on the first layer powder and a second layer compaction pressure on entire powder bed. The bonding formed between the first layer and the second layer particles is crucial for the mechanical strength of the bilayer tablet. The bonding and the contact forces between particles of the first layer and second layer are affected by the deformation and rearrangement of particles due to the compaction pressures. Our model takes into consideration the elastic and plastic deformations of the first layer particles due to the first layer compaction pressure, in addition to the mechanical and physical properties of the particles. Using this model, bilayer tablets with layers of the same material and different materials, which are commonly used pharmaceutical powders, are tested. The simulations show that the strength of the layer interface becomes weaker than the strength of the two layers as the first layer compaction pressure is increased. The reduction of strength at the layer interface is related to reduction of the first layer surface roughness. The reduced roughness decreases the available bonding area and hence reduces the mechanical strength at the interface. In addition, the simulations show that at higher first layer compaction pressure the bonding area is significantly less than the total contact area at the layer interface. At the interface itself, there is a non-monotonic relationship between the bonding area and first layer force. The bonding area at the interface first increases and then decreases as the first layer pressure is increased. These results are in agreement with findings of previous experimental studies.

Single Layer Extended Release Two-in-One Guaifenesin Matrix Tablet: Formulation Method, Optimization, Release Kinetics Evaluation and Its Comparison with Mucinex® Using Box-Behnken Design.

Guaifenesin, a highly water-soluble active (50 mg/mL), classified as a BCS class I drug. Owing to its poor flowability and compressibility, formulating tablets especially high-dose one, may be a challenge. Direct compression may not be feasible. Bilayer tablet technology applied to Mucinex®, endures challenges to deliver a robust formulation. To overcome challenges involved in bilayer-tablet manufacturing and powder compressibility, an optimized single layer tablet prepared by a binary mixture (Two-in-one), mimicking the dual drug release character of Mucinex® was purposed. A 3-factor, 3-level Box-Behnken design was applied to optimize seven considered dependent variables (Release "%" in 1, 2, 4, 6, 8, 10 and 12 h) regarding different levels of independent one (X1: Cetyl alcohol, X2: Starch 1500®, X3: HPMC K100M amounts). Two granule portions were prepared using melt and wet granulations, blended together prior to compression. An optimum formulation was obtained (X1: 37.10, X2: 2, X3: 42.49 mg). Desirability function was 0.616. F2 and f1 between release profiles of Mucinex® and the optimum formulation were 74 and 3, respectively. An n-value of about 0.5 for both optimum and Mucinex® formulations showed diffusion (Fickian) control mechanism. However, HPMC K100M rise in 70 mg accompanied cetyl alcohol rise in 60 mg led to first order kinetic (n = 0.6962). The K values of 1.56 represented an identical burst drug releases. Cetyl alcohol and starch 1500® modulated guaifenesin release from HPMC K100M matrices, while due to their binding properties, improved its poor flowability and compressibility, too.

Aspirin bilayer tablets prepared with 3D printer for drug controlled release / 中国药学杂志

OBJECTIVE: Taking aspirin as a model drug, the feasibility of the controlled release of aspirin tablets was discussed, which was based on the individual demand of 3D printing technology. METHODS: The experiment selected 10 000 mPa·s hydroxypropyl methyl cellulose (HPMC10000) and polyacrylic acid (PAA) as a hydrophilic matrix sustained-release layer; hydroxypropyl methyl cellulose 100 mPa·s (HPMC100) as a quick release layer binder, sodium carboxymethyl starch (CMS-Na) and sodium carboxymethyl starch (SSG) as a quick release layer disintegrating agent, the use of 3D printer to print the slow release of aspirin tablets. Select 100 mg·mL-1 and polyvinylpyrrolidone (PVPK30) as a quick release layer binder, crosslinking sodium carboxymethyl cellulose (CC-Na) as a quick release layer disintegrating agent, hydroxypropyl methyl cellulose (HPMC100) as the matrix material release layer, with the traditional press pressing speed of aspirin sustained-release tablet, as contrast agents. The physical and chemical properties of tablets produced in two different modes of production (film weight difference, hardness and thickness) and release profile were investigated. RESULTS: The physical and chemical properties of the two tablets are all in the Pharmacopoeia. Comparison of two kinds of drug release curve showed that the ASA-HPMC (14%, ω) and the press release curve of double layer tablets printing film is similar, and the release rate is higher than the tablet (6% ω. ASA-HPMC double layer tablets), ASA-HPMC (8%, ω) and ASA-HPMC (10%, ω) printing film final release amount increased with hydrophilic matrix HPMC. CONCLUSION: 3D printers print different shapes of tablets with different release profiles, in which the release of the package is higher than the other tablets.

Development and evaluation of bilayer tablets of combination of antibiotics for the treatment of sexually transmitted disease

ABSTRACT The present research work was envisaged to develop bilayer tablets to improve therapeutic efficacy of antibiotic combination for the treatment of sexually transmitted diseases. The combination of two antibiotics i.e. cefixime trihydrate and ofloxacin were used for the preparation of bilayer tablets which act against genito-urinary infections. The formulations comprise of cefixime trihydrate as immediate release layer formulated using different superdisintegrants and ofloxacin as extended release layer containing HPMC K100M. Evaluation of bilayer tablets were performed for the immediate release cefixime layer and sustain release ofloxacin layer with optimization of excipients. The immediate release layer of cefixime showed complete release within 30 min and ofloxacin release was extended up to 24 hours. The similarity factor value of ofloxacin sustained release layer was found to be 87.01 for initial and 80.35 after 3 months stability when compared with marketed reference product. The present study revealed that cefixime trihydrate and ofloxacin bilayer tablets were successfully developed for the use against sexually transmitted infections.

Effect of the surface free energy of materials on the lamination tendency of bilayer tablets.

Dosage forms with fixed dose combinations of drugs is a frequent and advantageous mode of administration, but their production involves a number of technological problems. Numerous interactions in a homogeneous vehicle may be avoided through the use of layered tablets. The mechanical properties of these dosage forms depend on numerous process parameters and material characteristics. The aim of the present study was a detailed investigation of the relationships between the surface characteristics and deformation properties of tableting materials and the tendency of bilayer tablets to undergo lamination. Bilayer tablets were compressed from unlubricated materials with different plastic-elastic properties and surface free energies according to a mixed 2 and 3-level half-replicated factorial design. The results revealed that the surface characteristics play the main role in the lamination of layered tablets and the effect of the plastic-elastic behavior cannot be interpreted without a knowledge of these properties.

Axial strength test for round flat faced versus capsule shaped bilayer tablets.

There has been increasing interest in fixed dose combination (FDC) therapy. Multi-layer tablets are a popular choice among various technologies to deliver FDCs. In most cases, round flat faced tooling is used in testing tablets as they have the simplest geometry. However, shaped tooling is more common for commercial products and may have an effect on bilayer tablet strength. Capsule shaped bilayer tablets, similar to a commercial image, and holders conforming to the tablet topology, were compared with similar round flat faced bilayer tablets and their corresponding holders. Bilayer tablets were subjected to an axial test device, until fracture and the quantitative breaking force value was recorded. As the second layer compression force increases, regardless of holder design, an increase in breaking force occurs as expected. This consistent trend provides insight regarding the breaking force of capsule shaped bilayer tablets. The results of this study show that at lower second layer compression forces, tablet geometry does not significantly impact the results. However, at higher compression forces, a significant difference in breaking force between tablet geometries exists. Therefore, using a test geometry close to the final commercial tablet image is recommended to have the most accurate prediction for tablet breakage.

Gastro-floating bilayer tablets for the sustained release of metformin and immediate release of pioglitazone: preparation and in vitro/in vivo evaluation.

Owing to the complementary mechanisms of action of metformin hydrochloride (MH) and pioglitazone hydrochloride (PG), combination therapy for type 2 diabetes mellitus using the two drugs is highly desired; on the other hand, MH is not well absorbed in lower gastrointestinal tract and has a short half-life, therefore compromising the therapeutic effects. Herein, the present study was to develop gastro-floating bilayer matrix tablets in which the two drugs were incorporated into two separate layers, aiming at sustaining MH release with enhanced absorption and achieving immediate release of PG. The tablets of the optimized formulation floated on the test medium for more than 24 h with 5 min of floating lag time, and sustained MH release for 12 h via a diffusion-dependent manner; and complete release of PG within 5 min were achieved. Moreover, a steady plasma concentration of MH with a 1.5-fold increase in bioavailability, decreased C(max) and reduced T(max) was obtained, and the in vivo behavior of PG was similar to the marked product. Summarily, sustained MH release with improved absorption and immediate release of PG were obtained simultaneously using the gastro-floating bilayer tablet, allowing strengthened combination therapy for diabetes mellitus.

Physiological relevant in vitro evaluation of polymer coats for gastroretentive floating tablets.

Gastroretentive drug delivery systems are retained in the stomach for a sufficient time interval, releasing the drug in a controlled manner. According to literature, the floating principle is the most frequently used formulation approach for gastric retention. However, many publications lack information of the floating forces, the impact of different pH-values and almost no information exist concerning the resistance of the floating performance against physiological relevant stress. Therefore, we evaluated the performance of CO2-generating floating bilayer (drug and floating layer) tablets with respect to robustness, drug release profile, pH dependence and floating behaviour. Bilayer tablets were coated with a flexible and water permeable, but CO2-retaining polymer film of either polyvinyl acetate or ammonio-methacrylate copolymer type A. Metformin-HCl was used as a relevant model drug due to its dose-dependent and saturable absorption from the proximal part of the small intestine. To mimic physiological relevant mechanical stress conditions, recently developed dissolution stress tests with pulsed pressures were applied in addition to release studies according to the pharmacopeia. Bilayer tablets coated with polyvinyl acetate showed short floating lag times, reasonable floating strength values, floating durations of more than 24h in simulated gastric fluid and a robust and pH independent release of Metformin-HCl. Tablets coated with ammonio-methacrylate copolymer type A showed a higher permeability for the active ingredient combined with a decreased robustness of the inflated tablets. Both polymers can be used for balloon-like floating devices. The appropriate polymer has to be chosen dependent from the properties of the active ingredient and requested application of the delivery device. Furthermore, the dissolution stress test analysis is able to indicate possible safety issues of gastroretentive formulations as well as to characterise the robustness of formulation principles towards mechanical stresses of bio-relevant intensity.