Solvent-free method for masking the bitter taste of azithromycin dihydrate using supercritical fluid technology.

INTRODUCTION AND PURPOSE: The unpleasant extremely bitter taste of the orally administered broad-spectrum antibiotic azithromycin decreases patient compliance, especially in pediatrics. This issue can be overcome by decreasing drug interaction with the tasting buds using insoluble polymers at salivary pH (6.8 - 7.4), like the cationic polymer Eudragit EPO. Supercritical fluid technology is a green synthesis method for preparing pharmaceutical preparations that replace organic solvents with safe supercritical CO2. This study aimed to mask the bitter taste of azithromycin using the supercritical fluid method and a pH-sensitive Eudragit EPO polymer. METHODS: A foaming process was investigated for preparing a formulation (TEST), which comprises treating the polymer with supercritical carbon dioxide (CO2) fluid to prepare a taste-masked dosage form without employing organic solvents or flavors. RESULTS: The use of the supercritical technique at 40 °C and 10 MPa for 2 h allowed the manufacturing of solvent-free polymeric foam with azithromycin dispersions; the average calculated percentage of apparent volume change was 62.5 ± 5.9% with an average pore diameter of 34.879 Å. The formulated sample showed low drug release in simulated salivary fluid while keeping its crystalline nature. Moreover, clinical studies on healthy subjects showed that the formula successfully masked azithromycin's bitter taste. CONCLUSIONS: Overall, it has been shown herein that the supercritical fluid technology foaming method is promising in masking the bitter taste of bitter ingredients.

Characteristics of Interpolyelectrolyte Complexes Based on Different Types of Pectin with Eudragit® EPO as Novel Carriers for Colon-Specific Drug Delivery.

Given that pectin is a well-known substance used for drug delivery, we aimed to obtain and further examine the efficacy of interpolyelectrolyte complexes based on citrus or apple pectin and the Eudragit® EPO for using these carriers in oral drug delivery. To characterize the physicochemical properties of these compounds, turbidity, gravimetry, viscosity, elementary analysis, FTIR spectroscopy, and DSC analysis were utilized. Diffusion transport characteristics were evaluated to assess the swelling ability of the matrices and the release of diclofenac sodium. To examine the release parameters, mathematical modeling was performed by using the Korsmayer-Peppas and Logistic equations as well. During the turbidity study, stoichiometry compositions were selected for the developed IPECs EPO/PecA and EPO/PecC at pH values = 4.0, 5.0, 6.0, and 7.0. The FTIR spectra of the complexes were characterized by an increase in the intensity of the bands at 1610 cm-1 and 1400 cm-1. According to the DSC analysis, IPEC has a certain Tg = 57.3 °C. The highest release rates were obtained for IPEC EPO/PecC_1 and EPO/PecC_4. The mechanism of drug transport from the matrices IPEC EPO/PecC, IPEC EPO/PecA_3, and EPO/PecA_4 can be characterized as Super Case II. Anomalous release (non-Fickian release) is typical for IPEC EPO/PecA_1 and EPO/PecA_2. Thus, the resulting systems can be further used for the effective delivery of the drugs to the colon.

The Effect of Process Variables and Binder Concentration on Tabletability of Metformin Hydrochloride and Acetaminophen Granules Produced by Twin Screw Melt Granulation with Different Polymeric Binders.

In twin screw melt granulation, granules are produced by passing mixtures of drug substances and polymeric binders through twin screw extruder such that temperatures are maintained below melting point of drugs but above glass transition of polymers used, whereby the polymers coat surfaces of drug particles and cause their agglomeration into granules. Since various formulation factors, such as binder type and concentration, and processing variables like extrusion temperature, screw configuration, and screw speed, can influence the granulation process, the present investigation was undertaken to study their effects on tabletability of granules produced. Three different types of polymeric binders, Klucel® EXF (hydroxypropyl cellulose), Eudragit® EPO (polyacrylate binder), and Soluplus® (polyvinyl caprolactam-co-vinyl acetate-ethylene glycol graft polymer), were used at 2, 5, and 10% concentrations. Metformin hydrochloride (HCl) (mp: 222°C) and acetaminophen (mp: 169°C) were used as model drugs, and drug-polymer mixtures with metformin HCl were extruded at 180, 160, and 130°C, while those with acetaminophen were extruded at 130 and 110°C. Other process variables included screw configurations: low, medium, and high shear for metformin HCl, and low and medium shear for acetaminophen; feed rates: 20 and 60 g/min; and screw speed of 100 and 300 RPM. Formulation and process variables had significant impact on tabletability. The target tensile strength of ≥2 MPa could be obtained with all polymers and at all processing temperatures when metformin HCl was granulated at 180°C and acetaminophen at 130°C. At other temperatures, the target tensile strength could be achieved at certain specific sets of processing conditions.

Impact of Drug-Polymer Interaction in Amorphous Solid Dispersion Aiming for the Supersaturation of Poorly Soluble Drug in Biorelevant Medium.

The aim of this study was to investigate the influence of the production method and the polymeric carrier on the ability to generate and maintain the supersaturation of a poorly soluble drug in biorelevant medium. The amorphous solid dispersion of sulfamethoxazole, an antibacterial drug, was produced using two different polymers by spray-drying or hot melt extrusion methods. When Eudragit EPO was used, supersaturation was maintained up to 24 h for both techniques at all drug-polymer proportions. However, when Soluplus was employed in hot melt extrusion, a smaller amount of drug was dissolved when compared to the amorphous drug. The proportion of 3:7 drug-Eudragit EPO (w/w) produced by spray-drying presented a higher amount of drug dissolved in supersaturation studies and it was able to maintain the physical stability under different storage conditions throughout the 90-day evaluation. Supersaturation generation and system stability were found to be related to more effective chemical interaction between the polymer and the drug provided by the production method, as revealed by the 1D ROESY NMR experiment. Investigation of drug-polymer interaction is critical in supersaturating drug delivery systems to avoid crystallization of the drug and to predict the effectiveness of the system. Chemical compounds studied in this article: Sulfamethoxazole (PubChem CID: 4539) and Methacrylate copolymer - Eudragit EPO (PubChem CID: 65358).

Methacrylate-Copolymer Eudragit EPO as a Solubility-Enabling Excipient for Anionic Drugs: Investigation of Drug Solubility, Intestinal Permeability, and Their Interplay.

The purpose of this work was to investigate the use of the dimethylaminoethyl methacrylate-copolymer Eudragit EPO (EPO) in oral solubility-enabling formulations for anionic lipophilic drugs, aiming to guide optional formulation design and maximize oral bioavailability. We have studied the solubility, the permeability, and their interplay, using the low-solubility nonsteroidal anti-inflammatory drug mefenamic acid as a model drug. Then, we studied the biorelevant solubility enhancement of mefenamic acid from EPO-based formulations throughout the gastrointestinal tract (GIT), using the pH-dilution dissolution method. EPO allowed a profound and linear solubility increase of mefenamic acid, from 10 µg/mL without EPO to 9.41 mg/mL in the presence of 7.5% EPO (∼940-fold; 37 °C); however, a concomitant decrease of the drug permeability was obtained, both in vitro and in vivo in rats, indicating a solubility-permeability trade-off. In the absence of an excipient, the unstirred water layer (UWL) adjacent to the GI membrane was found to hinder the permeability of the drug, accounting for this UWL effect and revealing that the true membrane permeability allowed good prediction of the solubility-permeability trade-off as a function of EPO level using a direct relationship between the increased solubility afforded by a given EPO level and the consequent decreased permeability. Biorelevant dissolution studies revealed that EPO levels of 0.05 and 0.1% were insufficient to dissolve mefenamic acid dose during the entire dissolution time course, whereas 0.5 and 1% EPO allowed complete solubility with no drug precipitation. In conclusion, EPO may serve as a potent solubility-enabling excipient for BCS class II/IV acidic drugs; however, it should be used carefully. It is prudent to use the minimal EPO amounts just sufficient to dissolve the drug dose throughout the GIT and not more than that. Excess amounts of EPO provide no solubility gain and cause further permeability loss, jeopardizing the overall success of the formulation. This work may help the formulator to hit the optimal solubility-permeability balance, maximizing the oral bioavailability afforded by the formulation.

Strategies for Improving Healing of the Gastric Epithelium Using Oral Solid Dispersions Loaded with Pentacyclic Triterpene-Rich Centella Extract.

The pentacyclic triterpenoid compounds in Centella asiatica extract, mainly consisting of asiaticoside (AS), asiatic acid (AA), madecassoside (MS), and madecassic acid (MA), possess wound healing and anti-ulcer properties, but their low aqueous solubility and dissolution rate are disadvantageous for oral administration. In this study, pentacyclic triterpene-rich centella extract (PRE) was combined with Eudragit® EPO as a hydrophilic polymer using solvent evaporation to produce a solid dispersion (PRE-ESD). The optimum PRE/Eudragit ratio of 1:2 enhanced the solubility and dissolution of glycosides (AS > 3.5 folds, MS > 2 folds) and aglycones (AA > 65 folds and MA > 56 folds) in 0.1 N hydrochloric acid (pH 1.2). DSC, XRD, and FT-IR analysis showed that the four pentacyclic triterpenes in PRE existed in the amorphous state in the solid dispersion. Moreover, almost 100% of the compounds were released from the solid dispersion within 2 h. The effects of PRE-ESD on cell proliferation and wound healing in vitro were investigated in human gastric epithelial cell lines (AGS cells). Exposure to PRE-ESD (equivalent to PRE concentration of 10 µg/mL) promoted cell proliferation and enhanced 'wound closure' in the scratch assay of wound healing by 82% compared with non-treated groups. Unformulated MA and AA aglycones did not exhibit a wound healing effect. Moreover, PRE-ESD was found to accelerate wound closure compared with either AS or MS, indicating that the wound healing properties of PRE-ESD are conferred by the active compounds AS and MS that are presented in PRE.

Preparation and characterization of a powder containing an oily liquid drug with Eudragit EPO or L100 copolymer.

Oily liquid drugs are not convenient for oral administration. We developed a powder containing clofibrate (CF), a model of an oily drug, using aminoalkyl methacrylate copolymer (EPO) or methacrylic acid copolymer (L100). CF or a mixture of CF and soybean oil was emulsified with EPO or L100 aqueous solution. Using a high-pressure homogenizer, a stable emulsion was obtained, and a powder was then obtained by lyophilization of the emulsion. The content of CF in the powder depended on the formulation, with the highest contents being 24.6% and 27.1% for EPO and L100, respectively. The incorporation ratio of CF was higher for L100 than for EPO. The powder using EPO was sticky because of leaked CF and the low glass transition temperature of EPO. The powder using L100 was a typical powder obtained by lyophilization. The leakage of CF from the powder was <2%, lower than for EPO powder. The dissolution of CF from powder using EPO was fast, regardless of the pH of the medium, but the powder using L100 showed enteric-soluble characteristics, indicating that CF is well incorporated in L100.

Formulation and in vitro evaluation of ketoprofen fast-dissolving tablets.

Drugs exhibiting satisfactory absorption from the oral mucosa or intended for immediate pharmacological action can be advantageously formulated as orally fast-disintegrating tablets (FDTs or ODTs). Therefore, taste masking of active ingredients becomes essential in these systems because the drug is entirely released in the mouth. Despite advances in the FDT technologies, formulation of drugs with a bitter taste is still a challenge, especially when the amount of drug is high. In this study, a new solution is being developed to incorporate higher doses of a model bitter taste drug; ketoprofen, without affecting the fast-disintegrating properties of the formulation. The unpleasant taste of the active drug usually masked by adding flavoring ingredients and sweeteners to improve taste and palatability but in this study a novel approach of using a polymer; Eudragit EPO and a granulation procedure of this polymer with the active drug was applied to mask the bitter taste of ketoprofen. In order to produce ketoprofen FDT formulations, a two-stepped procedure was followed; granulation process with the taste-masking agent (Eudragit EPO) and then direct compression (F3 and F4). In F1 and F2 formulations, granulation process was not implemented in order to observe the effect of application method of Eudragit EPO. As well as observing the effect of taste-masking agent, crospovidone and sodium starch glycolate were used in different concentrations (2, 4 and 8wt%) to examine the influence of superdisintegrants on FDT properties. All the FDTs containing 30 mg ketoprofen (F1, F2, F3 and F4) were evaluated by means of in vitro quality control tests.

Amorphous solid dispersion with increased gastric solubility in tandem with oral disintegrating tablets: a successful approach to improve the bioavailability of atorvastatin.

CONTEXT: Serious efforts have been made to overcome the bioavailability problems of ever increasing number of poorly soluble drugs, including atorvastatin (ATO); however, enhancing its gastric solubility has not received much attention. OBJECTIVES: To improve the bioavailability of ATO by increasing its gastric solubility in a stable oral disintegration tablet (ODT) formulation. MATERIALS AND METHODS: Amorphous solid dispersion (ASD) of ATO with Eudragit® EPO was used as API in ODT formulation. Characterization using Differential scanning calorimetry, Powder X-ray diffraction, Fourier transform infrared drug-polymer interaction simulated by molecular modeling, solubility, dissolution and stability studies together with in vivo evaluation. RESULTS AND DISCUSSION: In ASD there was uniform distribution of drug in the polymer and it retained the amorphous nature without any chemical interactions except the possibility of hydrogen bond formation, with substantially higher gastric solubility. The dissolution profile of the ODT containing ASD was significantly improved >90% within 15 min compared with 25% of plain ATO formulation. In vivo results showed an overall enhancement in the apparent bioavailability (83% and 434% more than Lipitor® and plain amorphous ATO tablets, respectively). Combining the ASD with ODT presents a reliable solution to overcome the low solubility and bioavailability problems of ATO in a simple, robust and cost effective formulation.

HME-assisted formulation of taste-masked dispersible tablets of cefpodoxime proxetil and roxithromycin.

Objectives: Antibiotics are the most commonly administered medications among pediatric patients. However most of the time, accurate dose administration to children becomes a problem due to the extremely bitter taste. Cefpodoxime proxetil (CP) and roxithromycin (ROX) are antibiotics often prescribed to the pediatric population and have a bitter taste. Marketed formulations of these drugs are dry suspension and/or tablets. The lyophilization method involves various steps and thus is time consuming and expensive. The objective of this study was to mask the bitter taste of CP and ROX without compromising the solubility and drug release profile compared to marketed formulations, as well as to overcome the disadvantages associated with the currently used lyophilization technique. Methods: Hot melt extrusion (HME) technology was used to process CP and ROX individually with Eudragit E PO polymer. The extrudates obtained were characterized by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry. The powdered extrudates were formulated as dispersible tablets and evaluated for in vitro and in vivo taste-masking efficiency. Results: The tablets prepared in this study showed comparable dissolution profiles but the taste-masking efficiency was significantly enhanced compared to the marketed tablets of CP and ROX. The results of in vivo human taste-masking evaluation were also in agreement with the in vitro taste-masking studies. Conclusion: The current work presents solvent-free, scalable, and continuous HME technology for addressing the bitter taste issues of CP and ROX. The disadvantages associated with the currently used lyophilization technique were overcome by developing the formulations using HME technology.

Simultaneous Delivery of Curcumin and Resveratrol via In Situ Gelling, Raft-Forming, Gastroretentive Formulations.

Curcumin and resveratrol are polyphenolic compounds that have been shown to exhibit synergistic therapeutic properties including anti-inflammatory, anticancer, and antiulcer activities, which may be exploited for the treatment of gastric diseases. However, both compounds have poor aqueous solubility and rapid metabolism, resulting in a low oral bioavailability. In situ gelling, liquid formulations were developed to produce a gastroretentive, raft-forming delivery vehicle to improve bioavailability. Solid dispersions containing a mixture of curcumin and resveratrol with Eudragit® EPO (Cur/Res-SD) were first prepared using solvent evaporation, to improve the solubility and dissolution of the compounds. Solid dispersions of a weight ratio of 1:10 curcumin/resveratrol to Eudragit® EPO were subsequently incorporated into in situ gelling, liquid formulations based on the gelling polymers, sodium alginate (low viscosity and medium viscosity), pectin, and gellan gum, respectively. Calcium carbonate and sodium bicarbonate were included to produce carbon dioxide bubbles in the gel matrix, on exposure to gastric fluid, and to achieve flotation. Moreover, the calcium ions acted as a crosslinking agent for the hydrogels. Optimized formulations floated rapidly (<60 s) in simulated gastric fluid (pH = 1.2) and remained buoyant, resulting in the gradual release of more than 80% of the curcumin and resveratrol content within 8 h. The optimized formulation based on medium-viscosity sodium alginate exhibited enhanced cytotoxic activity toward human gastric adenocarcinoma cell lines (AGS), compared with unformulated curcumin and resveratrol compounds, and increased anti-inflammatory activity against RAW 264.7 macrophage cells compared with the NSAID, indomethacin. These findings demonstrate that in situ gelling, liquid formulations, loaded with a combination of curcumin and resveratrol in the form of solid dispersions, show potential as gastroretentive delivery systems for local and systemic effects.

Taste-Masked Flucloxacillin Powder Part 1: Optimisation of Fabrication Process Using a Mixture Design Approach.

It is extremely challenging to formulate age-appropriate flucloxacillin medicines for young children, because flucloxacillin sodium (FS) has a lingering, highly bitter taste, dissolves quickly in saliva, and requires multiple daily dosing at relatively large doses for treating skin infections. In this paper, we describe a promising taste-masked flucloxacillin ternary microparticle (FTM) formulation comprising FS, Eudragit EPO (EE), and palmitic acid (PA). To preserve the stability of the thermolabile and readily hydrolysed flucloxacillin, the fabrication process employed a non-aqueous solvent evaporation method at ambient temperature. Optimisation of the fabrication method using a mixture design approach resulted in a robust technique that generated stable and reproducible FTM products. The optimised method utilised only a single solvent evaporation step and minimal amounts of ICH class III solvents. It involved mixing two solution phases-FS dissolved in ethanol:acetone (1:4 v/v), and a combination of EE and PA dissolved in 100% ethanol-to give a ternary FS:EE:PA system in ethanol: acetone (3:1 v/v). Solvent evaporation yielded the FTMs containing an equimolar ratio of FS:EE:PA (1:0.8:0.6 w/w). The fabrication process, after optimisation, demonstrated robustness, reproducibility, and potential scalability.

Taste-Masked Flucloxacillin Powder Part 2: Formulation Optimisation Using the Mixture Design Approach and Storage Stability.

Flucloxacillin is prescribed to treat skin infections but its highly bitter taste is poorly tolerated in children. This work describes the application of the D-optimal mixture experimental design to identify the optimal component ratio of flucloxacillin, Eudragit EPO and palmitic acid to prepare flucloxacillin taste-masked microparticles that would be stable to storage and would inhibit flucloxacillin release in the oral cavity while facilitating the total release of the flucloxacillin load in the lower gastrointestinal tract (GIT). The model predicted ratio was found to be very close to the stoichiometric equimolar component ratio, which supported our hypothesis that the ionic interactions among flucloxacillin, Eudragit EPO and palmitic acid underscore the polyelectrolyte complex formation in the flucloxacillin taste-masked microparticles. The excipient-drug interactions showed protective effects on the microparticle storage stability and minimised flucloxacillin release at 2 min in dissolution medium. These interactions had less influence on flucloxacillin release in the dissolution medium at 60 min. Storage temperature and relative humidity significantly affected the chemical stability of the microparticles. At the preferred storage conditions of ambient temperature under reduced RH of 23%, over 90% of the baseline drug load was retained in the microparticles at 12 months of storage.

Gastric ulcer healing by chebulinic acid solid dispersion-loaded gastroretentive raft systems: preclinical evidence.

Background: Chebulinic acid (CA), a component in Terminalia chebula, exhibits antiulcer activity, but has poor aqueous solubility. Raft-forming systems incorporating solid dispersions (SDs) of CA, were developed to overcome its poor biopharmaceutical properties and to prolong the gastric residence time for maximum activity. Methods: SDs were formulated by a solvent evaporation method using Eudragit EPO. Raft formulations consisted of sodium alginate as a polymer. Results: Release of CA in the dissolution medium was 40%, whereas SDs showed 95.45% release. The CA raft system (20 mg/kg) showed curative efficacy in an alcohol-induced gastric ulcer model and increased protection when compared with omeprazole (10 mg/kg) and CA suspension (20 mg/kg). Conclusion: These studies demonstrated SD raft systems to be a promising approach for antiulcer therapy by CA.

Development and Characterization of Eudragit® EPO-Based Solid Dispersion of Rosuvastatin Calcium to Foresee the Impact on Solubility, Dissolution and Antihyperlipidemic Activity.

Poor solubility is the major challenge involved in the formulation development of new chemical entities (NCEs), as more than 40% of NCEs are practically insoluble in water. Solid dispersion (SD) is a promising technology for improving dissolution and, thereby, the bioavailability of poorly soluble drugs. This study investigates the influence of a pH-sensitive acrylate polymer, EPO, on the physicochemical properties of rosuvastatin calcium, an antihyperlipidemic drug. In silico docking was conducted with numerous polymers to predict drug polymer miscibility. The screened-out polymer was used to fabricate the binary SD of RoC in variable ratios using the co-grinding and solvent evaporation methods. The prepared formulations were assessed for physiochemical parameters such as saturation solubility, drug content and in vitro drug release. The optimized formulations were further ruled out using solid-state characterization (FTIR, DSC, XRD and SEM) and in vitro cytotoxicity. The results revealed that all SDs profoundly increased solubility as well as drug release. However, the formulation RSE-2, with a remarkable 71.88-fold increase in solubility, presented 92% of drug release in the initial 5 min. The molecular interaction studied using FTIR, XRD, DSC and SEM analysis evidenced the improvement of in vitro dissolution. The enhancement in solubility of RoC may be important for the modulation of the dyslipidemia response. Therefore, pharmacodynamic activity was conducted for optimized formulations. Our findings suggested an ameliorative effect of RSE-2 in dyslipidemia and its associated complications. Moreover, RSE-2 exhibited nonexistence of cytotoxicity against human liver cell lines. Convincingly, this study demonstrates that SD of RoC can be successfully fabricated by EPO, and have all the characteristics that are favourable for superior dissolution and better therapeutic response to the drug.

Improved efficacy and safety of low doses of benznidazole-loaded multiparticulate delivery systems in experimental Chagas disease therapy.

Benznidazole (BZ) is a first-line drug for the treatment of Chagas disease; however, it presents several disadvantages that could hamper its therapeutic success. Multiparticulate drug delivery systems (MDDS) are promising carriers to improve the performance of drugs. We developed BZ-loaded MDDS intended for improving Chagas disease therapy. To assess their efficacy and safety, Trypanosoma (T) cruzi infected BALB/c mice were orally treated with free BZ or BZ-MDDS at different regimens (doses of 50 and 100 mg/kg/day, administered daily or at 2- or 5-days intervals) and compared with infected non-treated (INT) mice. At 100 mg/kg/day, independent of the administration regimen, both treatments were able to override the parasitemia, and at 50 mg/kg/day significantly reduced it compared to INT mice. BZ-MDDS at a dose of 100 mg/kg/day administered every 5 days (BZ-MDDS 100-13d) induced the lowest cardiac parasite load, indicating an improved efficacy with lower total dose of BZ when loaded to the MDDS. Reactive oxygen species produced by leukocytes were higher in INT and mice treated with BZ at 50 mg/kg/day compared to 100 mg/kg/day, likely because of persistent infection. BZ-MDDS treatments markedly reduced heart and liver injury markers compared to INT mice and those receiving the standard treatment. Therefore, BZ-MDDS exhibited enhanced activity against T. cruzi infection even at lower doses and reduced administration frequency compared to free BZ while increasing the treatment safety. They likely avoid undesired side effects of BZ by keeping a sustained concentration, avoiding plasmatic drug peaks. BZ-MDDS evidenced significant improvements in experimental Chagas disease treatment and can be considered as a potential improved therapeutic alternative against this illness.

Raft-forming gastro-retentive formulations based on Centella asiatica extract-solid dispersions for gastric ulcer treatment.

Liquid raft-forming formulations comprising solid dispersions of glycoside-rich Centella asiatica extract and Eudragit® EPO (GR-SD) were developed to achieve prolonged delivery of the glycosides, asiaticoside (AS) and madecassoside (MS) in the stomach and thus increase the effectiveness of gastric ulcer treatment. Solid dispersions of GR extract and Eudragit® EPO (GR-SD, weight ratio 1:0.5) resulted in the highest solubility of AS (41.7 mg/mL) and MS (29.3 mg/mL) and completed dissolution of both glycosides occurred in SGF within 10 min. The optimized raft-forming formulation was composed of alginate (2%), HPMC K-100 (0.5%), GR-SD (1.2%), and calcium carbonate (0.5%) as a calcium source and carbon dioxide producer. The formulation provided sufficient raft strength (> 7.0 g), rapid floating behavior in SGF (~30 s), and sustained release of AS (more than 80%) and MS (85%) over 8 h. GR-SD-based formulations administered once daily to rats for two days at a dose of 10 mg AS/kg reduced the severity of gastric ulcer induced by indomethacin with a greater curative efficacy than those of unformulated GR extract and a standard antiulcer agent: lansoprazole (p < 0.05). These findings demonstrate that GR-SD-based raft-forming systems offer significant promise for improving the treatment of gastric ulcers induced by non-steroidal anti-inflammatory drugs.

Supersaturating drug delivery system of fixed drug combination: sulfamethoxazole and trimethoprim.

Background: The drug supersaturation in the intestinal lumen for few hours could result in high bioavailability. The goal of this study was the development of a supersaturating drug delivery system containing sulfamethoxazole and trimethoprim at fixed dose combination (sulfamethoxazole:trimethoprim 5:1 w/w). Methods: The amorphous solid dispersions were formed at three different proportions containing 30, 50 and 70% of Eudragit EPO in the formulation. Results: The supersaturation state is formed by the amorphous drugs produced by spray drying technique, and the maintenance of this state is due to the chemical interactions between the drugs and the polymer selected, which was observed in the fluorescence interaction studies realized between the drugs and the polymer. The Formulation containing 70% of the polymer was able to produce and maintain the supersaturated state of both drugs for 24 h. Solid state characterization demonstrated the amorphization of the drugs in the solid dispersion and indicated the hydrogen bond formation responsible for the improvement in the apparent solubility. This formulation presented an improved antibacterial activity when compared to the combination of the drugs. Conclusion: For the first time, a supersaturating drug delivery system was developed to the complementary antibacterial drugs. This ternary formulation is a powerful alternative to improve oral absorption of recognized safety drugs, reducing the dose and consequently the antibiotic resistance emergence.

Preparation and Biopharmaceutical Evaluation of Novel Polymeric Nanoparticles Containing Etoposide for Targeting Cancer Cells.

OBJECTIVES: Polymeric nanoparticles are a promising novel drug delivery system and have advantages in cancer therapy. Etoposide is an anticancer agent that is used in the treatment of a variety of malignancies. The aim of the present study was to prepare and evaluate novel polymeric nanoparticles containing etoposide. MATERIALS AND METHODS: A 32 full factorial design was used to study the effect of Eudragit EPO and Pluronic F-68 on the characterization of nanoparticle suspensions. The polymeric nanoparticles were prepared by nanoprecipitation technique. The prepared nanoparticles was evaluated by percentage yield, drug polymer compatibility using fourier transform infrared (FTIR) spectroscopy and differential scanning calorimetric (DSC) analysis, drug content, entrapment efficiency, zeta potential, particle size, scanning electron microscopy, X-ray diffraction, in vitro drug release studies, kinetic modeling, stability studies, and in vivo animal studies. Response surface plots were studied, which were generated using PCP dissolution software. RESULTS: Scanning electron microscopic studies confirmed their porous structure with a number of nanochannels. The FTIR spectra showed the stable character of etoposide in a mixture of polymers and revealed the absence of drug-polymer interactions. The DSC study revealed that the drug was involved in complexation with nanoparticles. The average particle size of etoposide nanoparticles was in the range of 114.4 nm to 136.7 nm. The zeta potential values were attained to ensure good stability of nanosuspensions. In vitro release of the drug from nanoparticles follows the Peppas model and showed controlled release behavior for a period of 24 h. The optimized nanoparticles were subjected to stability studies at 4°C in a refrigerator and the most suitable temperature for storage of etoposide nanoparticles found. The average targeting efficiency of drug-loaded nanoparticles was 41.88±0.030% of the injected dose in the liver, 25.66±0.320% in the spleen 13.82±0.090% in the lungs, 4.52±0.300% in the kidney, and 4.18±0.490% in the brain. CONCLUSION: Etoposide loaded nanoparticles was found to be effective in sustained release.

Multi-dose oral abuse deterrent formulation of loperamide using hot melt extrusion.

Loperamide, an over the counter anti-diarrheal drug, also infamously referred to as "poor man's methadone". Due to the ease of availability and low price, people/patients abuse it by consuming more than 30 tablets to achieve euphoric effect and to combat opioid withdrawal. But supratherapeutic doses of loperamide result in severe respiratory depression, cardiac dysrhythmia and mortality. To address this issue, we developed a unique and innovative technology to deter multi-dose oral abuse. The concept is to design a tablet which can immediate release loperamide in diarrheic patients (single tablet) while stops loperamide release in case of intentional multi-dose ingestion. Loperamide was molecularly dispersed into gastric soluble cationic polymers - Eudragit® EPO and Kollicoat® Smartseal 100P using hot melt extrusion to obtain filament. Filaments were milled and compressed into tablets ((Eudragit® EPO (SJU1) and Kollicoat® Smartseal (SJU2)) with optimized amount of L-Arginine. Dissolution in 250 mL of Fasted state simulated gastric fluid (FaSSGF) revealed that single tablet of Imodium® (marketed formulation) and SJU1 showed >85% of release within 15 min. Most importantly, in multi-unit dissolution (15 tablets), Imodium® exhibited >90% release but SJU tablets showed <2% of drug release thus demonstrating its ability to deter multi-dose oral abuse.