Preparation and Evaluation of Cefuroxime Axetil Gastro-Retentive Floating Drug Delivery System for Improved Delivery via Hot-Melt Extrusion Technology

Purpose: The objective of the present study was to develop lipid-based gastro-retentive floating drug delivery system of amorphous Cefuroxime Axetil (CA) to minimize the enzymatic degradation in the gastro intestinal tract utilizing hot-melt extrusion technology for improved absorption. Methods: Preliminary studies were performed to select the appropriate lipids. Selected ratios of CA and lipids were extruded using a twin screw hot-melt extruder. Extrudates obtained were milled to obtain floating granules and were further evaluated for drug content, floating strength and micromeritic properties. In vitro drug release studies were performed in 900 mL of simulated gastric fluid (without enzyme) of pH 1.2. The formulations were also studied for their polymorphic nature. Differential scanning calorimetry (DSC) and hot-stage microscopy were used to assess the homogeneity of the formulations and to detect if there is any phase separation during processing and storage. Fourier transform infrared (FTIR) spectroscopy analysis was further used to assess any drug-excipients interactions. Results: Solubility studies revealed that CA was highly soluble in Kolliphor® TPGS and Gelucire® 44/14, and solubility increased linearly as the concentration increased. All the extruded granules shofloating lag time of less than 5 seconds and floated for more than 12 h simulated gastric fluid. Optimized formulation was able to give a sustained drug release profile for 12 hours. Micromeritic properties of optimized formulation shogood flow properties compared to the pure drug. Surface characterization revealed that granules had a smooth surface indicating the presence of lipids on the surface. DSC and hot-stage microscopy studies confirmed that there was no phase separation between CA and the excipients. The FTIR studies shothat there was no major interaction between the CA and excipients studied. Conclusion: Lipid-based gastro retentive floating drug delivery systems were prepared and shodesired sustained release profiles, which will ensure more complete dissolution of CA with potential improved absorption due to reduced enzymatic degradation and longer residence time in the stomach

DESIGN AND OPTIMIZATION OF PEDIATRIC CEFUROXIME AXETIL DISPERSIBLE TABLET CONTAINING ION-EXCHANGE RESIN

Objective: The aim of present work was to develop of pediatric cefuroxime axetil 125 mg dispersible tablets by using ion exchange resin as a taste masking agent and quality target product profile was defined based on the properties of the cefuroxime axetil. Methods: Initially, cefuroxime axetil and various resin complexes (DRC) were prepared with different conditions and evaluated for taste masking and drug loading. Optimized DRC was used to formulate the dispersible tablet. A 32 full factorial design was employed to study the effect of mannitol (X1) and microcrystalline cellulose PH-101 (X2) on drug release at 10 min and time taken to 80% drug release. In the present study, the following constraints were arbitrarily used for the selection of an optimized batch: Q10>65% and T80%<30 min. Multiple linear regression analysis, ANOVA and graphical representation of the influence factor by 3D plots were performed by using Sigmaplot 11.0. Checkpoint batch was prepared to validate the evolved model. Results: Among the various drug resins complex DRC-9 was found with less bitter taste which was containing kyron T-114 and among the all factorial batch F7 showed highest drug release at 10 min (Q10) and lowest time taken to 80% drug release (T80) hence batch F7 was selected as an optimized batch and it’s found to be stable in the stability evaluation. Conclusion: The results of full factorial design indicate mannitol and MCC PH-101 have a significant effect on drug release

DESIGN AND EVALUATION OF EXTENDED RELEASE CEFUROXIME AXETIL FLOATING TABLETS WITH IMPROVED GI ABSORPTION

Oral drug delivery system represents one of the frontier area of controlled drug delivery system. Floating drug delivery system belongs to oral controlled drug delivery system group, which is capable of floating in the stomach for prolong period of time. The objective of the present research work is to provide a gastroretentive system for sustained release of therapeutically active agent, cefuroxime axetil in upper part of gastro-intestinal tract in the form of floating tablet. Cefuroxime axetil, an oral prodrug shows a bioavailablity of 30% to 40% when taken on fasting and 5% to 60% whentaken after food. The cefuroxim axetil esterase can hydrolyze cefuroximeaxetil to the nonabsorbable cefuroxim in the gut lumen and is therefore, suspected as a possible cause of incomplete bioavailability. Which suggests an absorption mechanism through the mucosa with limited capacity. Cefuroxime axetil had saturation kinetics that could be overcome by slow release of drug from the formulation, by incorporating cefuroxime axetil in sustained drug delivery system. Keywords: Floating drug delivery system, Cefuroxime axetil, Gastro-intestinal tractÂ

Preparation and characterization of cefuroxime axetil solid dispersions using poloxamer 188

The main objective of the present work was to enhance the solubility and dissolution rate of poorly water-soluble drug cefuroxime axetil (CA) by formulating it into solid dispersions (SDs) with water soluble carrier poloxamer 188. Different methods were employed to prepare the dispersion, such as: Solvent method (SM), Kneading method (KM), Melt evaporation method (MEM) and Physical mixture (PM) in different drug: carrier ratios 1:1, 1:2 and 1:3 (cefuroxime axetil: poloxamer 188). The physical mixture(s) and solid dispersion(s) were characterized for drug carrier interaction, drug content, solubility, dissolution rate, differential scanning calorimetry (DSC) and FT-IR study. The dissolution rate of the prepared solid dispersion systems was determined in phosphate buffer (pH 6.8) for 1 h. The solubility of drug from different systems was also determined in water. All SD formulations were found to have a higher dissolution rate comparatively to pure CA. The dissolution rate was enhanced in the following order SM > MEM > KM. The enhancement of dissolution rate may be caused by increase wettability, dispersibillity reduction in particle size or the formation of CA β crystalline. The FT-IR study probability revealed that there was no chemical interaction between drug and poloxamer 188

Preparation and characterization of cefuroxime axetil solid dispersions using poloxamer 188

The main objective of the present work was to enhance the solubility and dissolution rate of poorly water-soluble drug cefuroxime axetil (CA) by formulating it into solid dispersions (SDs) with water soluble carrier poloxamer 188. Different methods were employed to prepare the dispersion, such as: Solvent method (SM), Kneading method (KM), Melt evaporation method (MEM) and Physical mixture (PM) in different drug: carrier ratios 1:1, 1:2 and 1:3 (cefuroxime axetil: poloxamer 188). The physical mixture(s) and solid dispersion(s) were characterized for drug carrier interaction, drug content, solubility, dissolution rate, differential scanning calorimetry (DSC) and FT-IR study. The dissolution rate of the prepared solid dispersion systems was determined in phosphate buffer (pH 6.8) for 1 h. The solubility of drug from different systems was also determined in water. All SD formulations were found to have a higher dissolution rate comparatively to pure CA. The dissolution rate was enhanced in the following order SM > MEM > KM. The enhancement of dissolution rate may be caused by increase wettability, dispersibillity reduction in particle size or the formation of CA β crystalline. The FT-IR study probability revealed that there was no chemical interaction between drug and poloxamer 188

A brief review on bilayer floating tablet

Bilayer tablet is innovative period for the successful improvement of controlled release formulation along with a variety of features to provide a technique of successful drug delivery system. Controlled release dosage forms have been comprehensively used to improve therapy with several important drugs. Inclusion of drug in controlled release gastro-retentive dosage forms which can remain in the gastric region for several hours would considerably extend the gastric residence time of drugs and improve bioavailability, reduce drug waste and enhance the solubility of drugs that are less soluble in high pH environment. Numerous approaches are presently utilized in the prolongation of Gastric Retention Time, including floating drug delivery system, swelling and expanding systems, polymeric bio adhesive systems, high-density systems, modified shape systems and other deferred gastric emptying strategy

Application of physiologically based pharmacokinetic (PBPK) modeling to study the impact of Roux-en-Y gastric bypass (RYGB) surgery on the bioavailability of oral antibiotics

Understanding the mechanisms that govern drug absorption and elimination is a critical component in pharmaceutical research and development, as the oral route remains the most common method of drug administration. The utilization of in silico physiologically based pharmacokinetic modeling and simulation (PBPK M&S) has enabled the extrapolation of modeling and simulation in special populations where concerns regarding alteration in overall drug exposure may arise, such as following gastrointestinal surgery. Roux-en-Y Gastric bypass (RYGB), or partial resection of the gastrointestinal tract, leads to multiple physiological alterations that affect drug absorption. The inability to generalize and predict changes in oral drug bioavailability (Foral) following gastric bypass surgery presents a considerable therapeutical challenge to clinicians. PBPK M&S is a widely used approach for predicting the bioavailability changes in different clinical scenarios. Infection post-surgery is the most common risk factor and should be monitored and treated with utmost care. There is limited literature assessing the bioavailability changes of oral antibiotics post-gastric bypass surgery. This thesis aimed to determine the impact of gastric bypass surgery on oral drug absorption and metabolism for antibiotics such as azithromycin, cefuroxime axetil, and metronidazole. This was accomplished by applying the PBPK M&S approach to identify and define essential intrinsic elements and parameters, model implementation, and validation within a general model development framework. The developed post gastric bypass surgery PBPK model provides a framework for investigating physiological mechanisms associated with changes in systemic drug exposure after oral administration, which may result from the interplay of disintegration, dissolution, absorption, and presystemic metabolism by the intestine and liver. The developed PBPK models of azithromycin, cefuroxime axetil, and metronidazole were used to evaluate the changes in antibiotic exposure in gastric bypass surgery patients after a solid and liquid formulation. The results from solid formulation bioavailability post gastric bypass surgery model simulations suggest that the current dosing regimen for azithromycin and cefuroxime axetil may not be sufficient for treating infections, and dose modifications might be necessary. At the same time, no significant changes were observed for metronidazole bioavailability post-surgery. The results from liquid formulations of these antibiotics suggest that the azithromycin suspension presents enhanced absorption and bioavailability than the tablet formulation. In contrast, the suspension of cefuroxime axetil followed the same trend as solid formulation. Overall, this thesis demonstrates the application of PBPK M&S in the extrapolation of oral drug exposure to special populations (e.g., RYGB). The PBPK approach shows oral bioavailability to provide clinicians with an evidence-based dose selection to prevent the risk of treatment failure due decreased drug exposure of oral antibiotics post gastric bypass surgery

EFFECTS OF FORMULATION PARAMETERS ON PROPERTIES OF GASTRIC FLOATING TABLETS CONTAINING POORLY SOLUBLE DRUG: DICLOFENAC SODIUM

Objective: The objective of this study was to prepare and investigate the effects of formulation parameters on the properties of gastric floating tablets containing diclofenac sodium (DICL) as a model of poorly soluble acidic drug, sodium bicarbonate (NaHCO3) or calcium carbonate (CaCO3) as gas-forming agent, hydroxypropyl methylcellulose (HPMC) K100M or K15M as swelling polymer and sodium lauryl sulfate (SLS) as wetting agent.Methods: DICL floating tablets were prepared using direct compression method. The compressed tablets were evaluated for tablet properties, swelling index, and in vitro buoyancy. The in vitro release under non-sink condition was determined. Molecular interaction was studied using differential scanning calorimetry and fourier transform infrared spectroscopy.Results: The tablet properties of all DICL floating tablets were within the acceptance criteria. The molecular interaction between DICL and excipients in the formulation was excluded. Depends on the formulation compositions, the swelling index at 3 h (SI) ranged from 44±11 to 1158±33 %, whereas the buoyancy properties namely floating lag time (FLT) and total floating time (TFT) were 0.33±0.03 to 10.04±0.04 min and 10.0±0.0 to>12 h, respectively. NaHCO3 showed higher swelling, buoyancy and release properties compared to those of CaCO3. NaHCO3 at 20% gave sufficient swelling (SI of 1074±16 %), buoyancy (FLT of 0.39±0.03 min, TFT of>12 h) and release properties (cumulative release of 5.83±0.02 %). HPMC K100M showed better swelling property of which its initial swelling rate was 1412±25 %/h compared to HPMC K15M (1042±31 %/h). HPMC K100M at 20% showed better buoyancy and release properties compared to those obtained from HPMC K100M at 30%. The release testing under non-sink conditions was able to distinguish the effect of formulation parameters on the DICL release profiles. Incorporation of SLS at 0.25% could enhance both release rate and cumulative release of DICL from the floating tablets. Nevertheless, it showed the unacceptable adverse effect on swelling and buoyancy properties of DICL floating tablets. The TFT of DICL floating tablets containing 0.25% SLS was only 0.5±0.0 h.Conclusion: DICL floating tablets were successfully prepared. Tablets possessing suitable swelling and buoyancy properties were obtained using NaHCO3 at 20% as a gas-forming agent, with HPMC K100M at 10 and 20% as floating matrix and swelling polymer. Addition of SLS as wetting and solubilizing agent showed the unacceptable adverse effect on the swelling and buoyancy properties of DICL floating tablets. The release under sink conditions and/or in vivo pharmacokinetic studies shall be further performed

FLOATING MULTIPLE UNIT MINITABLETS OF METOPROLOL SUCCINATE: FORMULATION, IN VITRO AND IN VIVO CHARACTERIZATION

Objective: In this present research, formulation of floating multiple unit minitablets of metoprolol succinate without using gas generating agent was attempted with an objective of increased residence time, sustained release, and improved oral bioavailability. Methods: Solid dispersions were prepared with lipophilic carriers such as compritol ATO888, Gelucire 43/01, Gelucire 39/01, and precirol ATO 05 was formulated using fusion technique. Neusillin US2 was used as an adsorbent. The solid dispersions were compressed into minitablets, weighing 20 mg, and then filled into ‘0’ size capsule. Results: Formulation F9, F10, F14, and F15 showed instantaneous floating lag time, i.e., 0 min, floating time more than 12 h, and sustained release up to 12 h. Pharmacokinetic study of the optimized formulation (F9) showed 2.46 times increase in area under the curve with increased residence time. Conclusion: Hence gelucire 43/01 based floating multiple unit minitablets of metoprolol succinate can be considered a promising approach