ABSTRACT
CONTEXT: Development of carvedilol-loaded transfersomes for intranasal administration to overcome poor nasal permeability and hepatic first pass effect so as to enhance its bioavailability. OBJECTIVE: The purpose of this study was to develop carvedilol-loaded transfersomes containing different edge activators (EAs) then evaluating the in vivo behavior of the optimized formula in rabbits. METHODS: The vesicles were prepared by incorporating different EAs including Span 20, Span 60, Tween 20, Tween 80, and sodium deoxycholate (SDC) in the lipid bilayer and each EA was used in three different ratios with respect to phosphatidylcholine (PC) including 95:5%, 85:15%, and 75:25% w/w (PC:EA). Evaluation of transfersomes was carried out in terms of shape, size, entrapment efficiency (EE), in vitro release, ex vivo permeation, confocal laser scanning microscopy (CLSM), and stability studies. The pharmacokinetic study of the optimized formula was conducted in rabbits. RESULTS: The mean diameter of the vesicles was in the range of 295-443 nm. Transfersomes prepared with 95:5% (w/w) (PC:EA) ratio showed highest EE% where Span 60 gave the highest values. Whereas those prepared using 85:15% w/w ratio showed highest percentages of drug release where SDC was superior to other EAs. The developed transfersomes exhibited significantly higher amounts of carvedilol permeated through nasal mucosa. CLSM of formula T14 containing SDC with 85:15% (w/w) (PC:EA) ratio revealed high permeation across the nasal mucosa. CONCLUSION: The nanotransfersomal vesicles were significantly more efficient in nasal delivery of carvedilol with absolute bioavailability of 63.4%.
Subject(s)
Carbazoles/administration & dosage , Carbazoles/pharmacokinetics , Drug Carriers/administration & dosage , Drug Delivery Systems/methods , Propanolamines/administration & dosage , Propanolamines/pharmacokinetics , Animals , Biological Availability , Carbazoles/chemistry , Carvedilol , Drug Carriers/chemistry , Drug Carriers/pharmacokinetics , Drug Liberation , Nasal Absorption/drug effects , Particle Size , Permeability , Propanolamines/chemistry , Rabbits , Skin AbsorptionABSTRACT
The aim of this work was to statistically optimize a novel high-dose, mesalazine colonic delivery matrix system, potentially suitable for once daily administration, using simple wet granulation method. A hydrophobic-hydrophilic polymeric blend was used to manipulate drug release. A three-factor, three-level Box-Behnken design was used to construct polynomial models correlating the dependent and independent variables. Independent formulation variables were the percentages of the hydrophilic polymer Carbopol® 940, hydrophobic polymer Eudragit® RS, and the superdisintegrant croscarmellose sodium. The cumulative percentages of drug released at 6, 10, and 14 h were selected as dependent variables and restricted to 7.5-22.5% (Y(1)), 42.5-57.5 % (Y(2)), and 72.5-87.5% (Y(3)), respectively. A second-order polynomial equation fitted to the data was used to optimize the independent formulation variables. Based on Box-Behnken experimental design, different mesalazine release profiles were obtained. The optimized formulation containing 5.72% Carbopol®, 9.77% Eudragit® RS, and 1.45% croscarmellose sodium was prepared according to the software determined levels. It provided a release profile which was very close to the targeted release profile, where the calculated values of f(1) and f(2) were 8.47 and 67.70, respectively, and followed zero-order release kinetics.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/chemistry , Colon , Excipients/chemistry , Mesalamine/chemistry , Models, Chemical , Models, Statistical , Polymers/chemistry , Technology, Pharmaceutical/methods , Acrylic Resins/chemistry , Administration, Oral , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Carboxymethylcellulose Sodium/chemistry , Chemistry, Pharmaceutical , Delayed-Action Preparations , Drug Administration Schedule , Drug Compounding , Drug Stability , Hydrophobic and Hydrophilic Interactions , Kinetics , Mesalamine/administration & dosage , Regression Analysis , Reproducibility of Results , Solubility , Tablets, Enteric-CoatedABSTRACT
Glucose monohydrate and sorbitol were evaluated as alternative carriers to á-lactose monohydrate in dry powder inhalations. Cromolyn sodium (CS) - carrier binary formulae were prepared and tested in vitro by aerosolization via a twin stage impinger using three types of inhaler devices; Spinhaler, Aerolizer and Handihaler. Glucose monohydrate and sorbitol-containing formulae that were inhaled via a Handihaler showed significantly higher drug fine particle fractions (P<0.001) than that of the same formulae aerosolized via other devices. Upon storage of the prepared formulae under uncontrolled humidity, that may be encountered during storage and use, marked reductions in these fractions were observed. Incorporation of an optimum Aerosil 200 concentration, as a ternary component, minimized this effect. A urinary excretion pharmacokinetic method was used to evaluate the bioavailability of the selected ternary formulae, inhaled via a Handihaler, relative to the marketed Intal Spincaps, inhaled via a Spinhaler. It was found that the relative bioavailability percentages of the developed formulae were more than twice that of the marketed one suggesting possible future utilization of these more effective ternrry formulae using the more efficient Handihaler inhaler device.
