Studies On Pulsatile And Self-Regulated Drug Delivery System

Three episodes were studied, development and mathematical simulation of theophylline pulsatile release tablets, development and mathematical simulation of salbutamol sulphate pulsatile release pellets and preparation and characterization of glucose-sensitive hydrogel submicron particles using inverse microemulsions.Episode 1 Development and mathematical simulation of theophylline pulsatile release tabletsThe lag time prior to release due to rupture of coating is mainly controlled by: (1) the permeation and mechanical properties of the polymer coating, and (2) the water uptake and the swelling behavior of the swelling layer. In this paper, the development of theophylline pulsatile release tablets consisting of a fast-swelling tablet core coated with a water-insoluble ethylcellulose layer was presented.1. Effects of formulation factors, including coating material, disintegrants, coating level, diluents, subcoating, plasticizer and viscosity of coating material on the lag time and dissolution were investigated.2. The swelling of superdisintegrants was previously determined on individual particles or pure disintegrants tablets, but it's not optimal model. With film coating, the swelling property under a load was more practical. So the swelling property of different superdisintegrants which were prepared into placebo tablets under a load was determined. Results showed that normalized swelling energy of one superdisintegrant under a load was constant.3. Mechanical property of films is an important factor for the pulsatile release system. Different polymer films were prepared by casting the organic polymer solution and the mechanical properties of the films in the dry and wet states were measured by a puncture test. Results showed that the mechanical properties of the films in the wet stated were more reliable for formulation screening studies.4. According to the swelling properties of disintegrants and mechanical properties of the films, the criterion of whether the films could be ruptured was established. 5. Two kinds of mathematical models based on Fick's law were also presented to predict the lag time which integrated the effect of the permeation and mechanical properties of the coating and the swelling behavior of tablet core. Results of the water uptake experiment were used to estimate the apparent diffusion coefficient of the coating tablets. The prediction of the lag time based on the presented model is in good agreement with the experimental results. These two methods were, compared.6. Given the complexity of the system and mathematical model method was complex for practical problems, which need a series of parameters., it may be better to present the estimation of lag time by regression correlation. So, a much easier and more applicable method was constructed.7. Model dependent and model independent methods including difference factor and similarity factor were applied to compare the dissolution profiles of theophylline pulsatile release tablets. The logistic model was that which fit best to the dissolution profiles. Results showed that all methods were applicable for the comparison of dissolution profiles.Episode 2 Development and mathematical simulation of salbutamol sulphate pulsatile release pellets1. The effect of formulation, including coating material, pellets circularity, pellets diameter, and coating level, subcoating, plasticizer and viscosity of coating material on the lag time and dissolution were investigated.2. Shape factor is a very important index for controlled release pellets. Compute aided image analysis methods were applied to evaluate the shape and size of pellets. Aspect ratio, circularity, projection sphericity and e_R were used to evaluate the pellets. Results showed that e_R of pulsatile pellets should be greater than 0.7 in order to get best pulsatile release and batch consistency.3. A mathematical model based on Fick's law was also presented to predict the lag time of salbutamol pulsatile pellets. The maximum increase of volume of the core the coating can withstand was calculated by the maximum extension at breakage of the coating. The experimental and calculated results were compared by one-sample t-test and results showed that there were significant difference. So the prediction of the lag time pelletes need further improvement.4. Pharmacokinetic in vivo by four beagle dogs was studied. The pharmacokinetic parameters of the test and reference formulation were calculated by first order model and complex model. Moment parameters and relative bioavailability were also calcualted. Statistical comparison of parameters was investigated. Results showed that the lag time of pulsatile release pellets was about 3 hr, Tmax was 6 hr, and the relative bioavailability was 105.8%.Episode 3 Preparation and Characterization of Glucose-Sensitive Hydrogel Submicron Particles Using Inverse Microemulsions1. The hydrogel beads with phenylboronic acid were made using a reverse phase suspension polymerization A novel reverse microemulsion mediated synthesis was developed to prepare hydrogel submicron.2. Pseudo-ternary phase diagram of inverse microemulsions was prepared and the effects of temperature and monomer concentrations on phase behavior were evaluated. Results showed that the reverse microemulsion existence field expands as temperature increases, but phase behavior doesn't change with the monomer concentration varying.3. Glucose integration property of hydrogel beads and hydrogel nanoparticles was compared. The hydrogel nanoparticles possess a log-normal size distribution with the 867.8 nm diameter. The amount of glucose integration is improved with the glucose concentratin increased which means the submicron particles have the potential property which provide insulin release proportional to the varying blood glucose level.