After oral administration the hydrophilic matrix tablets are influenced by broad spectrum of conditions in the aspect of surrounding media compositions and hydrodynamic – mechanic events. Therefore, drug release from the matrix could be significantly altered. The aim of the doctoral thesis was to investigate the effect of selected parameters from this broad spectrum. New methodologies were developed to enable observation and evaluation of tested parameters during drug relase and matrix swelling. In this manner, the optimization of tablet movement in glass bead device was performed for better simulation of physiological values and the camera system for monitoring matrix swelling was evaluated. Additionally, the presence of some food components on drug release and swelling of matrix tablet containing hypromellose (HPMC) was studied. Further, the influence of tablet contact with glass beads on drug release and matrix erosion was tested. With characterization and optimization of tablet movement in the glass bead device suitable tablet velocities and frequency of velocity fluctuations were provoked by varying the amount of glass beads (15, 30 or 55 g) and stirring rate (between 6 and 18 rpm) in order to reflect the physiological range of these two parameters in the fasted and fed state stomach. For the simulation of higher frequency of velocity fluctuations that can be expressed in antrum in fed state the use of higher amount of glass beads (55 g) is recommended. For achievement of short period with high velocities the high stirring rates (120 rpm) are applied. We believe that due to this research we made a step closer to enabling biorelevant dissolution testing.
Additionally, applicability of bottom-view cameras for evaluation of tablet behaviour during dissolution testing with paddle apparatus was performed. HPMC matrix tablets were observed in the aspects of swelling and drug release. A high correlation between the relative change in tablet volume using the camera system and relative change in tablet mass based on tablet weighing was demonstrated in tested media pH range. Drug release from the matrix is affected to great extent by drug solubility and influences the swelling and transparency of the gel layer. Bottom-view camera system enables tracking of dosage form behavior and provides supplementary information for understanding the dissolution process. Also the evaluation of the matrix swelling is provided without physical interruption of dissolution test. In the first part of section regarding influence of food component the effects of ionic strength on drug release and swelling of hydrophilic matrix tablet were investigated since a tablet in in vivo enviroment can be exposued to values of ionic strength within broad interval. Matrix tablets with paracetamol and HPMC (2906) of various viscosity grades (50, 400, 1500 and 4000 mPa·s) were tested for drug release and change of matrix mass in media with different ionic strengths (0,09; 0,15; 0,31 in 0,52 M) that are within physiological range and higher. At 0,31 M the matrices of higher viscosity grades express extensive initial swelling and drug release. Matrices of lower HPMC viscosity grade responded similar as in the case of lower ionic strength media where slow and gradual swelling as well as extended drug release is observed. Nevertheless, when massive initial swelling occurs shortly after exposure to the medium the high release rates and loss of extended release from the matrices can be expected. In media with critical concentration of solutes, that effect the HPMC (2906) hydration, higher ability for enabling extended release from lower viscosity grades matrices is expected. In previous studies it was demonstrated that higher viscosity grades provide higher resistance to high solutes concentrations, however the studied type of HPMC (2208) was different. Further, the influence of sucrose and pectin, two commomnly present components in everyday diet, was investigated on matrix tablet behavior. The known effect of media with high sucrose concentration on HPMC matrix tablet can be obviated with the use of pectin as a matrix component or constituent of dissolution media. Beside drug release studies and morphological observations other techniques were applied for investigation and characterization of polymer solutions properties. Measurements of turbidity indicated decrease in cloud point by pectin beside the sucrose therefore lower hydration of HPMC is assumed. The interaction between sucrose and pectin was detected using differential scanning calorimetry. Moreover, rheological measurements demonstrated more expressed dominance of storage modulus over loss modulus for pectin-HPMC solution in sucrose media with respect to HPMC solution. Therefore higher entanglement of pectin-HPMC solution is assumed. For pectin-HPMC matrices in sucrose media we assume that stronger gel layer with sufficient integrity was formed and thus water ingress and drug diffusion was restricted. The explanation for controlled release from HPMC matrices in pectin-sucrose media might be in interaction of pectin-sucrose-HPMC on the matrix surface or in higher viscosity of dissolution media that effects the hydration of the matrix. However, further examinations are needed for explanation of mechanisms in investigated interactions. In physiological environment of a tablet are present besides food components also hydrodynamic-mechanic events. In final section of the thesis both segments were linked and tested. Therefore, the influence of mechanical stress on matrix tablets behavoir in media with various solutes concentration (sucrose, sodium chloride) was evaluated. The glass beads device and USP paddle apparatus were used since different mechanical stress and hydrodynamic are enabled. High (90SH-100000SR) or low (90SH-100SR) HPMC viscosity grade was incorporated in matrix with soluble (lactose) or insoluble (microcrystalline cellulose, MCC) diluent. At higher solutes concentration of tested range the higher drug release was observed in glass beads device. We assume that removal of the matrix gel layer is enhanced by matrix movement on glass beads surface. The effect is more expressed at higher solutes concentration since the lower integrity of the gel layer is proposed. Additionally, tablets erosion and morphology of hydrated matrices were monitored. By both parameters higher influence of matrix erosion using glass beads was indicated. The glass bead device enables additional insight in behaviour of HPMC matrix tablet in critical media where formation of gel layer is affected by mechanical stress. Presented findings of the doctoral dissertation contribute to an improved knowledge of influences on drug release from HPMC matrix tablets, especially with understanding of the matrix sensitivity to hydrodynamic and mechanic stress as well as matrix ability to form high integrity matrix when certain food components are present in the media. Additionally, the methodologies were developed to enable evaluation and observation of tested parameters that influence the swelling and release from matrix tablets.
|
