Evaluation of hydrophilic polymers for applicability to swellable gastro-retentive drug delivery systems.

摘要

Gastro-retentive drug delivery systems (GRDDS) as novel oral drug delivery system present with an approach which has gained significant interest in recent years. Of many such systems, swellable GRDDS have demonstrated success and present with ease of fabrication.;The performance criteria of a swellable matrix based GRDDS were rationalized, i.e. rapid swelling should be achieved and the minimum size of the swollen matrix should be achieved, the release should be complete, the size of the matrix should be maintained through out the release period (predominantly Fickian release) and the system should have a pH independent release profile.;In this work, we have addressed all of the above issues while utilizing CR matrices with high energy solids (HES) serving as swellable GRDDS. Swellable polymers evaluated were hyrdoxypropyl methylcellulose (HPMC), Polyox RTM (polyethylene oxide) and CarbopolRTM (carbomer). Various grades of each were used with various diluents and additional agents in order to study their influence on release and most importantly, swelling behavior. To overcome the pH dependency of release, drug incorporated as HES was utilized. Dissolution data were analyzed by curve fitting to various models to estimate the predominant release mechanism. The dependence of dissolution on matrix erosion was also correlated to differentiate formulation effects.;For the HPMC based systems, it was found that matrices containing a swellable diluent like MCC 102 demonstrated predominantly Fickian mechanism of release, whereas soluble diluents (lactose and mannitol) contributed to a mixed mechanism of release. Addition of copovidone increased the swelling and survivability, whereas sodium chloride altered the erosion behavior. A correlation between matrix weight loss and drug release consolidated the analysis. Correlation for the soluble excipients was linear, whereas that for the swellable excipient was non-linear, implying predominance of Fickian release mechanism for the latter. A clear advantage in utilizing MCC 102 and copovidone was established in achieving the performance criteria of the GRDDS. Use of copovidone based HES in HPMC matrices to simultaneously overcome the solubility limitations and extend matrix survivability by preventing matrix weight loss was demonstrated.;PolyoxRTM systems demonstrated a predisposition towards erosion as predominant release mechanism with the exception of N6OK grade with MCC 102 as diluent while affording matrix survivability. It was also observed that addition of copovidone leads to matrix weight loss. However, N6OK also met the performance criteria of GRDDS.;CarbopolRTM systems demonstrated variability in drug release and showed a tendency for spontaneous matrix disruption. This property and control of release by a ternary mechanism (flakes) reduces its usefulness for the purpose of designing GRDDS.;Solubility parameters calculations using group contribution method were explored as a possible guiding tool for determining miscibility of drug substance with a polymer. Such a technique can be used to screen various polymers and consolidated by traditional methods such as thermal analysis.;GastroPlusRTM Simulations were used as a tool to visualize the PK implications of GRDDS. A comparison with the CR dosage form with similar release period of 10 hours showed that GRDDS yield with higher bio-availability (BA). Simulations were also illustrative of reduced fluctuations and provided with higher trough levels. Therefore, such systems can present with another method to dose adjust and if high tough to peak ratios presented by traditional CR dosage forms are to be minimized.;Hence, GRDDS using HES can effectively overcome the barriers presented by physiology and the drug substance properties, and meet the performance requirements for a successful GRDDS. (Abstract shortened by UMI.)