topiramate and ethyl-cellulose

In our previous study, polyvinylpyrrolidone (PVP) was used both as a binder and a pore-former to prepare ethylcellulose (EC)-coated pellets to deliver topiramate (TPM) for a controlled release profile. The objective of this work was to further optimize the formulation and evaluate the in vivo profiles of TPM sustained-release pellets. Similar to the previous formulation with no binder, the in vitro drug release of TPM sustained-release pellets with 50% PVP binder in drug layer was sensitive to pore-former PVP level ranged from 27.0% to 29.0%. The higher the level of PVP was, the quicker release rate in vitro was. Moreover, when the proportion of poreformer PVP decreased, the Cmax decreased, and the tmax and mean residence time of TPM coated pellets were both prolonged. The in vitro release profile of optimal formulation showed biphasic release characteristics similar to reference formulation Trokendi XR(®), i.e., involving immediate release of TPM in initial release stage followed by a sustained release up to 24 h. Moreover, the impact of the pH of release medium on the drug release rate of TPM sustained-release pellets was not significant. The release mechanism of TPM from the sustained-release pellets might be the interaction of diffusion (coating-film) and corrosion (drug layer). The in vivo pharmacokinetics results showed the TPM sustained-release pellets had the similar in vivo pattern compared with Trokendi XR(®). These studies provide valuable basis for further development of TPM sustained-release pellets.

Topics: Animals; Anticonvulsants; Biological Availability; Cellulose; Chemistry, Pharmaceutical; Delayed-Action Preparations; Diffusion; Dogs; Drug Implants; Drug Liberation; Fructose; Porosity; Povidone; Surface Properties; Topiramate

Delivering sparingly water-soluble drugs from ethylcellulose (EC) coated pellets with a controlled-release pattern remains challenging. In the present study, hydrophilic polyvinylpyrrolidone (PVP) was used both as a binder and a pore-former in EC coated pellets to deliver sparingly water-soluble topiramate, and the key factors that influenced drug release were identified. When the binder PVP content in drug layers below 20% w/w was decreased, the physical state of topiramate changed from amorphous to crystalline, making much difference to drug solubility and dissolution rates while modifying the drug release profile from first-order to zero-order. In addition, without PVP in drug layering solution, drug layered particles were less sticky during layering process, thus leading to a shorter process and higher loading efficiency. Furthermore, PVP level as a pore-former in EC coating layers mainly governed drug release from the coated pellets with the sensitivity ranging from 23% to 29%. PVP leaching rate and water permeability from EC/PVP film increased with the PVP level, which was perfectly correlated with drug release rate. Additionally, drug release from this formulation was independent of pH of release media or of the paddle mixing speed, but inversely proportional to the osmolality of release media above the physiological range.

Topics: Anticonvulsants; Cellulose; Chemistry, Pharmaceutical; Crystallization; Drug Carriers; Drug Implants; Fructose; Hydrophobic and Hydrophilic Interactions; Kinetics; Models, Chemical; Osmolar Concentration; Porosity; Povidone; Solubility; Surface Properties; Technology, Pharmaceutical; Topiramate; Water