Development of controlled release inhalable polymeric microspheres for treatment of pulmonary hypertension

Abstract

Pulmonary hypertension (PAH) is a condition of the lungs characterised by an elevated arterial pressure and increased vascular resistance. Existing medications have to be administered frequently, resulting in non compliance by patients. Little work has been reported to date where microspheres have been developed to control the release of drug for treatment of pulmonary hypertension. To transcend this drawback, controlled release microspheres were formulated to minimise the number of doses required for treatment of PAH. Nifedipine and polyvinyl alcohol (PVA) were used as the model drug and release modifier respectively. Microspheres were developed by varying the PVA concentration using the spray drying technique. The formulated microspheres were characterised in terms of particle size, morphology, crystallinity, interaction between PVA and nifedipine via Fourier transformed infra-red spectroscopy (FTIR) and differential scanning calorimetry (DSC), in vitro release profile by employing the United States Pharmacopeia Apparatus type II and in vitro aerosolisation profile by using multi-stage liquid impinger (MSLI). The toxicity of PVA on lung epithelial cells was tested using human alveolar basal epithelium A549 cell line. From the data, it was observed that the microspheres were within the inhalable range (1-10 μm) with spherical morphology. The X-ray diffraction demonstrated that the microspheres were amorphous. There was no interaction between PVA and nifedipine during the formation of microspheres as seen by FTIR. The in vitro release profile showed a burst release followed by controlled release. A more prolonged release can be achieved by increasing the PVA:nifedipine ratio. In vitro aerosolisation showed that the Fine Particle Fractionemitted of the microspheres is greater than 20%, which is similar to that of marketed inhalation formulations. PVA was found to have insignificant effect on cell viability after 48 h of exposure to A549 cell line. In conclusion, microspheres of nifedipine and PVA, prepared by spray drying were found to exhibit suitable properties to achieve controlled release by the inhalation route. © 2013 Elsevier B.V.