Bioadhesive Microparticles and Liposomes of Anti-Parkinson Drugs for Nasal Delivery

Abstract

The nasal route is highly promising for the delivery of drugs exerting local effects in the nose or for therapeutic molecules having systemic or CNS effect. This is attributed to the fact that the nasal epithelium is highly vascularized and permeable, which ensures rapid absorption of the drug. The limitation of short residence time of the formulations in the nose and poor bioavailability of hydrophilic drugs could be overcome by the inclusion of bioadhesive agents into formulation.
The main objective of this study was to develop novel bioadhesive microspheres and liposomes entrapping the anti-Parkinson drugs ropinirole hydrochloride (RH). The microspheres were prepared via spray drying in combination with chitosan or sodium alginate and the liposomes were prepared using the ethanol-based proliposome method. This study has investigated the potential of powdered mucoadhesive microparticles and liquid liposomes for nasal delivery via Miat® nasal insufflator and nasal spray devices respectively.
Optimum mucoadhesive chitosan microparticles were prepared by co-spray drying of chitosan glutamate and ropinirole hydrochloride (90:10 w/w). Characterization studies have revealed that the drug following spray drying was amorphous and the microparticles were spherical and offered drug entrapment efficiency values in the range of 93 - 99%. The optimum formulation provided maximum swelling capacity and slowest drug release. Ex vivo toxicity study using isolated sheep nasal mucosa proved the safety of the optimized formulations for intranasal delivery. Investigation of powder delivery demonstrated that the Miat® nasal insufflator could deliver 90% of the dose with the first puff regardless of the loading weight used to fill the capsule fitted into the nasal device. The spray cloud had elongated shape and was homogenous; this is expected to enhance the impaction of the formulation in the nose following delivery from the nasal device.
The properties of sodium alginate microparticles prepared via spray drying were highly dependent on inlet temperature of the spray drier, affecting particle morphology and product yield percent. The best performing particles were obtained when the inlet temperature was 140oC. Alginate to RH ratio had marked effect on particle size (2.60 - 4.37µm), entrapment efficiency (101 – 109%), physical state of the encapsulated RH, and morphology and surface smoothness of the particles as shown by scanning electron microscopy (SEM). In vitro drug release profile showed the amount of sodium alginate in formulations has controlled the rate of drug release. Results revealed that RH-alginate microparticles in 90:10 w/w polymer to drug ratio was the best performing spray dried formulation. Toxicity study proved safety of RH loaded sodium alginate for intranasal delivery. In contrast to RH-chitosan microparticles, particle trajectories was found from the cloud generated from emitted powder and laser diffraction demonstrated that powder was less likely to deposit in the lower respiratory tract owing to particle agglomeration.
Ethanol-based proliposome technology produced oligolamellar liposomes from lipid ethanolic solutions as revealed by transmission electron microscopy (TEM). The resultant liposomes entrapped approximately 23.30% of the drug. Using five different bioadhesive agents, inclusion of any of these agents (0.2% w/v) caused a decrease in drug entrapment except for carboxymethyl chitosan which had no effect on the drug entrapment (25.97%). Investigation of aerosolized liposome dispersion using a range of nasal spray devices demonstrated integrity of liposomes were not changed (i.e particle size, Span, and drug entrapment efficiency were unaffected) and RH-loaded liposomes were efficiently delivered from the devices.
In conclusion, the finding of this study explored mucoadhesive microspheres entrapped the anti-Parkinson drug, RH, and can potentially be applicable for nasal delivery to enhance nose to brain transport using nasal insufflator for improvement of the symptoms of Parkinson disease and Restless legs syndrome. Similar findings using nasal sprays were found for liposomes. In vivo studies are required in the future to determine the amount of the drug that may reach the blood circulation and brain.