DESIGN, IN VITRO AND IN VIVO EVALUATION OF CHRONOMODULATED DELIVERY SYSTEMS OF TERBUTALINE SULPHATE FOR NOCTURNAL ASTHAMA

The present study deals with the design and evaluation of chronomodulated delivery of terbutaline sulphate as a chronotherapeutic approach in the treatment of nocturnal asthma. The basic design is based on the Pulsincap technology and consisted of formaldehyde treated insoluble hard gelatin capsule body filled with glutaraldehyde cross-linked carboxymethyl chitosan microspheres of terbutaline sulphate and sealed with a hydrogel tablet plug. The entire device was enteric coated, so as to prevent the variable gastric emptying time. The glutaraldehyde cross-linked carboxymethyl chitosan microspheres appeared to be roughly spherical with the size range of 4.63±0.48 to 11.75±0.92µm. The prepared microspheres possessed good yield and high encapsulation efficiency. Particle size, encapsulation efficiency and release rate are dependent on the fabrication conditions of the microspheres. Drug release from the microspheres depended on the core: coat ratio, reaction time and the rotational speed used in the preparation of microspheres. Formaldehyde treatment efficiently rendered the hard gelatine capsule bodies water insoluble. The ejection of the plug from the chrnomodulated delivery system depended on the nature and concentration of polymer used in the preparation of table plug. A lag time of 3-8hrs was observed for the chronomodulated delivery systems prepared with different hydrogel plugging materials. Among the different polymers studied, HPC showed highest lag time compared to HPMC K4 M and sodium alginate. The Roentgenographic studies revealed the predicted in vivo performance of the developed chronomodulated delivery systems of terbutaline sulphate. Pharmacokinetic analysis revealed the significant increase in tmax, AUC and MRT of optimized chronomodulated system of terbutaline sulphate compared to that of pure drug. The results of the study conclusively proved the suitability of carboxymethyl chitosan microspheres and the adopted Pulsincap technology in the development of chronomodulated delivery systems for terbutaline sulphate in the treatment of nocturnal asthma. Key words: Nocturnal asthma; Terbutaline sulphate; Chronomodulated systems; Lag time; Roentgenography; In vivo pharmacokinetic