Formulation and Evaluation Controlled release drug delivery systems

The anatomical, physiological and pharmacological properties of the eye explain the short pre-corneal residence time and the poor bioavailability of most eye-DROP solutions. Many approaches have been proposed to increase ocular bioavailability of drugs. Therefore, the possibility of using liposomes, niosomes and nanospheres as ophthalmic drug delivery carriers for timolol maleate (TM) was investigated.The work in this thesis is divided into three parts:Part IFORMULATION AND EVALUATION OF TIMOLOL MALEATE LOADED LIPOSOMES AS AN OCULAR DRUGDELIVERY SYSTEM.1- TM was encapsulated in various types of liposomes i.e. large unilamellar vesicles (LUVs), small unilamellar vesicles (SUVs) and multilamellar vesicles (MLVs) having either positive, neutral or negative surface charge using egg lecithin, cholesterol (Chol), stearyl amine (SA) and dicetylphosphate (DCP).2- The prepared liposomes were evaluated and effect of variables like lipid composition (Chol content and incorporation of charge inducing agents), total lipid concentration, drug concenteration and method of preparation on entrapment efficiency, in-vitro release rate and in-vivo activity were studied.3- Entrapment efficiency of TM in different liposomal preparations was studied. It was found that negatively charged liposomes gave the highest entrapment efficiency, followed by positively charged and neutral liposomes, using the same egg lecithin to Chol ratio.4- Liposomes prepared by reverse–phase evaporation technique (REVs) resulted in more than 2 fold increase in the entrapment efficiency compared to MLVs. On the otherhand, it was found that SUVs showed the lowest entrapment efficiency.5- Increasing the concentration of TM from 2.5 mg/ml to 10 mg/ml was accompanied by an increase in the amount of drug entrapped per mmole lipid.6- Increasing total lipid concentration from 60 µmole to 200 µmole resulted in increasing the entrapment efficiency (%) from 9.8±0.2 to 20.35±0.1. However, the amount of encapsulated TM per mmole lipid decreased as the lipid concentration increased.7- The in-vitro release of TM from different liposomal preparations was studied. It was found that neutral liposomes gave the highest rate and extent of drug release followed by negatively and positively charged liposomes. On the otherhand, the release rate was faster from LUVs compared to MLVs.8- LUVs and MLVs Liposomes were also investigated by transmission electron microscope for characterization.9- The ocular bioavailability of TM loaded liposomes was assessed by measuring the intraocular pressure (IOP) lowering effect in normotensive albino rabbits using a tonometer over a period of 24 hours. Duration of action, area above the curve and time for maximum response intensity were estimated. All the liposomal preparations showed prolongation in IOP lowering effect more than that observed for the control TM solution. Positively charged MLVs were found to be superior compared to other formulations in extending ocular hypotensive effect. This could be of value for formulating a long acting TM ocular preparation.10- The ocular tolerability and sterilization of the formulations tested in-vivo were investigated. Ocular tolerability results showed no evidence of inflammation in rabbits eyes. The sterilization of liposomes by heating was found to be practicable specially on the drug entrapping efficiency in the oppositely charged liposomes.