Formulation and evaluation of epoxides derived from oxygen heterocyclic compounds and indane-1, 3-diones as possible specific targeting agents for cytotoxic activity.

Venkataraman, S (2008) Formulation and evaluation of epoxides derived from oxygen heterocyclic compounds and indane-1, 3-diones as possible specific targeting agents for cytotoxic activity. Doctoral thesis, K M College of Pharmacy, Madurai.

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Abstract

An effort was made to formulate the liposomes by thin film hydration technique. Process variables influencing the formulation were vacuum pressure maintained for evaporation of solvent, speed of flask rotation, hydration volume, hydration time and hydration temp. At an optimal vacuum of 355mm Hg, the lipid films were translucent and on hydration gave a better drug entrapment. The speed of flask rotation in flask evaporator was optimized at 150 rpm with the hydration time of 60 min. Hydration volume of 5 ml and hydration temperature of 60 ± 20C produced the liposomes of required vesicle size. The optimized ratio of Cholesterol: Phosphatidyl Choline was 1:15. Based on the above optimized variables, an effort was made to formulate methotrexate and coumarin epoxide liposomal delivery system. The hydration medium used for methotrexate liposomal formulation was pH 7.4 buffer. While using the buffer as hydration and in vitro release medium, the coumarin epoxide liposome formulation showed a decrease in cumulative percentage release. This fact was evident when the invitro samples were analysed by HPLC than that of by UV method. The presence of alkali in pH 7.4 buffer might have opened the ring of coumarin epoxide. This would have been the reason for decreased release. Hence, it was decided to use only double distilled water as hydration medium and also as in vitro release medium. Compared to sonicated type, the unsonicated liposomes have shown the release for an extended duration. Similarly, the addition of charge inducer Stearylamine was not beneficial in extending the release of encapsulated drug. Among the methotrexate formulations tried, the batch coded as M3 containing 1:15:1 ratio of Drug Phosphatidyl Choline:Cholesterol showed an extended cumulative percentage release of 85.03% (in vitro release samples estimated by HPLC) for 168h; Atomic florescence microscopy (AFM) revealed the average vesicle size as 100 nm. The amount of drug originally got entrapped in the vesicles was 92.10%. Among the coumarin epoxide liposomes tried, the batch coded as C2 containing 1:15:1 ratio of drug:phosphatidylcholine:cholesterol showed an extended cumulative percentage release of 89.01% for 168h (in vitro release samples estimated by HPLC). AFM showed the average particle size as 100 nm. The percentage of drug entrapment originally was found to be 90.5% From the above discussion, we can conclude that formulation M3 of methotrexate and C2 of coumarin epoxide were the optimized batches. They were found to follow zero order release pattern as revealed by the linearity shown from the plot of time versus concentration. Higuchi plot proved that the release from formulation M3 and C2 was diffusion mediated. Optimized formulations of M3 and C2 were stable with respect to the amount of drug retained for a period of 4 weeks at 40C and affirm that the drug leakage increased at a higher temperature. Thus, liposomal coumarin epoxide of formulation C2 (drug:phosphatidylcholine:cholesterol::1:15:1) has achieved the objectives of better drug entrapment, minimum leakage and smaller vesicle size showing an extended release equivalent as that of standard, methotrexate. As an extension of this work, the formulation C2 may be linked to a suitable monoclonal antibody to produce conjugated immuno liposomes.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: epoxides; oxygen heterocyclic compounds; indane-1; 3-diones; cytotoxic activity; Formulation; evaluation
Subjects: PHARMACY > Pharmaceutics
Depositing User: Devi S
Date Deposited: 28 Jun 2017 06:32
Last Modified: 28 Jun 2017 06:32
URI: http://repository-tnmgrmu.ac.in/id/eprint/507

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