Synthesis and Evaluation of Some Polymeric Drug Delivery Systems

Ravichandran, J K (2010) Synthesis and Evaluation of Some Polymeric Drug Delivery Systems. Doctoral thesis, The Tamilnadu Dr. M.G.R. Medical University, Chennai.


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This thesis deals with the investigations carried out by the writer on the synthesis, characterization and evaluation of some polymeric pro-drugs. The First chapter of the thesis deals with a brief introduction to controlled drug delivery systems, passive drug targeting and specific tissue targeting , cellular uptake of polymers, site specific drug release, polymer conjugates, incorporation of spacers in pro-drug conjugates, PEG chemistry and use of Dextran in drug delivery. The use of antiviral drug namely, zidivudine, problems associated with its use and a literature survey on the investigations that have been carried out on polymeric drug conjugates of zidovudine are briefly given. The Second chapter of the thesis deals with the scope and objective of the present investigations in detail. It explains, in particular, how when zidovudine is linked covalently to biocompatible polymers through succnic spacer should lead to a better drug delivery system capable of releasing of the drug in a sustained manner. The Third chapter of the thesis deals with the experimental procedures that are adopted in the preparation of the polymeric pro-drugs, estimation of the drug content, in vitro drug release studies, enzymatic hydrolysis, stability studies and bioavailability studies. The Fourth chapter of the thesis deals with the results obtained in the present study along with a detailed discussion of the results supported by chemical equations, tables, figures, etc. The following are some of the important findings in the present study: • Two macromolecular pro-drugs of the known antiviral drug zidovudine were synthesized by conjugating it with poly (ethylene glycol)1500, and detrain through succinic spacer. The pro-drugs were thoroughly characterized in terms of IR, and H1NMR. • In order to obtain some preliminary information about the potential use of the PEG-O-succinylzidovudine and DEX-O-succinylzidovudine as drug delivery systems for both oral and systemic administration, in vitro hydrolysis studies were performed by subjecting the conjugates to hydrolysis in buffer solutions at pH 1.1 (simulated gastric juice), at pH 5.5 (endosomal compartments) and at pH 7.4 (extracellular fluids) and at pH 8 in the presence and in the absence of α-chymotrypsin. It was found that, at all pH values considered, free zidovudine was always released from 5’-O-succinylzidovudine derivative. Even if 5’-O-succinylzidovudine was released from the macromolecular pro-drugs, it was in turn be hydrolysed to give free and active zidivudine. The amount of zidovudine released from PEG-O-succinylzidovudine was more than that from DEX-O-succinylzidovudine. It was also found that the release rate of zidovudine from 5’-O-succinylzidovudine derivative decreased as the pH value increased. A different trend was noticed in the case of release of zidovudine from the polymer drug conjugates. The release of drug was minimum at pH 5.5 buffer solution. This drug release can be attributed to influence of pH value on the hydrolysis rate of low molecular weight ester compounds. • It was found that nearly 45% and 28% and 16% of zidovudine was released from PEG-O-succinylzidovudine and DEX-O-succinylzidovudine and 5’-O-succinylzidovudine respectively. These results confirm the capacity of macromolecular conjugates to release free drug by hydrolytic activity of α-chymotrypsin. The ester bond between zidovudine and the succinic spacer would seem more susceptible to this enzymatic hydrolysis than the ester bond between 5’-O-succinylzidovudine and the polymeric carrier. • Stability studies carried out for the pro-drugs for a period of three months as per ICH guidelines indicate that no major physical and chemical changes occur in the polymeric pro-drugs during storage period indicating the stability of the pro-drugs. • The ability of the synthesized macromolecular pro-drugs to release free drug was also evaluated in human plasma. It was found that nearly 60% of linked zidovidine was released from PEG-O-succinylzidovudine within 12h, were as nearly 25 of zidovidine was released from DEX-O-succinylzidovudine. The plasmatic hydrolysis of 5’-O-succinylzidovudine showed that about 30% of the drug derivative was hydrolysed to give free zidovudine within 12h indicating that the amount of 5’-O-succinylzidovudine released from the polymeric pro-drug can in turn be hydrolysed to give free zidovudine. • The release of Zidovudine and 5’-O-succinylzidovudine from the macromolecular pro-drugs was found to be pH dependent. It was found that the release of Zidovudine and 5’-O-succinylzidovudine from PEG-O-succinylzidovudine follows first order kinetics at different pH. However, the release of zidovudine and 5’- -succinylzidovudine from DEX-O-succinylzidovudine follows zero order kinatics. • An analysis of pharmacokinetic data shows that there is a distinct difference in plasma concentration response between the free drug and the pro-drugs. There is a slower rate of drug absorption for the polymeric pro-drugs when compared to the free drug as evident from the delayed tmax values for the pro-drugs. Further, the extent of absorption of the pro-drugs is complete and is comparable with the free drug. This reveals the potential of the polymeric pro-drugs in the present study in sustaining the drug release in In-vivo conditions also. However it was found that the absorption of the drug was comparatively more in the case of DEX-O-succinylzidovudine than that from PEG-O-succinylzidovudine. This may be due to the biodegradation of dextran itself in the system by the enzyme dextranase. This reveals the potential of these pro-drugs in sustaining the drug release in In-vivo conditions thus leading to drug release systems capable of avoiding or minimizing the side effects. The macromolecular pro-drugs are thus capable of reducing the frequency of drug administration and improve patient compliance.

Item Type: Thesis (Doctoral)
Uncontrolled Keywords: Synthesis, Evaluation, Polymeric Drug Delivery Systems.
Subjects: PHARMACY > Pharmaceutical Chemistry
Depositing User: Devi S
Date Deposited: 27 Jun 2017 06:27
Last Modified: 16 Sep 2022 02:55

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