Long-circulating liposomes of indomethacin in arthritic rats — a biodisposition study
Introduction
Liposomes are phospholipid-based vesicles. These colloidal range carrier systems have been used as drug carriers in the last few decades. Liposomal drug delivery systems have resulted in increased therapeutic efficacy for a variety of substances in areas such as cancer chemotherapy (Kim, 1994), antimicrobial therapy (Sugarman and Pereg-Soler, 1992, Bakker-Woundenberg et al., 1993), vaccines (Alving, 1991), gene therapy (Smith et al., 1993), opthalmology (Niesman, 1992), inflammation therapy (Shoji et al., 1986) and diagnostic applications (Seltzer, 1989). Many of the applications are based on the fact that liposomes are widely taken up by the RES cells in liver and spleen. However, liposomal drug delivery to the cells other than RES has been difficult, as they are often eliminated from the circulation by cells of MPS (mononuclear phagocytic system) before effective delivery of the drugs to extravascular, and perhaps some intravascular, target sites can be achieved. The shortcomings with coventional liposomes have been overcome to some extent by modifying the bilayer surface with monosia gangliosides GM1 or grafting polymers such as polyethylene glycols (Allen, 1994).
Non-steroidal anti-inflammatory agents (NSAIDs), and in particular, indomethacin are the most widely used anti-inflammatory drug inspite of the severe adverse effects such as ulceration of gastrointestinal tract, frequent CNS disturbances and kidney toxicity. The ulceration can also be explained on the basis of inhibition of prostaglandin generation because these phospholipid metabolites are important for the maintanance of the protective mucus layer of the gut. It is assumed that incorporation of this drug in liposomes may reduce these side effects by reducing the availability of the drug in systemic circulation and increased accumulation in the sites of inflammation, possibly by extravascularization through the gaps formed between the endothelial cells of the vasculature (Simionescu, 1980)
The authors have already studied the effect of lipid composition and size on the targeting potential of liposome encapsulated indomethacin in arthritic rats (Srinath et al.,1999). The present work was aimed at increasing the circulation time of these liposomes by grafting polyethylene glycol-2000 to the lipid bilayer surface and understanding the distribution, elimination, localization profile of the drug in the inflammatory tissues.
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Materials
Phosphatidyl choline from egg yolk, phosphatidyl ethanolamine and cholesterol were purchased from Sigma, USA. Triethylamine (<99% purity) was a product of Aldrich. PE-PEG was synthesized as described in previous reports (Klibanov et al., 1990) and the structure was confirmed with NMR. Indomethacin was a gift sample from Astra IDL, Bangalore, India. Acetonitrile, methanol, water and acetic acid were of HPLC grade (Qualigens, India) and all other reagents were of analytical grade.
Preparation and characterization of liposomes
Two sets of
Results and discussion
Pharmacokinetics of drugs encapsulated in carrier systems is complicated by the intermingling of two separate pharmacokinetic processes, that of the carrier as well as the drug. However, the ultimate objective in performing such studies is to know the rate and extent of availability of the drug in the diseased organ/tissue. It is often very difficult to estimate the drug released in the organs as it is not possible to separate the encapsulated drug and the free drug from the tissue samples.
Acknowledgements
One of the authors P. Srinath, is grateful to CSIR, New Delhi, for awarding the Senior Research Fellowship. The authors thank Dr. K.V. Raghavan, Director, Indian Institute of Chemical Technology, Hyderabad and Prof. V.K. Dixit, Head, Department of Pharmaceutical Sciences, Dr. M.S. Gour University for providing necessary facilities.
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