Long-circulating liposomes of indomethacin in arthritic rats — a biodisposition study

doi:10.1016/S0031-6865(00)00023-6

Pharmaceutica Acta Helvetiae

Volume 74, Issue 4, April 2000, Pages 399-404

Pharmaceutica Acta H...

https://doi.org/10.1016/S0031-6865(00)00023-6 Get rights and content

Abstract

To improve the targeting efficiency of liposomes of indomethacin to the arthritic joints, circulation half-life of the liposomes was increased by grafting amphipathic polyethylene glycol-2000 to the bilayer surface. A comparative biodistribution study was performed between the conventional liposomes (PC:CH:PE — 1:0.5:0.16) and long-circulating liposomes (PC:CH:PE-PEG — 1:0.5:0.16) in arthritic rats. Pharmocokinetics of the drug changed significantly when administered in liposomal form. Pharmacokinetic parameters of the drug such as AUC_0-t (trapezoidal), clearance and t_1/2 (elimination half-life) changed significantly (p<0.05) when encapsulated in liposomes. Significant difference in pharmacokinetics was observed in AUC_0-t and clearance between the conventional liposomes and long-circulating liposomes. The increased AUC_0-t and reduced clearance of the durg with long-circulating liposomes, increased the availability of the drug by reducing RES uptake, in turn localization in arthritic paw tissue was also increased. A concentration of 0.33 μg of indomethacin/g of the tissue was achieved with S-liposomes after 24 h whereas it was only 0.26 μg of drug/g of the tissue with conventional liposomes. From the study, in may be concluded that the targeting efficiency of the long-circulating liposomes was about four times more than the conventional liposomes.

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.

Section snippets

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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Long-circulating liposomes of indomethacin in arthritic rats — a biodisposition study

Abstract

Introduction

Section snippets

Materials

Preparation and characterization of liposomes

Results and discussion

Acknowledgements

Adv. Drug Delivery Rev.

J. Immunol. Methods

Int. J. Pharm.

FEBS Lett.

J. Pharm. Sci.

Biochim. Biophys. Acta.

Pharm. Acta. Helv.

Git. Rev. Oncol. Hamatol.

Liposomes as carriers of antimicrobial agents or immunomodulatory agents in the treatment of infections

J. Clin. Microbial. Infect. Dis.