PHARMACOSOMES: AN OVERVIEW
Various types of vesicular systems such as liposomes, niosomes, transfersomes, and pharmacosomes, etc, have been developed in the transport and targeting of active agents. Pharmacosomes are the colloidal dispersions of drugs covalently bound to lipids, and may exist as ultrafine vesicular, Micellar, or hexagonal aggregates, depending on the chemical structure of drug-lipid complex.
This system shows low entrapment efficiency and drug leakage during storage for hydrophilic drugs. Pharamcosomes have some importance in escaping the tedious steps of removing the free from entrapped drug. Similar to other vesicular system pharmacosomes provide an efficient method for delivery of drug directly to the site of infection, leading to reduction of drug toxicity with no adverse effects also reduces the cost of therapy by improved bioavailability of medication, especially in case of poorly soluble drugs. Pharmacosomes are suitable for incorporating both hydrophilic and lipophilic drugs.
These are defined as colloidal dispersions of drugs covalently bound to lipids, and may exist as ultrafine vesicular, Micellar, or hexagonal aggregates, depending on the chemical structure of drug-lipid complex. The prodrug conjoins hydrophilic and lipophilic properties, and therefore acquires amphiphilic characters, and similar to other vesicle forming components, was found to reduce interfacial tension, and at higher concentrations exhibits mesomorphic behavior.(1) Many constraints of various classical vesicular drug delivery systems, such as problems of drug incorporation, leakage from the carrier, or insufficient shelf life, can be avoided by the pharmacosome approach. The idea for the development of the vesicular pharmacosome is based on surface and bulk interactions of lipids with drug. Any drug possessing an active hydrogen atom (-COOH, -OH, -NH2, etc.) can be esterified to the lipid, with or without spacer chain. Synthesis of such a compound may be guided in such a way that strongly result in an amphiphilic compound, which will facilitate membrane, tissue, or cell wall transfer, in the organism. Merits (3)
• Entrapment efficiency is not only high but predetermined, because drug itself in conjugation with lipids forms vesicles.
• Unlike liposomes, there is no need of following the tedious, time-consuming step for removing the free, unentrapped drug from the formulation.
• Since the drug is covalently linked, loss due to leakage of drug, does not take place. However, loss may occur by hydrolysis.
• No problem of drug incorporation
• Encaptured volume and drug-bilayer interactions do not influence entrapment efficiency, in case of pharmacosome. These factors on the other hand have great influence on entrapment efficiency in case of liposomes
• The lipid composition in liposomes decides its membrane fluidity, which in turn influences the rate of drug release, and physical stability of the system. However, in pharmacosomes, membrane fluidity depends upon the phase transition temperature of the drug lipid complex, but it does not affect release rate since the drug is covalently bound
• The drug is released from pharmacosome by hydrolysis (including enzymatic).
• Phospholipid transfer/exchange is reduced, and Solublization by HDL is low.
• The physicochemical stability of the pharmacosome depends upon the physicochemical properties of the drug-lipid complex.
• Due to their amphiphilic behavior, such systems allow, after medication, a multiple transfer through the lipophilic membrane system or tissue, through cellular walls piggyback endocytosis and exocytosis.
• Following absorption, their degradation velocity into active drug molecule depends to a great extent on the size and functional groups of drug molecule, the chain length of the lipids, and the spacer. These can be varied relatively precisely for optimized in vivo pharmacokinetics.
• They can be given orally, topically, extra-or intravascularly Preparation and characterization: The aqueous solution of these amphiphiles typically exhibits concentration dependent aggregation.
At low concentration the amphiphiles exists in the Monomer State. Further increment in monomers may lead to variety of structures i.e micelles of spherical or rod like or disc shaped type or cubic or hexagonal shape. Mantelli et al., compared the effect of diglyceride prodrug on interfacial tension, with the effect produced by a standard detergent dodecylamine hydrochloride, and observed similar effect on lowering of surface tension. Above the critical micelle concentration (CMC), the prodrug exhibits mesomorphic lyotropic behavior, and assembles in supramolecular structures. (2,3) The prepared prodrugs are generally characterized for their structural conformation (by IR, NMR spectrophotometry, thin layer chromatography (TLC), melting point determination), partition coefficient, surface tension, and prodrug hydrolysis. Hand-shaking method and ether injection method have been utilized for preparing vesicles. In hand-shaking method, the dried film of the drug-lipid complex (with or without egg lecithin) deposited in a round bottom flask upon hydration with aqueous medium, readily gives a vesicular suspension. In ether injection method, organic solution of the drug-lipid complex was injected slowly into the hot aqueous medium, wherein the vesicles are readily formed. (1, 3) Like other vesicular systems, pharmacosomes are characterized for different attributes such as size and size distribution, nuclear magnetic resonance (NMR) spectroscopy, entrapment efficiency, in vitro release rate, stability studies, etc. The approach has successfully improved the therapeutic performance of various drugs i.e. pindolol maleate, bupranolol hydrochloride, taxol, acyclovir, etc (4, 5) Stability (3) Kaiser studied the effect of different electrolyte media on physicochemical stability of bupranolol hydrochloride pharmacosomes. Since polar hydrophilic head group group is very sensitive towards different electrolytes, spontaneous aggregation was observed at at different concentration depending upon the valency of the electrolyte. However aggregation in the presence of non-electrolyte moderate to indifferent. Best candidate for isotonization was found to be 5 % glucose. Applications (3) The approach has successfully improved the therapeutic performance of various drugs i.e. pindolol maleate, bupranolol hydrochloride, taxol, acyclovir, etc. yang et.al. Found that CDP – diacyl prodrug initially forms large vesicles, which diminish in size and finally form micelles. They shows that slow kinetics are essential requirement for Phospholipid on bimembrane in order to confer stability to the lipid bilayer and prevent the rapid exchange of lipids between membranes of living cells.the phase transition temperature of pharmacosomes in the vesicular and Micellar state could have significant influence on their interaction with membranes. Pharmacosomes can interact with bimembranes enabling a better transfer of active ingredient this interaction leads to change in phase transition temperature of bimembranes thereby improving the membrane fluidity leading to enhance permiations.
Pharmacosomes bearing an unique advantages over liposomes and niosomes vesicles, have come up as potential alternative to conventional vesicles. Like other vesicular drug delivery systems, pharmacosomes, on storage, undergo fusion and aggregation, as well chemical hydrolysis. Similar to other vesicular system pharmacsomes still play an important role in the selective targeting, and the controlled delivery of the controlled delivery of various drugs. Current research trends are generally based on using different approaches like pegylation, biotinyzation etc. for cellular targeting.
1. Vaizoglu, O. and Speiser, P. P., Acta Pharm Suec, 1986, 23, 163.
2. Mantelli, S., Speiser, P. and Hauser, H., Chem. Phys. Lipids, 1985, 37, 329
3. N.K. Jain “advance in novel controlled drug delivery system” page no. 276.
4. Steve, A., U. S. patent US S, 534, 499 (C1 S14-25, A61K31/70), 1996, 9july, p 11.
5. Taskintuna, I., Banker, A. S., Flores-Aguilar, M., Lynn, B. G., Alden, K. A., Hostetler, K. Y. and Freeman, W. R., Retina, 1997, 17, 57.
6. Krishnan, L., Sal, S., Patil, G.B. and Sprott, G.D., J. Immunol, 2001, 166, 1885.