Pharmacosomes: A Potential Alternative to Conventional Vesicular Systems

An ideal controlled drug-delivery system should possess two characteristics: the ability to reach its therapeutic target and the ability to release the active pharamceutical ingredient in a controlled manner (1). One way to modify the original biodistribution of substances is to entrap them in submicroscopic drug carriers such as liposomes, transferosomes, niosomes, polymeric nanoparticles serum proteins, immunoglobulins, microspheres, erythrocytes, reverse micelles, monoclonal antibodies, and pharmacosomes (2, 3). However, these vesicular systems are associated with many problems. For example, drug carriers such as particulates (e.g., liposomes, nanoparticles, microemulsions) and externally triggered (e.g., temperature-, pH-, or magnetic-sensitive) carriers load drugs passively, which may lead to low drug-loading efficiency and drug leakage in preparation, preservation, and transport in vivo (1). Table I lists some vesicular system–specific problems.

Table I: Problems associated with conventional vesicular systems (4).

A potential solution for these problems is the use of pharmacosomes. Pharmacosomes are like a panacea for most of the problems associated with liposomes, transferosomes, niosomes, and so forth. They are an efficient tool to achieve desired therapeutic goals such as drug targeting and controlled release (see sidebar, "Advantages of pharmacosomes").

Advantages of pharmacosomes (4, 18).

Definition and usage. 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 the drug–lipid complex (4). Because the system is formed by linking a drug (pharmakon) to a carrier (soma), they are called pharmacosomes (5). Singh et al. used the expression "vesicular constructs" in common for pharmacosomes, liposomes, niosomes, and biosomes and encapsulated the antibiotic amoxicillin in their aqueous domains, which were prepared using phosphatidylethanolamine with various molar ratios of phosphatidyl-choline and cholesterol. They stabilized the formulation using an acylated protein base and reportedly improved cytoprotection and treatment of Helicobacter pylori infections in male rats (6).

In many aspects, pharmacosomes provide advantages over the use of other vesicular systems such as transferosomes, liposomes, and niosomes. Any drug possessing a free carboxyl group or an active hydrogen atom (–OH, NH₂) can be esterified (with or without a spacer group) to the hydroxyl group of a lipid molecule, thus generating an amphiphilic prodrug. An amphiphilic prodrug is converted to pharmacosomes upon dilution with water (7). The prodrug conjoins hydrophilic and lipophilic properties (thereby acquiring amphiphilic characteristics), reduce interfacial tension, and, at higher concentrations, exhibit mesomorphic behavior (4). Because of a decrease in interfacial tension, the contact area increases, therefore increasing bioavailability (8). Some formulation approaches and in vivo performances of pharmacosomes are presented in this article.

Preparation. Two methods have been used to prepare vesicles: the hand-shaking method and the ether-injection method. In the hand-shaking method, the dried film of the drug–lipid complex (with or without egg lecithin) is deposited in a round-bottom flask and upon hydration with aqueous medium, readily gives a vesicular suspension. In the ether-injection method, an organic solution of the drug–lipid complex is injected slowly into the hot aqueous medium, wherein the vesicles are readily formed. Like other vesicular systems, pharmacosomes are characterized for attributes such as size and size distribution, nuclear magnetic resonance (NMR) spectroscopy, entrapment efficiency, in vitro release rate, and stability studies (9, 10).

An alternative approach for producing pharmacosomes was recently reported in which a biodegradable micelle-forming drug conjunct was synthesized from the hydrophobic drug adriamycin and a polymer composed of polyoxyethylene glycol and polyaspartic acid. This approach has the benefit that although it may be possible to dilute out the micelle, the drug will probably not precipitate because of the water solubility of the monomeric drug conjunct (11). Muller-Goymann and Hamann produced fenoprofen pharmacosomes using a modified technique that involved diluting lyotropic liquid crystals of amphiphilic drugs (12).

Attempts have been made to attach drugs such as β-blockers to various glyceride-like groups, and the resulting amphiphilic molecules have been spontaneously dispersed. They were labeled pharmacosomes because of their tendencies to form unilamellar vesicles. It was suggested that these molecules should enhance lymph transport (13). Zhang et al. attempted to optimize the preparation of 3', 5'-dioctanoyl-5-fluoro-2'-deoxyuridine pharmacosomes. Their study found that the drug phosphatidylcholine ratio, pluronic F-68 concentration, and glycerol tristearate concentration have an influence on the mean particle size, entrapment ratio, and drug loading (14).

Zhang and Wang showed that the pharmacosomes can improve the ability of a drug to cross the blood–brain barrier and act as a promising drug-targeting system for the treatment of central nervous system disorders (15). In another study, didanosine pharmacosomes were prepared and the in vivo behavior in rats was investigated. The study revealed liver targeting and sustained-release effect in rats after i.v. administration. The study found that there was targeting in the lung and spleen and that drug elimination from the target tissues was slow (16).

The pharmacosomes prepared from the lipophilic diglyceride derivative of the drug (pindolol), enhanced the plasma concentrations of the drug three to five folds higher when compared with its free form. Moreover, the administration of pharmacosomes led to a lower renal clearance (17) (see Table II).

Table II: Effect on biological activity of drugs, after incorporation in pharmacosomes.

Conclusion

The approach of pharmacosomal drug delivery possesses many advantages over conventional vesicular systems. Pharmacosomes have immense potential, and further advantages of the vesicular system can be exploited by extending this approach to additional drugs. The influence of spacer groups and linkage also should be observed more rigorously for further improvement in drug-fate and biological activity of the drug to achieve the therapeutic goal.

Sandeep Sangwan is a research scholar, and Harish Dureja* is a lecturer, both at the department of pharmaceutical sciences, M.D. University, Rohtak 124 001, India, tel. +91 94163 57995, fax +91 1262 274169, harishdureja@rediffmail.com.

*To whom all correspondence should be addressed.

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