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Provesicles as Novel Drug Delivery Systems Zerrin Sezgin Bayindir and Nilufer Yuksel* Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey Abstract: Vesicular systems exhibit many attractive properties such as controlled drug release, ability to carry both hydrophilic and hydrophobic drugs, targetability and good biocompatibility. With these unique properties they can provide improved drug bioavailability and reduced side effects. Until now, many vesicular formulations have been studied in clinical and preclinical stages. Nevertheless, the major concern about these systems is their low physicochemical stability and high manufacturing expenses. The stability problems (fusion, aggregation, sedimentation, swelling, and drug leakage during storage) associated with the aqueous nature of vesicular systems hinders their effective usage. The advances on improving the stability of vesicular systems led to the emergence of provesicular systems, which are commonly described as dry, free flowing preformulations of vesicular drug delivery systems. Provesicles form vesicular systems upon hydratation with water and exhibit the advantages of vesicular systems with improved stability. The present article briefly reviews vesicular systems (particularly liposomes and niosomes) and enlightens about the innovations in the field. Overall investigations are reviewed and the provesicle approach is explained by giving detailed information on the composition, preparation, administration and characterization methods of provesicular systems (proliposomes and proniosomes). The scope of this article is expected to give insight to the researchers and industrialists to perform further research in this area.
Keywords: Administration routes, characterization, provesicles, proliposomes, proniosomes, vesicular systems. INTRODUCTION Under current conditions, the applications in pharmaceutical research area have shifted from the discovery of new chemical entities to the development of new drug delivery systems for effective and safe delivery of the existing drugs. Controlled drug delivery systems enhance patient compliance and convenience by providing drug release in the targeted site within desired periods and rates [1, 2]. In a review article, about the origin and evaluation of controlled drug delivery systems, Hoffman described the development of these systems in three stages [3]. The first stage in 1970s and 1980 was described as “macro era” and there were various macroscopic controlled drug delivery devices and implants such as mucosal inserts, implants, ingestible capsules, and transdermal patches. By further researches “macro era” was evolved to “micro era” that covered the sustained release, biodegradable microparticles and phase separated depot delivery systems. The commercial products of this era were introduced to market in 1980s and 1990s. Later on, the “nano era” that focuses on “nanotherapeutics” has started and up to now, there has been a tremendous progress in the development of nanoparticulate systems. Nanoscale drug delivery systems are designed to relevantly change the biodistribution and pharmacokinetics of the attached drug or to function as drug depots by releasing drug in a sustained manner, or both. Problems associated *Address correspondence to this author at the Ankara University, Faculty of Pharmacy, Department of Pharmaceutical Technology, Ankara, Turkey; Tel: 00 90 312 203 3155; Fax: 00 90 312 213 1081; E-mail:
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with the inherent drug properties such as low drug solubility, in vivo degradation, fast clearance rates, lack of selectivity for target tissues, non-specific toxicity, inability to cross biological barriers, and tissue damage on extravasations can be solved by these drug delivery systems [2, 4, 5]. Theoretically, the nanoscale drug delivery systems should be biocompatible, biodegradable and bioexcretable materials. The encapsulation efficiency should be high and for reduced side effects, it should be site-specific. In order to deliver the required amount of the drug to the target site, premature drug release should be zero or negligible [6]. Many nanoscale drug delivery systems are under investigation to catch the ideal conditions. The currently used nanoscale drug delivery systems include polymeric conjugates [7-9] , polymeric nanoparticles [7-8, 10] , polymeric micelles [7-8, 11, 12] , dendrimers [7-8] ,carbon nanotubes [7-8, 13] , lipid based vesicles such as liposomes [7-8, 14, 15], niosomes [15-18], and solid lipid nanoparticles [14, 19]. Among these systems, polymeric micelles, liposomes and polymeric conjugates have gained great attention. Some of them reached the drug market while the others are still under clinical investigations [4, 14, 20, 21]. In this review, we will principally describe the vesicular drug delivery systems as lipid base nanoscale drug delivery systems. In order to provide a theoretical basis, we will start by briefly reviewing the properties of the most commonly used vesicular systems; liposomes and niosomes. After evaluating the characterization methods and stability properties of vesicular systems, the article will focus on provesicular systems. These systems will be detailed by describing proliposomes and proniosomes. The compositions, prepara© 2015 Bentham Science Publishers
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tion methods, administration routes and applications of these systems will be reviewed in depth. 1. VESICULAR SYSTEMS Vesicular systems are colloidal spherical particles walled by single- or multiple-lipid bilayers in which they contain aqueous phase and behave similarly to biological membranes. These closed bilayer structures are formed by the self-assembly of amphiphilic molecules in aqueous media (Fig. 1). However the self-assembly requires an energy input such as hand shaking, ultrasound, heat, etc. The association of amphiphilic molecules as vesicles is induced by the high surface tension between the hydrophobic parts of these molecules and the aqueous phase. The transfer of hydrophobic chains into lipid bilayers in order to hinder from contacting water is associated with the free energy changes (∆G). The outcome of this is the distinct orderliness (negative entropy, ∆S) and the reduction in free energy (ΔG) along with the effect of hydrophobic chain length. So, van der Waals attractions, hydrogen bond formation and electrostatic interactions contribute to favorable enthalpy (ΔH) that leads the self-assembly of amphiphiles. The thermodynamically stable vesicles are formed in the presence of charge inducers that provide the colloidal stability, and by the addition of adequate amounts amphiphile molecule. The other physicochemical parameters are hydrophilic-lipophilic balance (HLB) and geometrical structure of the amphiphilic molecules [6]. The geometric parameter that affects the self-assembly of spherical vesicles is the relative size of the hydrophobic head to hydrophilic tail on the neutral amphiphilic molecules. CPP (the critical packing parameter) is calculated with the following equation: v/aolc in which v and lc are the volume and critical length of the hydrophilic tail and ao is the area of the hydrophobic head groups of the amphiphile (Fig. 2). Amphiphiles assemble bilayered structures, cylindrical vesicles, spherical vesicles or reverse micelles in respective cases:
Fig. (1). Schematic representation of the vesicular drug delivery systems.
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