The effect of added liposomes on the rheological properties of a hydrogel: A systematic study
Graphical abstract
The effect of adding different types and concentrations of liposomes in a gel on the gel rheological characteristics was studied.
Introduction
When mucosal or topical (especially vaginal) delivery of liposome formulations is considered [1], [2], the rheological and/or mucoadhesive properties of the liposome dispersions should be adjusted accordingly, depending on the intended route of administration. This can be achieved by adding gelling agents in liposome dispersions [3], [4], resulting in drug-in-liposome-in gel, complex formulations.
Such complex gel formulations have been recently studied in our lab in terms of vesicle integrity and drug release kinetics [5], [6]. In those studies it was demonstrated [5], that the integrity of liposomal vesicles when dispersed in gels is determined by the rigidity of their lipid membrane. Furthermore, it was observed that liposomal vesicles are protected from the disruptive effects of specific excipients when dispersed in gels, compared to aqueous media [6]. However, the release of drugs from such complex gels is determined by different factors according to the properties of the drug molecule [5]; for hydrophilic drugs (calcein was used as a model) release from complex gels is retarded when rigid-membrane liposomes are used (faster release from PC-compared to DSPC/chol-[liposome-containing] complex gels) while the release rate is not affected by the amount of lipid loaded in the gels. Oppositely, for amphiphilic/lipophilic drugs, as griseofulvin (that was used as a model drug), the release from complex gels is determined by the amount of lipid loaded (or better drug loaded, in the form of liposomes); at high drug loading levels (compared to the aqueous solubility of the drug), complex gels release the drug with constant rate irrespective of the liposome type (PC or DSPC/chol) they contain. In other words, in cases of amphiphilic or lipophilic drugs the lipid concentration added in the gels has a significant impact on the drug release kinetics, while liposome membrane rigidity is not important.
Depending on the specific therapeutic need, lower or higher lipid concentrations may be needed when formulating complex gels, in order to load the required amount of drug in the formulation. In such cases, depending on the drug physicochemical properties, the release kinetics of the drug can be adjusted according to the conclusions of our previous study [5], as discussed above. However, since it is well known that rheological properties of pharmaceutical gels that are intended for topical and especially vaginal administration are very important determinants of their therapeutic outcome [7], [8], it is also very important to know if, and to what extent, the presence of liposomes in gels influence their rheological properties. This is the purpose of the present study.
The physical techniques which are used for the study of polymer gel properties, are divided into three general categories [9]: (1) techniques that examine the details of cross-linking at the molecular level (e.g., spectroscopic methods- NMR, UV, IR, etc., with length scale of resolution between 0.1–10 nm); (2) techniques that probe over intermediate distances (e.g., rheo-optical methods, with length scale of resolution between 10 and 103 nm); and (3) techniques that probe over long distances (e.g., steady and oscillatory rheological tests, with length scale of resolution between 104 and 106 nm). The viscoelastic behavior of gels, detected by classical rheology (category 3), depends on various factors like the composition and concentration of the dispersed materials and the lag time between preparation and measurement [10], [11], [12]. Like polymer blends [13] the rheological properties of gels are expected to change drastically with the addition of liposomes into them. However, although some studies have been performed for specific formulations, no systematic study has been carried out to examine if and how rheological properties of gels are affected by addition of liposomes, and which liposome characteristics determine the magnitude of such modifications.
Herein we investigated the effect of adding increasing amounts of liposomes in hydrogels on the rheological properties of the hydrogel. Two different types of vesicles (small (sonicated) unilamellar (SUV) and multilamellar (MLV) (which are large vesicles)) consisting of three different lipid compositions (phosphatidylcholine PC, hydrogenated PC (HPC), and HPC/chol (cholesterol)) were added in the gel at different concentrations, in order to study the effects of liposome size, lipid membrane rigidity and lipid concentration on the rheological characteristics of the gel. PC and HPC lipids were selected as two lipids that form membranes with substantially different rigidity (PC forms liquid-state and HPC gel-state membranes). Additionally, since as natural lipids they would be preferable for construction of gels intended for vaginal delivery.
Carbopol 974, an acrylic acid-based polymer, as well as cellulose based hydroxyethyl-cellulose (HEC), are main components of many semisolid formulations (either commercially available or under preclinical evaluation) some of which are intended for vaginal drug delivery. It was recently proposed that mixtures of the above two polymer types have improved rheological properties for vaginal administration of drugs [14]. Indeed such mixture gels were found to be more stable toward temperature and pH changes, compared to the two gels when used individually [15]. For the above stated reasons we chose to use this specific type of mixture gel, in our study.
Section snippets
Materials and methods
Phosphatidyl-choline (PC, egg lecithin) and hydrogenated-PC (egg) (HPC) were purchased from Lipoid Gmbh (Ludwigshafen, Germany). The chemical purity of the phospholipids was verified by thin layer chromatography, as described before [16]. Cholesterol (99%) (chol), was purchased from Sigma–Aldrich Hellas (Athens, Greece). Hydroxyethylcellulose (HEC), as Natrosol 250 HX (Hercules Inc.) was kindly provided by Unipharma (Athens, Greece). Carbopol 974 P NF (CRB) was kindly provided by Chemix S.A
Liposome physicochemical properties
The size distribution (mean diameter and polydispersity index) and ζ-potential of some of the liposome dispersions was measured, and these values are presented in Table 2. As anticipated, MLV liposomes have mean diameters between 2.06 and 2.92 um, while SUV liposomes are a lot smaller with mean diameters ranging between 90 and 99 nm. The ζ-potential values measured show that these vesicles have no surface charge, since they are practically zero (when the SD of each measurement is considered).
Discussion
Liposome addition in a gel on the gel rheological characteristics was studied. The control gel used (in which liposomes were added to form complex gels) was a mixture of carbopol 974 and hydroxyethyl-cellulose which was recently reported to offer advantages toward vaginal delivery of microbicides [14], [15]. The effect of loading increasing concentrations (ranging from 1–20 mg/ml) of various types of liposomes, differing in size (MLV or SUV) or lipid composition and consequently membrane
Conclusions
The results of this study demonstrate that the lipid composition of liposomes added in complex gels is the most important liposome characteristic in respect to their ability to modify the rheological profile of gels, together with the lipid concentration added. In relevance to vaginal delivery, the addition of rigid type liposomes in gels composed of carbopol-hydroxyethyl cellulose mixtures may provide a method to improve the gel rheological characteristics. Indeed as the shear rate is low
Acknowledgements
This work received funding from the European Community's Sixth Framework Programme under contract number LSHP-CT-2004-503162 (Selection and development of microbicides for mucosal use to prevent sexual HIV transmission/acquisition) and is a partial requirement for the completion of the Master degree thesis (MΔE) of SM. The information in this document is provided as it is and no guarantee or warranty is given that the information is fit for any particular purpose. The user thereof uses the
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