Incorporation of small quantities of surfactants as a way to improve the rheological and diffusional behavior of carbopol gels
Introduction
Aqueous polymeric dispersions are very useful as platforms in drug delivery since they can resist the physiological stress caused by skin flexion, blinking, and mucociliar movement; adopting the shape of the application area and controlling the drug release [1], [2], [3]. Some of these systems combine gelling in situ behavior with high fluidity at the moment of administration: the low viscosity makes application easy, but later the temperature, pH, or ionic strength conditions of the application site cause its behavior to become viscous [2], [4].
The incorporation of small amounts of surfactants into a polymeric dispersion can dramatically alter the polymer conformation and the viscosity of the dispersion. Aggregation processes can appear as a consequence of hydrophobic interactions between the non-polar surfactant tail and the polymer backbone, electrostatic interactions between the polar heads of the surfactant and the charged groups of the polymer, or both [5]. Usually, the importance of the aggregation effects on the rheological properties of the mixture depends strongly on the relative proportion of both components showing, for a given system, very different and even opposite effects [6]. Surfactants can also greatly modify the responsiveness of temperature-sensitive polymers. These effects were reported for cellulose ethers [7], poloxamer-co-acrylic acid [8], or poly(N-isopropylacrylamide) [9].
The rheological parameters provide information useful for predicting the in vivo behavior of polymer dispersions [10], [11]. However, most of the studies of the influence of surfactants on the rheological properties of liquid or semisolid polymer-based formulations focus on the stability of low polymer concentration suspensions or emulsions, to which surfactants are added as wetting agents or to prevent microbiological growth [12]. There is an important lack of information about the effects of surfactants on the rheological properties of pharmaceutical gels, into which surfactants are frequently incorporated to modulate the drug release rate or promote the drug flux through the cellular membranes [13]. In addition to the effects on the bulk properties of the gel, it is foreseeable that polymer–surfactant interactions dramatically alter the microenvironment in which the solute diffusion occurs. The formation of polymer–surfactant aggregates or free micelles could modify the size of the water-filled regions or the mobility of the polymer chains. A reduction in the gel free volume or an increase in the path length due to obstructions restrict the diffusive movement of the drug and decrease the drug release rate [14]. In polymer dispersions or in surfactant solutions separately, it has been shown that the effects of the polymer concentration or the surfactant [15], [16], [17], [18] on the macroscopic flow properties of the system do not necessarily correlate with the effects on diffusion, which means that it is necessary to take the microviscosity of the medium into account.
Carbopol® is very useful as a major component of drug delivery gel systems for buccal [19], transdermic [20], ocular [4], rectal [21], and nasal [10] applications. The physical properties of the carbopol gels, the time they remain on the application area, and the drug release rate are extremely sensitive to the presence and concentration of additives [22]. The pH-induced gelling in situ capability and the control of drug release can be improved by addition of cellulose ethers [4] or polyvinylpyrrolidone [23], which causes structural changes that increase viscosity. In two recent papers [24], [25], the influence of some nonionic surfactants on the viscosity of carbopol dispersions was evaluated for high concentrations of Tween 80 and Pluronic F-127, using continuous flow measurements. The shear stress applied can have the important drawback of breaking the aggregates or dissolving the entanglement of the polymer, leading to loss of information about the structure of the systems. Nevertheless, both studies revealed strong changes in the gel strength caused by the surfactants and their important practical repercussions. No references were found regarding the microviscosity of carbopol/surfactant systems.
This paper reports on the analysis of the interactions and the effects exerted by the addition of small amounts of surfactants of different nature and low toxicities [26] (two non-ionic: Tween 80 and Pluronic F-127; and two ionic: sodium dodecylsulfate (SDS) and benzalkonium chloride) on the macro and microrheological properties and pH-responsiveness of Carbopol® 934 gels. We evaluated the behavior of carbopol-surfactant systems when the polymer is non-ionized (acidic) or completely ionized (neutral conditions). To obtain information about viscous and elastic behavior under shear conditions closer to the physiological, flow viscometry and oscillatory rheometry were used [11], [27], while information about the microstructure of the gels was obtained from probe particle diffusion using dynamic light scattering. Diffusion assays using chloramphenicol, as a model drug, were also carried out. The final aim was to establish what possibilities the incorporation of small quantities of surfactants may offer in the modulation of the rheological and diffusional behavior of the gels with a view to applying them to the different commonly used routes of delivery.
Section snippets
Materials
Carbopol® 934NF (molecular weight 29 400–39 400 Da, batch AB17796) was provided by BF Goodrich Europe, UK. Benzalkonium chloride, sodium dodecylsulfate (SDS), polyoxyethylene 20 sorbitan monoleate (Tween 80), polyoxyethylene–polyoxypropylene–polyoxyethylene triblock copolymer (Pluronic F-127), and chloramphenicol were from Sigma. Polystyrene latex nanospheres, diameter 162 nm, were provided by Duke Scientific Co. (Palo Alto, CA, USA). Purified water obtained by reverse osmosis (MilliQ®,
Results and discussion
The strong dependence on pH of the degree of ionization and the conformation of carbopol led us to evaluate the carbopol/surfactant interactions at pH 4, in which the polymer can be considered as non-ionized and suitable for administration, and at pH 7.4, a physiological value at which the carboxylic groups are completely ionized.
Conclusions
The addition of low proportions of surfactants commonly used in drug formulation has an important effect on the flow type, G′, G″, and microviscosity of carbopol gels at pH 4 and 7.4. Depending on whether a site-specific application is required or whether the drug has to be dispersed rapidly in a wide mucosal space, the formulation should be sufficiently consistent and elastic to remain at the application site or be easily spreadable, respectively [27], [50]. The increases in viscosity,
Acknowledgements
This work was supported by the Xunta de Galicia (PGIDT 00PX120303PR). The authors also express their gratitude to Xunta de Galicia for an equipment grant (DOG 04/06/97) and to BFGoodrich Europe for providing free samples of Carbopol®.
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