Rheological evaluation of thermosensitive and mucoadhesive vaginal gels in physiological conditions

https://doi.org/10.1016/S0378-5173(02)00232-6Get rights and content

Abstract

The timely gelation and retention of in situ-gelling vaginal formulations would be fundamental to improve the efficacy of drugs. In this study, various rheological properties of clotrimazole gels were evaluated for predicting their performance in vagina. Two kinds of thermosensitive and mucoadhesive formulations were composed of poloxamer 407 (P407, 15%), polycarbophil (0.2%), and different amounts of P188 (15 vs. 20%). Both formulations were Newtonian at 20 °C but non-Newtonian at 37 °C. Although both liquid formulations gelled below the vaginal temperature, they differed in gelation time and viscoelastic properties in the presence of vaginal fluid simulant. At body temperature, the formulation with 20% of P188 gelled within 35 s but it took two times longer for the other one gelled. Upon dilution with simulated vaginal fluid, the formulation with 20% of P188 retained the rheology of a gel, but the other one lost the viscoelastic properties typical for a gel. Moreover, after dilution with simulated vaginal fluid, the elastic modulus was orders of magnitude higher in the formulations with 20% of P188 relative to the other one. These results indicate that the rheological evaluation at the physiologic conditions needs to be preceded to develop more effective in situ-gelling vaginal formulations.

Introduction

In vaginal drug delivery, the physiological conditions imposed by the protective mechanisms of the vagina often lead to the limited contact time of administered drugs with vaginal mucosa and a short duration of therapeutic efficacy, making a frequent dosing regimen necessary. Moreover, conventional vaginal dosage forms such as inserts and ointments give discomfort to the patients. Although the patients are known to tolerate gels better than inserts or ointments, the direct application of gels into the disease sites of vagina might be difficult as well as inconvenient. Vaginal therapy would be thus significantly improved if an intravaginally administered drug can retain at the site of administration for prolonged period after more convenient dosing (Robinson and Bologna, 1994, Mandal, 2000, Garg et al., 2001, Valenta et al., 2001, D'Cruz and Uckun, 2001).

Recently, in situ-gelling liquids have been investigated as a more convenient dosage form of topical applications. The liquids applied to the topical areas such as eyes can make transition to gels as a result of a chemical/physical change induced by the physiological environments. The transition could be induced by the concentration of calcium ions as for Gelrite® (Rozier et al., 1989), and temperature as for poloxamers (Miller and Donovan, 1982, Gilbert et al., 1987). Poloxamer, a block copolymer made of polyoxyethylene and polyoxypropylene, is known for its excellent compatibility with other chemicals, high solubility capacity for different drugs, and good drug release characteristics (Morishita et al., 2001). Bioadhesion can be used as a means to improve intimacy of contact, as well as a way to increase dosage form residence time to various administration routes (Park and Robinson, 1985, Robinson et al., 1987, Lee et al., 2000).

Furthermore, in order to fortify the adhesion of administered drugs onto the mucosal surfaces, mucoadhesive polymers such as polycarbophil, carbopol, hydroxypropyl cellulose, polyvinylpyrolidone have been added to the in situ-gelling liquids (Park and Robinson, 1985, Chu et al., 1991, Jones et al., 1996). There are several ways to sustain the release of a drug from gels in order to take full advantage of the contact time. The drug can be dispersed in the gel, giving a concentration that is higher than that corresponding to the solubility of the drug (Veyries et al., 1999), formulated as particles (Albertsson et al., 1996, Desai and Blanchard, 2000), distributed in liposomes (Bochot et al., 1998, Paavola et al., 2000), interacting with an oil phase that has been included in the gel (Gao et al., 1995).

The evaluation of rheological properties for the gel type dosage forms would be important for predicting their behavior in vivo. The rheological properties of eye gels were reported to affect the ocular residence time of the gels (Carlfors et al., 1998, Edsman et al., 1998, Desai and Blanchard, 2000). The flow properties of semi-solid vaginal dosage forms might be of use to predict the spreading and coating of the formulations over the vaginal epithelia. Especially in the thermosensitive gels containing a mucoadhesive polymer, the rheologcal characteristics need to be controlled and understood since the multi-component gels might exhibit complex flow behaviors due to the feasible interaction among the components.

Despite the importance of rheologic information, there has been little attempt to evaluate the rheological properties of thermosensitive and mucoadhesive vaginal gels in physiological conditions. In most studies, the rheologic evaluation has been limited to test the sol/gel transition temperatures of thermosensitive gels. In this study, using the antimicrobial agent clotrimazole as a model drug, we formulated two kinds of thermosensitive and mucoadhesive gels for vaginal delivery, and evaluated their rheological properties in the conditions that mimic the vaginal environments. Here, we report that two thermosensitive and mucoadhesive formulations, although both look suitable in terms of gelation temperatures, could reveal dramatic differences in the viscoelastic properties upon dilution with simulated vaginal fluid.

Section snippets

Materials

Poloxamers (P407, P188) were supplied from BASF (Ludwigshafen, Germany). Polycarbophil (PC) was from BF Goodrich (Brecksville, OH, USA). Clotrimazole was kindly provided by Bayer Pharmaceuticals. All other chemicals were of reagent grade and used without further purification.

Preparation of formulations

Thermosensitive and mucoadhesive gels were prepared by using the cold method (Choi et al., 1998). In brief, PC (0.2 w/v%) was slowly added to citrate phosphate buffer (0.1 M, pH 4.0) at 4 °C with gentle mixing. P407 (15

Steady shear behavior

The steady shear behavior of the poloxamer-based formulations was influenced by the temperature and the content of P188 (Fig. 1). At 20.0 °C, two formulations composed of 15/15/0.2 or 15/20/0.2 of P407/P188/PC did not show notable changes in the viscosity over a broad range of shear rates. Both formulations, existing as a liquid form at 20.0 °C, similarly broad range of shear rates. Both formulations, existing as a liquid form at 20.0 °C, similarly exhibited a Newtonian behavior. But, the

Conclusions

We demonstrated that the subtle difference in the composition of the thermosensitive and mucoadhesive gel formulations might lead to a dramatic change in the rheological behaviors. Although the gelation temperatures of both formulations with 15 or 20% of P188 were below the human vaginal temperature, they differed in the rate of gelation and viscoelastic properties. Upon dilution with simulated vaginal fluid, the formulation with 15% of P188 lost the gelation property whereas the other

Acknowledgements

This work was supported by grant No. 1999-2-21700-001-3 from the interdisciplinary research program of the Korea Science and Engineering Foundation (KOSEF).

References (39)

Cited by (212)

View all citing articles on Scopus
View full text