Effect of cellulose polymers on supersaturation and in vitro membrane transport of hydrocortisone acetate

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Abstract

A systematic investigation on the influence of two cellulose polymers, methyl cellulose (MC) and hydroxypropyl cellulose (HPMC) on supersaturation and permeation of hydrocortisone acetate (HA) is reported. Diffusion of HA from a 0.5% Carbopol gel across a model silicone membrane was investigated using the Franz-cell technique. At constant polymer concentration, the flux increases proportionally with the degree of saturation up to 4.8× but decreases thereafter. For a particular degree of supersaturation (4.8×), the flux increases with the concentration of polymer up to 1% and decreases at higher concentrations. The behaviour is found to be consistent with crystallisation experiments. The results suggest that optimisation of supersaturation and polymer content is necessary to achieve both high permeation rates and inherent stability.

Introduction

The stratum corneum acts as an excellent barrier to drug permeation. There have been several attempts to increase permeation using both physical and chemical methods. While physical methods such as iontophoresis use complex delivery devices, chemical methods such as penetration enhancers alter the barrier properties of the stratum corneum. The latter have an additional problem that they may induce irritancy or toxicity. Recently supersaturated systems have been used to increase drug permeation which may minimise the above problems. Moreover it is a relatively inexpensive technique.

In general, the flux of a drug from a saturated system across a membrane is constant provided that the solvent or any other component in the formulation does not alter the properties of the membrane. Hence the flux of a given drug is limited by its solubility. Any concentration above its solubility limit will increase its chemical potential leading to an increase in the flux across the membrane and hence increased bioavailability. Higuchi (1960) recognised the importance of supersaturation as a means of enhancing flux beyond the limiting value achieved with saturated systems. However the main problem encountered with supersaturated systems is their physical instability. Being thermodynamically unstable, the drug crystallises out and in the process the flux decreases.

Some polymers have been shown to inhibit nucleation and sustain supersaturation for prolonged periods of time. This has been examined in recent studies (Davis and Hadgraft, 1991, Pellett et al., 1994, Megrab et al., 1995, Pellett et al., 1997, Schwarb et al., 1999). The studies show a great potential however there has been a lack of any systematic investigation on the mechanism and suitable choice of polymer.

In this paper we investigate, systematically, the influence of two cellulose based polymers, namely hydroxypropyl methyl cellulose (HPMC) and methyl cellulose (MC) on the supersaturation and permeation of hydrocortisone acetate (HA) from Carbopol gels through a model silicone membrane.

Section snippets

Materials

Hydrocortisone acetate was purchased from Sigma (Germany). Propylene glycol and HPLC grade methanol were obtained from Fisher Scientific International Company (UK). Hydroxypropylmethylcellulose grade 65SH-(viscosity 50cP) and methylcellulose grade SM (viscosity 100cP) both with the brand name of Metolose were obtained from Shin-Etsu Chemical (Japan). Carbopol 940 was provided by BF Goodrich Company (Cleveland, USA).

Triethanolamine was purchased from BDH Chemicals (UK) and silicone membranes

Solubility studies

Fig. 1 shows the saturated solubility plot of HA in the cosolvent system of propylene glycol and water at 32°C. The exponential increase in solubility values with increasing percent of propylene glycol is consistent with the data previously reported (Yalkowsky and Roseman, 1981, Davis and Hadgraft, 1991). Even though temperature can significantly affect the solubility, there does not appear to be any major influence in the present system. The solubility values obtained at 32°C from the present

Conclusions

The present studies have shown that the flux from supersaturated gels of hydrocortisone acetate is proportional to the degree of saturation up to 4.8× supersaturation. For a particular supersaturation (4.8×), the flux shows maximum enhancement for 1% polymer concentration and decreases at higher concentrations. The stability is better for gels with high polymer content. The results suggest that there is an optimum degree of supersaturation and polymer content to achieve high permeation rates.

Acknowledgements

The authors would like to acknowledge Engineering and Physical Science Research Council (EPSRC) and SmithKline Beecham Consumer HealthCare, Weybridge, UK for financial support. The authors would like to thank Monica Dias for help with the solubility studies.

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