As you can see from my CV, I stayed at Liverpool John Moores University for six month of my “preregistration year”. In that time I joined Dr. Ali Rajabi-Siahboomi´s group that did research in the field of delayed release formulations.

My task was to elucidate the interaction of hydroxypropylmethylcellulose (HPMC) and bile salts.

HPMC: Hydroxypropylmethylcellulose (HPMC / Methocel E,F and K) is a common carrier in matrix tablets. They control drug release by developing a relatively impervious micilaginous surface barrier on the contact with water or body fluids. This barrier retards further ingress of water and acts rate-controlling to drug release. Inside this hydrated surface, the tablet remains dry, providing a reservoir of drug and of polymer which replenishes the surface gel layer as it dissolves or is eroded in transit through the gastrointestinal tract. Drug release occurs by a combination of diffusion through the gel layer and erosion of the outer gel surface, with the proportion of drug released by each mechanism being determined by factors such as the properties of the gel layer, the solubility of the drug, and the degree of mechanical attrition to which the dosage form is subjected.

Bile salts: Bile acids are steroidal compounds based on 5-cholane. They are amphipathic and serve as physiological solvents. Although their function starts in the biliary system, where they solubilize cholesterol and phospholipids, their main field of action is the small intestine. There they have a double function:

1. To break up lipid aggregates, rendering a larger surface where lipases can come to action, and

2. to solubilize fatty acids, cholesterol and monoglycerides in aqueous environment (forming micelles), allowing the transport of these compounds to the surface of epithelial cells, where they are absorbed, together with the bile salts.

It has been known for quite a time that detergents alter the structure of gels. But it lasted until 1978 that the effect of bile salts on gels was researched as they do not form part of the classical repertoire of pharmaceutical technology. The first studies where in fact carried out by pharmacologists interested in the effect of bile salts to the mucus of the stomach. They found that bile salts very effectively destroyed bronchial mucus, used as a model. Possibly this is part of the effective principle of saponine drugs like Glycerrhizae radix or Saponariae radix, used as herbal cures for cough, as the contained saponines have a structure similar to bile salts.

Rationale: We were interested in the effects of bile salts to HPMC because of two reasons:

1. HPMC is a popular gel builder in matrix tablets and every matrix tablet will be confronted with bile salts on its passage through the body.

2. Bile salts are physiological and in small doses harmless substances. They could be convenient modulators to control drug release from HPMC matrices.

Model matrix tablets have been made from a variety of cellulose ethers. Both nominal viscosity and substitution type have been varied. The tablets were produced by direct compression and wet granulation. The tableting properties were evaluated and dissolution tests were carried out, both with sodium cholate in the formulations and in the dissolution medium.

Two model drugs were selected: propranolol-HCl as an example for a highly soluble and diclofenac-Na as a less soluble drug. This allows us to evaluate the importance of the factors erosion and diffusion, as diclofenac-Na is more dependent on erosion than the easily diffusing propranolol-HCl.

Results:

a) Effects of bile salts on HPMC gels: Consistent with earlier findings a major effect on thermal properties (temperature dependent changes in viscosity) and a minor change in viscosity was found.

b) Effects of bile salts on drug release from HPMC matix tablets: It could be show that cholane derivates had a very complex influence on the drug release, generally slowing down the release of propranolol-HCl and speeding up the release of diclofenac-Na. We established that the effect of sodium cholate is qualitatively the same for its addition to the tablet and to the dissolution medium, though the degree of the effect follows a complex pattern. Although different viscosity grades of HPMC show similar patterns, a variation of the substution level of the cellulose changes it. Most notably methylcellulose seems to be hardly influenced by sodium cholate.

Publication:

A. Rajabi-Siahboomi, J. Burbiel, S. Moghimi, ”The influence of bile salts on drug release from HPMC controlled release matrix tablets”, Pharm. Res. Suppl., 14 (11), 543-552 (1997)