A biopharmaceutic approach in designing a controlled release tablet of sodium monofluorophosphate: 1. In vitro and in vivo studies in beagle dogs.

The purpose of this study was to develop a controlled release tablet (CRT) of sodium monofluorophosphate (NaMFP) based on biopharmaceutic and pharmacokinetic principles. NaMFP was introduced in the early eighties to treat osteoporosis. The required dose size (200 mg of NaMFP) and time of drug delivery (8.3 h) were theoretically determined based on the pharmacokinetic parameters of fluoride (F-). A CRT was formulated with ethyl cellulose (EC) by the direct compression method. The ratio of drug to polymer was adjusted 1:1, after studying the in vitro release profiles. The release mechanism from the developed dosage form followed the square root of time relationship. This dosage form was evaluated for its in vivo performance in dogs. The pharmacokinetics of F-, after the IV and PO administration of NaMFP, was determined to standardize the animal model. F- followed a two-compartment model and no significant differences were found between the two routes of administration. The bioavailability in dogs was only 60%. The reason for this poor bioavailability was postulated to be the delivery of drug extended beyond the principal sites of absorption of the gastrointestinal tract. Hence, we decided to characterize the absorption sites of NaMFP and to modify the CRT.

Biopharmaceutic approach in designing a controlled release tablet of sodium monofluoro phosphate. Characterization of absorption sites and evaluation of modified dosage form.

Based on the results from in vivo study in dogs, it was decided to characterize the absorption sites of sodium monofluoro phosphate (NaMFP). It was hypothesized that bioavailability upon p.o. administration can be improved for controlled release dosage forms if the drug release is confined to segments of gastrointestinal tract responsible for absorption. To characterize the principal sites of absorption of NaMFP, in situ segmental absorption studies were carried out in rats. It was found that NaMFP is predominantly absorbed from the small intestine. The larger surface area and presence of alkaline phosphatase enzymes, are attributed to the higher absorption from the small intestine. Based on these results the delivery time was limited to 6 h to restrict the release of the drug within the principal sites of absorption. The dose was adjusted to 160 mg of NaMFP. After studying in vitro release profiles, the drug to polymer ratio was adjusted to 1: 1.1. The modified dosage form was finally subjected to bioavailability studies in humans. An immediate release dosage form was used to compare the efficacy in a two-period crossover study. The extent of bioavailability was 99% and the dosage form was effective in reducing the fluctuations.