IN-VITRO AND IN-VIVO RELEASE OF METOCLOPRAMIDE FROM A SUBDERMAL DIFFUSION MATRIX WITH POTENTIAL IN PREVENTING FESCUE TOXICOSIS IN CATTLE

An auricular implant (0.5 x 3.7 cm) containing metoclopramide was deve loped for use in cattle as a therapeutic aid in antagonizing the harmf ul effects associated with grazing of endophyte-infected fescue pastur es. The implant matrix was prepared from the biodegradable polymer, po lyhydroxybutyrate and its copolymer polyhydroxyvalerate using compress ion-melt and solvent-evaporation compression techniques. Fabrication v ariables evaluated in in vitro dissolution studies included concentrat ion of copolymer, drug payload, salt form vs. free base form of drug, and degree of compression. The optimal system consisted of a matrix co ntaining 24% copolymer with a 50% drug payload that was prepared with the compression-melt technique. An in vivo study in cattle was conduct ed to assess biocompatibility and verify the dissolution rate in the w hole animal. No adverse reactions occurred. The metoclopramide implant had a dissolution rate of 12 mg/day and was vascularized by the surro unding connective tissue. The matrix sham had no observable vasculariz ation. An additional study used twelve pairs (one implanted, the other control) of steers placed on four different endophyte/nitrogen grazin g treatments. The total ergot content (0.2-2.2 mug/g) of the twelve fe scue paddocks was measured by HPLC, and fraction of Acremonium endophy te infection (23-67%) was determined by aniline stain. The implant res ulted in an improvement in suppressed tail temperature (P < 0.01) amon g all endophyte /nitrogen treatments, and cholesterol (P < 0.01) among the high endophyte / nitrogen treatments.