Therapeutic index drug control testing

Implementation of dissolution testing by BP was in a tiered program similar to that employed at the time by USP. For the first category, products would conform to 75% release in 45 min. Where the drug had a narrow therapeutic index and should not release too rapidly, was known to exhibit a brief plasma half-life, or have site-specific absorption, additional testing to satisfy the need for greater control would be considered. Dissolution tests were included in 1980 for 14 tablet and four capsule monographs (15,16). 

Secondly, nanospheres-bound ampicillin was tested in the treatment of experimental salmonellosis in C57/BL6 mice, a model involving an acute fetal infection (Fattal et al, 1989). All mice treated with a single injection of nanoparticle-bound ampicillin survived whereas all control mice and all those treated with imloaded nanospheres died within 10 days postinfection. With free ampicillin, an effective-curative effect required 3 doses of 32 mg each. Lower doses (3 x 0.8 mg and 3x16 mg) delayed but did not reduce mortality. Thus, the therapeutic index of ampicillin, calculated on the basis of mice mortality, was increased by 120-fold w hen the drug was bound to nanospheres. 

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