I. Gonda

A semi-empirical model of aerosol deposition in the human respiratory tract for mouth inhalation.

A mathematical model for regional deposition of aerosols following inhalation via mouth has been developed. The model is in the form of algebraic equations which make it particularly efficient for computation of deposition of polydisperse aerosols. The parameters of the model were derived from average experimental data for‘head’ and tracheobronchial deposition which were supplemented by results of previous theoretical calculations and mass balance considerations. An example is presented to illustrate an application of the model to a problem in formulation of inhalation aerosols. To make the calculations more reliable for particular patho‐physiological groups of patients, some modifications of the parameters used in the model are necessary. The model may be suitable, e.g. for testing the changes in regional deposition which would be likely to result from modification of particle size and related formulation properties of inhalation aerosols.

Hexamethylmelamine aerosols prepared in an evaporation-condensation generator

Abstract Homogeneous hexamethylmelamine (HMM) aerosols were prepared by evaporation and condensation of the drug in a simple generator. The aerodynamic size distribution of the solid particles was found to be logarithmic-normal, characterized by mass median diameters of about 4 μm and geometric standard deviations of approximately 1.3. There was no evidence of decomposition of HMM. Rapid cooling of the HMM vapour yielded a new polymorph of the drug. The generator was found to operate in a stable and reproducible manner for at least an hour at an airflow rate of 2 dm3/min. The method appears suitable for in situ generation of HMM aerosols (∼ 20 mg/min) and for small-scale preparation of fine HMM particles.

Analysis of the Phamacokinetics of Ribostamycin in Serum and Perilymph of Guinea Pigs after Single and Multiple Doses

The pharmacokinetics of ribostamycin in serum and perilymph of guinea pigs was studied after a single s.c. injection of 400 mg/kg or 14 daily injections of the same dose. The repetitive administration of ribostamycin did not produce functional impairment of the kidney and ototoxicity was slight. The pharmacokinetic data were analysed by non-linear least mean squares regression. Ribostamycin did not accumulate in either serum or perilymph after multiple dosing. The half-life of the drug in perilymph was 15.8 h after a single injection, but 7.6 h after the last of 14 injections. The area under the ribostamycin concentration in perilymph against time curve was also reduced after multiple dosing. These changes were found to be due to a marked increase in the rate of transfer of the drug from perilymph to serum after multiple dosing.

Accumulation in the peripheral compartment of a linear two-compartment open model

Accumulation factors for the peripheral compartment in a two-compartment open model are derived. These expressions are contrasted with some previously published statements concerning drug accumulation. The utility of the new indices of accumulation is illustrated by reference to studies of gentamicin tissue uptake and its proposed relation to nephrotoxicity.

Analytical approximations of sensitivities of steady state predictions to errors in parameter estimation

The sensitivity theory is applied to derive a linear approximation to the functional dependence of some steady state quantities of therapeutic significance on pharmacokinetic parameters obtained from the biexponential response to a single drug dose. The error of a steady state prediction depends in general on two terms. The first one may be viewed as an approximate sensitivity of the prediction to the parameter errors, and this depends solely on the algebraic relation between the prediction and the parameters. The second term is the relative error in parameters, and this may be affected by experimental design and the method of data analysis. Comparisons are made with Monte Carlo simulations and “a posteriori”estimates of variance of a prediction.

Comparison of retention of activity of soluble and insolubilized forms of trypsin in a simulated gastric medium

grating spectrophotometer, i.e. at 61Cb620 cm-’ for each of the different forms. These differences have since been confirmed in a personal communication from Drs Axon & Mitchell. Our results suggest that at least two polymorphic forms of methisazone exist. The unground and micronized materials both give evidence of a phase change in the shape of their endothermic peaks using differential analysis. The milled sample appears to give results somewhere between the unground and micronized samples for both X-ray and differential thermal analysis as might be expected from their previous history. The unground material is probably prepared by precipitation as shown by the similarity of the two thermograms (Figs 2A, D), whereas a single crystalline variety is produced by seeding or slow recrystallization (Figs 2E, F). The unground methisazone may change crystal structure at elevated temperature as evidenced by its thermogram (Fig. 2A). Grinding of this material (Figs 2C, B) leads to the formation of a more active poly. morph, which will revert more rapidly to a more stable polymorph as evidenced from the work of Deavin Mitchell (1965). This would also account for the reported (Axon, 1972) increased solubility, biological activity and instability obtained with use of the micronized form in pharmaceutical formulations. November 23, 1976