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The effect of different routes and modes of administration of niacin (nicotinic acid) on its hypolipidaemic activity has been evaluated. Our working hypothesis was that the major sites of niacin action are located presystemically (i.e. in the gut wall or the liver, or both) which would make niacin a gastrointestinal drug. For such drugs continuous administration to the gastrointestinal tract is expected to augment their efficacy compared with bolus oral administration or parenteral administration. The hypothesis was examined in two rat models of experimentally induced hyperlipidaemia—Model A, based on a cholesterol-enriched diet, and Model B, in which acute hyperlipidaemia is induced by intraperitoneal administration of triton (225 mg kg−1). Continuous administration of niacin into the duodenum at 1.66 mg h−1 (total dose 40 mg kg−1 day−1) for up to 7 days (Model A) or at 2.22 mg h−1 over 18 h (Model B) had significantly greater lipid-reducing effects both on total cholesterol and on triglyceride levels (15–25%) and elevation of high-density lipoprotein (HDL) cholesterol levels than did bolus oral administration of the same dose. Continuous duodenal infusion of niacin also had an even greater lipid-reducing effect than continuous intravenous infusion of the drug at the same rate and dose. The results indicate that the site(s) of action are located presystemically and that continuous duodenal administration of a low dose of niacin (40 mg kg−1) has a greater lipid-lowering effect than a higher dose (200 mg kg−1) administered by peroral bolus administration. These conclusions were validated by administration of a specially designed niacin sustained-release matrix tablet formulation that was non-invasively administered to hyperlipidaemic rats. The hypolipidaemic activity of the sustained-release tablet was of similar magnitude to that resulting from continuous duodenal administration, thus providing a pharmacodynamic rationale for this mode of administration.

Fine, homogeneous, positively-charged emulsions with a mean droplet size of 138 ± 71 nm and a zeta potential value of 41.06 mV were prepared using a combination of emulsifiers comprising phospholipids, poloxamer 188, and stearylamine. The pH of these emulsions decreased with time. However, the extent of decrease was dependent on the storage temperature. The mean droplet size of the emulsions that had been prepared with 1% poloxamer began to increase slightly after six months’ storage, particularly when stored at 23 and 37°C. However, emulsions prepared with 2% poloxamer remained stable for at least 10 months at 4°C, suggesting that the poloxamer 188 concentration is critical for prolonged emulsion stability. The results of the ocular tolerance study in rabbit eye indicate that hourly administration of a positively-charged emulsion vehicle was well tolerated without any toxic or inflammatory response to the ocular surface during the five days of the study. Scanning electron microscopy revealed a normal corneal surface, which was not different from that of the animals treated with physiological saline. No marked acute toxicity was observed when 0.6 mL of positively-charged emulsion was injected intravenously to BALB/c mice. Furthermore, no difference was noted between this group of animals and the group injected with the marketed Intralipid emulsion. These results were further confirmed in a rat study where there were no deaths following intravenous injection of 3.3 mL per rat of the positively-charged emulsion or Intralipid. Neither emulsion elicited any hepatotoxic or nephrotoxic effects. The overall results suggest that the novel positively-charged emulsion is suitable for parenteral use, and for ocular application.

Methacrylate copolymers were used for microencapsulation of paracetamol by phase separation from chloroform with polyisobutylene 6% in cyclohexane. With polyisobutylene as an anti-aggregating agent, high quality microcapsules were obtained. Drug release appeared to fit both first order and Higuchi matrix model kinetics. However, on application of the differential rate treatment, the evidence supported the first order description, which was further supported by computed simulations of the models. Variation of production conditions showed that increasing the proportion of core material raised the microcapsule drug content and the release rate. Reduction of core particle size correlated with reduced coating thickness and faster release rate. The rate constants correlated with the estimated surface areas and wall thicknesses of the various batches. The data were used to estimate an apparent permeability constant for paracetamol in Eudragit RS microcapsules, which was constant and comparable with values found single core, non-aggregated microcapsules containing other similar drugs and different wall materials.

Release kinetics of active substances from ensembles of microparticles such as microcapsules, cells, droplets and liposomes constituted of individual entities releasing their contents at constant rates may follow zero order, first order, sigmoid or biphasic equations. The release equation observed depends upon the statistical distribution of release-determining parameters among the population. Typical cases are presented in terms of the distribution of two parameters, payload (m∞ and time for complete payload release (t∞) which also define the release rate constant (k). Heterogeneity of the two parameters generally leads to first order ensemble behaviour, whereas heterogeneity of one parameter only may lead to different ensemble release equations, viz. zero order (m∞ heterogeneous) or first order (t∞ heterogeneous). Biphasic distribution can lead to an apparent ‘burst’ effect, with apparent change of kinetics. The presence of a third heterogeneous parameter, lag time, yields a sigmoid ensemble release curve. These conclusions are demonstrated by simulations or experimentally, and are also valid for linearized curves of microparticles following matrix kinetics.