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The effect of suppository bases on rabbit rectal mucosa was investigated using six triglyceride bases, polyethylene glycol, and a triglyceride base combined with monoglycerides or fatty acids and methyl esters of those acids. Rectal irritation was evaluated and scored according to defined pathological features. "Pure" triglycerides and a triglyceride to which a nonionic surfactant was added caused severe mucosal damage with ulceration and inflammation. Hyperemia was characteristic for irritation by polyethylene glycol suppositories. Mucosal damage by a pure triglyceride combined with monoglycerides or fatty acids and methyl esters of those acids was similar but statistically less pronounced than with all other bases.

The bioadhesive characteristics of tablets for oral use made from modified starch, polyacrylic acid (PAA), polyethylene glycol (PEG) and sodium carboxymethylcellulose (CMC) were investigated. Adhesion force and energy were determined in-vitro and maximal adhesion time was evaluated in-vivo in human subjects. In-vitro, PAA showed the best bioadhesive properties, followed by modified maize starch and PEG with a mol. wt of 300,000-400,000 daltons. The presence of 0.1 mg of fluoride as NaF did not lead to significant differences in adhesion force and energy for the same formulation. The in-vivo bioadhesion was not strongly correlated to the in-vitro data. PAA, despite its excellent adhesion, proved to be irritating to the mucosa. PEG with a mol, wt of 200,000 daltons was subject to erosion. CMC showed good bioadhesive properties but the mechanical strength of the tablets was low. Modified maize starch tablets containing 5% (w/w) PAA and PEG with a mol. wt of 300,000 daltons proved to be the most suitable formulations for a fluoride-slow-release tablet with bioadhesive properties. In-vitro, the tablets released all of the fluoride within the 8 h period, with a high initial release. The release rate was related to the water absorption rate of the tablets. The PAA-containing formulations and the CMC formulations had the fastest release. In-vivo, fluoride levels with a minimum of 150 and a maximum of 1000 micrograms mL-1 were maintained for 8 h in the oral cavity. These fluoride levels were sustained significantly longer than those obtained with the administration of fourfold the amount of fluoride in the form of a fluoride-containing toothpaste. The release characteristics in-vivo exhibited a high variation. The use of bioadhesive polymers in oral pharmacotherapy seems promising.

The percutaneous absorption of indomethacin from transparent oil in water gels (TOW gels) has been studied in rabbits and compared with absorption from a hydrophilic gel and from a spray formulation. The area under the curve and the Cmax values in plasma were significantly higher for the TOW gels in comparison with the other formulations after single application. The pH of the aqueous phase of the TOW gels did not significantly influence the bioavailability. After multiple application the TOW gels induced a larger increase in AUC (vs first application) in comparison with the other formulations. None of the formulations without drug damaged the skin after multiple application. For indomethacin formulations skin damage was more pronounced with the hydrophilic gel than for the TOW gels and spray formulation.

Several applications of microcapsules for the encapsulation of living cells or macromolecules require well defined pore sizes. The molecular weight cut-off of alginate-polylysine microcapsules has been determined using a range of fluorescent labelled dextran molecules. The diffusion of the fluorescein isothiocyanate labelled (FITC)-dextrans into the microcapsules was followed by fluorescence and confocal laser scanning microscopy. The permeability of microcapsules for FITC-dextrans with a molecular weight of 4,700 daltons and the impermeability for FITC-dextrans with a molecular weight of 40,500 daltons was confirmed with both techniques. Determination of the molecular weight cut-off, using confocal laser scanning microscopy was more reliable and required a smaller sample than fluorescence measurements.

Tissue and plasma concentrations were determined after intravenous and oral administration of erythromycin to pigeons to establish the pharmacokinetics and bioavailability of the drug. A short mean half-life of elimination of 0.9 h was found. The relative bioavailability after direct crop administration of erythromycin thiocyanate or erythromycin ethylsuccinate at a dosage rate of 100 mg/kg was less than 10%. At a drug concentration in drinking water of 1 g/l, erythromycin plasma levels were barely detectable, whilst lung and trachea concentrations reached a maximum of 1.6 micrograms/ml. Even after crop administration of 100-mg/kg erythromycin thiocyanate, low plasma levels were obtained, whilst lung and trachea concentrations were substantially higher. Prescribed drinking-water regimens seemed unable to yield therapeutic tissue concentrations. Only individual crop administration seemed an appropriate medication method. The use of erythromycin ethylsuccinate did not present any advantage in comparison with erythromycin thiocyanate.

The influence of feeding on the bioavailability of ronidazole (5 mg per animal) formulated as a hydrophilic-matrix tablet or as lipophilic pellets, was evaluated in pigeons. Administered to fed pigeons, prolonged drug absorption was obtained for both formulations. In non-fed pigeons an immediate grinding of the formulations in the gizzard resulted in rapid drug absorption. This indicates that prolonged residence of the prolonged-release formulations in the crop obtained in the fed condition seemed the only possible means of obtaining prolonged drug release in pigeons.

The sorption of isosorbide-5-mononitrate, diluted in 0.9% NaCl or 10% glucose solutions, to intravenous delivery systems was investigated. Infusion bags, burettes, a syringe, infusion tubings and end-line filters were tested in static and in dynamic experiments. No clinically significant sorption was detected during those experiments. The use of PVC tubings of different hardness did not influence the results.

Fifteen different isolates of Pseudomonas aeruginosa were used to study the kinetics of adhesion to 304 and 316-L stainless steel. Stainless steel plates were incubated with approximately 1.5 X 10(7) CFU/ml in 0.01 M phosphate-buffered saline (pH 7.4). After the plates were rinsed with the buffer, the number of adhering bacteria was determined by a bioluminescence assay. Measurable adhesion, even to the electropolished surfaces, occurred within 30 s. Bacterial cell surface hydrophobicity, as determined by the bacterial adherence to hydrocarbons test and the contact angle measurement test, was the major parameter influencing the adhesion rate constant for the first 30 min of adhesion. A parabolic relationship between the CAM values and the logarithm of the adhesion rate constants (In k) was established. No correlation between either the salt aggregation or the improved salt aggregation values and the bacterial adhesion rate constants could be found. Since there was no significant correlation between the bacterial electrophoretic mobilities and the In k values, the bacterial cell surface charge seemed of minor importance in the process of adhesion of P. aeruginosa to 304 and 316-L stainless steel.

The crystalline structure of two different batches of chloroquine diphosphate was studied. Differential thermal analysis showed the existence of two polymorphic modifications in one of the batches, whilst spectral analysis did not reveal any differences. This discrepancy is attributed to the fact that the second modification is formed during the transition phase when analysed by differential thermal analysis. This recrystallization process is initiated by the presence of seed material. The ratio of transition heat of both modifications is dependent on particle size and heating rate during analysis.

In this study Betnelan-V cream was diluted with Beeler's basis and Cold cream. Cold Cream reduced the skin-blanching activity of the original cream more than Beeler's base. The stability of betamethasone-17-valerate was better in a Beeler's basis dilution than in a Cold cream dilution.

The influence of aluminium hydroxide and magnesium oxide on the oral bioavailability of quinidine, procainamide and propranolol in the dog was investigated. The administration of aluminium hydroxide with a quinidine sulfate capsule causes a significant decrease of maximal plasma concentration (Cpmax) and a shift in tmax (time to reach Cpmax). The area under the curve is not significantly decreased. Administration of magnesium oxide together with a quinidine sulfate capsule or a sustained-release preparation of quinidine bisulfate causes a significant decrease of both Cpmax and the area under the curve. A shift of tmax was observed for the conventional preparation only. The administration of aluminium hydroxide with procainamide hydrochloride diminishes only Cpmax in a significant way. Administration of magnesium oxide together with procainamide hydrochloride has no influence on the different parameters. Administration of aluminium hydroxide or magnesium oxide with propranolol hydrochloride has a significant negative influence on both the Cpmax and the area under the curve.

The stability and the sorption by intravenous delivery systems of the calcium antagonist diltiazem dissolved into either 5% dextrose or 0.9% sodium chloride solutions have been investigated, under conditions simulating current clinical practice. Static experiments showed an excellent stability and no sorption after 48 h. Dynamic experiments, at a perfusion rate of 20 mg h-1, showed no sorption of the drug by infusion fluid containers, burettes or administration sets. For end-line filters a temporary decrease of the recovered amount of diltiazem was observed but only with the 0.9% NaCl solution. It is concluded that the stability and the sorption of diltiazem offers no problem with regard to clinical efficacy.

Four commonly used end-line filters, one with a charge-modified hydrophilic nylon filter (ELD96; Pall Biomedical Ltd., Portsmouth, United Kingdom), one with an unmodified nylon filter (FAE020; Pall Biomedical), and two with hydrophilic cellulose ester filters (Ivex-HP, Millipore Corp., Bedford, Mass.; Sterifix, Braun-Gelman, Brussels, Belgium), were evaluated for their endotoxin-removing capacity in saline and 5% glucose. Natural endotoxins derived from Escherichia coli 8739 and the lipopolysaccharide mutant Pseudomonas aeruginosa PA220-R2 and a purified E. coli serotype O111:B4 lipopolysaccharide preparation were used to challenge the four end-line filters. No endotoxin-removing capacity was observed for the Ivex-HP and Sterifix filters. Both the FAE020 and the ELD96 end-line filters showed excellent endotoxin-eliminating capacities in 5% glucose. Increasing the NaCl concentration in 5% glucose, however, greatly reduced the endotoxin-removing efficiency of especially the ELD96 filter for the purified E. coli lipopolysaccharide preparation. Obviously, both the nature of the endotoxin and the ionic strength of the solution had a major influence on the endotoxin end-line filtering efficiency.

The influence of non-active ingredients in the manufacture of pellets on in-vitro dissolution rate and on bioavailability of hydrochlorothiazide has been studied. Pellets were formulated using either microcrystalline cellulose or microcrystalline cellulose-carboxymethylcellulose sodium blends as matrix, and hydrochlorothiazide as the active ingredient. In-vitro drug release from the different pellet formulations was retarded in comparison to a conventional tablet formulation and was dependent on the nature of the non-active ingredient and, for the microcrystalline cellulose-carboxymethylcellulose sodium blend, of the dissolution medium. In-vivo bioavailability of both pellet formulations was low compared with that of the conventional tablet and the plasma concentration-time profiles did not suggest slow release.

The binding of diazepam, digoxin, dopamine and fentanyl to different 0.2 microns end-line filters was investigated under simulated infusion conditions. All the drugs were diluted in either 5% dextrose or 0.9% NaCl infusion fluid. For digoxin and diazepam a marked reduction in the amount of drug delivered to the patient in the first 20-60 min of infusion is observed. For dopamine, the drug loss was less pronounced and no fentanyl was absorbed to the filters during the infusion experiment.

The pharmacokinetics of ronidazole and the bioavailability of a prolonged release tablet were studied in the homing pigeon. After intravenous administration of 5 mg ronidazole, the drug plasma concentration profile fitted a one-compartment open model. The mean half-life of the drug was 11 h and the volume of distribution was 0.86 l/kg. Total body clearance was 0.056 l/h/kg. A sustained release matrix tablet exhibited prolonged drug release in vitro. After oral administration of the matrix tablet to pigeons drug absorption was nearly complete. When given on an empty stomach, the tablet failed as a prolonged release system. Administration to previously fed pigeons resulted in an increase in tmax and a decrease in Cpmax.

The influence of preparation methodology and storage conditions on pH and procaine stability, in a cardioplegic solution, was studied. A solution prepared with carbon dioxide in the head space and stored at -10 degrees C showed acceptable stability.

The sorption of isosorbide dinitrate from 0.9% sodium chloride and 10% glucose solutions, by intravenous delivery systems has been investigated under simulated infusion conditions. Isosorbide dinitrate was stable in both 0.9% sodium chloride and 10% glucose solutions. Intravenous fluid containers, burettes, a syringe, infusion sets and end-line filters were evaluated. Glass containers, methacrylate butadiene styrene burettes and polybutadiene giving sets did not sorb isosorbide dinitrate. Neither did polypropylene syringes when a 10% glucose solution was used. The sorption of isosorbide dinitrate to end-line filters was unimportant but there was a significant loss to the PVC tubing used to connect the filter housing to the catheter.

The sorption of nitroglycerin, from 5% glucose solution, by infusion sets was investigated under simulated perfusion conditions. Several burettes, sets and catheters were evaluated. The stability of the drug in the presence of glucose was also determined. High density polyethylene and glass proved satisfactory for its perfusion in solutions. A method for the evaluation of its uptake under simulated perfusion conditions is described.

The lay-out of a small-scale production facility for the preparation of total parenteral nutrition infusions is presented. Its concept and the configuration of the production equipment and the operational procedures are explained. The cleaning and sterilization process are also described.