Biomedical subjects
Publications and source records attributed to M Donbrow.
A bacterial virus, suspended in three different vehicles, was introduced into the rectum of rabbits. The virus was detected in the circulating blood as early as 10 min after the administration. The quantity of virus found in blood and the duration of its presence, were enhanced when a non-ionic surfactant was used as vehicle of the virus.
Indomethacin microspheres based on a combination of ethylcellulose and polyethyleneglycol were prepared using the solvent evaporation process. Release profiles of ensemble and individual microspheres were measured. Both were found to follow first-order kinetics, in contrast to what was expected. This was attributed to the fact that all the particles showed the same kinetic pattern and had a greater degree of homogeneity in the payload, mean particle size and shape, and k1 values than in ensembles of microcapsules.
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 infinity) and time for complete payload release (t infinity) 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 infinity heterogeneous) or first order (t infinity 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.
A method is described for simultaneous microscopic observation of individual microcapsule core material dissolution together with quantitative measurement of the individual kinetics of release of the contents. These may be conductimetric in the case of ionized materials or spectrophotometric otherwise. This enables correlation of changes in core surface area during dissolution with kinetics. Surprisingly, both ethyl cellulose- and polymethacrylate-coated cores of potassium dichromate crystals, used as a model, showed localized internal dissolution universally, providing evidence of the exit of the salt via pores in the membrane, in spite of the kinetics being invariably zero order, as expected for individual microcapsules. The advantages of the method are presented.
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.
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Microcapsules were prepared by the ethylcellulose coacervation process which is based on the differential thermal solubility in cyclohexane. When a protective colloid, polyisobutylene, was present in adequate concentration, individually film-coated core particles formed. However, they were accompanied by small empty coacervate droplets, detectable by microscopic observation. Below the critical colloid concentration, the product had the form of aggregate, in contrast to individual film-coated microcapsules. Increase of colloid concentration yielded microcapsules of higher drug content, because coating became progressively thinner; there was a corresponding increase in the release rate of drugs from the microcapsules. Since the initial wall polymer/drug ratio and the particle size are constant, the drug content varied with the thicknesses of the wall membrane. This is shown here by removal of empty coacervate droplets by repeated decantations, enabling determination of drug content by chemical analysis. In contrast to results reported in the literature, in the presence of a protective colloid, microcapsule drug content decreased with decreasing particle size of the drug. This was caused by more complete uptake of the wall polymer on the increased surface of core material. The effect of protective colloid concentration on the apparent loss of wall polymer as empty droplets closely paralleled its effect on the size of stabilized droplet formation is a side reaction when core material is present, causing changes in wall thickness. This reaction not only affects the efficiency of the coating process but may be utilized to control wall thickness. First-order constants for drug release from salicylamide and theophylline microcapsules followed the same pattern as wall thickness and confirmed the validity of the measurements.
Release rates of theophylline from ethyl cellulose-coated microcapsules were measured as a function of wall thickness and core particle size. The kinetic data conformed with first order release and also the Higuchi matrix model. However, application of the differential rate treatment, hitherto applied only to drug matrix dispersions, showed that release from the microcapsules definitely followed the first order equation. For the purpose of confirming that the release process was membrane-controlled, the experimental rate constants were transformed into effective permeability constants (P1) with the aid of the microcapsule dimensional parameters needed in the relevant equations and compared with the permeability constant (P) of theophylline measured experimentally using planar ethyl cellulose membranes. P1 values decreased linearly to a moderate extent with wall thickness, probably due to decrease in porosity during wall-formation. P1 values of the thicker-walled microcapsules were found to be of the same order as the membrane P value, supporting a release mechanism of membrane control under non-steady state conditions.
Stability constants and thermodynamic parameters have been evaluated for the complexation reaction in aqueous solution of caffeine with beta-naphthoxy acetic acid. The values were higher than those previously reported for the complexation of other ligands with methyl xanthines. In nearly all aromatic ligands complexing with caffeine and theophylline for which data are available, both entropy and free energy of complexation were linearly related to the enthalpy, giving an isoequilibrium relationship. Salicylamide, sodium benzoate and cis-methyl cinnamate exhibited slight deviations on the delta G-delta H plot; the non-aromatic dehydroacetic acid showed the largest deviation. The isoequilibrium relationship was shown to be valid statistically (349-365 K, caffeine systems; 353-372 K, caffeine and theophylline systems) indicating underlying chemical causation. Thermodynamic equations are presented for analysis of the factor involved, which are attributed to a combination of substrate-ligand interactions and solvent effects. The substrate-ligand overlap area is considered as a common parameter through which the solvent and interaction forces might cooperate to give rise to linearity in the isoequilibrium relationship. The increasingly negative experimental values of the enthalpy and entropy with increase in ligand planar overlap area are discussed in relation to the underlying forces involved in the complexation.
Release rates of salicylamide from single-core ethyl cellulose (EC) coated microcapsules were measured as a function of wall thickness and core particle size. Whereas up to ca 50% release zero order kinetics were observed, the overall reaction fitted the first order and Higuchi matrix treatment. These were distinguished by the differential rate treatment, which showed that the overall release in fact followed the first order pattern. For investigating whether the process was membrane-controlled, the experimental rate constants were transformed into effective permeability constants (P0 and P1) with the aid of the microcapsule dimensional parameters needed in the relevant equations and compared with the salicylamide permeability constant for planar ethyl cellulose membranes (P), measured experimentally. P0 and P1 values obtained for a given microcapsule preparation were not identical: P0 was of the same order as P, P1 being much lower. While membrane-controlled release is evident, it is apparently accompanied by a first order concentration gradient change inside the microcapsule.
This study was concerned with the effect of Cetomacrogol (polyethylene glycol 1000 monocetyl ether), a nonionic surfactant, on the absorption of gentamicin and amikacin from the gastrointestinal tract of rats. A 200-mg dose of Cetomacrogol coadministered orally with 10 mg of gentamicin resulted in a mean peak gentamicin blood concentration of 14.1 microgram/ml, compared with 67.8 microgram/mg when the same gentamicin dose was administered intramuscularly. The area under the curve after administration of the oral mixture was 23% of that after the intramuscular dose. The rectal administration of the mixture resulted in a mean peak gentamicin blood level of 8.2 micrograms/ml, compares to 16.5 microgram/ml when the mixture was administered orally. A 50-mg dose of amikacin coadministered orally with 200 mg of Cetomacrogol resulted in a mean peak amikacin blood level of 13.3 microgram/ml, compared to 310 microgram/ml when this amikacin dose was administered intramuscularly. Cetomacrogol augments the intestinal absorption of gentamicin and amikacin in rats. If the toxicity of the combination in humans is limited, the combination may be potentially clinically useful.
Insulin injected intra-jejunally together with the non-ionic surfactant cetomacrogol was effective in streptozocin-induced diabetes in the rat, as measured by the hypoglycaemic effect. The reduction in blood sugar was maximal at about 2 h after administration but continued at a high level for the 4 h of the experiment. No hypoglycaemic effect was observed in controls injected with insulin or saline alone. Intestinal absorption of insulin has thus been effected by the addition of cetomacrogol, which appears to enhance membrane-permeability to insulin rather than to function as a protective agent preventing insulin degradation, as in liposome-encapsulation. In support of this, a significant hypoglycaemic action was still obtained when the insulin injection was given half-hour after that of the cetomacrogol, both intra-jejunally. Furthermore, oral administration of the surfactant followed by intra-jejunal injection of the insulin also gave a hypoglycaemic effect. The use of this agent to enhance insulin absorption offers the possibility of a new approach to oral insulin therapy.
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Cast films composed of different ratios of polyethylene glycol and ethylcellulose containing salicylic acid, caffeine, and tripelennamine as model dispersed drugs were prepared and exhibited sustained release. The drug content of the film declined at an apparent first-order rate initially, whereas the drug quantity released was proportional to the square root of time. Data analysis validated the latter treatment, which is in accordance with the diffusional matrix model, and disproved the validity of the apparent first-order conformity. The release rates were independent of film thickness and proportional to drug concentration in pure ethylcellulose films; in polyethylene glycol--ethylcellulose films, a positive deviation from linearity was observed. The logarithm of the rate constant was proportional to the fraction of polyethylene glycol in the film. Unlike in pure ethylcellulose films, the release rate in mixed films was altered by a change in the external fluid pH.
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A drug delivery system is proposed constituted of spherical placebo granules as cores with polymeric surface films containing drug. This timed release dosage form has been prepared by means of a fluidized bed coating technique using ethyl cellulose as the polymeric film and caffeine and salicylic acid as model drugs. The release of the drugs from the dosage form (a) at different drug concentrations and (b) into solutions of different pH showed that drug release was linearly related to the square root of time. Good agreement was found between the theoretical release rate of caffeine, calculated according to Higuchi's equation for a homogenous matrix using membrane permeation parameters measured on linear films, and the experimental results in the case of low drug concentrations. Deviation of the release rate from the homogenous model at high drug concentrations could be explained by crystallization of the drug from the film.
Dissolution rates of salicylamide in water and caffeine solutions under perfect sink conditions were predicted by theoretical diffusion equations applicable to dissolution in complexing media. Experimental dissolution rates were measured using a compartmentalized rotating-basket apparatus under two sets of conditions. Agreement was found between experimental and predicted rates. Use of the theoretical equation for estimating dissolution rates involves simple calculations of diffusion coefficients and diffusion layer thickness under the operative dissolution conditions. The increase in dissolution rate caused by addition of the complexant can be calculated for diffusion-controlled dissolution directly if the stability constant and the drug solubility in water are known or measured.