S. Benita

Nanocapsule formation by interfacial polymer deposition following solvent displacement

Abstract Indomethacin-loaded nanocapsules were prepared by deposition of poly-( D,L -lactide) polymer at the o/w interface following acetone displacement from the oily nanodroplets. An attempt was made to elucidate the mechanisms of formation in terms of interfacial turbulence between two unequilibrated liquid phases involving flow, diffusion and surface tension decrease (Marangoni effect).

A new in vitro technique for the evaluation of drug release profile from colloidal carriers - ultrafiltration technique at low pressure

Abstract A new in vitro technique, ultrafiltration at low pressure, is proposed for the evaluation of drug release profile from colloidal carriers such as submicron emulsions and nanoparticles. A thorough description is given after having reviewed the various available techniques for drug release evaluation from colloidal carriers. The results yielded by the new technique clearly show that miconazole release from either the submicron emulsion or a marketed micellar aqueous solution was very rapid under perfect sink conditions. This fact raised doubts and practically rules out the possibility of using submicron emulsions as a controlled-release drug delivery system for i.v. administration. The in vitro indomethacin release profile from PLA or PLGA nanoparticles was found to be biphasic with an immediate release of 40–80% of the initial drug concentration, followed by a slower exponential release which lasted a few hours. It was deduced from the overall kinetic results that the ultrafiltration method at low pressure was versatile, sensitive and capable of distinguishing between different kinetic behaviors. The technique offers the possibility of identifying the underlying release mechanism of drug from colloidal carriers.

Drug release from submicronized o w emulsion a new in vitro kinetic evaluation model

Abstract The in vitro release of diazepam from a submicron o/w emulsion was evaluated using the dialysis bag technique diffusion and the bulk-equilibrium reverse dialysis bag technique. Irrespective of the nature of the sink solution used, the release rate of diazepam from different emulsion dosage forms remained slow and incomplete as compared to a diazepam hydroalcoholic solution using the dialysis bag technique. This was attributed to a marked decrease in the aqueous drug gradient of drug available for membrane diffusion in the presence of the oily internal phase, rendering the permeation through the dialysis membrane the rate-limiting step in the overall kinetic process. It can definitely be deduced that the dialysis bag technique could not be considered an appropriate method to evaluate the true release mechanism of a drug from a colloidal carrier. An in vitro kinetic model is therefore proposed where the colloidal drug carrier suspension is directly placed in the release solution and has the opportunity to release the drug content under maximum dilution and perfect sink conditions. The drug released sampling is performed through immersed dialysis bags previously filled and equilibrated with the sink solution in the receptor compartment. The release profiles of diazepam from the actual submicron emulsion was similar to that observed from marketed aqueous and emulsion dosage forms correlating well with pharmacokinetic results reported in the literature. It was found that the release rate from the oily nanodroplets was faster than the permeation rate through the dialysis membrane which should be the slowest step governing the overall kinetic process despite rapid and complete diffusion of dissolved drug within less than 1 h. In view of the overall results it can be concluded that the release of diazepam from submicron emulsion is very rapid under perfect sink conditions.

Design and characterization of a submicronized o/w emulsion of diazepam for parenteral use

Abstract An innovative, injectable, submicronized emulsion delivery system into which diazepam was incorporated has been developed. This emulsion has been formulated to meet all the requirements for injection either i.v. or i.m. The technique utilized a high shear mixer followed by a two stage pressure homogenizer yielding a very fine monodispersed emulsion, the mean droplet size of which ranged from 100 to 150 nm. The combination of purified egg yolk phospholipid and non-ionic emulsifier, as a complex emulgator, together with a highly efficient emulsification technique yielded a fine diazepam emulsion with improved stability properties. An increase in the oil phase volume ratio caused a moderate but significant increase in the mean droplet size of the diazepam emulsion. A sharp and parallel elevation in mean droplet size and viscosity was observed in the emulsions containing 30% or more oily phase. The ζ-potential of the emulsified droplets was affected by the alteration of the pH, whereas no significant effect on mean droplet size was observed. The mean droplet size of diazepam emulsion decreased with increasing concentrations of the non-ionic emulsifier until reaching a minimum constant value. Mean droplet size of diazepam emulsion decreased, while ζ-potential increased with increasing phospholipid concentration. No changes in the various physicochemical properties were observed with increasing diazepam concentration.

Charge-dependent interaction of self-emulsifying oil formulations with Caco-2 cells monolayers: binding, effects on barrier function and cytotoxicity.

A positively charged self-emulsifying oil formulation (SEOF), aimed to enhance oral bioavailability of drugs poorly soluble in water, was recently developed. In the present study the Caco-2 cell model was used for the investigation of the charge-dependent interactions of this SEOF with human intestinal epithelial cells. The positively charged emulsions affected the barrier properties of the cell monolayer at high concentrations and reduced the cell viability. However, at the dilution with aqueous phase used in the present study (1:2000), the positively charged SEOF did not induce any detectable cytotoxic effect. The binding of the fluorescent dye DiIC(18)(3) was much higher from the positively charged SEOF, compared to the negatively charged formulation, suggesting an increased closer adhesion of the droplets to the cell surface due to the electrostatic attraction. No transepithelial transport of this compound across Caco-2 cell monolayers was observed with any SEOF formulation.

Release kinetics of sparingly soluble drugs from ethyl cellulose-walled microcapsules: theophylline microcapsules

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.

Characterization of diazepam submicron emulsion interface: role of oleic acid.

Oleic acid markedly improved the physical stability of a diazepam submicron emulsion. The zeta potential of the emulsion increased with increased oleic acid concentration. This effect suggested that adjustment of the diazepam submicron emulsion pH to 7.8-8.0 led to the ionization of oleic acid molecules at the oil/water (o/w) interface without being excluded from the surface regions of the oil droplets. TEM freeze-fracturing examination revealed that a mixed-emulsifier monolayer film was established at the o/w interface of the submicron emulsion. No liquid crystal or liposome formation was detected. This was confirmed by the results of phosphatidylethanolamine surface labelling at the o/w interface of the emulsion. The improved stability properties conferred to the emulsion by oleic acid should be attributed not only to the zeta potential increase, but also to the strengthening of the molecular interactions occurring between phospholipid and poloxamer emulsifiers in the presence of an ionized form of oleic acid at the o/w interface of the emulsified oily droplets as evidenced in independent monolayer studies.

Fundamentals of release mechanism interpretation in multiparticulate systems: determination of substrate release from single microcapsules and relation between individual and ensemble release kinetics

Abstract For assessing theories underlying release kinetics of contents from ensembles of microparticles in multiparticle dispersions, population release studies are incapable of revealing the operative physicochemical mechanism, in spite of attempts by many authors to interpret such cumulative data. The present study pioneers techniques for determining release kinetics from single microparticles, using microcapsules as model systems with microconductimetric or spectrophotometric measurement of contents released into the external medium. In four systems giving overall first-order release from populations, the individuals all released their contents at constant rates almost to total payload. A statistical model relating the sum of individual release to cumulative release was applied to the data. It was based on the distribution of two fundamental parameters of the individuals, m ∞ the payload and t ∞ the time to complete release. Statistical analysis of the experimental data validated the proposed relation in the four systems. The conditions required to obtain first-order cumulative kinetics from summated single constant rate data are either: (1) gamma-distribution with shape parameter = 2 of t ∞ and independence of m ∞ and t ∞ ; or (2) exponential distribution of t ∞ and correlation betw m ∞ and t ∞ . Cumulative kinetics and rate constants based on an approximation to a standard release equation are useful for characterization of batch release properties (e.g. in checking repeatability, effects of production variables, sustained release character under controlled conditions) but do not reveal the underlying release mechanism or the actual distribution of parameters, which require studies on individuals. Cumulative kinetics may in fact be altered if the distribution profile of the population undergoes accidental or pre-determined change.

Positively charged submicron emulsions — a new type of colloidal drug carrier

A positively charged submicron emulsion was prepared and stabilized by forming a mixed film comprising phospholipids, poloxamer and stearylamine at the o/w interface of the oil droplets. This was confirmed concomitantly by the selective adsorption of the thiocyanate anion and the lack of adsorption of Ca2+ onto the emulsified oil droplets of the actual emulsions. The incorporation of various drugs in the new type of submicron emulsions altered neither the nature of the surface charge nor the mean droplet size. These results clearly demonstrated that the positively charged submicron emulsion can be used as a new type of colloidal drug carrier.

Fundamentals of release mechanism interpretation in multiparticulate systems: the prediction of the commonly observed release equations from statistical population models for particle ensembles

Abstract The kinetics of release from a population of microparticles is determined by the distribution of a small number of parameters governing the release function in a heterogeneous population. A general model for treatment of the distribution is developed for any release pattern common to a whole population, which is shown to lead to a variety of different cumulative release equations, including those hitherto considered to govern the release mechanism from microcapsules. Thus, the main case, that of constant release rate from individuals differing in rate constant, is shown to yield, according to the statistical distribution of the parameters, ensemble kinetics following first-order, square-root of time (Higuchis equation), cube-root law (Hixson-Crowell) or a combination of initial zero-order followed by square-root of time relationships, all of which have been used to describe experimental systems studied. It is demonstrated that the cumulative release kinetics observed in a multiparticle system, being a function of the statistical distribution of parameters, does not characterize the basic release mechanism, which can only be determined directly from studies on individuals. The treatment also shows that in the case of first-order release by individuals, the ensembles cannot also observe first-order kinetics, except in the rare case of homogeneity of the determining parameters in the population.