Drug distribution in enteric microparticles.

The aim of this study was to assess the distribution of three fluorescent drug or drug-like molecules in enteric microparticles. Microparticles were prepared using the pH-responsive methylmethacrylate polymer Eudragit L by an emulsion solvent evaporation process. In the process drug and polymer are dissolved in ethanol, and dispersed in a liquid paraffin external phase using sorbitan sesquioleate as stabiliser. The incorporation and distribution of riboflavin, dipyridamole and acridine orange into these microparticles were investigated using confocal laser scanning microscopy (CLSM). The influence of the physicochemical properties of the molecules (solubility in the inner phase, partition coefficient [ethanol/paraffin]) on the distribution, encapsulation efficiency and pH-responsive dissolution behaviour of the microparticles were examined. The drug that tended to partition in ethanol rather than liquid paraffin (riboflavin) was efficiently encapsulated and evenly distributed. In contrast, compounds which partitioned in favour of the liquid paraffin localised towards the surface of the microparticles and exhibited lower encapsulation efficiency (dipyridamole and acridine orange). All three sets of drug-loaded microparticles showed a limited release in acid (<10% release); drug distribution appeared to have a minimum effect on drug release. This microparticle technology has the potential to provide effective enteric drug release with a wide variety of molecules.

Fabrication and in vivo evaluation of highly pH-responsive acrylic microparticles for targeted gastrointestinal delivery.

Acrylic enteric microparticles for oral drug delivery were prepared by an oil-in-oil emulsion solvent evaporation process. The novel use of sorbitan sesquioleate as a surfactant produced Eudragit L55, L and S (pH thresholds of 5.5, 6 and 7, respectively) microparticles of good morphology (spherical, smooth surfaced), size (<100microm) and size uniformity. The process was efficient (yield approximately 90%) and the encapsulated model drug (prednisolone) was in the amorphous form. The Eudragit L and S microparticles showed excellent pH-responsive drug release in dissolution studies (negligible drug release at pH 1.2; rapid drug release above the polymers' pH thresholds). In contrast, Eudragit L55 particles aggregated in fluid and showed poor control of drug release. In vivo in rats, Eudragit L microparticles released their drug load rapidly (T(max)<1h) and the C(max) and AUC were higher than those of a control suspension of prednisolone. Drug absorption from Eudragit S microparticles was low which was attributed to the fact that the threshold pH of Eudragit S was not reached in the rat intestine and drug release was therefore incomplete. It was concluded that although the rat is an inappropriate model for the investigation of Eudragit S microparticles, the positive results seen with the Eudragit L microparticles indicate its potential use in pH-targeted drug delivery.

The robustness and flexibility of an emulsion solvent evaporation method to prepare pH-responsive microparticles.

A microparticle preparation method based on an emulsion of ethanol in liquid paraffin stabilised using sorbitan sesquioleate which produces enteric microparticles of excellent morphology, size and pH-sensitive drug release was assessed for its robustness to changes in formulation and processing parameters. Prednisolone and methacrylic acid and methyl methacrylate copolymer (Eudragit S) were the drug and polymer of choice. Emulsion solvent evaporation procedures are notoriously sensitive to changes in methodology and so emulsion stirring speed, drug loading, polymer concentration and surfactant (emulsifier) concentration were varied; microparticle size, encapsulation efficiency, yield and in vitro dissolution behaviour were assessed. The yield and encapsulation efficiency remained high under all stirring speeds, drug loadings and polymer concentrations. This suggests that the process is flexible and efficiency can be maintained. Surfactant concentration was an important parameter; above an optimum concentration resulted in poorly formed particles. All processing parameters affected particle size but this did not alter the acid resistance of the microparticles. At high pH values the smaller microparticles had the most rapid drug release. In conclusion, the microparticle preparation method was resistant to many changes in processing, although surfactant concentration was critical. Manipulation of particle size can be used to modify the drug release profiles without adversely affecting the gastro-resistant properties of these pH-responsive microparticles.