When developing new drugs, candidates often show poor water solubility, resulting in low bioavailability. One approach to overcome this problem is their incorporation into advanced drug delivery systems, such as self(micro)emulsifying ones (S(M)ESs). Defined as isotropic mixtures of oils, surfactants, hydrophilic solvents or cosurfactants and drug, they rapidly form oil-in-water (micro)emulsion upon gentle agitation (that can be provided physiologically by the peristalsis) followed by dilution in an aqueous media. In those systems drug is already dissolved in emulsion droplets, so the dissolution, a limiting step in absorption, is avoided. But once they enter our body, lipids in S(M)ESs are subjected to digestion, which reduce solubilisation capacity so supersaturated solution is formed. It can also be result of greater amount of drug in the system or migration of hydrophilic excipients towards aqueous phase upon dispersion. Theoretically supersaturation causes enhanced flux across the intestinal wall, but a drug in supersaturated solution has the tendency to return to the equilibrium state (lowest chemical potential) by precipitation. That is why the inclusion of polymeric precipitation inhibitors (PPIs) can lead to improvement of conventional S(M)ESs. PPIs should maintain a metastable supersaturated state of an active pharmaceutical ingredient (API) in the GIT lumen for a time period sufficient for absorption. Inhibition effect may be achieved thermodynamically (by increasing solubility and therefore reducing degree of supersaturation) or kinetically (by forming bonds with drug). With any of those mechanisms both stages of precipitation, nucleation and crystal growth, are slowed down.
In experiments performed for this thesis we were adding two amphiphilic polymers, poloxamer 407 and Soluplus®, to two differenty composed S(M)ESs already containing active ingredient naproxen. We wanted to find out if they are successful precipitation inhibitors, what is their mechanism of action, if the systems after their addition still form (micro)emulsions and if they somehow change crystal structure of incorporated drug. After our experimental work we can conclude that inclusion of both PPIs improved conventional S(M)ESs, but Soluplus® turned out to be much more effective than used poloxamer. With measurements of droplet size and polydispersity index we proved that even after the addition of chosen polymer our systems can still be classified as SMESs. We confirmed the formation of hydrogen bonds between inhibitors and naproxen and consequently their kinetic mechanism of action with infrared spectroscopy and after testing the solubility of API in solutions with increasing concentrations of PPIs we also proved their thermodynamic inhibition. Lastly, by using differential scanning calorimetry we showed that not incorporation into S(M)ES alone or even inclusion of PPI cause any crystal modification of naproxen.
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