Because of its many advantages oral drug delivery still remains the preferred route of drug administration. To achieve therapeutic effect good bioavailability is crucial. It is determined by the drugs solubility and its permeability. Almost half of newly discovered active pharmaceutical ingredients exhibit low solubility in water, which limits the bioavailability. Recently much attention has been focused on lipid based drug delivery systems, especialy self microemulsifying drug delivery systems. One of the greatest advantages of incorporating poorly soluble drugs into such formulations is that the drug is delivered in a disolved state and thus avoiding the limiting step. After administration of lipid based drug delivery systems enzymatic digestion takes place in the small intestine of the gastrointestinal tract. Simultaneously with the digestion of the lipid components the drug is released into the gastrointestinal medium. In vitro evaluation of lipid-based drug delivery systems is an important step to help predict in vivo performance. As a part of my master's thesis, we evaluated the effect of in vitro lipolysis of self (micro)emulsifying drug delivery systems on naproxen release. Naproxen is a weak acid (pKa ~ 4,15), which means it's mostly in the non-ionised form in the acidic environment of the stomach. Because of adverse effects and low solubility in the stomach environment, naproxen is often incorporated into gastro-resistant pharmaceutical form. In the mentioned case the release of naproxen occurs only after passing through the small intestine of the gastrointestinal tract. With the help of pH-stat method and in vitro lipolysis, we simulated the conditions in which naproxen was released. At higher pH values in the small intestine the solubility of naproxen improves, at the same time permeability decreases on the account of higher percentage of ionised naproxen. From this point of view, the incorporation of naproxen into self (micro)emulsifying systems seems reasonable, since surfactants also improve permeability. We prepared four different type III on lipids based formulations. The formulations consisted of: Capmul MCM EP, castor oil, Kolliphor RH 40, Kolliphor HS 15, Kolliphor EL, PEG 400, Miglyol 812, glyceryl monooleate and Gelucire 44/14. All four formulations contained naproxen at 100 % saturated solubility. We performed in vitro lipolysis at different conditions simulating fasted state, fed state, addition of 250 mL of water and observed the effect on naproxen release. Naproxen exhibited the highest solubility in non-ionic surfactants and the lowest solubility in oils, this has to be taken into account when we decide which components we use in our formulations. Naproxen solubility in gastrointestinal media is highly dependent on the pH value. From the amount of NaOH used with the pH-stat method we determined the extent of the in vitro lipolysis for each formulation. The gathered data indicates that release of naproxen from self (micro)emulsifying systems is not dependent on digestion type III lipid based drug delivery systems. With the help of foton correlation spectroscopy we showed that after dilution of self (micro)emulsifying systems in water, visual evaluation is not a sufficient method to determinate whether a microemulsion forms or not. In conclusion in vitro lipolysis showed that despite good solubility in the chosen pH a part of the incorporated naproxen always precipitates because loss of solubility capacity of the self (micro)emulsifying systems occurs. The loss of solubility capacity of the system is not dependent on digestion, procentage of the oil phase or the oil droplet size after dispersion of the formulation in the media. With addition of water the loss of solubility capacity is even more extensive. In future researches it would be reasonable to also include the gastric part of in vitro lipolysis and thus enhance the predictive power of the used pH-stat method. Also testing formulations with different amounts of incorporated naproxen would be a reasonable step.
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