Solubility of a drug is one of the most important parameters by which a therapeutic concentration of a drug is ensured in the systemic bloodstream. However, because 40 to 70% of newly developed drugs are poorly water soluble, the development of effective drug delivery systems is crucial. After oral administration, poorly water-soluble drugs show limited bioavailability and high inter- and intraindividual variability.
One modern approach for the solubilization of poorly water-soluble drugs is lipid-based self-microemulsifying drug-delivery systems (SMEDDS), which in physiological media spontaneously form optically transparent and thermodynamically stable o/w microemulsions (ME), containing drug already dissolved. Only liquid SMEDDS formulations in the form of hard and soft gelatin capsules are available on the market. Their production is limited by compatibility and stability problems and high production costs. This is why several studies are ongoing with a view to combining the advantages of SMEDDS formulations and solid dosage forms. Therefore, this doctoral dissertation focuses on the solubilization of a poorly water-soluble drug with a SMEDDS formulation incorporated into solid dosage forms. The introduction to the dissertation focuses on SMEDDS formulation and provides a critical overview of methods for solid SMEDDS preparation. The spray-drying method, which was also used in the experimental work, is described in greater detail. Chapter 1 reviews lipid-based drug delivery systems (LBDDS). An extended comparison is made between ME and nanoemulsions (NE) due to the discrepancy in the literature using these terms. The first part of the dissertation (Chapter 2) focuses on the development and evaluation of liquid SMEDDS based on the Gelucire® 44/14 surfactant. The aim was to select a formulation that shows self-microemulsifying properties (mean droplet size of ME after dilution < 100 nm) and is able to solubilize the highest amount of the model drug (i.e., naproxen) using a minimal concentration of selected surfactants. Based on a solubility study of naproxen in selected excipients and construction of (pseudo)ternary diagrams, the most promising formulation consisted of a 60% w/w oil phase Miglyol 812®1:PeceolTM 2 = 1:1) and a 40% w/w surfactant/co-surfactant (S/co-S) mixture (Gelucire® 44/143:Solutol® HS 154 = 1:1). This composition was able to solubilize 6% w/w of naproxen and form droplets of 39.9 ± 0.1 nm upon dilution. The effect of incorporated naproxen on self-microemulsifying properties was observed. This is attributed to the good solubility of naproxen in a S/co-S mixture, promoting greater curvature of the surfactant film and consequently reducing the ME droplet size. In order to evaluate the effect of SMEDDS on dissolution profiles, an in vitro dissolution study was performed. The results obtained confirmed the prediction that incorporating naproxen into the SMEDDS formulation significantly improves its extent and dissolution rate. The aim of the second part of the dissertation was to combine the advantages of LBDDS and solid dosage forms. Thus, the developed liquid SMEDDS is transformed into a solid dosage form by using different solidification techniques: filling into hard gelatin capsules, spray drying, adsorption onto solid carriers, and melt granulation, and using a suitable solid carrier for each method (Chapter 4). The solidification techniques were comparatively evaluated with regard to the self-microemulsifying properties of the powders obtained. Based on these results, spray-drying techniques in combination with maltodextrin (MD) as a solid carrier were selected for further experimental work. After this, design of experiments (DoE) on the spray-drying process using MD was performed using a three-factor, two-level full factorial design (23) in order to evaluate the influence of process parameters on self-microemulsifying properties (mean droplet size after reconstitution and PDI) of the powders obtained and the yield of the process. Based on the results, the spraying pressure and pump speed had a major and significant influence on mean droplet size and PDI, exhibited an antagonistic effect. The results obtained confirmed the prediction that DoE can optimize formation of solid SMEDDS. The settings of key spray-drying process parameters were defined based on DoE. Based on these, optimal composition of the dispersion for spray drying was also selected and naproxen-loaded solid SMEDDS were prepared. The obtained results confirmed that, with the transformation of liquid to solid SMEDDS, self-microemulsifying properties were preserved and an enhanced solubility and dissolution rate of naproxen was achieved. Namely, solid SMEDDS show a lower dissolution rate of naproxen in comparison to liquid SMEDDS (first the solid carrier MD needs to be dissolved, in which droplets of liquid SMEDDS are entrapped), but the incorporated drug is release to the same extent, which is the result of spontaneous ME formation. Chapter 3 also examines the influence of a solid carrier and the concentration of the incorporated drug on key characteristics of SMEDDS formulation. The results obtained showed that drug concentration and the type of carrier used influenced the self-microemulsiufying and morphological properties of solid SMEDDS. In addition, an influence on the degree of encapsulation and dissolution profile was observed. Moreover, the supersaturated concentration of the incorporated drug also influenced its physical properties. The third part of the dissertation focuses on preparing self-(micro)emulsifying tablets and minitablets, with the aim of verifying the prediction that by using DoE it is possible to optimize a solid SMEDDS formation and prepare tablets and minitablets with preserved self-microemulsifying properties and enhanced naproxen solubility (Chapter 4). Tablets and minitablets were prepared from spray-dried solid SMEDDS containing naproxen in two different concentrations (6% and 18% w/w). The results obtained showed that tablets and minitablets do not exhibit self-microemulsifying properties after reconstitution, but they do form emulsions. Nevertheless, they still show enhanced solubility and dissolution rate of naproxen incorporated into a SMEDDS formulation in comparison to pure drug. The results of this dissertation will contribute to a better understanding of the influence of various solidification methods, solid carriers, and incorporated drug concentration on self-microemulsifying and morphological properties of solid SMEDDS. By selecting an appropriate solid carrier, both immediate and modified drug release from solid SMEDDS may be achieved with an improved dissolution rate and extent of drug release in comparison to pure drug. The implementation of DoE for defining the process parameters of the method for self-microemulsifying powder preparation and the Raman mapping method, which is an innovation in studying solid SMEDDS, make it possible to study the issue in depth and to formulate solid SMEDDS for the target physicochemical and biopharmaceutical properties of the final product. This supports the technological competiveness of SMEDDS formulations for solubilization of poorly water-soluble drugs.
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