Lipid based drug delivery systems are gaining importance as a tool to improve bioavailability and enable commercial use of poorly soluble drugs. The numbers of the latter are importantly increasing in the field of drug discovery. Incorporation of the drug in lipid based delivery systems facilitates its appropriate solublilization and consequently improves the solubility of the drug. However, use of these systems also comes with their unique challenges regarding their development and evaluation.
Aside from solubility improvement, lipid based delivery systems can also affect stability of the drug in the gastrointestinal tract (GIT), absorption of the drug from the GIT as well as the possibility for the drug to be absorbed in the lymph circulatory system. Digestion of the lipid based delivery systems in the GIT and variable conditions that are present in the GIT are the main obstacle in efficient in vitro evaluation and predicament of the in vivo fate of the formulations. The content of the Chapter 1 is focused on the presentation of the physiological events that follow the peroral delivery of lipid based delivery systems as well as the overview of the existing models of in vitro lipolysis that were developed for the purpose of evaluation of the lipid based delivery systems.
Lately, naturally occuring active ingredients are gaining recognition. Among them, polyphenols are a class of chemicals that encompasses over 8000 compounds with perspective biological activities. One of the best studied representatives of the group is resveratrol, with its trans- stereoisomer (in continuation of the thesis referred to in a simplified form as »resveratrol«) excerting many promising biological activities. Nevertheless, its clinical use is compromised by its unfavourable biopharmaceutical properties, such as poor water solubility. Therefore, development of the novel self-microemulsifying drug delivery system (SMEDDS) with mixed lipid phase, incorporated with resveratrol, is described in Chapter 2. SMEDDS, the most perspective formulations among lipid based delivery systems, are defined as isotropic mixtures of oil phase, surfactant, co-surfactant and hydrophillic cosolvents. Subsequently to their entrance into the GIT the dilution of the formulations with the liquid present in GIT takes place. This process results in the microemulsion formation from SMEDDS. The use of heterogenous lipidic phase, composed from castor oil (long chained triglycerides) and Capmul MCM (medium chained mono- and dig-glycerides), enabled formulation of SMEDDS with lesser content of surfactants (down to 60 % Kolliphor EL/RH 40/RH 60). Large quantities of surfactants may cause the irritation of the GIT.
Following successful improvement of resveratrol solubility, the impact of its incorporation into SMEDDS on permeability properties and cytotoxicity of resveratrol was also evaluated. Firstly, novel SMEDDS composed of heterogenous lipid (castor oil/Capmul MCM 1:1 w/w) as well as heterogenous surfactant phase (Kolliphor EL/Kolliphor RH 40 1:1 w/w) with excellent self-microemulsifying properties was developed. This formulation enabled also immediate release of resveratrol (Chapter 3). Despite its poor solubility, resveratrol exhibits satisfactory absorption. In spite of its good adsorption the bioavailability of resveratrol is low, due to its extensive first pass metabolism. Rat intestine and Caco-2 cells were used as a model to illustrate the impact of resveratrol incorporation into SMEDDS on lowering of the efflux of two metabolites (glucuronide and sulfate) in the secretory direction. This enhanced the concentration of metabolites, which could transform back into resveratrol at the site of action. It was further confirmed, that this is the consequence of the inhibition of MRP and P-gp transportes, caused by the surfactants in SMEDDS. No cytotoxic effects were discovered, when Caco-2 cells were in contact with the SMEDDS alone. This was not the case for resveratrol solution, although we did manage to partially alleviate the cytotoxicity of resveratrol with its incorporation in SMEDDS.
Due to the nature of its components, lipid based drug delivery systems are usually liquids. While some liquid formulations can be found on the market, they are unfavoured by both the patients as well as pharmaceutical industry. Filling of lipid formulations into gelatin capsules can be problematic in particular because of possible incompatibilities between the filling contents and the capsule.
Transformation of liquid SMEDDS and into self-microemulsifying (SME) powders and tablets is described in Chapter 4. SME powders were prepared with adsorption on solid carriers (amorphous silicon dioxide, Sylysia® 350 and Syloid® 244FP; granulated magnesium alumino-metasilicate Neusilin® US2). Powders were later pressed into 600 mg SME tablets. Both SME powders and SME tablets managed to successfully retain self-microemulsifying properties of the liquid SMEDDS. It must be drawn to the attention, that during the standard dissolution test desorption of SMEDDS from the solid carrier was incomplete, resulting in incomplete dissolution of resveratrol. Unexpectedly, this occurrence cannot be predicted through the monitoring of free fatty acid release during in vitro lipolysis of SMEDDS. Both liquid and solid SMEDDS formulations managed to mainain the stability of resveratrol during accelerated stability testing (90 days at 40°C), as more than 90 % of resveratrol remained in the formulations.
Lastly, development of multiparticulate self-microemulsifying solid dosage form was attempted. Improvement of the vibrating membrane method to produce microcapsules with the SMEDDS core is described in Chapter 5. Our aim was the development of the procedure that would enable repeatable manufacturing of microcapsules (MC) with high loadig efficiency of the model drug furosemide. SMEDDS formulations of furosemide is of interest due to its poor solubility as well as inadequate absorption properties. Specifically, shell of the microcapsules was optimised for alginate and pectine ratio (A/P) as well as hydrophillic filler content. MC exhibiting the best loading efficiency were prepared from the polymer solution with the A/P ratio of 75:25 and 10 % lactose, using one-step hardening procedure. Subsequently, MC were dried in fluid bed and evaluated for the furosemide release as well as swelling of the polymer shell. The results showed that the addition of hydrophillic fillers to the shell phase successfully restricted leaking of the core during MC preparation and drying. Furthermore, it was discovered that hydrophilic fillers in the shell have the ability of modifying the drug release pattern from the A/P microcapsules.
The doctoral thesis highlighted the critical aspects of the difficulties that are encountered during development of lipid based drug delivery systems, contributing to better understanding of these specific formulations. This will lead to the development of more efficient lipid based delivery systems. In the future, registered products with lipid based delivery systems on the market are expected to grow in number.
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