Magister Pharmaceuticae - MPharm / Sutherlandia frutescens is a traditional plant medicine widely used in South Africa. Traditionally, the leaves of S. frutescens are mainly used as a tea, but these traditional dosage forms have several disadvantages, including that they are not particularly convenient to prepare and store, encourage dosage inaccuracy and are highly susceptible to microbial contamination. To solve these problems, dried aqueous extract forms, e.g. freeze dried aqueous extract (FDAE) of S. frutescens were prepared, but they, in turn, may still suffer from instability and contain mainly hydrophilic phytoconstituents that are poorly absorbed and delivered for in vivo activity. Modified forms of the FDAE, i.e. the active phytopharmaceutical ingredient (API), may be a better solution. Therefore this study sought to prepare liposomes and phytosomes of the freeze dried aqueous extract of Sutherlandia frutescens, as a means of increasing the total the surface area of the API, thus improving its release and dissolution in gastrointestinal fluids. Liposomes and phytosomes of the FDAE of Sutherlandia frutescens obtained were prepared using a thin film hydration method at ratios of lecithin: S. frutescens (3:1) and phosphatidylcholine: S. frutescens (2:1) respectively. The physical characteristics (i.e. particle size, size distribution, zeta potential, and morphology), of flavonoid glycosides (i.e. sutherlandins A to D; API) as well as content and release profiles of each dosage form (i.e. FDAE liposome or phytosomes) at pH 1.2 and pH 6.8 was determined. A validated HPLC assay was used to determine and compare the flavonoid glycoside content and release profiles of the liposomes and phytosomes. Both liposomes and phytosomes were successfully prepared, in moderate yields (± 30 %, and ± 50 %, respectively), using the thin film hydration method. The liposomes had a significantly smaller size, lower size distribution, higher zeta potential and better stability than the phytosomes (p < 0.05). The phytosomes, however, had significantly higher flavonoid glycoside encapsulation efficiency than the liposomes (±50 % vs ±26 %; p < 0.01). In addition, the release at 120 minutes, of flavonoid glycosides from the liposomes (63%, 58%, 76% and 46% % at pH 1.2, and 78%, 76%, 87% and 89 % at pH 6.8 for sutherlandins A, B, C and D, respectively) was significantly higher and faster than that of the phytosomes (52%, 41%, 51% and 39 % at pH 1.2, and 31% 31%, 33%and 45% % at pH 6.8, for sutherlandins A, B, C and D, respectively). The differences in release were likely due to differences in particle size and size distribution of the two modified API forms. Overall, liposomes and phytosomes can be considered promising vehicles for delayed delivery of herbal crude extracts. Based on its characteristics (i.e. narrower size distribution, and better stability), the liposomes were preferred compared to the phytosomes offering a better kinetic release profile. The phytosomes had higher encapsulation than the liposomes that may be due to complex formation between the API and the lipid.

Transdermal drug delivery systems (TDS) are pharmaceutical devices that are designed to deliver specific drugs to the human body by diffusion through skin. The TDS effectiveness suffers from crystallization in the patch when they are kept in storage for more than two years. It has been reported that there are two types of crystals in the patch: needle and aggregate, and growth of drug crystals in TDS generally occurs only in the middle third of the polymer layer. In our study, fluorescence microscopy, EDS (SEM) and Raman microspectroscopy were used to further characterize the crystals. The results show that the needle crystals most probably contain estradiol and acrylic resin conjugate. The FTIR spectrum of the model sample proved the occurrence of a reaction between estradiol and acrylic resin. Crystal growth in an unstressed matrix of a dissolved crystallizable drug component was simulated using a kinetic Monte Carlo model. Simulation using Potts model with proper boundary condition gives the crystals in the middle of matrix in the higher temperature. Bond fluctuation model is also being implemented to study representative dense TDS polymer matrix. This model can account for the size effect of polymer chain on the crystal growth. The drug release profile from TDS was also studied by simulating the diffusion of drug molecules using Monte Carlo techniques for different initial TDS microstructure. The release rate and profile of TDS depend on the dissolution process of the crystal. At low storage temperature, the grains are evenly distributed throughout the thickness of the TDS patch, thus the release rate and profile is similar to the randomly initiated system. Further work on stress induced crystallization is currently under development. Although the study was specifically done for drug in a polymer medium, the techniques developed in this investigation is in general applicable to any constrained crystallization in a polymer medium.

This dissertation is focused on the controlled release of drugs from a biodegradable amphiphilic hydrogel based on hydrophobic poly(lactic acid), poly(glycolic acid) and hydrophilic poly(ethylene glycol) (PLGA-PEG-PLGA, ABA) and its modification with itaconic anhydride (ITA). The resulting ,-itaconyl(PLGA-PEG-PLGA) copolymer is referred to as ITA/PLGA-PEG-PLGA/ITA or ITA/ABA/ITA. Itaconic acid provides reactive double bonds and a functional carboxyl group at the ends of the PLGA-PEG-PLGA copolymer chain, thereby rendering the modified ITA/ABA/ITA copolymer less hydrophobic and offering the possibility of forming a carrier for hydrophilic drug substances. These functional copolymers are thermosensitive and change in the external environment (e.g. temperature) causes a sol-gel phase transition due to the formation of micellar structure. The bioactive substances can thus be mixed with a copolymer which is in a low viscous phase (sol phase) and subsequently the mixture can be injected into patient's body at the target site where it forms a gel at 37 °C. This hydrogel becomes a drug depot, which gradually releases the active substance. Prediction of the substance’s release profile from the hydrogel is an effective tool to determine the frequency of administration, potentially enhancing efficacy, and assessment of side effects associated with dosing. The analgesic paracetamol and the sulfonamide antibiotic sulfathiazole were used as model drugs, representing hydrophilic and hydrophobic substances, respectively. The active substances had a significant effect on the resulting hydrogel stiffness. Type of solvent, incubation medium and nanohydroxyapatite also influenced on the gel stiffness and subsequent stability of the hydrogel-drug system. Controlled release of drugs took place in simulated conditions of the human body. Verification of Korsmeyer-Peppas (KP) drug-release model is also discussed in this thesis. The KP model was found suitable for simulating the release of sulfathiazole from ABA and ITA/ABA/ITA hydrogels. On the contrary, the performance of KP model was not suitable for describing the release of paracetamol from the ABA hydrogels. Therefore, a new regression model suitable for both buffered simulated media and water has been proposed. The proposed model fitted better the release of both sulfathiazole and paracetamol from composite material prepared from ABA hydrogel and nanohydroxyapatite.