| Přispěvatelé: |
Hamman, J.H., Steyn, J.D., Kotzé, A.F., 10081097 - Hamman, Josias Hendrik (Supervisor), 12297305 - Steyn, Johan Dewald (Supervisor), 10200142 - Kotzé, Abraham Frederik (Supervisor) |
| Popis: |
PhD (Pharmaceutics), North-West University, Potchefstroom Campus Drug products and dosage forms are seldom taken in complete isolation. The possibility exist to ingest drugs together with foods, herbs, dietary supplements and/or other drugs, which may result in pharmacokinetic or pharmacodynamic interactions between the compounds. Such interactions have predominantly been associated with negative outcomes such as inefficacy, adverse effects and toxicity. However, the same interactions may be used in a strategic manner to potentially be beneficial to the patient. Beneficial pharmacokinetic interactions include enhancing absorption, inhibiting metabolism and/or decreasing excretion, resulting in improved bioavailability and prolongation of a drug’s plasma levels, respectively. Beneficial pharmacodynamic interactions include additive or synergistic effects at drug receptor level. Enhancement of absorption during beneficial pharmacokinetic interactions can mechanistically be attributed to increased membrane permeation through tight junction opening or structural changes in membrane conformation, modulation of carrier proteins through inhibition of efflux proteins or stimulation of uptake transporters. The nasal cavity has been identified as a potential alternative drug delivery route for large molecular weight compounds, compounds that are extensively metabolised or compounds that possesses unfavourable physico-chemical properties for oral delivery. The reason for this is because the nasal cavity’s epithelial layer has a relatively high permeability, large surface area and drug delivery that occur directly into the systemic circulation. The aim of this study was to identify and investigate the potential beneficial pharmacokinetic interactions (i.e. enhanced nasal drug delivery) of selected natural compounds (i.e. different plant extracts and materials) with different model compounds in two different in vitro nasal models. A literature review article was published in the journal “Pharmaceutics”, which discussed potential beneficial pharmacokinetic interactions that selected foods, herbs, dietary supplements and drugs may have on concomitantly administered drugs that can be exploited in the future to the benefit of the patient. Based on the literature review that pharmacokinetic interactions may be used to the benefit of the patient a variety of natural compounds were investigated for possible nasal drug delivery enhancement. The natural compounds that were selected for this investigation included two pepper extracts, namely capsaicin and piperine, as well as the gel and whole leaf extract of three aloe species (Aloe vera, A. ferox and a newly cultivated hybrid A. muth-muth). These plant extracts and materials have not been studied for nasal drug delivery enhancement before. Various pepper fruits have traditionally been used for seasoning of food, but also as perfuming agents and as herbal medicines. Furthermore, phytochemicals isolated from different pepper species have been found to alter the pharmacokinetic profile of orally administered drugs with regards to transporter modulation and metabolism inhibition. In the current contribution, it was shown that capsaicin inhibited p-glycoprotein (P-gp) efflux of rhodamine 123 (R123) to a larger extent as piperine in nasal epithelial cells. However, piperine modulated a higher increase in FITC-dextran 4400 (FD4) permeation across the nasal epithelium via mechanisms that still need to be confirmed in future studies. Cytotoxicity studies on the RPMI 2650 cell line indicated that capsaicin was non-cytotoxic up to a concentration of 200 μM and piperine up to a concentration of 500 μM (based on cell viability above 80%). The histological analysis of the excised nasal tissue and cultured RPMI 2650 cell layers was in coherence with each other, indicating that some damage occurred after treatment with 200 μM capsaicin, but no changes were observed for piperine up to a concentration of 50 μM. With regards to the selected aloe species, multiple medicinal applications for different extracts and materials from these plants have been known for centuries. However, beneficial pharmacokinetic interactions through opening of tight junctions and inhibition of efflux were only recently discovered. It has been hypothesized that these pharmacokinetic interactions may be used as a tool to improve bioavailability of poorly absorbed drugs, especially peptide molecules and other large molecular weight drugs, which are not sufficiently delivered via the oral route of administration. It was concluded from this study that the gel and whole leaf extract materials from all three aloe species could enhance permeation of FD4 across the nasal epithelium, albeit to different extents and rates. Similar permeation enhancement trends were found in the RPMI 2650 cell model and the excised sheep nasal tissue model. Histological analysis showed that some of the leaf materials had detrimental effects on the nasal epithelium, except those from A. ferox and A. muth-muth, which caused relatively low toxicity in both nasal epithelial models. Furthermore, two nasal delivery models (i.e. the RPMI 2650 cell line and excised sheep nasal mucosa) were compared with regards to epithelial thickness, selected tight junction protein expression, extent of P-gp related efflux and paracellular permeation of marker compounds. It was found that the epithelial thickness of the RPMI 2650 cell line compared well with that of the excised sheep nasal tissue (53.3 ± 8.1 μm and 52.9 ± 4.4 μm, respectively). Although the location and distribution of tight junction proteins and F-actin differed between RPMI 2650 cell layers grown at the air-liquid interface (ALI) from those in the excised sheep nasal epithelial tissue, the extent of paracellular permeation of FD4 was similar in these two models (Papp = 0.48 x 10-6 cm.s-1 and 0.46 x 10-6 cm.s-1). Similarly, a P-gp substrate (R123) presented with an identical efflux ratio value of 2.33 in both models. It was concluded that the two models can be deployed interchangeably and will yield similar results in nasal membrane permeation studies. In conclusion, this research showed for the first time the possibility of the selected natural compounds to be used as functional excipients in nasal drug delivery, specifically to increase their epithelial permeation and subsequently bioavailability with relatively low toxicity. Doctoral |
