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Shrestha, Sony C. (2020) Formulation and characterisation of plant stanol ester loaded solid lipid nanoparticles for the management of hypercholesterolaemia. Doctoral thesis, London Metropolitan University.
Background:
Well-powered and rigorous surveys and studies conducted in developed countries demonstrate that lipid-lowering agents have adverse effects of variable severity. Although the use of these agents has increased exponentially in developing countries, such as Nepal, there is a scarcity ofreliable data about adverse reactions. The adverse drug reaction reporting system is not properly implemented or monitored in some of these countries. In addition, there is evidence of ambivalent attitude and practice towards reporting of adverse drug reactions among healthcare professionals due to insufficient knowledge of pharmacovigilance. There is a need to assess the system of reporting adverse drug reactions in Nepal, and to develop cholesterol-lowering compounds without the adverse reactions associated with hypolipidaemic agents. Phytostanols are naturally occurring compounds which reduce blood cholesterol level significantly. However, their aqueous insolubility poses formulation challenges.
Aims:
The aims of this study were to: (1) investigate awareness, knowledge, attitude, and practice of adverse drug reactions reporting and pharmacovigilance among health professionals (2) have an insight on the adverse effects of statins in Nepal, and (3) formulate and characterise phytostanol ester loaded solid lipid nanoparticles for the management of hypercholesterolaemia.
Methods:
Pharmacovigilance survey: One hundred twenty-five (n=125) health professionals (doctors, pharmacists/assistant pharmacists and nurses) who consented to participate in the study were recruited from health care institutions in Kathmandu, Nepal. Electronic and paper survey data were collected with the use of a validated questionnaire developed for the study. Informed consent from the volunteers and ethical approval from London Metropolitan University and the Nepal Health Research Council were obtained.
Solid lipid nanoparticles: Phytostanol ester solid lipid nanoparticles were formulated by the microemulsion method. They were characterised for particle size distribution, polydispersity index, zeta potential, entrapment efficiency, shape and surface morphology, stability, spectroscopic and thermal analysis. The uptake of the formulation by cell lines and its effect on cell viability were evaluated. The collected data were analysed with the use of the statistical software, Statistical Package for the Social Sciences (SPSS, version 25).
Results:
Pharmacovigilance survey: One hundred (80%) of the participants (44 doctors, 32 pharmacists/assistant pharmacists, 24 nurses) completed and returned the self-administered questionnaire. Pharmacovigilance knowledge, attitude, practice scores of those who responded were 71%, 81%, and 53%, respectively. There was a significant difference between the number of health professionals who were knowledgeable (71 vs. 29%, p < 0.05) and had favourable attitudes (81 vs. 19%, p< 0.05) towards adverse drug reaction reporting and pharmacovigilance compared with those who did not. The number of health professionals who did not spontaneously report adverse drug reactions was higher than those who did (90 vs. 10%, p < 0.05). The study clearly demonstrates a gap between knowledge and attitude, and practice. This discrepancy is due to the lack of proper guidelines on good pharmacovigilance practice, reporting mechanism, and monitoring, and unavailability of adverse drug reaction reporting forms. The adverse reactions of statins commonly observed by the participating health professionals were muscle symptoms (62%), elevated activity of liver enzymes (25%), gastrointestinal symptoms (9%) and high glucose levels (4%).
Solid lipid nanoparticles: We have successfully optimised the formulation of solid lipid nanoparticles by varying the type of lipids and their concentration relative to that of surfactants. The optimised phytostanol ester solid lipid nanoparticles had an average diameter of 171 ± 9 nm, a negative surface charge of -23 ± 0.8 mV and were generally spherical in shape. We report high levels of drug entrapment at 89± 5% in amorphous form, drug loading of 9.1 ± 0.5%, nanoparticle yield of 67 ± 4% and drug excipient compatibility. The biological safety and uptake of solid lipid nanoparticles were demonstrated on hepatic and intestinal cell lines.
Conclusions:
Pharmacovigilance survey: The findings of this survey indicate that in spite of the knowledge and willingness of health professionals to report adverse drug reactions, the practice of pharmacovigilance remains low in Nepal. There is a need for clear and enforceable regulations for monitoring and reporting adverse drug reactions, and effective educational interventions to promote pharmacovigilance practices.
Solid lipid nanoparticles: Phytostanol ester solid lipid nanoparticles were successfully formulated and characterised. The suitability of solid lipid nanoparticles as a novel drug delivery system for phytostanols which lower cholesterol without causing any adverse reactions have been demonstrated. Phytostanol ester solid lipid nanoparticles that can be integrated within the lifestyle intervention has the potential to emerge as a significant innovation to treat hypercholesterolaemia. This can contribute to the better management of cardiovascular diseases, especially in developing countries where adverse drug reactions are not regularly monitored.
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