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  • Item
    Essential oil-loaded polymeric film for antimicrobial application to a urinary catheter
    (2022) Singh, Leschika
    Catheter-associated urinary tract infections (CAUTIs) account for 80% of hospital-acquired infections worldwide. With these infections often being associated with the development of antimicrobial resistant infections, preventative strategies such as technological advances in medical devices and the use of alternative antimicrobials are seen as an emerging and rewarding field. The use of alternative antimicrobials such as essential oils has become an area of interest in amalgamating alternative therapeutics with medical devices to curb the observable resistance patterns. The aim of this study was to identify the most antimicrobially active essential oil, for encapsulation into Beta-cyclodextrin (βCD) biopolymer for development of a formulation intended to coat urinary catheters for the prevention of CAUTI development. The study design was carried out in three stages, antimicrobial screening, formulation, and validation of antimicrobial activity. In stage 1, a total of 26 essential oils were evaluated using the broth microdilution assay to obtain the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) against 29 UTI causative pathogens. The MIC studies demonstrated that five (Cinnamomum zeylanicum, Santalum austrocaledonicum, Syzygium aromaticum, Thymus vulgaris, and Vetiveria zizanioides) of the 26 evaluated essential oils displayed noteworthy (≤1.00 mg/mL) broad-spectrum antimicrobial activity. The MBC assay showed that C. zeylanicum exhibited the best bactericidal activity at concentrations ≤1.00 mg/mL against 10 of the 29 pathogens tested. The antibiofilm assay evaluated the five most antimicrobially active essential oils against the five most prevalent biofilm-forming UTI causative pathogens (Escherichia coli, Enterococcus faecalis, Klebsiella pneumoniae, Proteus mirabilis, and Staphylococcus aureus). Results showed that C. zeylanicum inhibited biofilm formation of all five pathogens. This broad-spectrum biofilm inhibitory activity, coupled with the most broad-spectrum planktonic inhibitory and bactericidal activity, demonstrated that C. zeylanicum was the best essential oil to be taken forward into formulation. In stage 2, encapsulation of C. zeylanicum in βCD was carried out at five ratios of essential oil: βCD (5:95, 10:90, 11:80, 15:85, and 20:80) using the co-precipitation method. Thereafter physicochemical characterisation of the inclusion complex was carried out by Fourier-transform infrared spectroscopy (FTIR), Powder-X-Ray diffraction (PXRD), Zeta potential and size measurements, and thermogravimetric analysis (TGA). The percentage encapsulation was determined followed by antimicrobial evaluation of each inclusion complex. Characterisation (FTIR) verified the incorporation of the essential oil into βCD as evident, by shifts and increased intensities of characteristic βCD bands indicating that complexation had taken place. The highest encapsulation efficacy was exhibited at a ratio of 15:85 (Essential oil: βCD), whereas the best antimicrobial activity was observed for the 11:80 ratio. A crosslinked PVAbased film was formulated incorporating the 11:80 βCD complex and physicochemical and physico-mechanical properties were characterised. Thermal stability was seen well above the physiological temperature (37 °C). Swelling and degradation profiles indicated desirable characteristic with a low swelling ratio for 4% PVA (10.19), 4% PVA-βCD (7.98), and 4% PVA-CZ (7.68), and slow degradation was observed for the three films over 21-28 days. The final entrapment efficacy and encapsulation efficiency of C. zeylanicum in the 4% PVA-CZ film was 0.52 mg/mL and 29.71%, respectively. The in vitro release study of the C. zeylanicum loaded film and the C. zeylanicum inclusion complex were carried out in artificial urine and depicted as a slow release of C. zeylanicum from the film over a three-day period, with ~80.00% of the C. zeylanicum contents being released, relative to the 24-hour release from the inclusion complex with only ~44.00% C. zeylanicum released. In stage 3 the antimicrobial efficacy of the C. zeylanicum loaded film formulation was carried out and exhibited inhibition of growth of E. coli, E. faecalis, K. pneumoniae, P. mirabilis, and S. aureus over a 72-hour period in comparison to the control 4% PVA-βCD film tested without essential oil. The successful entrapment of C. zeylanicum essential oil and incorporation into a pharmaceutical formulation whilst retaining its antimicrobial activity serves as a proof of concept for the effective antimicrobial application on to a urinary catheter.
  • Item
    In vitro investigation of Rosa Rubiginosa (rosehip) oil and essential oil combinations for the topical treatment of acne
    (2022) Ramburrun, Shivani
    Acne vulgaris is the eighth most prevalent disease worldwide. Cutibacterium acnes overgrowth and inflammation are responsible for acne pathogenesis. Essential oils are one of the leading natural products used for dermatological applications, including acne. Essential oils are combined with fixed oils to reduce irritation and toxicity, however, the effect of fixed oils on essential oil bio-activity requires further investigation. This study aimed to investigate the in vitro antimicrobial, toxicity, anti-inflammatory, and associated cytotoxicity, as well as the skin absorption and retention properties of Rosa rubiginosa (rosehip) fixed oil independently and in combination with essential oils to treat the pathophysiological mechanisms involved in acne. For the antimicrobial activity, the minimum inhibitory concentration (MIC) was determined using the broth microdilution assay. The fractional inhibitory concentration index (ƩFIC) was calculated to evaluate the antimicrobial interactions of the oil combinations. Rosa rubiginosa fixed oil combined with Cinnamomum zeylanicum (true cinnamon) essential oil displayed antimicrobial synergy (mean MIC = 0.42 mg/mL, mean ƩFIC = 0.45) against three acneinducing reference strains (C. acnes, Staphylococcus epidermidis, and Staphylococcus aureus). Rosa rubiginosa fixed oil combined with either Eugenia caryophyllata (clove), Kunzea ericoides (kanuka), Melaleuca quinquenervia (niaouli), Melissa officinalis (lemon balm), Rosa damascena (Damask rose), or Styrax benzoin (gum benjamin) essential oil displayed antimicrobial additive interactions. Rosa rubiginosa fixed oil combined with Santalum austrocaledonicum (New Caledonia sandalwood) essential oil displayed antimicrobial antagonism. These eight oil combinations were further analysed in various ratios. The ƩFIC for the various ratios were expressed graphically on isobolograms, which revealed that most of the antimicrobial effects were attributed to the essential oils rather than R. rubiginosa fixed oil. When the toxicity was evaluated using the brine shrimp lethality assay, R. rubiginosa fixed oil was found to be non-toxic with a percentage mortality of 0.35-1.64% after 24 hrs and 0.74- 2.00% after 48 hrs, across all concentrations in the range of 0.03-1.00 mg/mL. For the combinations, R. rubiginosa fixed oil combined with K. ericoides essential oil at 0.25 mg/mL produced the greatest reduction in toxicity, where the percentage mortality decreased significantly from 100% (K. ericoides essential oil independently) to less than 3% (1:1 oil combination) at 24 hrs (p-value = 0.04) and 48 hrs (p-value = 0.03). For the anti-inflammatory and associated cytotoxicity studies, nitric oxide inhibition was investigated in lipopolysaccharide (LPS) induced RAW 264.7 murine macrophages treated with R. rubiginosa fixed oil and the eight essential oils. Simultaneous evaluation of cell viability (MTT assay) was used to confirm the absence of cytotoxicity of the test samples. Rosa rubiginosa fixed oil reduced LPS induced nitrite production by 18.75%, and the combination of R. rubiginosa fixed oil with S. benzoin essential oil reduced nitrite production by 33.80%, relative to the LPS control. Cytotoxicity in A549 human epithelial cells was ascertained by measuring cell viability, using a dual-staining method. The combination of R. rubiginosa fixed oil with M. quinquenervia essential oil showed the best non-cytotoxicity in A549 epithelial cells relative to the cell culture medium. Skin absorption (via diffusion) and retention of topically applied R. rubiginosa fixed oil and the eight essential oils were studied using excised porcine skin. Fourier Transform Infrared spectroscopy (FTIR) was used to obtain the qualitative infrared profiles depicting the vibration transitions of R. rubiginosa fixed oil and the essential oils. Differences in the wavenumber positions and peak intensities (percentage transmittance) of the oils at various concentrations, were noted. The combinations of R. rubiginosa fixed oil with either C. zeylanicum, E. caryophyllata, S. benzoin, or R. damascena essential oil, were extracted from the skin after 24 hrs and qualitatively detected using FTIR. This suggested that FTIR could be a suitable method for detection and qualitative analysis of R. rubiginosa fixed oil and essential oils within the concentration range of 1.25-100.00% v/v. This study revealed that R. rubiginosa fixed oil (containing 41.93% of linoleic, 35.73% of linolenic, and 15.45% of oleic acids) with S. benzoin essential oil (containing 72.20% of dimethyl phthalate, 7.20% of benzyl acetate, and 5.70% of ethyl cinnamate) is an effective inhibitor of LPS induced nitrite production (as a parameter of anti-inflammatory activity). Rosa rubiginosa fixed oil with S. benzoin essential oil is a promising non-cytotoxic oil combination, able to absorb into and be retained within the skin when topically applied, which may be used to potentially treat the pathophysiological mechanisms involved in acne vulgaris. Future experimental analysis entails quantitative permeation studies of R. rubiginosa fixed oil and essential oils across an in vitro and/ or ex vivo skin model, to further support the use of these oils and combinations for treating acne pathogenesis.
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    Cannabidiol formulation development: in vitro and ex vivo investigation of cannabidiol containing transfersomal formulations for the management of haemorrhoids
    (2022) Moqejwa, Thope
    Cannabidiol is a non-psychoactive compound of cannabis that has been demonstrated to alleviate pain and inflammation. However, its clinical application is hampered by disadvantages such as limited oral bioavailability, photo- and heat instability, and uneven release and absorption. Adapting nanotechnology into rectal delivery system can counteract drawbacks of cannabidiol (CBD). In this study, the transfersomes colloid were developed to enhance CBD bioavailability, absorption, and stability as a rectal colloid, that can be used to manage haemorrhoidal pain and inflammation. Thin film evaporation was used to produce transfersomes containing variable amount of polysorbate 80, cholesterol (30mg) and soya lecithin (60 mg), which were then tested for size, entrapment capacity%, shape, release profile, ex vivo permeability, and stability. The advanced transfersomes colloid was incorporated into ratios of 95% P407:5%PEG1000 and 75% PEG1000:25% PEG6000 bases to form suppositories using fusion mould method. Drug release study, hardness, mass difference, content homogeneity, disintegration time, cytotoxicity, and in vitro anti-inflammatory study were performed on suppositories. The advanced transfersome colloids had a particle size of 130.1 nm ± 0.64, polydispersity index of 0.285 ± 0.0056, and surface charge of -15.97 mV ± 1.30, the advanced formulation for rectal distribution entrapped up to 80.0% ± 0.077 of CBD. The morphological study of transfersomes using scanning electron microscope (SEM) and transmission electron microscope (TEM) revealed their spherical shape and nanoscale, which attributed to improved ex vivo permeability of CBD-transfersomes colloid across the excised rat colonic membrane compared to free CBD. The CBD-loaded transfersomes suppositories controlled the release of CBD, with 95% CBD released within the period of 6 hours. In vitro anti-inflammatory studies proved the anti-inflammatory properties of CBD, CBD inhibited protein modification at all concentrations, with the highest inhibition of 96.4% at 75 mg/mL. The anti-inflammatory properties of CBD were comparable with the well-known potent antiinflammatory drug diclofenac. Additionally, transfersomes increased the stability of the entrapped CBD for up to half a year at ambient environmental conditions. CBD-transfersomes colloid reduced CBD toxicity on caco2 cells by around 70%. Because of the controlled release profile of CBD, CBD-loaded transfersomes colloid suppositories have the potential to relieve pain for an extended period. Moreover, enhanced stability of CBD under ambient environmental conditions implies that CBD-transfersomes colloid improve CBD shelf life. Overall, this study demonstrated the effectiveness of CBD to manage inflammation and pain associated with haemorrhoids, furthermore this formulation can be useful to patients under palliate care.
  • Item
    Global adverse drug reactions trends of anastrozole, fulvestrant and tamoxifen using vigibase® data
    (2022) Maharaj, Juhi
    Introduction: Breast cancer is the leading cancer subtype and accounts for the most significant number of cancerrelated deaths in females. Cancer patients have an elevated risk of experiencing adverse drug reactions before, after, and while on treatment. Pharmacovigilance prioritises drug and patient safety, however, due to extensive under-reporting, more so in low-to-middle income countries, signal detection and the consequent changes to policy and practice are lacking. Thus, there is a need to analyse the global database of individual case safety reports on anastrozole, fulvestrant and tamoxifen, commonly used hormonal agents for treating breast cancer. Methods: A quantitative, secondary approach was taken where descriptive and statistical analysis was conducted on data obtained from the Uppsala Monitoring Centre’s global individual case safety report database, VigiBase®. A total of 43 411 anonymised reports were analysed, using Microsoft Excel for data organisation, cleaning, and numerical coding. The seriousness of the reported adverse drug reactions was evaluated and categorised. The statistical analysis program STATA was used. Pearson chisquared analysis was conducted to determine statistical associations. Further binary logistic regression was conducted, using a p-value of < 0.05 to show statistical significance. Comparisons between the reported adverse drug reactions and those listed on the drug’s package inserts were also done. Results: The majority of the adverse drug reactions were reported from the “Americas” and “Europe”. Most of the reports were from females in the “45 – 64 years” age group. The most frequently reported ADR for anastrozole, fulvestrant, and tamoxifen were “arthralgia”, “fatigue”, and “death” respectively. The type of adverse drug reactions reported from Africa, albeit few, were not entirely similar to the other continents. The adverse drug reactions that were most frequently found to be statistically significant with the demographic variables were “arthralgia” for anastrozole, “malignant neoplasm progression” and “asthenia” for fulvestrant, and “arthralgia” for tamoxifen. Despite most of the adverse drug reactions listed in the medicines package insert, there were other commonly reported reactions not listed in the leaflet. Conclusion: Well-known and frequently reported adverse drug reactions have demonstrated statistically significant associations to several age groups and continents. This research can be used to warrant targeted adverse drug reaction monitoring in specific populations to safeguard and better manage patients at greater risk of adverse reactions that impact patient quality of life and have considerable cost implications.
  • Item
    Development and characterization of a solid lipid nanoparticle-loaded thermosensitive gel for the delivery of timolol to the eye
    (2022) Lynch, Courtney Rose
    The delivery of drugs to the eye is notoriously challenging. This is due to various physiological barriers which prevent the movement of foreign bodies and substances from getting into the eye, such as the cornea and conjunctiva. In addition to this, biomechanical processes such as the blinking reflex and rapid nasolacrimal drainage removes substances from the surfaces of the eye leading to a very short residency time. The first line treatment for most anterior segment conditions of the eye is the daily administration of drops. These solutions are known to have a low bioavailability, leading to frequent dosing schedules which are often not adhered to by patients correctly. This can be highly detrimental, especially in the case of glaucoma, a condition which is known to cause irreversible blindness due to increased intraocular pressure and subsequent optic nerve damage if not treated adequately from the time of diagnosis. In this study, an innovative formulation composed of drug loaded solid lipid nanoparticles embedded within a thermosensitive gel was developed for the topical administration of timolol to the eye. The polymers employed for the gel were hyaluronic acid and methylcellulose, natural polymers which have been used previously in ophthalmic preparations and are known to be mucoadhesive and biocompatible. The choice of these polymers was aimed at increasing the residency time of the formulation at the surface of the eye to allow for better penetration through the layers protecting the eye. This is of particular importance as the current commercially available eye drops are known to be largely removed from the surface of the eye within 30 seconds of administration. The lipids selected were Compritol® 888 ATO and oleic acid, and the solid lipids nanoparticles (SLNs) were formulated using a nanoemulsion method. This method involved the homogenization of a hot lipid phase upon addition to a cold hydrophilic phase, resulting in the formation of SLNs. The formulated solid lipid nanoparticle gel (SLN-G) system was characterized through various techniques including Fourier Transform Infra-Red (FTIR), thermogravimetric (TGA) and differential scanning calorimeter (DCS) analysis. These characterizations showed a system in which the drug, timolol, was effectively incorporated into the SLN with an encapsulation efficiency of 97.18% and a drug loading capacity of 56.12%. This encapsulation efficiency was further highlighted in the thermal analysis of the SLN-G, TGA and DSC, where the graphs of the drug loaded SLN-G did not show the characteristic peaks of timolol thereby confirming that it was effectively incorporated into the system. Results of the rheology studies revealed that the gel underwent the sol-gel transition at 33 °C when not nano-enabled and at 28 °C when embedded with the SLNs. These are appropriate temperatures for application at the surface of the eye. The average size of the SLNs was 54.75nm and they were spherical in morphology, as confirmed through scanning electron microscopy (SEM) imaging. In addition to this, the in vitro drug release showed an extended drug release profile of approximately 24 hours in comparison to the commercially available product, which releases the drug instantaneously, and could potentially be administered once daily. The current first line glaucoma treatment, timolol eye drops are administered twice daily. By decreasing the frequency of the dosing schedule, patient compliance increases. The SLN-G and its components were also tested for biocompatibility using two different cell lines, Caco-2 and Human Retinal Pigment Epithelial (HRPE) cells. The cell viability was shown to be above 76% for the HRPE after 48 hours of exposure to the drug-loaded SLN-G and above 86% for the Caco-2 cell line, highlighting that the biocompatibility of the formulation. Through these results, it is proposed that an effective alternative to eye drops was developed. The resulting SLN-G illustrates an exciting development in the realm of ophthalmic drug delivery. The primary future prospect of this study would be through further testing in an animal model and, if successful, in a clinical trial model in order for the formulation to be made available on the commercial market. The limitations of the further development would largely be dependent on financial backing. However, due to the extensive positive impact this formulation would have on the quality of the lives of so many people around the world, the effort and financing of future developments would be well worth it.