dc.contributor.advisor | Škalko-Basnet, Natasa | |
dc.contributor.author | Jøraholmen, May Wenche | |
dc.date.accessioned | 2021-09-01T06:55:46Z | |
dc.date.available | 2021-09-01T06:55:46Z | |
dc.date.issued | 2016-02-19 | |
dc.description.abstract | <p>The vaginal inflammation and infection are one of the major female health issues, and unfortunately rather neglected. The anatomical structure and physiological conditions make vagina vulnerable to inflammation and infection, which if not successfully treated, can lead to deteriorating female health conditions. In pregnant patients, the pregnancy outcome can be severely affected. Although a standard treatment for vaginal infection is available, it is often not successful and recurrence rates are high. Therefore, a patientfocused drug development targeted at the vaginal inflammation and infection is the current social demand. Research and practice have shown that the topical treatment by the drugs against vaginal inflammation and infection can be superior comparing to the classical oral drug administration. However, the thick vaginal mucus lining the luminal surface of vagina and cervix, which protects the underlying tissue, limits the ability of a drug to reach vaginal mucosa. The success of mucosal delivery is highly dependent on a suitable drug carrier. Current dosage forms suffer from limited residence time at administration site and unpleasant leakage of dosage forms residues due to the self-cleansing action of the vagina, resulting in a reduced therapeutic effect. Therefore, liposomal drug delivery systems, with the ability to incorporate poorly soluble drugs and assure their stability, would be suitable for this purpose. Moreover, the modification of liposomal surface with mucoadhesive or mucoresistant polymers, might further enable improved mucosal drug delivery by providing prolonged residence time or rapid mucuspenetration, respectively.
<p>We selected chitosan as a mucoadhesive polymer due to its biocompatibility, low toxicity and intrinsic anti-microbial potential. By combining the liposomal carrier and the mucoadhesive chitosan, an optimized vaginal drug delivery system with specific, prolonged and controlled drug release properties might be developed. Alternatively, improved drug delivery to vaginal mucosa can be provided through mucoresistant properties of the delivery system. Polyethylene glycol (PEG) plays an important role in this approach, and PEGylated liposomes enable controlled drug release in close proximity to the vaginal epithelium. Three model drugs/active ingredients were tested in mucoadhesive/mucoresistant liposomebased delivery systems, namely clotrimazole, resveratrol and interferon. Particularly interesting were the anti-oxidative and anti-inflammatory properties of resveratrol, which has a great potential in the treatment of vaginal inflammation and infection, however, its low solubility and poor bioavailability accompanied by poor stability limit its therapeutic effects. Liposomal system enhanced its activities and confirmed its potential.
<p>The <i>in vitro</i> drug release and <i>ex vivo</i> penetration confirmed a sustained release of all liposomallyassociated drugs/active molecules. PEGylated liposomes (mucoresistant) assured improved penetration of interferon. By modulation of liposomal surface properties to be either mucoadhesive or mucoresistant it is possible to achieve prolonged residence time or deeper penetration of drug within vaginal epithelium, respectively. Moreover, the system can be modified for the different drugs, regardless of their molecular size and physicochemical characteristics. | en_US |
dc.description.doctoraltype | ph.d. | en_US |
dc.description.popularabstract | Vaginal infections are common in women of all ages; in pregnant women, they are associated with serious consequences such as infertility, preterm delivery, increased neonatal mortality and morbidity. Untreated or poorly treated infections lead to inflammation and often malignancy. Recent reports show a significant increase in sexually transmitted infections in 2014, the first such rise since 2006. In spite of the increasing incidence and serious consequences, the therapeutic options remain to be limited. Current dosage forms such as creams, foams, gels and tablets suffer from limited residence time at administration site and leakage due to the self-cleansing action of the vagina resulting in reduced therapeutic effect. Resveratrol is a natural-origin substance, commonly found in the grape skin, juice and red wine. Among many promising activities, such as anti-viral, it also exhibits strong anti-oxidant and anti-inflammatory activities and its local administration has a potential in treatment of vaginal inflammation. However, it is poorly water-soluble and its bioavailability and stability are rather limited. Therefore, there is a need for a suitable drug delivery system that not only enables its controlled delivery, but also offers protection from environmental and chemical changes.
The aim of this part of my PhD project was the development of a mucoadhesive drug delivery system for improved topical therapy. Liposomes are spherical vesicles that form spontaneously when phospholipids interacts with water that enables the incorporation of poorly soluble compounds. Liposomal resveratrol exhibited stronger anti-oxidative and anti-inflammatory activities as compared to resveratrol solution. We confirmed our hypothesis that the mucoadhesive liposomes may assure prolonged retention time at vaginal site and prolonged and controlled resveratrol release properties, enhancing its activity. This will, subsequently improve the patient compliance due to less frequent dosing as well as maximize the effect. The system seems to be safe to be applied to pregnant patients. This PhD project was funded by Norske Kvinners Sanitetsforening (Norwegian Women’s Public Health Association). | en_US |
dc.description.sponsorship | This PhD project was funded by Norske Kvinners Sanitetsforening (Norwegian Women’s Public Health Association). | en_US |
dc.identifier.uri | https://hdl.handle.net/10037/22331 | |
dc.language.iso | eng | en_US |
dc.publisher | UiT The Arctic University of Norway | en_US |
dc.publisher | UiT Norges arktiske universitet | en_US |
dc.relation.haspart | <p>Paper I: Jøraholmen, M.W., Vanić, Ž., Tho, I. & Škalko-Basnet, N. (2014). Chitosan-coated liposomes for topical vaginal therapy: Assuring localized drug effect. <i>International Journal of Pharmaceutics, 472</i>(1-2), 94-101. Also available at <a href=https://doi.org/10.1016/j.ijpharm.2014.06.016>https://doi.org/10.1016/j.ijpharm.2014.06.016</a>. Accepted manuscript version available in Munin at <a href=https://hdl.handle.net/10037/7243> https://hdl.handle.net/10037/7243</a>.
<p>Paper II: Jøraholmen, M.W., Škalko-Basnet, N., Acharya, G. & Basnet, P. (2015). Resveratrol-loaded liposomes for topical treatment of the vaginal inflammation and infections. <i>European Journal of Pharmaceutical Sciences, 79</i>, 112-121. Also available at <a href=https://doi.org/10.1016/j.ejps.2015.09.007>https://doi.org/10.1016/j.ejps.2015.09.007</a>. Accepted manuscript version available in Munin at <a href=https://hdl.handle.net/10037/8163> https://hdl.handle.net/10037/8163</a>.
<p>Paper III: Jøraholmen, M.W., Basnet, P., Acharya, G. & Škalko-Basnet, N. PEGylated liposomes for topical vaginal therapy: Mucus-penetration improves delivery of interferon alpha. (Manuscript).
Now published with the title: PEGylated liposomes for topical vaginal therapy improve delivery of interferon alpha. <i>European Journal of Pharmaceutics and Biopharmaceutics, 113</i>, 2017, 132-139, available at <a href=https://doi.org/10.1016/j.ejpb.2016.12.029>https://doi.org/10.1016/j.ejpb.2016.12.029</a>. Accepted manuscript version available in Munin at <a href=https://hdl.handle.net/10037/12458>https://hdl.handle.net/10037/12458</a>. | en_US |
dc.rights.accessRights | openAccess | en_US |
dc.rights.holder | Copyright 2016 The Author(s) | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-sa/3.0 | en_US |
dc.rights | Attribution-NonCommercial-ShareAlike 3.0 Unported (CC BY-NC-SA 3.0) | en_US |
dc.subject | VDP::Medisinske Fag: 700::Basale medisinske, odontologiske og veterinærmedisinske fag: 710::Biofarmasi: 736 | en_US |
dc.subject | VDP::Medical disciplines: 700::Basic medical, dental and veterinary science disciplines: 710::Biopharmacy: 736 | en_US |
dc.title | Surface modification of liposomes increases drug efficacy in local vaginal therapy | en_US |
dc.type | Doctoral thesis | en_US |
dc.type | Doktorgradsavhandling | en_US |