Nano-delivery system for bioavailability enhancement of an antihypertensive drug / By Rinada Hussien Sadek Hassan, Bachelor of pharmaceutical Sciences, faculty of pharmacy, Future university in Egypt, Demonstrator at department of pharmaceutics & pharmaceutical technology, Faculty of pharmaceutical sciences & pharmaceutical industries, Future university in Egypt; under supervision of Prof. Dr. Rania Aziz Helmy Ishak, professor of pharmaceutics and industrial pharmacy, faculty of pharmacy, Ain Shams University, Prof. Dr. Dalia Samuel, Professor of pharmaceutics and pharmaceutical technology, Faculty of Pharmacy, Future University in Egypt, Dr. Heba Abdel Moniem Gad, Associate Professor of Pharmaceutics and Industrial Pharmacy Faculty of pharmacy, Ain Shams University.

Supervision of Prof. Dr. Rania Aziz Helmy Ishak, professor of pharmaceutics and industrial pharmacy, faculty of pharmacy, Ain Shams University, Prof. Dr. Dalia Samuel, Professor of pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy, Future University in Egypt, Dr. Heba Abdel Moniem Gad, Associate Professor of Pharmaceutics and Industrial Pharmacy Faculty of pharmacy, Ain Shams University.

Thesis (M.Sc.)-Ain Shams University, Faculty of pharmacy, Department of Pharmaceutical Technology, 2022.

Includes bibliographical references.

Hypertension (HTN) is another name for high blood pressure. It can lead to severe health complications. It is considered a significant independent contributor to cardiovascular morbidity and death, with an average risk increase of three times across all age groups and genders. The main fatal consequence of HTN today is the coronary heart diseases, which affect hypertensives more frequently than normotensives by a rate two to three times. Managing blood pressure is vital for preserving health and reducing the risk of these dangerous conditions. Many antihypertensive drugs can be used to manage this disease, but the main problem is their low oral bioavailability. In this concern, nasal-oriented therapeutics vehiculation strategies are promising approaches for effective treatment of HTN.
Olmesartan medoxomil (OLM) is used to treat high blood pressure. It belongs to a class of drugs called angiotensin receptor blockers (ARBs). It works by relaxing blood vessels so that blood can flow more easily. It is practically insoluble in water and sparingly soluble in organic solvents. OLM is available as film-coated tablets for oral administration with different doses; 5 mg, 20 mg, or 40 mg.
In this thesis, OLM loaded chitosan nanoparticles (CS NPs) were prepared and administered via the nasal route to overcome the problems of oral delivery for treatment of HTN. OLM loaded CS NPs were formulated and optimized using ionic gelation method. The optimized NPs were evaluated for their particle size (PS), polydispersity index (PDI), zeta potential (ZP) and entrapment efficiency (EE). The ex vivo studies were carried out to evaluate the permeation parameters through sheep nasal


mucosa. The morphology of the selected formula was assessed by transmission electron microscopy. Furthermore, a stability study was conducted on the optimized formula over a period of three months storage under refrigeration (5 ± 3°C) and at room temperature (25 ± 3 °C). A pharmacokinetic study was carried out to determine the biological availability of OLM in plasma from the selected CS NPs when administered by nasal route compared to OLM suspension taken by both oral and nasal administration routes. Moreover, a pharmacodynamic study was conducted to assess the effectiveness of the optimized formula on lowering the high blood pressure compared to drug suspension. Nitro-L- arginine-methyl ester (L-NAME) was utilized for the induction of HTN in Wistar albino rats. Histological examinations were further performed to evaluate the safety of CS NPs on the nasal mucosa.
CS NPs showed a uniform homogenous PS in the nanometer scale, positive surface charge, high EE%, and good stability. Ex vivo experiments demonstrated that CS NPs can improve OLM penetration through sheep nasal mucosa. More significantly, the in vivo studies proved that the intranasal route has the capacity to shield medications from degradation, boost absorption, and slow clearance, which allows for a reduction in dose frequency and adverse effects as well through sequencing. Additionally, CS provided additional advantages when administered intranasally due to its mucoadhesive effects, which extended the t1/2 by 2.7 times and 7.2 folds as compared to intranasal OLM suspension and oral OLM suspension, respectively. Moreover, a significant increase in the biological availability of OLM in plasma when administered via intranasal route, either as suspension or CS NPs in comparison to oral OLM suspension (p<0.05), this was confirmed by higher Frel values reaching 11.30 and 3.20-folds


recorded for suspension and CS NPs relative to oral administration of OLM susp., respectively.
Normal histological structures of the nasal tissue were noticed without significant alterations after the administration of OLM loaded CS NPs.
Additionally, intranasal OLM loaded CS NPs had the ability to reduce the systolic and diastolic blood pressure up to normal range, with no significant difference in HR compared to normal control group (p>0.05).

Text in English, abstracts in English and Arabic.