Files and links (1)
David Nakhla_Thesis manuscript_05.03..2023_Final3.73 MB
Embargoed Access, Embargo ends: 06/26/2027
Dissertation
Microencapsulation formulation strategies to control the release and improve the solubility of small-molecules targeting chronic diseases
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2023
DOI: 10.25820/etd.007884
Abstract
Chronic diseases remain a major cause of morbidity and mortality in the United States of America (USA) and worldwide. Individuals who live with chronic conditions suffer from a reduced quality of life and sometimes disability. One of the reasons these individuals have a reduced quality of life is their dependence on multiple medications that must be taken at specific times every day otherwise they will experience symptom flare-ups and in serious cases, death. This research investigates microencapsulation formulation approaches to improve the delivery and prolong the release of pharmaceutical agents targeting chronic conditions (fibromyalgia and cystic fibrosis (CF)), thereby improving the quality of life of individuals living with these chronic conditions by significantly reducing the dosing frequency of their medications (from daily to once per month) and thus improve their compliance to the treatment regimen and ultimately, ensure positive treatment outcomes.
In the first part of this work, we propose a selective androgen receptor modulator (SARM) as a novel, non-opioid alternative for the treatment of chronic musculoskeletal pain (fibromyalgia). Our preclinical experiments have shown that the daily subcutaneous administration of SARM is effective in alleviating muscle hyperalgesia in mice. To eliminate the need for the daily administration of SARM, we developed an injectable, long-acting, poly (lactic acid-co-glycolic acid) (PLGA) microparticle formulation loaded with SARM. These formulations provided sustained plasma levels of SARM over 1 month following its subcutaneous administration in mice (on day 1 and day 7) and were effective in alleviating muscle pain while being non-addictive and non-toxic. These data suggest that a SARM microparticle formulation can be an effective treatment strategy for patients suffering from fibromyalgia and can improve their quality of life by having to administer the medication only once or twice per month.
The second part of this research focuses on CF and employing microencapsulation formulation approaches (e.g. cyclodextrin (CD) inclusion complexes and PLGA microparticle formulations) to improve the solubility and bioavailability of ivacaftor (IVA - a medication used for the treatment of CF) and provide a formulation that can be administered only once per month.
We developed IVA-CD inclusion complexes using hydroxypropyl-beta-CD that improved the solubility and bioavailability of IVA in comparison to the commercial Kalydeco tablets and unencapsulated free IVA. When these formulations were given orally to sows pregnant with fetuses that had CF, the complexes allowed IVA to cross the placenta and reach the blood circulation of the fetus and ultimately rescued them from developing lethal CF manifestations at birth. This data provide a new indication for IVA to be given to pregnant mothers who are carriers of the CFTR mutations (causing CF) to rescue their newborns from developing lethal CF manifestations at birth.
Further, we developed injectable, long-acting PLGA microparticle formulations loaded with IVA. These formulations provided a prolonged in vitro and in vivo release of IVA over one month and thus overcame the need for twice-daily administrations of IVA (typical dosing regimen of IVA). These injectable long-acting formulations of IVA can potentially be used by patients suffering from CF to improve their compliance with the treatment regimen and ensure treatment success.
Details
- Title: Subtitle
- Microencapsulation formulation strategies to control the release and improve the solubility of small-molecules targeting chronic diseases
- Creators
- David Shehata Fouad Georgy Nakhla
- Contributors
- Aliasger K. Salem (Advisor)Lewis Stevens (Committee Member)Reza Nejadnik (Committee Member)Gary Milavetz (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacy
- Date degree season
- Spring 2023
- DOI
- 10.25820/etd.007884
- Publisher
- University of Iowa
- Number of pages
- xxiii, 171 pages
- Copyright
- Copyright 2023 David Shehata Fouad Georgy Nakhla
- Grant note
- National Institutes of Health grant AR073187 (JBL, KAS). National Institutes of Health grant GM067795 (JBL). National Institutes of Health grant P30CA086862 (DSN, AKS). Foundation for Physical Therapy Research Promotion of Doctoral Studies (PODS I) (JBL)
- Language
- English
- Date submitted
- 04/23/2023
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 158-171).
- Public Abstract (ETD)
- Chronic disease (long-term disease) is defined as a medical condition that lasts for more than 6-12 months. Many people worldwide and in the USA suffer from different kinds of chronic conditions. Chronic conditions can cause serious disabilities. Individuals who suffer from chronic conditions usually have a poor quality of life not only because of the disease itself but because of its consequences such as poor mental and physical health, which can lead to job loss and poor relationships. In addition, individuals with chronic conditions usually have to administer several medications multiple times a day every day to control their condition which can be very inconvenient and can result in poor adherence to the planned treatment schedule. From a medical point of view, it is difficult to cure chronic conditions and sometimes it is impossible to do so. However, there is one thing we could do to improve the quality of life of these individuals and help them live a life as close to normal as possible. This can be achieved by designing drugs that can be taken only once per month or once every 3 months instead of every day. This can significantly improve the quality of life of these individuals and ensure that they don’t miss any of their scheduled medication administrations. In this research, we focus on two chronic conditions, chronic muscle pain (also known as fibromyalgia) and cystic fibrosis (CF - which is characterized by dysfunction in multiple organs in the body). We first introduce a potential new class of drugs for the treatment of fibromyalgia (SARM), and we then employ two formulation techniques, one to allow SARM and IVA (drug used for CF) to be effective for longer periods of time following one or two injections per month and another to make IVA more soluble in water and thereby allow for a lower dose and less side effects. x The first formulation technique relies on encapsulating the drug into spheres made of a synthetic plastic-like material (a polymer that is significantly softer than plastic) that is approved by the Food and Drug Administration (FDA) for administration to humans since, when administered, the body can break it down and safely excrete it without any adverse reactions. The advantage of encapsulating the drug into these polymeric spheres is that it extends the action of the drug by slowly releasing it as the polymer degrades. This allows the drug to be effective for an extended time following a one or two injections per month. We tested our extended-release formulations loaded with SARM or IVA and both demonstrated detectable levels in mice for up to one month following only one or two injections. The extended-release SARM formulations were effective in the treatment of chronic pain in mice and were safe and non-addictive. The second formulation technique we employed was to improve the water solubility of IVA for the treatment of CF. This was done by loading IVA into a starch-like material that possesses physical properties that allowed for the loading of IVA and consequently improved its water solubility. In addition, our IVA formulation showed improved blood concentrations of IVA when compared to the commercial IVA tablets (Kalydeco) after oral administration in mice. Finally, our IVA formulation rescued newborn piglets from developing lethal CF manifestations at birth when the formulation was given to sows pregnant with CF fetuses. Taken together, our research has provided 1- a potential (extended-release) novel treatment of chronic muscle pain, 2- an extended-release CF treatment and, 3- a novel formulation of IVA that will potentially allow it to rescue newborns babies with CF from developing lethal manifestations at birth.
- Academic Unit
- Pharmacy; Craniofacial Anomalies Research Center
- Record Identifier
- 9984831126002771
Metrics
18 Record Views