Development of Levodopa-loaded inhalable dry powders for treatment of Parkinson's disease via the pulmonary system

• Main Author: Paul, Mahasweta
• Other Authors: Raymond Lau Wai Man
• Format: Thesis-Doctor of Philosophy
• Language: English
• Published: Nanyang Technological University 2022
• Subjects: Engineering::Chemical engineering::Biotechnology; Engineering::Bioengineering
• Online Access: https://hdl.handle.net/10356/158934
• Institution: Nanyang Technological University

Parkinson’s Disease (PD) is a progressive disorder characterized by gradual loss of dopaminergic neurons. The deficiency of dopamine in return disrupts the motor & non-motor skills, which significantly reduces the quality of life in the elderly depending upon the stage and severity of the disease. The symptoms range from loss of voluntary movements to difficulty in swallowing to sometimes even dementia. Conventional treatment is usually oral intake of Levodopa. Yet as the disease progresses, this route of delivery tends to create more difficulties in the patient. The irregular gastric emptying and intermittent drug dosing by the elderly with PD often leads to loss of control over motor movements, while the gastric enzymes degrade the ingested Levodopa, causing reduced gastro-intestinal adsorption. This leads to a half-life of only 60 to 90 mins in the blood, leading to patients needing multiple oral doses a day. This study intends to develop inhalable treatment strategy that takes into consideration the limitations enforced on motor control by the symptoms of disease and the restrictions imposed on the pulmonary system of the patients due to age, in the form of easy-to-administer respirable Levodopa-loaded powder. To develop the inhalable formulations, this dissertation first focused on first improving the microcarriers themselves by imparting good aerosolization properties and dispersibility – two important criteria to ascertain deep lung delivery of drug-loaded inhalable therapeutics. The study revealed that introduction and alteration of the concentration of the amino acid, L-leucine could directly affect several microcarrier properties. Higher L-leucine concentration led to improved powder yield, drug entrapment and powder flowability while the average particle size decreased. Aerosolization studies demonstrated marked improvements in Fine Particle Fraction and Emitted Dose values, implying a directly proportional relationship between the L-leucine content and dispersibility of a dry powder. The insights provided by this study have the potential to be utilized for the development of lacto-polymeric powders with the correct L-leucine concentrations for intended pulmonary Levodopa delivery in PD patients. The second part of the work focused on addressing one of the main challenges of administering inhalable powders in the elderly. PD patients mainly constitute of the aging population and thus it is important to consider the physiological and anatomical condition of the aging lung while designing inhalable therapeutics. Delayed mucociliary clearance in the aging lung reportedly leads to accumulation of mucus. In such a scenario, the therapeutic efficiency of pulmonary drug delivery of Levodopa might get affected due to entrapment of the drug particles by the mucus layer. The main aim of this work had thus been to develop Pluronic-Levodopa-loaded dry powders which were not only stable in mucus but also displayed mucopenetrative properties. Two kinds of PLGA were used with differing molecular weights along with the Pluronic or poloxamer 188, 0.8% (w/v) L-leucine and Lactose to fabricate blank and Levodopa-loaded microcarriers. The drug dissolution studies in the Simulated Lung Fluids revealed comparable cumulative drug release of nearly 90% for both the Levodopa-loaded formulations. This was due to the presence of poloxamer 188 and its hydrophilic chains which improved the interaction of the microcarriers with the dissolution media regardless of the polymer weight of PLGA. The stability of Levodopa within the formulations was also greatly enhanced by the presence of the poloxamer as was observed from the stability study of the microcarriers in the artificial mucus. In case of the mucopenetrative study, both drug-loaded microcarriers displayed mucus permeation properties as the drug availability in the agarose gel layer increased with time. The insights obtained from the present study indicated that the presence of poloxamer 188 affected the physicochemical properties of the microcarriers to some degree irrespective of the excipient polymer weight, improved the stability of Levodopa within the formulations and imparted mucus permeation properties to the latter. This is promising for the development of muco-stable and mucopenetrating dry powders for pulmonary drug delivery in the elderly. The overall aim of the dissertation was to design convenient alternative Levodopa therapeutics that not only treated and helped to control the symptoms of PD but also helped to maintain the quality of life of the elderly so that they are able to thrive with dignity.