Olubi, Rebecca
(2024)
Improving drug delivery to the lungs as a function of excipient choice.
PhD thesis, University of Nottingham.
Abstract
Drug delivery to the lungs remains an attractive target for the administration of local as well as systemic therapies. Recent developments in pulmonary drug delivery have been centred around advancing and improving drug delivery devices. However, other challenges persist such as the limited range of approved excipients for inhaled formulations. A review of the FDA inactive ingredients database (IID) revealed that only 18% (63 excipients) appear on the FDAapproved drug products currently marketed for delivery by inhalation. The limited range of excipients poses a challenge in tailoring inhaled formulations to meet the complex therapeutic demands for managing respiratory diseases. Even for existing excipients with well characterised safety profiles, there are still ongoing endeavours to understand the interaction between excipients and Active Pharmaceutical Ingredients (APIs). However, the majority of these studies have been focused on transporter systems in the gastrointestinal tract which may not be representative of the respiratory system. Therefore, the aim of this project was to provide a better understanding of the effects of excipients on inhaled drug before, during, and after administration. The investigations of this study were
performed using budesonide inhalation suspension (BIS) as a model. BIS contains micronized budesonide as the API and polysorbate 80 as the stabilizing excipient.
The first objective was the development and validation of a high-pressure liquid chromatography (HPLC) method for the detection and quantification of budesonide (Chapter 2). A stability indicating method was initially developed followed by a bioanalytical method. The development of these HPLC methods were pivotal in this PhD work, as they allowed the evaluation and characterisation of several budesonide formulations developed in this project.
One of the key challenges of pharmaceutical suspension is stability. The next objectives looked to address formulation challenges in inhaled drug development by exploring the appropriate choice of stabilizers.
There is growing evidence of the susceptibility of polysorbate 80 to oxidative degradation. This in addition to residual impurities of polysorbate 80 have been reported to contribute to the instability of APIs. Therefore, the effect of selected grades of polysorbate 80 on the physical and chemical stability of BIS formulations were determined over 6 months (Chapter 3). The findings of this chapter demonstrated that selected grades of polysorbate 80 did not significantly affect the physical stability of BIS formulations, some differences were observed in the chemical stability according to the formation of specific degradation products. The main findings of this chapter showed that in some instances, the selected grade of polysorbate 80 had an impact on the stability of BIS formulations either by protecting or promoting the formation of degradation products.
Following this, selected stabilizers not seen in approved inhaled products were also explored in the physical stability of budesonide nanosuspension formulations (Chapter 4). Nanosuspension formulations are increasingly being used as a strategy to overcome limitations associated with poorly water-soluble drugs. The solubility of budesonide is 10.7 mg/mL in water at 25oC making it a suitable poorly soluble model for nanosizing. Nanosuspension preparations of budesonide have also been reported to have significantly shorter nebulization time compared to the microsuspension. Therefore, in this chapter, budesonide nanosuspensions were developed using a novel proof-of-concept miniaturised nanomilling approach. Alongside polysorbate 80, crodasol HS HP and lecithin were selected as stabilizers. The findings of this chapter demonstrated the success of the miniaturised nanomilling approach in generating budesonide particles in the nanometre range. The developed nanosuspensions displayed
good physical stability over 30 days stored at room temperature.
Furthermore, to determine whether the selected excipients can affect the delivery of budesonide formulations, the aerosolization performance of the nebulized budesonide microsuspension and nanosuspensions were assessed using the Next Generation Impactor (NGI) as an in vitro lung deposition model (Chapter 4). Favourable nebulization properties such as higher total delivered dose and fine particle fraction was displayed by the nanosuspensions formulations compared to the microsuspension. Although differences were seen between the micro vs nanosuspensions of budesonide, the selected excipients did not demonstrate a significant difference in the aerosolization behaviour of budesonide. In summary, the aerosolization of the developed nanosuspensions produced particles in the respirable range to achieve meaningful lung deposition, and could therefore have promising applications.
Finally, functional excipients such as surfactants have been reported to affect the fate of API by interacting with the plasma membrane and thereby enhancing permeability. This effect has also been linked to their cytotoxicity. Therefore, the effect of micro and nanosuspensions of budesonide prepared with the selected surfactants on the toxicity of Calu-3 airway epithelial cell model were investigated (Chapter 5). This was achieved by assessing their effect on membrane integrity, and the transepithelial transport of budesonide. Unfortunately, in this preliminary investigation, a conclusive determination could not be drawn as the applied method required further refinement and
optimisation.
In conclusion, the findings of this thesis expanded upon the knowledge that excipients do indeed affect the fate of inhaled drug. For the first time, the findings of this thesis have shown that the grade of polysorbate 80 affects the chemical stability of BIS. This can help inform the selection of the most suitable excipient grade during excipient compatibility studies in early drug product development. Given this understanding, formulators must exercise caution when selecting excipient grades which can lead to unwanted degradation products. Improving drug product stability profile can impact the shelf-life assignment, therefore improving drug product safety, utilisation, and outcome for patients. In addition to this, nanosizing significantly increased the delivery of budesonide during aerosolization studies. Further exploration of this may be translated to the reduction of dosing frequency and improved patient compliance. Nevertheless, additional work is required to elucidate the mechanisms of how excipients may affect the fate of API during and after delivery to the lungs, and further influence the choice of excipients in medicines developed for inhalation as well as other routes of administration.
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