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Investigation into the in-vitro lung deposition of liposomal formulations of the dual fixed-dose combination inhaler


   Faculty of Life Sciences

  Dr Khaled Assi,  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

Asthma and Chronic Obstructive Pulmonary Disease (COPD) are diseases associated with the airflow in the lungs (WHO, 2013). Inhalation is the most effective route of administration for treating asthma and COPD (Labiris and Dolovich, 2003). Several combination therapies are available on the market in the form of a physical mixture of dry powder inhaler (DPI) for the treatment of asthma and COPD, for example a combination of a LABA:LAMA (indacaterol:glycopyrronium; umeclidinium/vilanterol) and ICS:LABA (Budesonide/formoterol, fluticasone furoate/vilanterol ) formulated as DPIs. Formulation properties are determined by physicochemical properties of the carrier: particle size, shape, density, surface area, roughness, morphology and associated forces of drug-to-drug cohesion and drug-to-carrier adhesion. The higher the surface energy of the carrier, the higher the drug-to-carrier adhesion interaction. Therefore, the reduction in adhesion forces between drug particles and lactose carrier particles appeared to result in drug particles sticking to each other (via cohesive forces) (Zhou and Morton, 2012, Dickhoff et al., 2003). As a result, they display poor flowability and aerosolisation performance and have the tendency to remain within the inhaler. Hence, it is necessary to maintain the balance between cohesive and adhesive forces that gives sufficient adhesion between the carrier and the drug to get a stable formulation. Moreover, this balance facilitates the separation of (drug-carrier) during inhalation process (Hamishehkar et al., 2012, Zhang et al., 2012). The delivery of uniformed dose is essential to ensure the control of the disease which is a major challenge for DPI formulation. This challenge will be much more complicated with dual combination inhalers such as Ultibro Breezhaler®, Seretide and many more. This is due to the fact that the individual drugs have different physiochemical properties and therefore their adhesive/cohesive forces are different. Hence it is highly unlikely that the delivered dose and fine particle dose would still maintain the same ratio of both drugs during inhalation and deposition in the lung considering the fact that most asthma and COPD patients inhale at different flow rate (Abadelah et al., 2017).

Liposomes are vesicles comprising a phospholipid bilayer surrounding an inner aqueous core. Due to their biphasic characteristic and diverse design, composition and construction, liposomes offer dynamic and adaptable technology for modern drug delivery (Hefesha et al., 2011). Furthermore, in contrast to other carrier systems, liposome formulations have ‘generally regarded as safe (GRAS)’ status. They can load hydrophilic, amphiphilic and liphophilic drugs and have been successfully used in many therapeutic applications (mostly by injections) such as anticancer therapy with much improved pharmacokinetic and pharmacodynamic profiles (Anders CK. Et al., 2013).

For the last three decades, liposome delivery systems have been investigated for the treatment of Pulmonary diseases by inhalation in order to enhance the efficacy and reduce the systemic adverse effect, and some products by using nanoliposomes as carriers are being assessed in clinical trials.

Despite these promising results, a systematic study of the effects of physicochemical properties of the liposomes (including phospholipid composition, bilayer membrane fluidity, surface charge, transition temperature and liposome size) on the efficacy of the pulmonary delivery has not yet been investigated. In this study, by choosing the phospholipids with different physicochemical properties (in terms of lipid composition, transition temperature, charge and size), we will examine the effect of liposomal properties on the aerosolization performance of the drugs combination with the aim to enhance content uniformity and the release profile of the drugs, and prolong its residence time in the lung and thus achieve a longer duration of effect. We will use formoterol / budesonide as the dual model drugs to be loaded in liposomes for this study.

Project aims:

  1. To prepare liposomal formulations using different types of liposomes for some of dual-combination inhalers that are available as physical mixture such as formoterol / budesonide and then to assess the effect of the physicochemical properties of the selected liposomes on the drugs aerosolisation performance at different inspiratory flow rates.
  2. By choosing the optimal liposomal formulations, we aim to modify the release profile of the drugs in the selected dual combination inhalers (formoterol / budesonide) and prolong their residence time in the lung and thus achieve a longer duration of effect.

Funding Notes

This is a self-funded PhD project; applicants will be expected to pay their own fees or have a suitable source of third-party funding. A bench fee may also apply to this project, in addition to the tuition fees. UK students may be able to apply for a Doctoral Loan from Student Finance for financial support.

References

Al ayoub, Y., Gopalan, R.C., Najafzadeh, M., Mohammad,A., Anderson, D., Paradkar,A., Assi, K.H. (2019). “Development and evaluation of nanoemulsion and microsuspension formulations of curcuminoids for lung delivery with a novel approach to understanding the aerosol performance of nanoparticles’’, International Journal of Pharmaceutics 557, 254-263.
Abadelah, M., Chrystyn, H., Bagherisadeghi, G., Abdalla, G., Larhrib, H., 2017a. Study of the emitted dose after two separate inhalations at different inhalation flow rates and volumes and an assessment of aerodynamic characteristics of indacaterol Onbrez Breezhaler150 and 300 lg. AAPS PharmSciTech
Anders CK. et al. (2013) Pharmacokinetics and Efficacy of PEGylated Liposomal Doxorubicin in an Intracranial Model of Breast Cancer, PLOS ONE, 8, Issue 5, e61359.
Asthma Fact sheet N0307. 2013. WHO
Hefesha H., Loew, S., Liu X., May S., Fahr A. (2011) Transfer mechanism of temoporfin between liposomal membranes. J Control Release 150, 279–286
Kaialy, W., Ticehurst, M. and Nokhodchi, A. (2012) Dry powder inhalers: Mechanistic evaluation of lactose formulations containing salbutamol sulphate. International Journal of Pharmaceutics, 423 (2), 184-194.
Labiris NR and Dolovich MV. 2003. Pulmonary drug delivery. Part I: Physiological factors affecting therapeutic effectiveness of aerosolized medications. 2003. Journal of Clinical Pharmacology. (56), 588-599.
Dickhoff, B. H. J., de Boer, A. H., Lambregts, D. and Frijlink, H. W. (2003) The effect of carrier surface and bulk properties on drug particle detachment from crystalline lactose carrier particles during inhalation, as function of carrier payload and mixing time. European Journal of Pharmaceutics and Biopharmaceutics, 56 (2), 291-302.
Hamishehkar, H., Rahimpour, Y. and Javadzadeh, Y. (2012) The Role of Carrier in Dry Powder Inhaler.
Vestbo J. 2013. Global Strategy for the diagnosis, management and prevention of Chronic Obstructive Pulmonary Disease. Global Initiative for Chronic Obstructive Lung Disease. 1-7.
Zhang, X., Ma, Y., Zhang, L., Zhu, J. and Jin, F. (2012) The development of a novel dry powder inhaler. International Journal of Pharmaceutics, 431 (1-2), 45-52.
Zhou, Q. and Morton, D. A. V. (2012) Drug–lactose binding aspects in adhesive mixtures: Controlling performance in dry powder inhaler formulations by altering lactose carrier surfaces. Advanced Drug Delivery Reviews, 64 (3), 275-284.

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