Advanced drug delivery systems have shown immense success through
nanotechnology which overcomes the challenges posed by large sized particles
such as poor solubility, bioavailability, absorption, and target-specific delivery.
This study focuses on nano sizing by application of microreactor technology and
nanoparticles to obtain polymeric particulate with a selection of model drugs for
inhalation drug delivery routes. The development of nanoparticles of two
challenging compounds in terms of solubility and permeability, namely
Ibuprofen (IBU) and Salmeterol (SAL), was conducted using a continuous,
controlled, and scalable system offered by microfluidic reactor with the
incorporation of anti-solvent approach. The research explores the potential of
this technology to enhance absorption rate and hence bioavailability of IBU via
oral route, and SAL via inhalation.
IBU, an anti-inflammatory drug, is classified as BCS Class II drug with low
solubility and high permeability. SAL is a selective long acting β2-agonist which
is co-dispensed along with a short-acting β2-agonist for quick relief of acute
bronchoconstriction due to its long onset of action. This lack of the ‘kick’ effect
in SAL can be attributed to its relatively higher lipophilicity which causes a delay
in the diffusion to the β2 receptors on the smooth muscles. It is therefore
feasible to assume that increasing the dissolution and/or diffusion rate of SAL in the interstitial fluids would reduce the delay between administration and the
onset of action of this drug which would be beneficial to patients.
Process and formulation parameters were investigated to optimize the
production and stability of nano particles of both drugs using Y shaped microfluidic reactors.
IBU results show that the smaller the angle between the two inlets were the
smaller the particle size achieved. Moreover, the particle size increased with
increasing the concentration of IBU solution. The effect of the polymer mixture
ratio (PVP/HPMC) on the initial particle size was not clear though. The smallest
particle size (113 nm) was achieved using 10° Y shaped chip with IBU
concentration of 1 mg/mL and a polymer mixture of 0.3% w/v PVP and 0.5%
w/v HPMC. Using a polymer mixture of 0.5% w/v of each polymer though
yielded a better PDI (140nm and PDI of 0.5).
Same observations were noted when the syringe pumps were replaced with a
non-pulsatile pressure pump. Particle size though dropped significantly to
33nm. Stability data showed that all systems were practically stable regardless
of the process or formulation parameters.
In addition, a considerable 2.5 fold increase in dissolution rate was observed in
the first 20 minutes when compared to the raw material.
The optimized parameters were applied to SAL to produce nanocrystals with
best result (59 nm) were obtained using 50µg/mL Salmeterol with microfluidics
inlet angle 10° with non-pulse syringe pump. The stabilizing mixture was PVP
0.8% w/v and Tween 80 at a concentration of 0.02%. This approach offered a
basis for the generation of nano sized SAL particles with higher fine particle fraction and better deposition in NGI than currently marketed formulations, thus
providing a more efficient drug dose delivery and lung deposition.
| Identifer | oai:union.ndltd.org:BRADFORD/oai:bradscholars.brad.ac.uk:10454/19273 |
| Date | January 2021 |
| Creators | Obeed, Muthana M. |
| Contributors | Assi, Khaled H., Isreb, Mohammad |
| Publisher | University of Bradford, School of Pharmacy and Medical Sciences |
| Source Sets | Bradford Scholars |
| Language | English |
| Detected Language | English |
| Type | Thesis, doctoral, PhD |
| Rights | <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/"><img alt="Creative Commons License" style="border-width:0" src="http://i.creativecommons.org/l/by-nc-nd/3.0/88x31.png" /></a><br />The University of Bradford theses are licenced under a <a rel="license" href="http://creativecommons.org/licenses/by-nc-nd/3.0/">Creative Commons Licence</a>. |
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