Biopolymeric Inhalable Dry Powders for Pulmonary Drug Delivery

Abstract

Natural and synthetic biopolymers are gaining popularity in the development of inhaled drug formulations. Their highly tunable properties and ability to sustain drug release allow for the incorporation of attributes not achieved in dry powder inhaler formulations composed only of micronized drugs, standard excipients, and/or carriers. There are multiple physiological barriers to the penetration of inhaled drugs to the epithelial surface, such as the periciliary layer mucus mesh, pulmonary macrophages, and inflammation and mucus compositional changes resulting from respiratory diseases. Biopolymers may facilitate transport to the epithelial surface despite such barriers. A variety of categories of biopolymers have been assessed for their potential in inhaled drug formulations throughout the research literature, ranging from natural biopolymers (e.g., chitosan, alginate, hyaluronic acid) to those synthesized in a laboratory setting (e.g., polycaprolactone, poly(lactic-co-glycolic acid)) with varying structures and compositions. To date, no biopolymers have been approved as a commercial dry powder inhaler product. However, advances may be possible in the treatment of respiratory diseases and infections upon further investigation and evaluation. Herein, this review will provide a thorough foundation of reported research utilizing biopolymers in dry powder inhaler formulations. Furthermore, insight and considerations for the future development of dry powder formulations will be proposed.

Keywords: biopolymers; dry powder inhalers; poly(lactic-co-glycolic acid); polycaprolactone; polysaccharides.

Figure 1

Drug exposure following oral (left) and pulmonary (right) delivery illustrating anticipated tissue concentration. Figure reproduced with permission [5]. Copyright 2016, Elsevier.

Figure 2

The airway surface layer. (Left): representation of the classic gel-on-liquid model showing a mucus layer (comprised of gel-forming mucins MUC5AC and MUC5B) and the periciliary layer (PCL) as a liquid-filled “sol” domain. (Right): gel-on-brush model depicting a MUC5B- and MUC5AC-populated mucus layer juxtaposed to the PCL comprised of “brush-like” epithelial-tethered mucins MUC1, MUC4, and MUC16. Figure reproduced with permission [32]. Copyright 2022, American Physiological Society.

Figure 3

ASL mesh sizes. (A) Calculated mucus mesh size vs. mucus concentration. (B) The dependence of exclusion of the PCL-G (z) vs. the size of dextran molecules (green) and polystyrene particles (red). Figure reproduced with permission [30]. Copyright 2012, American Association for the Advancement of Science.

Figure 4

Biopolymeric MPs for dry powder systems, including (A) MPs, (B) nano-embedded MPs, and (C) porous NP aggregates.

Figure 5

Chemical structures of natural polysaccharides, including (A) chitosan, (B) alginate, (C) β-cyclodextrin, (D) dextran, (E) hyaluronic acid, and (F) cellulose.

Figure 6

SEM micrographs of (A) curcumin-loaded acetylated dextran nanocomposite MPs and (B) curcumin-loaded acetylated dextran MPs. Scale bar = 2 µm. Figure reproduced with permission [112]. Copyright 2017, Elsevier.

Figure 7

SEM photomicrographs of (A) losartan microplex at 9000× magnification (scale bar = 2 µm) and (B) spray-dried losartan microplex at 4000× magnification (scale bar = 10 µm). (C) In vitro release profile of losartan (LS, red square) and spray-dried losartan microplex (LS-MC-DPI; black diamond) over 24 h. Figure reproduced with permission [133]. Copyright 2019, Elsevier.

Figure 8

Chemical structures of synthetic biopolymers, including (A) polycaprolactone, (B) poly(ethylene glycol), (C) poly(vinyl pyrrolidone), (D) poly(vinyl alcohol), (E) polylactic acid, and (F) poly(lactic-co-glycolic acid).

Figure 9

(A) SEM image of optimized linezolid-loaded PCL microspheres at 500× magnification. Scale bar = 20 µm. (B) Drug release of free linezolid in phosphate buffer with a pH of 7.4 (blue) and acetate buffer with a pH of 4.4 (orange) compared to drug release from linezolid-loaded PCL microspheres with pHs of 7.4 (gray) and 4.4 (yellow). Figure reproduced with permission [146]. Copyright 2023, Elsevier.

Figure 10

Lung and plasma distribution of ethionamide (ETH) in NP DPI formulation (ETH NPs) or as pure drug. Figure reproduced with permission [170]. Copyright 2017, Elsevier.