Biodegradable polymeric microspheres for systemic peptide delivery through the pulmonary route

INTRODUCTION

Considerable amounts of biomolecules (proteins and peptides) have been developed and some of them are in the market while others are still in the clinical trial stage; for example, hormones, antibodies, cytokine anti-infective agents in addition to growth factors, among others but the specific properties, the thing that demands a careful consideration of the formulation process, because the traditional dosage forms are sometimes unable to meet the requirements of these molecule formulation and delivery in the appropriate mode.

The vast majority of the protein and peptide drug molecules that are already available in the market are injectable, and the nature of the diseases that are treated using these molecules is chronic ones and that is not the preferable route for most patients.^[1] Hence, the pulmonary route with its characteristics like large surface area for drug absorption coupled with the thin alveolar epithelium makes it a good alternative for the injection counterpart.^[2,3]

Further, the pulmonary route is preferable in comparison with the gastrointestinal for many considerations like the avoidance of the first-pass metabolism in addition to the enzymatic systems.^[1,4]

The ideal microsphere properties for lung delivery are 2–3 microns, with an apparent density lower than 0.45.^[5]

PULMONARY PHYSIOLOGICAL BARRIERS

In principle, there are three kinds of physiological barriers that will interact with the inhaled microspheres, mucus, pulmonary surfactants in addition to macrophages that are distributed in different sites of the respiratory system.^[6]

Macrophages interact with the insoluble particles that are deposited in the alveolar region in two modes firstly by the clearance through the lymphatic system and secondly the transfer of these particles into the ciliated airways along currents in alveolar fluid and consequently to be cleared by the mucociliary escalator.^[7] This process may be achieved within several weeks up to months.^[8] Soluble drug particles that are located in the alveolar area can be absorbed into the systemic circulation.^[9] Lung epithelium is more resistant to soluble particle transport than the endothelium or the interstitium.^[10]

The metabolizing enzymes that are found in the lungs are similar to that in the liver (CYP450) but at a lower rate (5–20 times lower).^[11,12]

The lungs are supplied by a considerable amount of the cardiac output so it is the best perfused organ in the body.^[13]

After inhalation, the drug efficacy that is absorbed into the circulation can be enhanced by the redistribution into the poorly accessible areas.^[14,15]

DISCUSSION

It has been found that biodegradable-based polymeric microspheres have the ability to release peptide molecules through the pulmonary route; for example, insulin-loaded poly(lactic-co-glycolic) acid (PLGA)/hydroxypropyl-beta-cyclodextrin was able to reach alveoli, release insulin, which is absorbed in its bioactive form.^[16] Moreover, gelatin-coated hydrogel microspheres of ~3 μm revealed the ability to target the pulmonary tract as a drug delivery system.^[17] Furthermore, spray-dried powders loaded on cross-linked hyaluronic acid were found to be feasible to prepare inhalation for sustained pulmonary drug delivery applications.^[18]

Fernández-Paz et al., mentioned that chitosan-based nanoparticles are a promising candidate for gene delivery.^[19]

In a study for gelatin microsphere availability after pulmonary administration of salmon calcitonin in positively charge gelatin microspheres with particle sizes of 3.4 and 11.2 microns was approximately 50%, the thing that reveals that the gelatin microspheres are a good candidate for pulmonary delivery of salmon calcitonin.^[20]

In an in vitro study, alginate/hyaluronic acid aerogel microspheres with a low density and high porosity and 5 μm diameter revealed that the microspheres have properties that make it good candidates for drug delivery through the pulmonary route.^[21]

Yamamoto et al., reported that modification of the surface of PLGA nanospheres using chitosan with a diameter of 6.5 μm demonstrated that the modified nanospheres had enhanced mucoadhesiveness and enabled pulmonary delivery of peptide elcatonin that was orally administrated, above that chitosan has the property of increasing drug absorption by opening the intercellular tight junction of the lung epithelium.^[22] However, the cytotoxicity and cellular uptake of inhaled chitosan-based nanoparticles are size dependent.^[23]

PLGA-nanoparticles or microparticles were utilized for the sustained release of insulin following pulmonary administration.^[24] However, protein-loaded PLGA microparticles or nanoparticles often experience initial burst release followed by sustained releases. In addition, the hydrophobic nature of PLGA also affects its mucus penetration.^[25]

Emami et al. reported that PLGA microparticles with 1–5 μm may deposit in the lung and release the loaded proteins in a controlled manner. However, particles in this size range are ideal for phagocytosis by alveolar macrophages^[26] and to highlight this phagocytosis,^[26] Zhao et al., prepared porous PLGA microparticles with a low density, and small aerodynamic diameters, in addition to large geometric diameters, for the protein delivery through the pulmonary route,^[27] and within the same context, Yaqoubi et al. found that porous PLGA microparticles with mass densities below 0.4 g cm^–2 and geometric diameters surpassing 5 μm represent ideal aerodynamic diameters for deep lung deposition.^[28] and not far from that Yang et al. reported that larger porous PLGA particles, with geometric diameters of 9.5–18.2 μm, revealed a significant reduction of macrophage internalization compared to non-porous PLGA microparticles sized at 2.9 μm.^[29]

Ye Tong et al. revealed that the incubation of porous protein- loaded microparticles at 40°C for 2 hours (self healing process) was able to reduce leaking and the thing that positively affected the inhaled single dose SARS -CoV-2 dry powder vaccine sustain release profile,^[30] because this porosity induces contact between peptide drugs and lung surfactant leading to particles aggregation, which the thing that will affect their dissolution and accelerate their clearance through alveolar macrophage.^[31]

Möbus et al., reported that zinc ions Zn (2+)-cross-linked alginate microparticles prepared by spray drying revealed satisfying results regarding BSA (Möbus et al.) loading and release profile the thing that makes it as good candidate for controlled pulmonary delivery of proteins.^[32] Furthermore, cross-linked alginate-poloxamer microparticles with an appropriate size range were found to be a suitable platform for a deep lung delivery within a controlled protein release profile (hours to days).^[33]

CONCLUSION

It is clear that the pulmonary route of administration for the systemic delivery of peptides using biodegradable microspheres is still in the early stages and needs to be more intensively studied, and the key elements that should be addressed are the mechanisms of peptide molecules absorption through the pulmonary route, in addition to the characteristics of the carrier microspheres (size, morphology).