It has always been challenging to prepare polymeric microspheres (MS) with controlled porous structures for bio-therapeutic applications. Due to the irregular porous structure in micro-matrix and inhomogeneous particle size, controlled and sustained release to drugs is always a daunting task. Especially for pulmonary delivery, control over particle size (1–5 µm) and optimal porosity is extremely crucial for efficient release of drug to the lungs. Dr. Rahul Verma et al. from Institute of Nano Science and Technology, Mohali recently developed an elegant strategy to design hierarchically porous polymer microspheres with variable pore architecture for controlled delivery of a variety of loaded biotherapeutic molecules of different sizes. They used precisely optimized concentrations of several types of porogens/osmogens to specifically control the porosity and size of the micromatrix which are important parameters to make them inhalable.

A series of customized inhalable mono-dispersed poly-L-lactide microspheres (PLA-MS) having hierarchical pore structures with either open or closed porosity were synthesized by double emulsion solvent evaporation method using various molar concentrations of porogens. A wide range of porogens/osmogens e.g. hydrogen peroxide, sodium bicarbonate, sodium chloride, polyethylene glycol, sucrose, ammonium bicarbonate and phosphate buffer saline (PBS) were utilized for fabricating and tuning the size of the pores, surface morphology and internal structure of micro-matrix (Scheme 1). Four model drugs and biomolecules with significant size and solubility difference were used in the study to be encapsulated inside the MS of hierarchically porosity. [Isoniazid (137.14 g/mol, a small molecule drug; solubility 140 mg/ml of de-ionized H2O at 25 °C), Rifampicin (882.92 g/mol, an average molecule drug; solubility 2.5 mg/ml of de-ionized H2O at 25 °C), IDR1018 peptide (1535.93 Da short peptide; sequence RLIVAVRIWRR-NH2, solubility 51 mg/ml of deionized H2O at 25 °C), bovine serum albumin (BSA) (66,463.00 Da protein; solubility 40 mg/ml of de-ionized H2O at 25 °C)]. Particles were investigated for their physiochemical and aerodynamic characterization.

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Scheme 1. Schematic illustration of the formulation and evaluation of microspheres

They demonstrated a simple method for large scale, reproducible synthesis of hierarchically porous PLA-MS, controlling 3D morphologies with well-ordered porosity ranging from ∼2.5 to 850 nm (Figure 1). Also, these hierarchically porous PLA-MS particles are spherical in shape with uniform size distribution and regular pore morphology. The MS were capable of efficiently encapsulating model molecules of variable molecular sizes.

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Figure 1. Electron microscopic images of the surface of porous microspheres

Regulating concentrations of porogens considerably influenced pore density on the surface and inside the micro-matrix, but the pore diameter remained unchanged. The pore diameter varied as a function of nature of porogens. Owing to the internal porous structure with numerous binding sites, the limitations of nonporous MS with low encapsulation efficiency and slow release of bio-therapeutics can be circumvented. The pore size can be seamlessly tuned to incorporate drugs of variable molecular sizes e.g. Isoniazid, Rifampicin (small molecules) and IDR-1018 (large peptide).

The results confirm that prototypes with potential therapeutic utility for pulmonary delivery of drugs can be prepared by this convenient protocol. Furthermore, tailoring pore size can modify phagocytosis and drug release of bioactives from PLA-MS. The accessibility of this simple and scalable method of fabricating uniform porous PLA-MS is likely to explore, initiate and transforms several novel applications and new technologies in various biomedical applications, especially in drug delivery and tissue engineering.

Reference: Ankur Sharma, Kalpesh Vaghasiya and Rahul Kumar Verma, Inhalable microspheres with hierarchical pore size for tuning the release of biotherapeutics in lungs, Microporous and Mesoporous Materials, Volume 235, November 2016,195–203.