(644a) Next Generation Lipid-Based Excipients: Overcoming the Challenges of Spray Drying Applications on the Development of Inhalable Lipid-Microparticles

Lipid-based excipients (LBE) are natural and biodegradable materials that have been extensively used in pharmaceutical dosage forms. The characteristic solid-state transitions of LBE, viz. polymorphism and phase separation, often make their application challenging. These transitions are strongly linked to the limited processability of LBE through certain pharmaceutical manufacturing processes such as spray drying. During spray drying, the crystallization of LBE into metastable polymorphs or phase separation into low-melting-point fractions impair the formation of solid particles. In a previous work of our group novel LBE, polyglycerol esters of fatty acids (PGFAs), were introduced (brand name: Witepsol PMF). The molecular structure and composition of PGFAs hinders polymorphism and provide crystallization into a monophasic system. In this work, the processability of PGFAs via spray drying, in order to produce inhalable lipid microparticles for inhalation, in the final dosage form of dry powder (DPI) is presented. Applications in organic solvent and aqueous-based spray drying processes were evaluated. Distinctive particle attributes of readily inhalable lipid-microparticles were envisaged to provide systemic or local effect after pulmonary administration.

Lipid-microparticles loaded with ibuprofen intended for systemic delivery of analgesics were manufactured under an organic solvent-based spray drying process. For effective systemic delivery, large particles (VMD>3 µm) of low density (<0.4 g/cm³) are intended to provide median mass aerodynamic diameter in the range of 1 - 5 µm for reaching lung deposition and diminish lung clearance. PG3-C22 partial ester (WITEPSOL® PMF 123) was used as the particle matrix in a lipid:drug ratio of 70:30. A solution of 1.5% w/w solid content in tetrahydrofuran was sprayed through a 0.2 mm-nozzle at a feed rate of 3 g/min into a closed-loop system at 71°C. The process showed no impairments and resulted in high yield of solid particles (70.1%). Unimodal particle size distribution, volume mean diameter (VMD) of 6.6 ± 1.1 µm and density of 0.389 ±0.007 g/cm³ were achieved. Residual solvent < 50ppm was determined, which is below the limit for pharmaceutical products (<720ppm). The application of the particles as DPI was tested in Aerolizer dry powder inhaler coupled to a next generation impactor. The MMAD of 3.57 ± 0.11 µm evidenced the inhalability of the particles. In vitro lung deposition with high fine particle fraction of 45.2 ± 1.3% was reached. Crystalline dispersion of ibuprofen and PG3-C22 partial ester with eutectic composition was observed in the particles. Dissolution of the deposited particles in simulated lung fluid showed 38.9 ± 6.9% drug released in the first hour and 60.1 ± 0.1% after 6 hours.

Lipid-microparticles for local delivery of rifampicin were produced through an aqueous-based spray drying process. Particle attributes were designed for a median particle size < 4 µm (optimal 2.1 µm) to facilitate phagocytosis from alveolar macrophages in the treatment of tuberculosis. An aqueous suspension of drug-loaded PG2-C22 full ester (WITEPSOL® PMF 222) was prepared by melt-emulsification and stabilized with the lipid-based emulsifier IMWITOR® 372P (glyceryl stearate citrate). Lipid-microparticles loaded with 2.5% w/w rifampicin, encapsulation efficiency of 95.2 ± 0.0% and median particle size of 2.11 ± 0.02 µm were achieved. The suspension with 0.5% w/w solid content was spray dried through a 0.4 mm-nozzle at a feed rate of 2 g/min into an open-loop system at 75°C. The process yielded solid particles (83%) without impairments. The produced particles showed a unimodal and sharp particle size distribution (span = 1.8) with a median particle size of 2.53 µm. Crystalline state of the lipids within the particles was determined. Neither polymorphism nor phase separation was observed.

The use of PGFAs on organic solvent and aqueous-based spray drying processes led to high yield of drug-loaded solid particles. The systemic and local application of the produced particles is currently under investigation on in vitro cell culture studies. The processability of PGFAs is attributed to the absence of solid-state transitions, especially polymorphism. Conventional LBE crystallize in metastable polymorphs, which increases the degree of supercooling, namely the difference between melting and recrystallization temperature. Although crystallization via spray drying is mostly driven by solvent evaporation, melt-crystallization also occurs in LBE. The high degree of supercooling of conventional LBE delays the formation of solid particles. The absence of polymorphism in PGFAs led to a low degree of supercooling, thus achieving high processability via spray drying. In conclusion, the use of PGFAs is an attractive approach for developing lipid-based engineered particles for diverse applications in the pulmonary field.

Acknowledgment: IOI Oleo GmbH, the Austrian Funding Agency (FFG) and the Doctoral Academy NanoGraz, University of Graz.