Formulation and Evaluation Monoporous Hollow Microspheres of Itraconazole- for Pulmonary Drug Delivery

Abstract

Background: Itraconazole is a broad-spectrum triazole antifungal drug, but its poor aqueous solubility, variable oral bioavailability and first-pass metabolism limit predictable therapeutic exposure. Pulmonary delivery can provide high local antifungal concentration in lung tissues while reducing systemic exposure. Objective: The present study aimed to formulate, optimize and evaluate itraconazole-loaded monoporous hollow microspheres as a sustained pulmonary drug delivery system. Methods: Microspheres were prepared by an emulsion solvent evaporation technique using PLGA and Eudragit RS100 as release-retarding polymers and ammonium bicarbonate as a gas-forming pore-forming agent. Formulations F1-F9 were prepared according to a factorial design and evaluated for preformulation attributes, drug-excipient compatibility, particle size, percentage yield, entrapment efficiency, morphology, mass median aerodynamic diameter (MMAD), flow properties, in-vitro drug release and accelerated stability. Results: Itraconazole was practically insoluble in water and showed lambda max at 262 nm in methanol. FTIR and DSC studies indicated no major drug-excipient incompatibility. Particle size ranged from 1.8 to 3.6 µm and entrapment efficiency from 70 to 99%. Batch F3, containing 100 mg itraconazole, 250 mg PLGA, 500 mg Eudragit RS100 and 50 mg ammonium bicarbonate, was optimized because it showed mean particle size of 2.4 µm, yield of 88%, entrapment efficiency of 99%, spherical hollow porous morphology, MMAD of 2.9 µm, Carr index of 16.7%, Hausner ratio of 1.20 and 95% drug release at 8 h. After 3 months, F3 retained particle size of 2.5 µm, entrapment efficiency of 97.9%, MMAD of 2.8 µm and 87.8% cumulative release at the stability endpoint. Conclusion: The optimized itraconazole monoporous hollow microspheres demonstrated suitable micromeritic, aerodynamic, entrapment and sustained-release characteristics, supporting their further investigation as a pulmonary antifungal delivery platform.

Introduction

Microspheres are spherical polymeric drug carriers (1–1000 µm) extensively used for controlled and targeted drug delivery. For pulmonary administration, monoporous hollow microspheres are particularly advantageous because their low density and suitable aerodynamic diameter enable deep lung deposition, improve dispersibility, reduce pulmonary clearance, and provide sustained drug release. Itraconazole, a BCS Class II triazole antifungal drug, has poor aqueous solubility, variable oral absorption, and extensive first-pass metabolism, limiting its therapeutic effectiveness. Pulmonary delivery of itraconazole-loaded hollow microspheres offers the potential to deliver high drug concentrations directly to the lungs while minimizing systemic adverse effects.

The present study aimed to develop itraconazole-loaded monoporous hollow microspheres using PLGA and Eudragit RS100 as polymeric carriers and ammonium bicarbonate as a pore-forming agent. Preformulation studies confirmed that itraconazole is a white to off-white crystalline powder with a melting point of 166–170°C, practically insoluble in water but freely soluble in methanol and chloroform. UV spectrophotometric analysis established a λmax of 262 nm, and the calibration curve demonstrated good linearity for quantitative drug estimation. FTIR and DSC compatibility studies showed that itraconazole was compatible with the selected polymers and excipients, with no significant chemical interactions observed.

A three-level factorial design was employed to optimize the formulation by investigating the effects of PLGA, Eudragit RS100, and ammonium bicarbonate concentrations on particle size and entrapment efficiency. Nine formulations (F1–F9) were prepared using the solvent evaporation method. During preparation, ammonium bicarbonate decomposed to generate gases, producing hollow cores and porous structures within the microspheres. The formulations were evaluated for particle size, percentage yield, entrapment efficiency, surface morphology, aerodynamic properties (MMAD), micromeritic characteristics, in vitro drug release, and accelerated stability.

The results demonstrated that the developed microspheres possessed particle sizes ranging from 1.8 to 3.6 µm, making them suitable for pulmonary drug delivery. Entrapment efficiency ranged from 70% to 99%, indicating efficient drug incorporation within the polymeric matrix. FTIR and DSC analyses confirmed compatibility between itraconazole and formulation excipients, while the UV analytical method proved reliable for drug quantification. Overall, the findings suggest that PLGA/Eudragit RS100-based monoporous hollow microspheres represent a promising inhalable drug delivery system capable of improving the pulmonary delivery and therapeutic efficacy of itraconazole for the treatment of fungal lung infections.

Conclusion

Itraconazole-loaded monoporous hollow microspheres were successfully formulated using the emulsion solvent evaporation technique with PLGA and Eudragit RS100 as polymeric carriers and ammonium bicarbonate as a pore-forming gas-forming agent. Preformulation studies confirmed the poor aqueous solubility of itraconazole and supported the need for a specialized pulmonary delivery system. FTIR and DSC studies indicated compatibility of itraconazole with selected excipients. Statistical optimization showed that polymer concentration, particularly PLGA, significantly affected particle size and entrapment efficiency. Among all formulations, batch F3 was selected as the optimized batch because it showed particle size of 2.4 µm, yield of 88%, entrapment efficiency of 99%, spherical hollow porous morphology, MMAD of 2.9 µm, acceptable flow properties and 95% release at 8 h. Stability testing for 3 months confirmed maintenance of physicochemical, aerodynamic and release characteristics. The developed monoporous hollow microspheres may therefore serve as a promising carrier system for sustained pulmonary delivery of itraconazole. Further work should include aerodynamic cascade impactor studies, dry powder inhaler device compatibility, in-vivo lung deposition, pulmonary safety and pharmacokinetic evaluation.

References

[1] Freiberg S, Zhu XX. Polymer microspheres for controlled drug release. International Journal of Pharmaceutics. 2004;282(1-2):1-18. [2] Soppimath KS, Aminabhavi TM, Kulkarni AR, Rudzinski WE. Biodegradable polymeric nanoparticles as drug delivery devices. Journal of Controlled Release. 2001;70(1-2):1-20. [3] Bodmeier R, Paeratakul O. Sustained-release microspheres prepared by solvent evaporation methods. Journal of Controlled Release. 1989;10(1):1-15. [4] Eisha G. Microspheres as targeted drug delivery carriers: Recent advances and pharmaceutical applications. Journal of Drug Delivery and Therapeutics. 2025;15(1):88-101. [5] Amidon GL, Lennernas H, Shah VP, Crison JR. A theoretical basis for a biopharmaceutic drug classification. Pharmaceutical Research. 1995;12(3):413-420. [6] Savjani KT, Gajjar AK, Savjani JK. Drug solubility: importance and enhancement techniques. ISRN Pharmaceutics. 2012;2012:1-10. [7] Lipinski CA. Drug-like properties and the causes of poor solubility and poor permeability. Advanced Drug Delivery Reviews. 2004;46(1-3):3-26. [8] Loftsson T, Brewster ME. Pharmaceutical applications of cyclodextrins. Journal of Pharmaceutical Sciences. 2010;85(10):1017-1025. [9] Tao T. Advancements in sustained-release microspheres for controlled drug delivery systems. International Journal of Pharmaceutical Sciences and Drug Research. 2025;17(2):145-158. [10] Patil C. Preparation and evaluation of hollow microspheres of zidovudine using solvent diffusion evaporation method. International Journal of Pharmaceutical Sciences Review and Research. 2011;8(2):120-126. [11] Gupta P. Formulation and evaluation of gastroretentive pantoprazole sodium microballoons by emulsion solvent evaporation technique. International Journal of Biological Macromolecules. 2017;103:896-905. [12] Ammar HO. Optimization of gastroretentive cinnarizine microballoons using Box-Behnken design. Drug Development and Industrial Pharmacy. 2016;42(6):978-988. [13] Jain S. Development and evaluation of floating microballoons of nizatidine for gastric retention and sustained drug delivery. International Journal of Pharmaceutics. 2016;499(1-2):230-240. [14] Sinha VR. Biodegradable PLGA microspheres for controlled delivery of proteins and peptides: A review. Journal of Controlled Release. 2016;240:90-102. [15] Siepmann J, Peppas NA. Higuchi equation and drug release modeling. Advanced Drug Delivery Reviews. 2011;63(3):163-174. [16] Hariharan M. Controlled release formulations: formulation and evaluation aspects. Drug Development and Industrial Pharmacy. 2006;32(6):661-669. [17] Colombo P. Swelling-controlled release systems. European Journal of Pharmaceutics and Biopharmaceutics. 2000;45(2):149-157. [18] Park K. Controlled drug delivery systems: past forward and future back. Journal of Controlled Release. 2014;190:3-8. [19] Sawant KK, Patil SB. Mucoadhesive microspheres as a drug delivery system: A review. Journal of Pharmacy Research. 2013;7(1):1-9. [20] Rao YS, Chowdary KPR. Mucoadhesive microspheres in controlled drug delivery: A review. International Journal of Pharmaceutical and Biomedical Research. 2012;3(4):188-196. [21] Andrews GP, Laverty TP, Jones DS. Mucoadhesive polymeric platforms. European Journal of Pharmaceutics and Biopharmaceutics. 2009;71(3):505-518. [22] Smart JD. The basics and underlying mechanisms of mucoadhesion. Advanced Drug Delivery Reviews. 2005;57(11):1556-1568. [23] Dash M, Chiellini F, Ottenbrite RM, Chiellini E. Chitosan - a versatile semi-synthetic polymer in biomedical applications. Progress in Polymer Science. 2011;36(8):981-1014. [24] Lee KY, Mooney DJ. Alginate: properties and biomedical applications. Progress in Polymer Science. 2012;37(1):106-126. [25] Kumar S. Solubility enhancement methods: an overview. International Journal of Pharmacy and Pharmaceutical Sciences. 2013;5(3):45-57.

Copyright

Copyright © 2026 Mahesh Kadam, Dr. Vaishali Kate. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.