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Formulation and Delivery - Chemical

(M1430-09-52) Development of Dry Powder Formulation of PAV-104 for Pulmonary Drug Delivery

Monday, October 21, 2024
2:30 PM – 3:30 PM MT
Purpose: Pulmonary drug delivery has been effective in COVID-19 treatment. With the lungs being the primary site of infection and progression, pulmonary drug delivery is an ideal approach for the treatment. PAV-104 is a novel candidate for the treatment of infections by the major respiratory viruses including SARS-CoV-2, influenza, and RSV. However, the compound has poor aqueous solubility restricting its delivery options. To overcome these solubility issues, we aimed to develop dry powder-based formulation of PAV-104. Dry powder blending and spray drying was evaluated to determine the ability to develop inhalable dry powder formulation. Since the intrinsic particle size of the active ingredient was too large for inhalation to the lungs, efforts were made to reduce the particle size of API.

Methods: Spray drying: A Buchi Mini spray dryer B-290 was used for spray drying purposes. The API suspension in lactose solution was stirred continuously during spray drying process to mitigate settling and segregation. Different feed rates were evaluated during spray drying to assess its impact on yield, moisture content and particle size. Particle size analysis: A Malvern 3000 mastersizer was used for evaluating particle size of the API and spray dried particles. Dispersion media were either water (with 0.01% tween) or Ethanol. Sonication and mixing speed were altered for method development. Precipitation: A flash precipitation using reverse addition of an anti-solvent was used to yield drug particles of inhalable sizes. Particle size of the precipitated material was confirmed after drying of the material. Dry-powder blending: The dry powder blending relied on a carrier based ordered mixture using alpha lactose monohydrate (lactose) as carrier. The carrier comprised two different grades of lactose. One coarse and one fine grade. While the coarse fraction with 95% w/w serves as the actual carrier, the 5% w/w fine fraction is thought to pre-occupy the high energy binding sites on the larger carrier crystals. After pre-blending of the coarse and fine lactose grades, the API was added and blended for 6h using a Turbula mixer. Blend uniformity was assessed using HPLC. Microscopy: Nikon Eclipse 50iPOL was used for microscopic studies. APSD testing: Next Generation Impactor (NGI) was used for APSD testing of dry powder formulation.

Results: Solubility studies showed good solubility of PAV-104 in organic solvents but limited or no solubility was observed in organic-water mixture making it difficult to develop solution-based formulation. To overcome this, we tried developing dry powder formulation. Spray drying did not produce inhalable particles. Inherent particle size of PAV-104 is not suitable for inhalation; hence particle size reduction was done. An anti-solvent-based precipitation method was used and was successful in producing inhalable drug particles (Particles of ≤ 5 μm). Dry powder formulations were made of both precipitated and untreated API. APSD data did not show significant difference in data of precipitated and untreated API formulations. Additional efforts are required to achieve formulation with deposition in the lungs.

Conclusion: We were able to reduce the particle size of PAV-104 using the precipitation approach. Dry powder formulations developed were not effective enough to achieve optimum lung delivery. Though the delivery to lower stages was poor, there was an increase in fine particle fraction. For precipitated API formulation higher deposition was observed in pre-separator. The reason for this could be either bi-modal API PSD or presence of API agglomerates which did not break loose and might require additional shear or high energy blending. Further studies are required to optimize the formulation to achieve optimum lung deposition.

References: 1. Du, L., Deiter, F., Bouzidi, M.S. et al. A viral assembly inhibitor blocks SARS-CoV-2 replication in airway epithelial cells. Commun Biol 7, 486 (2024).
2. Alipour S, Mahmoudi L, Ahmadi F. Pulmonary drug delivery: an effective and convenient delivery route to combat COVID-19. Drug Deliv Transl Res. 2023 Mar;13(3):705-715.
3. Woodward IR, Fromen CA. Recent Developments in Aerosol Pulmonary Drug Delivery: New Technologies, New Cargos, and New Targets. Annu Rev Biomed Eng. 2024 Jul;26(1):307-330.
4. Michon M, Müller-Schiffmann A, Lingappa AF, Yu SF, Du L, Deiter F, Broce S, Mallesh S, Crabtree J, Lingappa UF, Macieik A, Müller L, Ostermann PN, Andrée M, Adams O, Schaal H, Hogan RJ, Tripp RA, Appaiah U, Anand SK, Campi TW, Ford MJ, Reed JC, Lin J, Akintunde O, Copeland K, Nichols C, Petrouski E, Moreira AR, Jiang IT, DeYarman N, Brown I, Lau S, Segal I, Goldsmith D, Hong S, Asundi V, Briggs EM, Phyo NS, Froehlich M, Onisko B, Matlack K, Dey D, Lingappa JR, Prasad DM, Kitaygorodskyy A, Solas D, Boushey H, Greenland J, Pillai S, Lo MK, Montgomery JM, Spiropoulou CF, Korth C, Selvarajah S, Paulvannan K, Lingappa VR. A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex. Open Biol. 2024 Jun;14(6):230363.

Microscopy of the drug

Spray drying sample details

APSD data comparison of dry powder formulations