Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability

The aim of this study was to develop antisense oligonucleotide tablet formulations using high-speed electrospinning. Hydroxypropyl-beta-cyclodextrin (HPβCD) was used as a stabilizer and as an electrospinning matrix. In order to optimize the morphology of the fibers, electrospinning of various formulations was carried out using water, methanol/water (1:1), and methanol as solvents. The results showed that using methanol could be advantageous due to the lower viscosity threshold for fiber formation enabling higher potential drug loadings by using less excipient. To increase the productivity of electrospinning, high-speed electrospinning technology was utilized and HPβCD fibers containing 9.1% antisense oligonucleotide were prepared at a rate of ~330 g/h.

Furthermore, to increase the drug content of the fibers, a formulation with a 50% drug loading was developed. The fibers had excellent grindability but poor flowability. The ground fibrous powder was mixed with excipients to improve its flowability, which enabled the automatic tableting of the mixture by direct compression. The fibrous HPβCD–antisense oligonucleotide formulations showed no sign of physical or chemical degradation over the 1-year stability study, which also shows the suitability of the HPβCD matrix for the formulation of biopharmaceuticals. The obtained results demonstrate possible solutions for the challenges of electrospinning such as scale-up and downstream processing of the fibers.

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Materials

Hydroxypropyl-beta-cyclodextrin (HPβCD) (Kleptose^® HPB, MS nominal value: 0.62) purchased from Roquette Pharma (Lestrem, France) was used for electrospinning. Purified water prepared by reverse osmosis with a Zeneer UP S-UV (Human Corporation, Seoul, Republic of Korea) water system and analytical-grade methanol purchased from Merck. (Darmstadt, Germany) was used to prepare the solutions for electrospinning. Antisense oligonucleotides (ASO1 and ASO2) were kindly supplied by Janssen Pharmaceuticals.

For the tableting of ASO1-containing electrospun formulations microcrystalline cellulose (MCC, Vivapur 200) purchased from JRS Pharma (Rosenberg, Germany), mannitol (Pearlitol 400DC) kindly supplied by Roquette Pharma (Lestrem, France), croscarmellose sodium (Ac-Di-Sol) obtained from DuPont (Budapest, Hungary), silicon dioxide (Aerosil^® 200, Evonik Industries, Essen, Germany), and magnesium stearate provided by Hungaropharma (Budapest, Hungary) were used.

Hirsch, E.; Nacsa, M.; Pantea, E.; Szabó, E.; Vass, P.; Domján, J.; Farkas, A.; Nyíri, Z.; Eke, Z.; Vigh, T.; Andersen, S.K.; Verreck, G.; Marosi, G.J.; Nagy, Z.K. Oligonucleotide Formulations Prepared by High-Speed Electrospinning: Maximizing Loading and Exploring Downstream Processability. Pharmaceutics 2023, 15, 855. https://doi.org/10.3390/pharmaceutics15030855