Pharmaceutical applications of aqueous scaled-up electrospinning

Thesis findings
A solid formulation of a model biopharmaceutical drug (β-galactosidase) was developed and produced by high-speed electrospinning for the first time. A fully aqueous polymeric solution was successfully electrospun with a 30 mL/h feeding rate, which is about 30x higher than the feeding rate usually attained with single-needle electrospinning. According to X-ray diffraction measurements, the mixture of polyvinyl alcohol, polyethylene oxide matrix, and β-galactosidase was in amorphous state in the fibers, whereas mannitol was crystalline (δ-polymorph). The presence of crystalline mannitol and the low water content enabled the grinding of the fibrous sample without secondary drying. The ground powder, mixed with tableting excipients, was successfully compressed into tablets. β-Galactosidase remained stable during each of the processing steps and for at least 1 year of storage at room temperature in the tablets.

A water-soluble cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin (HP-β-CD) was used as a novel polymer-free matrix for the scaled-up electrospinning of a model protein- type drug. High feeding rate (400 mL/h which equals ~270 g solid product per hour) could be achieved this way. The new solid form was found suitable for grinding and tableting by direct compression. The model protein-type drug (β-galactosidase) remained stable during each of the processing steps (electrospinning, grinding, tableting) and for at least 6 months of storage at room temperature in the tablets.

An amorphous solid dispersion of a poorly soluble drug (voriconazole (VOR)) and a polymer-free matrix (SBE-β-CD) was electrospun with high production rate (~240 g/h) for the first time. This productivity is more than 12x higher than the highest aqueous electrospinning production rate reported so far. According to X-ray diffraction and differential scanning calorimetry, no traces of crystalline VOR were detectable in the fibers. Furthermore, Raman mapping and energy dispersive spectroscopy measurements showed a uniform distribution of amorphous VOR in the fibers.

An intravenously injectable reconstitution powder dosage form was produced by electrospinning from an aqueous solution for the first time. High-speed electrospinning with a novel continuous (cyclone) collection was used to manufacture the innovative

formulation of the poorly water-soluble antifungal VOR with sulfobutylether-β- cyclodextrin (SBE-β-CD). This dosage form was compared to the freeze-dried, marketed product with the same composition, Vfend®. Reconstitution tests, carried out with the ground fibrous powder, showed complete dissolution resulting in a clear solution within 30 s (similarly to Vfend®).

Anaerobic bacteria-containing electrospun fibers were prepared with high production rate (~150 g/h) for the first time. Butyrate (an anti-inflammatory molecule) production capacity of the bacteria was retained after electrospinning. The fibers were pressed into tablets by direct compression after milling (by an oscillating mill) and mixing with tableting excipients. No significant decrease in bacterial viability was observed after either of the processing steps (milling and tableting).

Long-term stability of a model anaerobic bacterium from the gut microbiome (Clostridium butyricum) incorporated into fibers of a water-soluble cyclodextrin matrix (HP-β-CD) was studied for the first time. Effect of the growth conditions of the bacteria and storage conditions of the fibers (temperature, presence of oxygen) on the viability of the bacteria in the fibers was investigated. High viability was preserved in the fibrous sample containing both spores and vegetative anaerobic bacteria after 12 months of storage at room temperature in the presence of oxygen.

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PhD Thesis by Panna Vass – Pharmaceutical applications of aqueous scaled-up electrospinning –
BUDAPEST UNIVERSITY OF TECHNOLOGY AND ECONOMICS DEPARTMENT OF ORGANIC CHEMISTRY AND TECHNOLOGY GEORGE A. OLAH DOCTORAL SCHOOL

Materials: β-Galactosidase, Clostridium butyricum, Voriconazole, Polyvinyl alcohol (PVA) Mowiol® 18-88, Polyethylene oxide (PEO) POLYOX™, Mannitol Mannogem EZ, 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD) Kleptose® HPB, Sulfobutylether-β-cyclodextrin sodium (SBE-β-CD) Dexolve™, Microcrystalline cellulose (MCC) Vivapur® 200, Croscarmellose sodium Ac-Di-Sol®, Mannitol Pearlitol® 400DC, Silicium dioxide Aerosil® 200, Magnesium stearate (MgSt), Cross-linked polyvinylpolypyrrolidone Kollidon Cl