From Laboratory to Pilot Scale: Advanced Dosage Forms of Protein/Peptide Medicines

T. Jin1,2, Z. Hu1, S. Yang1, X. Hong1, W. Yuan1, F. Wu1, H. Zhu2, and Z. Yin2

1Shanghai Jiao Tong University School of Pharmacy, Shanghai 200240, CHINA
2BioPharm Solutions, Inc., New Jersey 08536, USA

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Summary
We report two formulation processes to produce sustained-release microspheres of uniform sizes and 90%+ biologic encapsulation efficiency (named EasySphere), and phase-transition microneedle (PTM) patches capable for efficient and accurate transdermal delivery of proteins/peptides at pilot scale.

The microsphere process comprises a stir-free unit operation to form and solidify embryonic microspheres from a drug-loaded polymer solution efficiently. This process causes no breaking or fusion of the dispersed polymer droplets, the two factors causing protein/peptide leaking and uneven sizes. For proteins having tertiary structures, a pre-formulation step involving aqueous-aqueous emulsification was used to pre-load the drug into solvent resistant dextran fine particles without contacting water-oil interfaces prior to microencapsulation into EasySpheres. For proteins having highly delicate conformations, microencapsulation was achieved by organic solvent-free partition into pre-made porous polylactic-co-glyclic acid (PLGA) microspheres, followed by a low temperature pore-sealing step.

The PTM patches were produced using a unique Teflon mold which is permeable to air due to its porous matrix but impermeable to water due to its hydrophobicity. A polyvinyl alcohol (PVA) solution loaded with proteins/peptides was casted on the mold mounted on a vacuum through, socked into the microholes by vacuum, and subjected to a freeze-thaw treatment to form nano-crystalline domains as the cross-linking junctions of the hydrogel network. The gelled microneedle sheet was detached from the mold, dried, and punched to designed sizes.

The EasySphere and PTM technologies were examined by applying them in formulating a series of proteins/peptides (erythropoietin [EPO], insulin and exenatide) into respective dosage forms. Physical characterization and animal trials for PK, efficacy and immunogenicity using monkey and pig models confirmed that all the design criteria of the two systems are met.

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