Utilizing the unique virtue of polyvinyl alcohol (PVA) of forming microcrystalline domains as the cross‐linking junctions, a new microneedle system, phase‐transition microneedle (PTM) patch, is invented, which enables highly efficient transdermal delivery of insulin without depositing the needle tip materials to the skin. PTM, formed of biocompatible PVA as the main component, is sufficiently strong for its needle tip to penetrate the epidermis in the dry state, release preloaded cargos by absorbing body fluid in the dermis layer nearly as fast as subcutaneous injection, and retain mechanical toughness in the hydrated state to ensure complete removal from the skin. The microcrystalline cross‐linking enables a protein‐friendly fabrication process free of hazardous cross‐linking agents required for chemical and ionic cross‐linking. Pharmacokinetic and efficacy studies of insulin‐loaded PTM using pig models indicate a transdermal bioavailability over 20%, similar deviations and peak width, only 18 min behind Tmax, and lower glycated hemoglobin (HbA1c) as compared with injection pens. The complete removability of hydrated needle tips may endow PTM with an additional safety insurance, terminating medication whenever hypoglycemia becomes a concern. PTM patch is practically applicable to a variety of protein/peptide medicines requiring frequent dosing by offering painless administration, freedom of refrigeration, and minimal safety concerns.

While polymer microneedles may easily be fabricated by casting a solution in a mold, either centrifugation or vacuumizing is needed to pull the viscous polymer solution into the microholes of the mold. We report a novel process to fabricate polymer microneedles with a one-sided vacuum using a ceramic mold that is breathable but water impermeable. A polymer solution containing polyvinyl alcohol and polysaccharide was cast in a ceramic mold and then pulled into the microholes by a vacuum applied to the opposite side of the mold. After cross-linking and solidification through freeze-thawing, the microneedle patch was detached from the mold and transferred with a specially designed instrument for the drying process, during which the patch shrank evenly to form an array of regular and uniform needles without deformation. Moreover, the shrinkage of the patches helped to reduce the needles' size to ease microfabrication of the male mold. The dried microneedle patches were finally punched to the desired sizes to achieve various properties, including sufficient strength to penetrate skin, microneedles-absorbed water-swelling ratios, and drug-release kinetics. The results showed that the microneedles were strong enough to penetrate pigskin and that their performance was satisfactory in terms of swelling and drug release.

This review is aimed at providing critical comments on selected approaches to formulating protein drugs into particulate forms feasible as practical pharmaceutical dosage forms. From a practical point of view, the need to formulate protein therapeutics into particulate forms includes inhalation and sustained-release delivery proteins, stabilizing and incorporating proteins into tissue engineering scaffolds and medical devices, as well as protecting and targeting protein therapeutics in an in vivo environment. For either of the applications, a common challenge is that proteins are easily denatured during particle-forming processes in which water-oil or water-air interfaces, multivalent ions or polyelectrolytes, strong shear stress and/or reactive crosslinking agents are often involved. Moreover, methods to protect proteins during the particle-forming processes must not compromise their pharmaceutical objectives, such as encapsulation efficiency, burst-free controlled release and storage convenience. Although numerous methods have been reported to formulate proteins into particulate systems, few of them meet the criteria above. To stimulate critical and interactive readings of the vast and booming information, the authors also provide their analysis regarding the feasibility of the formulation strategies summarized in this review.

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