Formulating protein therapeutics into particulate forms

Abstract

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.

Preparation of bioactive interferon alpha– loaded polysaccharide nanoparticles using a new approach of temperature-induced water phase/water-phase emulsion

“…The protein-protective mechanisms occurred because the dextran nanoparticles could provide a glassy state, and the glassy matrix could decrease the encapsulated IFNα-2b mobility and was more resistant to stresses of temperature and moisture. 19,37,41,42 In vivo efficacy study…”

“…These results confirmed that the dextran nanoparticles could also preserve protein activity in vivo. 19,37 This was because the controlled method (W/O/W) produced a larger amount of oil-water interfaces at which IFNα-2b easily aggregated and lost antiviral activity. 19,37,41,42 Samples A, B, C, and D were the same as in Figures 1A-C and 2D.…”

“…19,37 This was because the controlled method (W/O/W) produced a larger amount of oil-water interfaces at which IFNα-2b easily aggregated and lost antiviral activity. 19,37,41,42 Samples A, B, C, and D were the same as in Figures 1A-C and 2D. The antiviral activity of the IFN-α was determined on the basis of the activity to inhibit the cytopathic effects of the Sindbis virus on FL cells.…”

“…A sustained or controlled drug-delivery system has also been used for IFNα-2b delivery, [3][4][5][6][7][8][9][10] but it often results in activity lost and incomplete release Spray-drying, antisolvent precipitation, spray-freezedrying, and supercritical fluid technology have been investigated for preparing protein nanoparticles. [18][19][20] However, due to pressure, interfaces, heating, and organic solvents involved in different manufacturing steps, these methods are potentially detrimental to the structures and functions of proteins. 21 Other methods, such as manufacturing approaches (emulsion methods) for polymer nanoparticles (including nanogels), inorganic nanoparticles, and liposomes have been developed for preparing protein nanoparticles.…”

“…However, some also expose the hydrophobic cores, leading to protein instability (eg, poly(lactic-co-glycolic acid) [PLGA], PLGA-PEG nanoparticles), burst release, irregular nanospherical shapes or low encapsulating efficiency (eg, nanogel, liposomes, polymersomes), and incomplete release. [22][23][24][25][26][27][28][29][30][31][32][33] We have studied a solution that avoids vapor-water and water-oil interfaces for the preparation of bioactive protein microparticles, 19,[34][35][36][37] but the solution cannot be prepared for nanoscale particles, which has resulted in no further preparation of a targeteddelivery protein system.…”