Recent developments in protein and peptide parenteral delivery approaches

Abstract

Discovery of insulin in the early 1900s initiated the research and development to improve the means of therapeutic protein delivery in patients. In the past decade, great emphasis has been placed on bringing protein and peptide therapeutics to market. Despite tremendous efforts, parenteral delivery still remains the major mode of administration for protein and peptide therapeutics. Other routes such as oral, nasal, pulmonary and buccal are considered more opportunistic rather than routine application. Improving biological half-life, stability and therapeutic efficacy is central to protein and peptide delivery. Several approaches have been tried in the past to improve protein and peptide in vitro/in vivo stability and performance. Approaches may be broadly categorized as chemical modification and colloidal delivery systems. In this review we have discussed various chemical approaches such as PEGylation, hyperglycosylation, mannosylation, and colloidal carriers including microparticles, nanoparticles, liposomes, carbon nanotubes and micelles for improving protein and peptide delivery. Recent developments on in situ thermosensitive gel-based protein and peptide delivery have also been described. This review summarizes recent developments on some currently existing approaches to improve stability, bioavailability and bioactivity of peptide and protein therapeutics following parenteral administration.

Figure 1. Polysialylated constructs

DDS: Drug delivery systems. Reproduced with permission from [37]

Figure 2. Colloidal carriers for protein and peptide parenteral delivery

MWNT: Multiwalled carbon nanotubes; SWNT: Single-walled carbon nanotubes.

Figure 3. Release profile of IFNα-2b

(A) Release profile of the optimized IFNα-2b microspheres in rats. (B) Profile of IFNα-2b concentration following administration of IFNα-2b solution in rats. Six rats were administrated with a single subcutaneous dose of 200,000 IU. Reproduced with permission from [61].

Figure 4. Pharmacokinetic and pharmacodynamic of TNF-related apoptosis-inducing ligand or PEG-TNF-related apoptosis-inducing ligand microspheres

(A) In vivo pharmacokinetic profiles of TRAIL or PEG-TRAIL microspheres after subcutaneous administration (100 μg/rat; n = 5); (B) Tumor growth suppressions by TRAIL or PEG-TRAIL microspheres (300 μg/mouse, subcutaneous). TRAIL: TNF-related apoptosis-inducing ligand. Reproduced with permission from [67].

Figure 5. Blood glucose level–time curve after subcutaneous injection of insulin solution at a dose of 1 IU/kg, in saline and INS–PLC–NPs at a dose of 4 IU/kg to diabetic male Sprague–Dawley rats (220–280 g)

Data presented as mean ± SD (n = 5). *p <0.05; **p <0.001. INS–PLC–NPS: Poly(hydroxybutyrate-co-hydroxyhexanoate) nanoparticles. Reproduced with permission from [102].

Figure 6. PLA/hGH polyelectrolyte complex-loaded hydrogel

AMPEG: α-Amino-ω-methoxy-PEG; ILeOEt: L-isoleucine ethyl ester; PLA: Polylactic acid. Reproduced with permission from [159].

Figure 7. Comparative in vivo release profiles of PEGylated octreotide and octreotide loaded into in situ gels, octreotide solution (insert) and placebo in situ forming gel as control (n = 4)

Reproduced with permission from [160].