Fighting type 2 diabetes: Formulation strategies for peptide-based therapeutics

Abstract

Diabetes mellitus is a major health problem with increasing prevalence at a global level. The discovery of insulin in the early 1900s represented a major breakthrough in diabetes management, with further milestones being subsequently achieved with the identification of glucagon-like peptide-1 (GLP-1) and the introduction of GLP-1 receptor agonists (GLP-1 RAs) in clinical practice. Moreover, the subcutaneous delivery of biotherapeutics is a well-established route of administration generally preferred over the intravenous route due to better patient compliance and prolonged drug absorption. However, current subcutaneous formulations of GLP-1 RAs present pharmacokinetic problems that lead to adverse reactions and treatment discontinuation. In this review, we discuss the current challenges of subcutaneous administration of peptide-based therapeutics and provide an overview of the formulations available for the different routes of administration with improved bioavailability and reduced frequency of administration.

Keywords: Amylin mimetics; Biotherapeutics; Controlled-release formulations; Drug delivery systems; Exenatide; Glucagon-like peptide-1 receptor agonists; Microparticles; Nanoparticles; Peptide delivery; Subcutaneous administration; Type 2 diabetes mellitus.

Graphical abstract

Figure 1

Milestones in GLP-1 and amylin therapy development since their discovery.

Figure 2

Challenges of subcutaneous administration of biotherapeutics.

Figure 3

HypoSkin® scheme.

Figure 4

Formulation strategies for the administration of GLP1-RAs.

Figure 5

SNAC effect on the oral absorption of semaglutide. SNAC enhances the transcellular absorption of semaglutide by increasing the pH.

Figure 6

(A) Activity of GLP-1 formulations in an intraperitoneal glucose tolerance test in rats. (B) Serum GLP-1 concentrations in rats after intravenous administration of GLP-1 formulations. Figure reproduced and modified with permission from Ref. . Copyright © 2009 Elsevier B.V.

Figure 7

Exenatide blood levels vs. time profiles after subcutaneous (SC) or intranasal (IN) administration of exenatide (EXT) in solution or included in CaCl₂ or MgCl₂ hydrogels. Values are expressed as the mean ± SD (n = 5). Figure reproduced and modified with permission from Ref. . Copyright © 2018 Elsevier B.V.

Figure 8

Systemic absorption and brain transport of GLP-1 and its analogue exendin-4, after single intranasal administration of GLP-1 and exendin-4 with or without l- or d-penetratin (2.0 mM) to male ddY mice. Each data point represents the mean ± SEM of n = 3–4. ∗P < 0.05, ∗∗P < 0.01 indicate significant difference with the control group receiving GLP-1 or exendin-4 solution. Figure reproduced and modified with permission from Ref. . CC-BY 4.0.

Figure 9

(A) Photograph of the patch with a microneedles array. Scale bar, 0.5 cm (B) SEM image of the microneedles array. Scale bar, 500 μm. (C) Single microneedle. Scale bar, 100 μm. Figure reproduced and modified with permission from Ref. . CC-BY 4.0.

Figure 10

(A) Plasma concentrations of exenatide after a single extended-release exenatide injection (0–12 weeks) (B) Plasma concentrations of exenatide after repeated weekly exenatide injection (0–27 weeks). Figure reproduced and modified with permission from Ref. . Copyright © 2018 Elsevier B.V.

Figure 11

In vitro release profiles of exenatide loaded PLGA microspheres prepared with PLGA of different molecular weights and different copolymer compositions in HEPES buffer pH 7.4. Figure reproduced and modified with permission from Ref. . Copyright © 2013 Elsevier B.V.

Figure 12

Schematic illustration of spray dryer (A) and ultrafine particle processing system (UPPS) (B) for the manufacture microparticles. Figure reproduced and modified with permission from Ref. . Copyright © 2015 Elsevier B.V.