Injectable controlled release depots for large molecules

Abstract

Biodegradable, injectable depot formulations for long-term controlled drug release have improved therapy for a number of drug molecules and led to over a dozen highly successful pharmaceutical products. Until now, success has been limited to several small molecules and peptides, although remarkable improvements have been accomplished in some of these cases. For example, twice-a-year depot injections with leuprolide are available compared to the once-a-day injection of the solution dosage form. Injectable depots are typically prepared by encapsulation of the drug in poly(lactic-co-glycolic acid) (PLGA), a polymer that is used in children every day as a resorbable suture material, and therefore, highly biocompatible. PLGAs remain today as one of the few "real world" biodegradable synthetic biomaterials used in US FDA-approved parenteral long-acting-release (LAR) products. Despite their success, there remain critical barriers to the more widespread use of PLGA LARproducts, particularly for delivery of more peptides and other large molecular drugs, namely proteins. In this review, we describe key concepts in the development of injectable PLGA controlled-release depots for peptides and proteins, and then use this information to identify key issues impeding greater widespread use of PLGA depots for this class of drugs. Finally, we examine important approaches, particularly those developed in our research laboratory, toward overcoming these barriers to advance commercial LAR development.

Keywords: Biodegradable; Controlled release; Depot; PLGA; Peptide; Protein.

Fig. 1

Representative LDPI images of mouse hindlimbs at 6 weeks post-surgery; S — stabilized (bFGF + standard stabilizers + bulk excipient + microclimate control), PS — partially stabilized (bFGF + standard stabilizers + bulk excipient microclimate control), US — unstabilized (bFGF only), and B — blank (no drug + standard stabilizers + bulk excipient + microclimate control). The right hindlimbs (left in the images) were subjected to the surgery to develop ischemia at the beginning. The left hindlimbs (right in the images) were kept intact and represent healthy controls. Standard stabilizers: 0.01% heparin, 0.01% EDTA, and 2.3% sucrose; bulk excipient was 15.7% gum arabic for PS and 12.7% BSA for S and B; microclimate control: 3% Mg(OH)₂. Reproduced with permission from [103].

Fig. 2

Recovery of hindlimb blood flow over 6 weeks post surgery. The intensity ratios of the right (ligated) to left (healthy) limbs from LDPI images were calculated only for mice with remaining limbs; the values were expressed as mean ± SEM. Reproduced with permission from [103].

Fig. 3

Determination of P_i for primary acids responsible for the lowering of microclimate pH(L₂A, LA and GA) by equilibration in very thin PLGA films at 37 °C before significant hydrolysis could occur. Data from [110].

Fig. 4

Active self-healing microencapsulation of tetanus toxoid (TT) in PLGA microspheres. The surface morphology of 3.2 wt.% Al(OH)₃-PLGA-3.5 wt.% trehalose-5 wt.% diethyl phthalate microspheres before and after encapsulation of the antigen. Reproduced from [97] with permission.

Fig. 5

Controlled release of immunoreactive TT from self-healed PLGA Al(OH)₃/PLGA microspheres. The release kinetics of TT is shown for the initial burst (A) and long-term release (B) into PBST + 0.2% BSA at 37 °C Formulations were unencapsulated Al(OH)₃ (●), TT/PLGA microspheres prepared by w/o/w emulsion solvent evaporation (▲), and TT/adjuvant/plasticizer/PLGA microspheres prepared by self-healing encapsulation 3.2 wt.% Al(OH)₃-PLGA-3.5 wt.% trehalose-5 wt.% diethyl phthalate (DEP) (□), 3.2 wt.% Al(OH)₃-PLGA-3 wt.% trehalose-5 wt.% tributyl acetylcitrate (TBAC) (◆), and 3.2 wt.% Al(OH)₃-PLGA-1.5 wt.%trehalose-1.5% MgCO₃-5 wt.% TBAC (○). Reproduced from [97] with permission.