Sustained release subcutaneous delivery of BMS-686117, a GLP-1 receptor peptide agonist, via a zinc adduct

Abstract

BMS-686117 is an 11-mer GLP-1 receptor agonist with a short intrinsic pharmacokinetic half-life (t_1/2) of ∼2 h. In order to develop an extended release formulation for once-daily (QD) subcutaneous administration, a non-covalently bonded Zn/BMS-686117 adduct with very low aqueous solubility was prepared through mixing zinc acetate and BMS-686117 solutions, followed by filtration or spray drying. At pH 6.8, free BMS-686117 concentration decreased continuously with the increase of Zn:BMS-686117 ratio. Furthermore, free BMS-686117 concentration increases in the presence of ethylenediaminetetraacetic acid (EDTA), indicating the reversibility of the zinc–peptide association. As solids, the glass transition temperature of Zn/BMS-686117 adduct increases with the increase of Zn:BMS-686117 ratio. A Zn/BMS-686117 adduct suspension, with a molar ratio of zinc:BMS-686117 of 3:1, was dosed subcutaneously to dogs along with two other solution formulations. The Zn/BMS-686117 adduct showed a prolonged BMS-686117 terminal t_1/2 of 8.5 h, a mean residence time (MRT) of 16 h, and a C_max value 6–8 times lower than the solution formulations. Additionally, the Zn/BMS-686117 was encapsulated into poly(lactide-co-glycolide) (PLGA) microspheres. The Zn/BMS-686117 microspheres showed an almost zero-order release profile in vitro for at least 18 days, with minimal initial burst, indicating the potential of using this approach for long-term sustained release.

Introduction

Glucagon-like peptide-1 (GLP-1) is secreted from gut endocrine cells in response to nutrient ingestion and plays multiple roles in metabolic homeostasis following nutrient absorption. GLP-1 administration by continuous infusion or subcutaneous injection acutely normalizes elevated plasma glucose in the fasting and the fed state with low risk of hypoglycemia, lowers glucagon concentrations, delays gastric emptying of solid and liquid meals, reduces caloric intake, and causes weight loss in type II diabetic patients. GLP-1 treatment has been shown to improve beta cell function in aged and diabetic rats, suggesting that this mechanism may also improve glucose tolerance and potentially delay or prevent the progression of diabetes in humans with chronic treatment (Drucker, 2001, Kjems et al., 2003, Nourparvar et al., 2004, Holst and Orskov, 2004).

BMS-686117 is a potent 11-mer GLP-1 receptor agonist (Fig. 1). Following subcutaneous administration in dogs, BMS-686117 has a bioavailability of 93%, a short t_1/2 of ∼2 h and mean residence time (MRT) of ∼4 h. While this peptide clearly does not possess the adequate pharmacokinetic properties to be a QD subcutaneous product, clinical study has indicated that GLP-1 peptide blood level must be maintained to obtain the optimal therapeutic effect (Larsen et al., 2001). As a chronic use product for diabetic patients, the drug product is intended for self-administration and patient compliance is of great importance. Therefore, a QD formulation that delivers ∼1 mg/ml dose, combined with a fine syringe needle (27 gauge or smaller) for subcutaneous injection, are highly desirable for clinical and marketing success.

Various drug delivery technologies have been developed for sustained release of peptides (Putney and Burke, 1998, Maa and Prestrelski, 2000, Shi and Li, 2005, Sadrzadeh et al., 2007). Common approaches include PEGylation (Schmidt et al., 2007, Nande et al., 2008, Yu et al., 2008), polymers depots (biodegradable microspheres, hydrogels) (Okada and Toguchi, 1995, Tamber et al., 2005, Mok and Park, 2008, Garbayo et al., 2008, Jin et al., 2008, Yu et al., 2008), polymeric micelles (Giddi et al., 2007, Wang et al., 2008, Xiong et al., 2008), complexation (Ye et al., 2006), or combination of the above. However, many of the above technologies are not suitable for the formulation requirement of BMS-686117. For a relatively small peptide like BMS-686117 (MW 1528.7), PEGylation with a long PEG chain (usually > 5 K (Hadziyannis and Papatheodoridis, 2003, Cooksley, 2005, Ye et al., 2006)) is very likely to shield the peptide from its binding site. Biodegradable polymeric systems, such as PLGA, are typically used for longer term sustained release (once monthly or longer) instead of QD; also the typical low drug loading (∼10%) will increase the daily injection mass significantly and make the injection through fine needle much more difficult. In this paper, investigation of a zinc–peptide adduct formulation as a potential sustained release delivery system for BMS-686117 is reported. The adduct suspension is suspendable for months in aqueous medium, easy to inject through a 27 G needle and demonstrated sustained release profile in vivo in dogs. When the Zn/BMS-686117 adduct is encapsulated in a biodegradable polymer, a long-term sustained release formulation with a much decreased initial burst and an almost zero-order release profile can be developed.