Developing an injectable co-formulation of two antidiabetic drugs: Excipient impact on peptide aggregation and pharmacokinetic properties.


AstraZeneca, Biopharmaceutical Development, BioPharmaceuticals R&D, Granta Park, Cambridge CB21 6GH, United Kingdom. Electronic address: [Email]


Combination therapy in Type 2 Diabetes Mellitus is necessary to achieve tight glycaemic control and reduce complication risk. Current treatment plans require patients to take several drugs concomitantly leading to low therapy adherence. This study describes the development and characterisation of a stable parenteral co-formulation of a sodium glucose co-transporter 2 inhibitor (dapagliflozin) and a therapeutic lipidated peptide, using hydroxypropyl-β-cyclodextrin as an enabling excipient. Using NMR, calorimetry, computational modelling and spectroscopic methods, we show that besides increasing the solubility of dapagliflozin, cyclodextrin prevents self-association of the peptide through interaction with the lipid chain and amino acids prone to aggregation including aromatic groups and ionisable residues. While those interactions cause a dramatic secondary structure change, no impact on potency was seen in vitro. A subcutaneous administration of the co-formulation in rat showed that both drugs reach exposure levels previously shown to be efficacious in clinical mono-therapy studies. Interestingly, a faster absorption rate was observed for the peptide formulated within the cyclodextrin vehicle with respect to the buffer vehicle, which could trigger an earlier onset of action. The cyclodextrin based co-formulation is therefore a promising approach to develop a fixed dose combination of a therapeutic peptide and a small molecule drug for increased patient adherence and better blood glucose control.


Aggregation,Combination therapy,Dapagliflozin,Diabetes,Peptide,

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