Formulation for a novel inhaled peptide therapeutic for idiopathic pulmonary fibrosis

Abstract

A caveolin-1 scaffolding domain, CSP7, is a newly developed peptide for the treatment of idiopathic pulmonary fibrosis. To develop a CSP7 formulation for further use we have obtained, characterized and compared a number of lyophilized formulations of CSP7 trifluoroacetate with DPBS and in combination with excipients (mannitol and lactose at molar ratios 1:5, 70 and 140). CSP7 trifluoroacetate was stable (>95%) in solution at 5 and 25 °C for up to 48 h and tolerated at least 5 freeze/thaw cycles. Lyophilized cakes of CSP7 trifluoroacetate with excipients were stable (>96%) for up to 4 weeks at room temperature (RT), and retained more than 98% of the CSP7 trifluoroacetate in the solution at 8 h after reconstitution at RT. The lyophilized CSP7 formulations were stable for up to 10 months at 5 °C protected from moisture. Exposure of the lyophilized cakes of CSP7 to 75% relative humidity (RH) resulted in an increase in the absorbed moisture, promoted crystallization of the excipients and induced reversible formation of CSP7 aggregates. Increased molar ratio of mannitol slightly affected formation of the aggregates. In contrast, lactose significantly decreased (up to 20 times) aggregate formation with apparent saturation at the molar ratio of 1:70. The possible mechanisms of stabilization of CSP7 trifluoroacetate in solid state by lactose include physical state of the bulking agent and the interactions between lactose and CSP7 trifluoroacetate (e.g. formation of a Schiff base with the N-terminal amino group of CSP7). Finally, CSP7 trifluoroacetate exhibited excellent stability during nebulization of formulations containing mannitol or lactose.

Keywords:

• CSP7 trifluoroacetate
• idiopathic pulmonary fibrosis
• lyophilization
• nebulization
• bulking agent
• mannitol
• lactose
• aggregation
• crystallization
• stabilizing effect

Acknowledgements

The authors would like to acknowledge Dr. Ian M Riddington and Jordan Dinser for their assistance on the LC/MS and Michelle V Gadush for her assistance on the MALDI-TOF MS studies.

Disclosure statement

There is no conflict of interest.

Additional information

Funding

This study was supported in part by National Institutes of Health grants R01HL133067–01 and R21ES025815, and Flight Attendant Medical Research Institute Clinical Innovator Awards CIA150063 and CIA082380, and American Heart Association grant GRNT19020001.