Stabilizing alkylglycoside compositions and methods thereof

Inventors

Maggio, Edward T.

Assignees

Aegis Therapeutics LLC

Abstract

The present invention relates to alkylglycoside-containing compositions and methods for increasing the stability, reducing the aggregation and immunogenicity, increasing the biological activity, and reducing or preventing fibrillar formation of a peptide, polypeptide, or analog thereof, for example parathyroid hormone (PTH) or PTH analogs, amylin, insulin, Peptide T or analog thereof, gastrin, gastrin releasing peptides, gastrin releasing peptide-like (GRP) proteins, epidermal growth factor or analog thereof.

Core Innovation

The disclosure describes pharmaceutical compositions comprising parathyroid hormone (PTH) or an analog thereof and a stabilizing agent comprising at least one alkylglycoside. The alkylglycoside is selected from dodecyl-β-D-maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, and sucrose mono-tetradecanoate. The compositions are described for increasing stability of PTH or an analog thereof, reducing aggregation, and reducing immunogenicity.

The background problem addressed is that therapeutic peptides/proteins such as PTH and PTH analogs can undergo aggregation and fibril formation, which can also be associated with reduced biological activity and/or increased immunogenicity. The disclosure links the described alkylglycoside stabilizers to decreased aggregation, decreased fibril formation, and decreased immunogenicity while preserving or increasing biological activity of the therapeutic peptide/protein.

The disclosure further characterizes stabilization behavior for alkylglycosides, including that alkylglycosides exhibit low critical micelle concentration and that stability decreases with α-anomer contamination rather than β-anomer forms. Formulation options described include lyophilized formats and reconstitution outcomes, including retention of biological activity after reconstitution, alongside related formulation elements for delivery contexts.

In addition, the disclosure discusses fibril suppression/disruption approaches using trifluoroethanol (TFE) and HFIP, and describes properties of D-Ala-Peptide T (DAPTA) fibril formation as being concentration/temperature-dependent and biologically inactive when fibril forms are present. Documented evaluation includes in vivo/in vitro assessments such as ELISA anti-insulin antibodies in rats and measurement approaches for aggregation and instability across proteins using light scattering (including Rayleigh scattering).

Claims Coverage

The partial content includes two independent claims, one directed to a pharmaceutical composition and one directed to a method for increasing stability of PTH or a PTH analog. Each independent claim centers on alkylglycoside surfactants selected from a specified list, and each claim identifies the intended outcome of increasing stability.

Across the independent claims, the main inventive coverage is the use of specified alkylglycoside surfactants as stabilizing agents in a pharmaceutical composition (and, for the method claim, together with a buffering agent) to increase stability of PTH or a PTH analog, with the composition claim also expressly targeting reducing aggregation or reducing immunogenicity.

Stated Advantages

Documented Applications