For reducing aggregation or immunogenicity of peptide or polypeptide including an alkylglycoside, especially dodecyl maltoside, tridecyl maltoside, sucrose monododecanoate, sucrose monotridecanoate, or sucrose monotetradecanoate; treatment of obesity
Inventors
Assignees
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Publication Number
US-7998927-B2
Publication Date
2011-08-16
Expiration Date
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 glucagon-like peptide-1 (GLP-1) or an analog thereof.
Core Innovation
The invention relates to alkylglycoside/saccharide-alkyl ester surfactant compositions for stabilizing glucagon-like peptide-1 (GLP-1) and analogs, including pharmaceutical compositions and methods that increase stability. The disclosed compositions use at least one alkylglycoside stabilizing agent, exemplified by dodecyl-β-D-maltoside, and are formulated to address instability problems of aggregation and fibril formation.
The invention further addresses a background problem of protein aggregation and the related formation of fibrils and self-associating peptide/protein species during pharmaceutical manufacturing and concentration stresses. The disclosed formulations are designed to reduce aggregation and fibrillar formation, and to reduce immunogenicity associated with administering GLP-1 or an analog.
A key aspect described is that specific alkylglycoside surfactants stabilize GLP-1/analogs while meeting an insulin-free requirement, and that biological activity is preserved. The disclosure includes discussion that β-anomer purity is relevant, with β-anomer-enriched surfactants being associated with improved stabilization compared with α-anomer contamination.
The document also describes stability characterization and formulation routes, including characterization using light scattering, and formulation examples such as injectable/lyophilized/spray routes. For manufacturing, non-aggregated aqueous solutions are prepared by admixing an alkylglycoside surfactant with an aqueous solution comprising GLP-1 or an analog and then concentrating the composition.
Claims Coverage
The partial content includes four independent claims that cover using dodecyl-β-D-maltoside or specified β-anomer alkylglycosides to increase stability, reduce aggregation, reduce immunogenicity, and manufacture non-aggregated aqueous GLP-1 solutions.
Insulin-free GLP-1 stabilizing composition comprising alkylglycoside
A pharmaceutical composition for increasing the stability, reducing aggregation or reducing immunogenicity of glucagon-like peptide-1 (GLP-1) or an analog thereof comprising glucagon-like peptide-1 (GLP-1) or the analog thereof, and a stabilizing agent comprising at least one alkylglycoside, wherein the alkylglycoside is dodecyl-β-D-maltoside, with the proviso that the composition is insulin free.
Admixing GLP-1 with alkylglycoside surfactant to increase stability
A method for increasing the stability of a glucagon-like peptide-1 (GLP-1) or an analog thereof comprising admixing the glucagon-like peptide-1 (GLP-1) or the analog thereof and a stabilizing agent to form a composition, wherein the stabilizing agent is at least one alkylglycoside surfactant, thereby increasing the stability of the glucagon-like peptide-1 (GLP-1) or the analog thereof, and wherein the alkylglycoside is dodecyl-β-D-maltoside, with the proviso that the composition is insulin free.
Admixing GLP-1 with alkylglycoside aggregation reducing agent
A method for reducing aggregation of a glucagon-like peptide-1 (GLP-1) or analog thereof comprising admixing the glucagon-like peptide-1 (GLP-1) or analog thereof and an aggregation reducing agent to form a composition, wherein the aggregation reducing agent is at least one alkylglycoside surfactant, thereby reducing aggregation of the glucagon-like peptide-1 (GLP-1) or analog thereof, and wherein the alkylglycoside is dodecyl-β-D-maltoside, with the proviso that the composition is insulin free.
Reducing immunogenicity with β-anomer alkylglycoside surfactant and antibody determination
A method for reducing immunogenicity of a glucagon-like peptide-1 (GLP-1) or an analog thereof upon administration to a vertebrate, comprising admixing the glucagon-like peptide-1 (GLP-1) or the analog thereof with an agent to form a composition, wherein the agent is at least one alkylglycoside surfactant, wherein the surfactant reduces immunogenicity upon administration of the glucagon-like peptide-1 (GLP-1) or the analog thereof, wherein the alkylglycoside is a β-anomer of dodecyl maltoside, tridecyl maltoside, tetradecyl maltoside, sucrose mono-dodecanoate, sucrose mono-tridecanoate, or sucrose mono-tetradecanoate, and wherein the reduced immunogenicity of the composition is determined by injecting the composition into a suitable vertebrate host, waiting a suitable time to allow an immune response to develop, and determining the presence or absence of antibody in the host blood or plasma.
Manufacturing non-aggregated aqueous GLP-1 solutions by admixing alkylglycoside and concentrating
A method of manufacturing non-aggregated aqueous solutions of a glucagon-like peptide-1 (GLP-1) or an analog thereof comprising admixing at least one alkylglycoside surfactant with an aqueous solution comprising the glucagon-like peptide-1 (GLP-1) or the analog thereof to form a composition and concentrating the composition, wherein the alkylglycoside is dodecyl-β-D-maltoside.
Across the independent claims, the claim coverage centers on using dodecyl-β-D-maltoside or specified β-anomer alkylglycosides to increase stability, reduce aggregation and immunogenicity of GLP-1 or analogs, with an insulin-free requirement for the composition and stability/aggregation claims, and a separate manufacturing claim for preparing non-aggregated aqueous GLP-1 solutions.
Stated Advantages
Increase stability of glucagon-like peptide-1 (GLP-1) or an analog thereof.
Reduce aggregation of glucagon-like peptide-1 (GLP-1) or an analog thereof.
Reduce immunogenicity of glucagon-like peptide-1 (GLP-1) or an analog thereof upon administration to a vertebrate.
Increase and preserve biological activity associated with the stabilized composition, including retention after reconstitution as described in dependent claims.
Provide non-aggregated aqueous solutions of glucagon-like peptide-1 (GLP-1) or an analog thereof.
Documented Applications
Pharmaceutical compositions and methods for increasing the stability of glucagon-like peptide-1 (GLP-1) or an analog thereof using an insulin-free alkylglycoside stabilizing agent.
Methods for reducing aggregation of glucagon-like peptide-1 (GLP-1) or analog thereof by admixing with an alkylglycoside aggregation reducing agent.
Methods for reducing immunogenicity of glucagon-like peptide-1 (GLP-1) or an analog upon administration to a vertebrate by using β-anomer alkylglycosides and determining antibody presence or absence in host blood or plasma.
Methods of manufacturing non-aggregated aqueous solutions of glucagon-like peptide-1 (GLP-1) or an analog thereof by admixing alkylglycoside surfactant with an aqueous solution and concentrating the composition.
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