Conjugate based systems for controlled drug delivery
Inventors
Zion, Todd C. • Lancaster, Thomas M.
Assignees
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Publication Number
US-9265838-B2
Publication Date
2016-02-23
Expiration Date
Abstract
Conjugates which comprise a drug and a ligand which includes a first saccharide; wherein the conjugate is characterized in that, when the conjugate is administered to a mammal, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a second saccharide. Exemplary conjugates and sustained release formulations are provided in addition to methods of use and preparation.
Core Innovation
The invention relates to an insulin conjugate comprising an insulin molecule conjugated to one or more ligands, wherein at least one ligand comprises aminoethylfucose (AEF). The conjugate is characterized such that, when administered to a mammal in the absence of an exogenous multivalent saccharide-binding molecule, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a saccharide.
The disclosed insulin conjugates include insulin variants and insulin mutants, with insulin defined to include wild-type or modified insulin molecules. The document describes specific insulin conjugation attachment sites, including A1 amino acid residue, B1 amino acid residue, and the epsilon-amino groups of Lys B29, Lys B28, and Lys B3, together with general conjugate framework formulae and parameterized structural definitions.
The document also describes conjugate architectures using general formulas, including representative chemical structures and variable framework parameters governing branching, substitution patterns, and ligand or drug attachment. In addition, long-acting formulation and glucose-responsive pharmacokinetic/pharmacodynamic behavior are described in the context of sustained release and serum insulin or conjugate measurements.
Claims Coverage
The claim coverage centers on an insulin-ligand conjugate containing at least one AEF ligand and having a pharmacokinetic or pharmacodynamic property sensitive to serum saccharide concentration when no exogenous multivalent saccharide-binding molecule is administered. Five inventive features are directly supported across the items, with further refinements for insulin attachment sites, structural framework definitions, sustained-release formulation, and hyperglycemia treatment.
Insulin conjugate with AEF and serum saccharide sensitivity
A conjugate comprising an insulin molecule conjugated to one or more ligands wherein at least one ligand comprises aminoethylfucose (AEF), characterized such that when the conjugate is administered to a mammal in the absence of an exogenous multivalent saccharide-binding molecule, at least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a saccharide.
Insulin conjugation through defined attachment sites
The insulin molecule is conjugated through A1 amino acid residue or B1 amino acid residue or through the epsilon-amino groups of Lys B29, Lys B28, or Lys B3.
Parameterized conjugate architecture
The conjugate is defined by general formulae and constrained integer parameters, with variable substituents and regions for saccharide-containing ligand and drug-containing moiety, and with at least one ligand comprising aminoethylfucose (AEF).
Sustained-release formulation including the AEF-insulin conjugate
A sustained-release formulation that includes the claimed insulin conjugate.
Treatment of hyperglycemia by administering the formulation
A method for treating hyperglycemia by administering a specified formulation to a mammalian patient who needs it.
Overall, the claims are directed to an AEF-containing insulin conjugate whose pharmacokinetic or pharmacodynamic property is sensitive to serum saccharide concentration without an exogenous multivalent saccharide-binding molecule, with dependent and related coverage specifying attachment sites, parameterized structural frameworks, sustained-release formulation, and hyperglycemia treatment.
Stated Advantages
Lectin-free saccharide-responsive behavior where pharmacokinetic or pharmacodynamic properties are sensitive to serum saccharide concentration without administering an exogenous multivalent saccharide-binding molecule.
Improved differentiation of pharmacokinetic or pharmacodynamic behavior under fasted versus hyperglycemic conditions.
At least one pharmacokinetic or pharmacodynamic property of the conjugate is sensitive to serum concentration of a saccharide when no exogenous multivalent saccharide-binding molecule is administered.
Documented Applications
Treating hyperglycemia in a mammalian patient by administering a formulation that includes the claimed conjugate or sustained-release formulation.
Use of a sustained-release formulation including the conjugate.
Long-acting formulation and testing framed around glucose-responsive pharmacokinetic/pharmacodynamic behavior following glucose challenge, using serum insulin or conjugate measurements.
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