Alza Corporation

Leslie A Holladay

Kevin R Oldenburg

Jeremy C Wright

Judy A Magruder

James B Eckenhoff, Deceased

John P Carr

John J Leonard, Jr

Sally A Tao

Iris K Leung

Lynda G Treat-Clemons

Patricia Margaret Bassett

Methods of modifying polypeptide drugs in order to enhance their transdermal electrotransport flux are provided. The polypeptide is modified by substituting a histidine residue (His) for one or more glutamine (Gln), threonine (Thr) and/or asparagine (Asn) residue(s). The His for Gln substitution is particularly preferred from the standpoint of retaining biological activity of the parent polypeptide. Compositions containing the modified polypeptide, which are useful for transdermal electrotransport delivery, are also provided.

Method of enchancing electrontransport polypeptide flux by amino acid substitution with histidine

Method of making an electrotransport device containing an analog of a parent polypeptide having one or more amino acid residues substituted relative to the parent polypeptide with an amino acid residue selected from the group consisting of proline, glycine and asparagine.

Method of making an electrotransport device

An electrotransport device (,) for the electrotransport delivery of agents having at least one hydrophobic site thereon, such as peptides and proteins, contains donor and counter electrodes (,and,), a power source and electrical control circuitry (,). The donor electrode (,) contains, in addition to the agent, an electrotransport enhancer such as non-ionic surfactants or zwitterionic surfactants without a net charge. A method of increasing electrotransport flux of agent shaving at least one hydrophobic site thereon utilizes non-ionic or zwitterionic surfactants in the solution or suspension containing the agent. A method for the electrotransport delivery of an agent with at least one hydrophobic site through a body surface relies on the incorporation of a non-ionic surfactant or a zwitterionic surfactant without a net charge, into the solution or suspension containing the agent to decrease its hydrophobicity.

Composition and method for enhancing electrotransport agent delivery

Methods for modifying polypeptide agents to enhance their transdermal electrotransport flux are provided. The polypeptide is modified by reducing the potential of the polypeptide for forming &agr;-helical or &bgr;-sheet segments. In particular, amino acid residues known to stabilize &agr;-helical and &bgr;-sheet segments can be replaced with destabilizing residues and known helix breakers. Modified molecules and compositions including the molecules are also provided.

Method for increasing the electrotransport flux of polypeptides

The present invention provides improved compositions for improving the chemical and physical stability of peptides and proteins. The invention provides a liquid beneficial agent formulation containing a liquid suspension comprising at least 5% by weight beneficial agent and having a viscosity and beneficial agent size which minimizes settling of the agent in suspension over the extended delivery period.

Peptide/protein suspending formulations

Methods for modifying polypeptide agents to enhance their transdermal electrotransport flux are provided. The polypeptide is modified by reducing the potential of the polypeptide for forming .alpha.-helical or .beta.-sheet segments. In particular, amino acid residues known to stabilize .alpha.-helical and .beta.-sheet segments can be replaced with destabilizing residues and known helix breakers. Modified molecules and compositions including the molecules are also provided.

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Mountain View, CA, United States of America

Leslie A Holladay