# US 2009/0275877 A1 · Method of Enhancing Electrotransport Polypeptide Flux By Amino Acid Substitution with Histidine

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- Number: US 2009/0275877 A1
- Document ID: US20090275877A1
- Status: Published application
- Kind: A1
- Application number: 11/945,536
- Filed: 2007-11-27
- Published: 2009-11-05
- Earliest claimed: 1995-06-06
- Assignees: Alza Corporation
- Inventors: Leslie A. Holladay
- Web page: https://patentgrep.com/patent/US20090275877A1

## CPC

- C07K 1/1075: {by covalent attachment of amino acids or peptide residues}
- C07K 1/107: by chemical modification of precursor peptides
- C07K 14/535: Granulocyte CSF; Granulocyte-macrophage CSF
- C07K 14/60: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
- C07K 14/635: Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
- A61K 9/0009: {involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis}
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

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.

## Claims

### Claim at position 1

1-16. (canceled)

### Claim 17

An electrotransport device for delivering a pharmaceutical polypeptide agent through a body surface, comprising:
a donor electrode assembly comprising a donor electrode and an agent reservoir, wherein the agent reservoir comprises a synthetic analog of a parent polypeptide in which at least one amino acid residue of the parent polypeptide has been replaced with a histidine residue;
a counter electrode assembly comprising a counter electrode and an electrolyte reservoir; and
an electrical power source, wherein the donor and counter electrode assemblies are electrically connected to the electrical power source.

### Claim 18 (depends on 17)

The electrotransport device of claim 17 wherein the one or more amino acid residues of the parent polypeptide that have been replaced with histidine residues are amino acid residues that have polar but uncharged side chains.

### Claim 19 (depends on 17)

The electrotransport device of claim 17 wherein the one or more amino acid residues of the parent polypeptide that have been replaced with histidine residues are glutamine, threonine, or asparagine residues.

### Claim 20 (depends on 19)

The electrotransport device of claim 19 wherein the one or more amino acid residues of the parent polypeptide that have been replaced with histidine residues are glutamine residues.

### Claim 21 (depends on 17)

The electrotransport device of claim 17 wherein the synthetic analog has increased hydrophilicity relative to that of the parent polypeptide.

### Claim 22 (depends on 17)

The electrotransport device of claim 17 wherein the synthetic analog and the parent polypeptide exhibit at least about the same type and amount of biological activity.

### Claim 23 (depends on 17)

The electrotransport device of claim 17 wherein the synthetic analog has a greater overall charge than that of the parent polypeptide at a pH of about 3.5 to 8.0.

### Claim 24 (depends on 17)

The electrotransport device of claim 17 wherein the synthetic analog has a greater positive charge than that of the parent polypeptide at a pH in the range of about 5.0 to 6.0.

### Claim 25 (depends on 17)

The electrotransport device of claim 17 wherein the overall charge of the synthetic analog is positive at a pH in the range of about 5.0 to 6.0 but is substantially isoelectric at a pH of 7.4.

### Claim 26 (depends on 17)

The electrotransport device of claim 17 wherein the transdermal flux of the synthetic analog is greater than that of the parent polypeptide.

### Claim 27 (depends on 26)

The electrotransport device of claim 26 wherein the transdermal flux of the synthetic analog is at least about 20% greater than that of the parent polypeptide.

### Claim 28 (depends on 17)

The electrotransport device of claim 17 wherein the current applied by the device is in the range of about 50 to 400 μA/cm2.

### Claim 29

An electrotransport device for delivering a hormone through a body surface, comprising:
a donor electrode assembly comprising a donor electrode and an agent reservoir, wherein the agent reservoir comprises a synthetic analog of a parent hormone in which at least one amino acid residue of the parent hormone has been replaced with a histidine residue;
a counter electrode assembly comprising a counter electrode and an electrolyte reservoir; and
an electrical power source, wherein the donor and counter electrode assemblies are electrically connected to the electrical power source.

### Claim 30 (depends on 29)

The electrotransport device of claim 29 wherein the one or more amino acid residues of the parent hormone that have been replaced with histidine residues are amino acid residues that have polar but uncharged side chains.

### Claim 31 (depends on 29)

The electrotransport device of claim 29 wherein the one or more amino acid residues of the parent hormone that have been replaced with histidine residues are glutamine, threonine, or asparagine residues.

### Claim 32 (depends on 31)

The electrotransport device of claim 31 wherein the one or more amino acid residues of the parent hormone that have been replaced with histidine residues are glutamine residues.

### Claim 33 (depends on 29)

The electrotransport device of claim 29 wherein the synthetic analog has increased hydrophilicity relative to that of the parent hormone.

### Claim 34 (depends on 29)

The electrotransport device of claim 29 wherein the synthetic analog and the parent hormone exhibit at least about the same type and amount of biological activity.

### Claim 35 (depends on 29)

The electrotransport device of claim 29 wherein the synthetic analog has a greater overall charge than that of the parent hormone at a pH of about 3.5 to 8.0.

### Claim 36 (depends on 29)

The electrotransport device of claim 29 wherein the synthetic analog has a greater positive charge than that of the parent hormone at a pH in the range of about 5.0 to 6.0.

### Claim 37 (depends on 29)

The electrotransport device of claim 29 wherein the overall charge of the synthetic analog is positive at a pH in the range of about 5.0 to 6.0 but is substantially isoelectric at a pH of 7.4.

### Claim 38 (depends on 29)

The electrotransport device of claim 29 wherein the transdermal flux of the synthetic analog is greater than that of the parent hormone.

### Claim 39 (depends on 38)

The electrotransport device of claim 38 wherein the transdermal flux of the synthetic analog is at least about 20% greater than that of the parent hormone.

### Claim 40 (depends on 29)

The electrotransport device of claim 29 wherein the current applied by the device is in the range of about 50 to 400 μA/cm2.