US2009275877A1PendingUtilityA1

Method of Enhancing Electrotransport Polypeptide Flux By Amino Acid Substitution with Histidine

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Assignee: ALZA CORPPriority: Jun 6, 1995Filed: Nov 27, 2007Published: Nov 5, 2009
Est. expiryJun 6, 2015(expired)· nominal 20-yr term from priority
Inventors:Leslie A. Holladay
C07K 1/1075A61K 9/0009C07K 1/107C07K 14/535C07K 14/60C07K 14/635
56
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Claims

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

exact text as granted — not AI-modified
1 - 16 . (canceled) 
     
     
         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.   
     
     
         18 . 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. 
     
     
         19 . 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. 
     
     
         20 . 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. 
     
     
         21 . The electrotransport device of  claim 17  wherein the synthetic analog has increased hydrophilicity relative to that of the parent polypeptide. 
     
     
         22 . 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. 
     
     
         23 . 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. 
     
     
         24 . 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. 
     
     
         25 . 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. 
     
     
         26 . The electrotransport device of  claim 17  wherein the transdermal flux of the synthetic analog is greater than that of the parent polypeptide. 
     
     
         27 . 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. 
     
     
         28 . The electrotransport device of  claim 17  wherein the current applied by the device is in the range of about 50 to 400 μA/cm 2 . 
     
     
         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.   
     
     
         30 . 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. 
     
     
         31 . 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. 
     
     
         32 . 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. 
     
     
         33 . The electrotransport device of  claim 29  wherein the synthetic analog has increased hydrophilicity relative to that of the parent hormone. 
     
     
         34 . 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. 
     
     
         35 . 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. 
     
     
         36 . 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. 
     
     
         37 . 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. 
     
     
         38 . The electrotransport device of  claim 29  wherein the transdermal flux of the synthetic analog is greater than that of the parent hormone. 
     
     
         39 . 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. 
     
     
         40 . The electrotransport device of  claim 29  wherein the current applied by the device is in the range of about 50 to 400 μA/cm 2 .

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