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

a polypeptide and electrotransport technology, applied in the direction of peptide sources, parathyroid hormones, therapy, etc., can solve the problems of inconvenient treatment regimen, inability to achieve therapeutic effects, and low transdermal diffusion flux,

Inactive Publication Date: 2009-11-05
ALZA CORP
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention relates to improving the electrotransport drug delivery of polypeptides and proteins through the skin by replacing certain amino acids in the polypeptides with certain amino acids to enhance the flux of drugs through the skin. This method involves replacing certain amino acids in the polypeptides with other amino acids that have higher electrotransport flux. The technical effect of this invention is to improve the effectiveness of transdermal electrotransport drug delivery for polypeptides and proteins.

Problems solved by technology

Unfortunately, many drugs exhibit transdermal diffusion fluxes which are too low to be therapeutically effective.
Polypeptides and proteins are, however, inherently short acting in their biological activity, requiring frequent injections, often several times a day, to maintain the therapeutically effective levels needed.
Patients frequently find this treatment regimen to be inconvenient, painful and with an attendant risk of, e.g., infection.
Unfortunately to date, these alternative routes of polypeptide / protein delivery have met with only limited success.
Electrotransport delivery of polypeptides and proteins has also encountered technical difficulties.
Unfortunately, many polypeptides and proteins are unstable (i.e., they become hydrolyzed, oxidized, denatured or otherwise degraded) in the presence of water.
In addition, certain polypeptides / proteins, particularly those that are not native to the animal being treated, may cause skin reactions, e.g., sensitization or irritation.

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

example 1

hg-CSF Analog

[0061]Human G-CSF (hG-CSF) is a pharmaceutical protein used to treat patients recovering from chemotherapy. It is also used as an adjunct therapy for treating bacterial infections. An analog of G-CSF is prepared according to the known and conventional methods described hereinbefore in which glutamine residues at positions 107, 119, 120, 131, 134, 145, 158 and 173 are replaced with histidine residues (SEQ ID NO:4). This analog has a net charge at pH 6 of close to +4.

[0062]An anodic donor reservoir is prepared comprising an aqueous solution of the G-CSF analog in a hydroxyethyl cellulose (HEC) hydrogel matrix. The formulation contains 5 mg / mL hG-CSF analog in 5 mM pH 6 histidine buffer in a 3% HEC hydrogel containing 1% glycerol.

[0063]The hG-CSF analog-containing donor reservoir is used in an electrotransport delivery device. The delivery device includes a silver foil anodic electrode placed on one surface of the donor reservoir, and a silver chloride counter-electrode pl...

example 2

h-PTH Analog

[0065]Human parathyroid hormone (h-PTH) is a pharmaceutical polypeptide used to treat osteoporosis. An example of an analog of h-PTH is one in which the glutamine residue at position 29 is replaced by histidine to increase the net charge by about +1 at pH 5. Replacement of the glutamine residue at position 29.6 retains the approximate biological activity of the parent compound (SEQ ID NO:7).

[0066]An anodic donor reservoir is prepared comprising an aqueous solution of the h-PTH analog in an HEC hydrogel matrix. The formulation contains 10 mg / mL PTH analog in 5 mM pH 5 acetate buffer in a 3% HEC hydrogel containing 1% glycerol.

[0067]The h-PTH analog-containing donor reservoir is used in a device similar to that described in Example 1 hereinbefore except that the electrotransport current generating and control circuit operates in one of two modes. The first mode is a continuous delivery mode as described in Example 1, and the second is an intermittent delivery mode wherein ...

example 3

h-GHRH Analog

[0069]Human GHRH (h-GHRH) is used to treat growth deficient (i.e., short) children and frail elderly adult patients. An analog of h-GHRH is prepared in which the glutaminyl residues at positions 16, 24, 30 and 31 are replaced by histidyl residues (SEQ ID NO:10). Such an analog would have the net charge increased by about +4 at pH 5.

[0070]An anodic donor reservoir is prepared comprising an aqueous solution of the h-GHRH analog in an HEC hydrogel matrix. The formulation contains 4 mg / mL h-GHRH analog in 5 mM pH 5 acetate buffer in 3% HEC hydrogel containing 1% glycerol.

[0071]The h-GHRH analog-containing donor reservoir is used in a device as described in Example 1. The device is placed on a patient's skin and delivers h-GHRH analog continuously over the 24-hour wearing period.

[0072]Blood samples are collected and analyzed as described in Example 1, and the results show improved electrotransport and plasma levels compared to unmodified h-GHRH.

[0073]In summary, the substitu...

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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.

Description

TECHNICAL FIELD[0001]The invention relates generally to electrotransport drug delivery, and more particularly to transdermal electrotransport drug delivery. Specifically, the invention relates to a method of improving electrotransport flux of polypeptide drugs by replacing certain amino acids in the polypeptide.BACKGROUND OF THE INVENTION[0002]Transdermal (i.e., through the skin) delivery of therapeutic agents (e.g., drugs) is an important medicament administration route. Transdermal drug delivery bypasses gastrointestinal degradation and hepatic metabolism. Most commercial transdermal drug delivery systems (e.g., nitroglycerin, scopolamine, estradiol, testosterone skin patches) deliver drug by passive diffusion. The drug diffuses from a reservoir in the patch into the skin of the patient by means of the concentration gradient which exists, i.e., the drug diffuses from the high concentration in the patch reservoir to the low concentration in the patient's body. The flux of drug thro...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61N1/30A61K38/00A61K9/00C07K1/107C07K14/47C07K14/535C07K14/60C07K14/635
CPCA61K9/0009C07K1/107C07K14/635C07K14/535C07K14/60C07K1/1075
Inventor HOLLADAY, LESLIE A.
Owner ALZA CORP
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