Electrolytic transdermal delivery of proteins

• US 4,940,456 A
• Filed: 12/01/1988
• Issued: 07/10/1990
• Est. Priority Date: 02/10/1987
• Status: Expired due to Term

• Current Assignee: Dan Sibalis, Sanford Rosen
• Original Assignee: Dan Sibalis, Sanford Rosen
• Inventors: Rosen, Sanford, Sibalis, Dan
• Primary Examiner(s): Pellegrino, Stephen C.
• Assistant Examiner(s): Lewis, Ralph
• Application Number:
  US07/279,315
• Time in Patent Office: 586 Days
• Field of Search: 604/20, 128/798, 128/802, 128/803, 424/447, 424/448, 424/449
• US Class Current: 604/20
• CPC Class Codes: A61K 9/0009 involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis microelectromechanical systems A61K9/0097
• CPC Class Codes: A61N 1/044 Shape of the electrode
• CPC Class Codes: A61N 1/0448 Drug reservoir

Abstract

A chemical composition for electrolytic transdermal transport of a protein to the blood stream of the patient comprises:

(a) a protein,

(b) a cosolvent with negative Setschenow constants, and

(c) water.

Some of the preferred proteins are: insulin, protamine sulfate, calcitonin, glucagon, and corticotropin. Some of the preferred dissociating agents with negative Setschenow constants are: urea, propylurea, potassium iodide, sodium perchlorate, and guanidine hydrochloride.

The electrolytic device containing the composition to be transdermally delivered comprises:

two electrode elements separated by barrier means,

a reservoir containing the composition of the invention,

an electronic/electrolytic circuit including a source of a power,

a cover, and

adhesive means holding the device to the patient'"'"'s skin.

A semipermeable membrane between the patient'"'"'s skin and the electrolytic device is optional.

Claims

1. A transdermal patch for delivering at least one protein drug to the bloodstream of the patient comprising:

a. at least one protein drug comprising at least one nonionic protein having more than 20 peptide units, water, and a water-destructuring agent with a negative Setschenow constant, contained in a drug reservoir, and

b. electrolytic means comprising a power source connected to at least one electrode in electrolytic contact with said reservoir for transdermal transport of the nonionic protein having a current density from about 0.5 microampere/cm² to about 10 milliampere/cm², impressed voltage between 1 and 40 volts, and a migratory water volume between 0.00I/ml/cm² hr and 0.0I ml/cm² /hr, whereby the skin of the patient is neither irritated nor erythematized.

2. A transdermal patch as in claim 1, wherein the at least one nonionic protein drug is an insulin.

3. A transdermal patch as in claim 1, wherein the current density is between 0.5 microampere/cm², the voltage is between 3 and 10 volts, and the migrating water volume is between 0.002 and 0.005 ml/cm² /hr.

4. A transdermal patch as in claim 1, wherein the water destructuring agent is selected from the group consisting of urea, alkylderivatives of urea, gaunidine salt, butanol, 2-butanol, water-soluble amides with more than three carbon atoms, sodium chloride, sodium acetate, sodium bromide, calcium chloride, sodium proprionate, sodium butyrate, sodium thiocyanate, potassium iodide, sodium perchlorate, sodium iodide, any water-soluble salt with a negative Setschenow constant, and mixtures thereof.

5. A transdermal patch as in claim 1, wherein the nonionic protein or the uncharged protein at its isoelectric point is selected from the group consisting of glucagon, protamines, adrenal cortex proteinaceous hormones, calcitonin, albumins, globulins, insulins, and mixtures

6. A transdermal patch as in claim 1, wherein the nonionic protein or the uncharged protein at its isoelectric point is a polypeptide having more than about 20 peptide units.

7. A transdermal patch as in claim 1, wherein the reservoir has a liquid volume of from about 0.01 ml to about 15 ml.

8. A transdermal patch as in claim I, further comprising a semipermeable membrane on the side of the reservoir adapted to be placed on the skin of the patient.