Method for increasing the electrotransport flux of polypeptides

• US 5,747,453 A
• Filed: 06/06/1995
• Issued: 05/05/1998
• Est. Priority Date: 06/06/1995
• Status: Expired due to Term

• Current Assignee: ALZA Corporation (Johnson & Johnson)
• Original Assignee: ALZA Corporation (Johnson & Johnson)
• Inventors: Oldenburg, Kevin R., Holladay, Leslie A.
• Primary Examiner(s): Tsang, Cecilia J.
• Assistant Examiner(s): HARLE, JENNIFER I
• Application Number:
  US08/468,275
• Time in Patent Office: 1,064 Days
• Field of Search: 514/12, 514/13, 514/14, 514/21, 604/20, 530/325, 530/324, 530/326, 530/327
• US Class Current: 514/11.8
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• 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 1/30 Apparatus for iontophoresis, i.e. transfer of media in ionic state by an electromotoric force into the body, or cataphoresis
• CPC Class Codes: C07K 1/107 by chemical modification of precursor peptides
• CPC Class Codes: C07K 14/635 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: C07K 14/815 from leeches, e.g. hirudin, eglin

Abstract

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 α-helical or β-sheet segments. In particular, amino acid residues known to stabilize α-helical and β-sheet segments can be replaced with destabilizing residues and known helix breakers. Modified molecules and compositions including the molecules are also provided.

Claims

1. A method of delivering an agent through a body surface by electrotransport comprising the steps of:

providing a bioactive polypeptide analog having 10-50 amino acid residues and at least one substituted amino acid residue having a lower Pα

value disrupting at least one α

-helical segment; and

,

delivering said polypeptide analog through the body surface with an electrotransport device.

2. The method of claim 1, wherein the substituted amino acid residue is a member selected from the group consisting of Pro, Gly and Asn and wherein the polypeptide analog has 10-40 amino acid residues.

3. The method of claim 1, wherein said parent polypeptide is a parathyroid hormone molecule, Seq. Id. No. 6.

4. The method of claim 3, wherein said polypeptide analog is parathyroid hormone analog 1, Seq. Id. No. 7.

5. The method of claim 3, wherein said polypeptide analog is parathyroid hormone analog 2, Seq. Id. No. 8.

6. The method of claim 1, wherein said parent polypeptide is hirulog as depicted in FIG. 2A.

7. The method of claim 6, wherein said polypeptide analog is hirulog-B2 as depicted in FIG. 2C.

8. A parathyroid hormone (PTH) analog comprising the amino acid sequence depicted in FIG. 1B.

9. A parathyroid hormone (PTH) analog comprising the amino acid sequence depicted in FIG. 1C.

10. A method of delivering an agent through a body surface by electrotransport comprising the steps of:

providing a bioactive polypeptide analog having 10-50 amino acid residues and at least one substituted amino acid residue having a lower Pβ

value disrupting at least one β

-sheet segment; and

, delivering said polypeptide analog through the body surface with an electrotransport device.

11. The method of claim 10, wherein the substituted amino acid residue is a member selected from the group consisting of Pro, Gly and Asp and wherein the polypeptide analog has 10-40 amino acid residues.

12. The method of claim 10, wherein said parent polypeptide is a parathyroid hormone molecule, Seq. Id. No. 6.

13. The method of claim 12, wherein said polypeptide analog is parathyroid hormone analog 1, Seq. Id. No. 7.

14. The method of claim 12, wherein said polypeptide analog is parathyroid hormone analog 2, Seq. Id. No. 8.

15. The method of claim 10, wherein said parent polypeptide is PTH analog 2, Seq. Id. No. 9.

16. The method of claim 15, wherein said polypeptide analog is hirulog-B2, Seq. Id. No. 11.