Chimeric peptides for neuropeptide delivery through the blood-brain barrier

• US 4,801,575 A
• Filed: 07/30/1986
• Issued: 01/31/1989
• Est. Priority Date: 07/30/1986
• Status: Expired due to Term

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Pardridge, William M.
• Primary Examiner(s): Hazel, Blondel
• Application Number:
  US06/891,867
• Time in Patent Office: 916 Days
• Field of Search: 424/85, 514/2, 514/3.4, 530/395, 530/303, 530/302, 530/350, 530/362, 530/351, 530/311, 530/315, 530/323, 530/402
• US Class Current: 514/1.2
• 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 47/62 the modifying agent being a protein, peptide or polyamino acid
• CPC Class Codes: C07K 1/1075 by covalent attachment of amino acids or peptide residues
• CPC Class Codes: C07K 14/62 Insulins
• CPC Class Codes: C07K 14/655 Somatostatins
• CPC Class Codes: C07K 14/675 Beta-endorphins
• CPC Class Codes: C07K 14/695 Corticotropin [ACTH]
• CPC Class Codes: C07K 7/16 Oxytocins; Vasopressins; Related peptides
• CPC Class Codes: Y10S 930/15 Oxytocin or vasopressin; related peptides
• CPC Class Codes: Y10S 930/16 Somatostatin; related peptides
• CPC Class Codes: Y10S 930/26 Containing cys-cys disulfide bridge between nonadjacent cysteine residues

Abstract

Chimeric peptides adapted for delivering neuropharmaceutical agents, such as neuropeptides into the brain by receptor-mediated transcytosis through the blood-brain barrier. The chimeric peptides include a peptide which by itself is capable of crossing the blood-brain barrier by transcytosis at a relatively high rate. The transportable peptide is conjugated to a hydrophilic neuropeptide which by itself is transportable only at a very low rate into the brain across the blood-brain barrier. The resulting chimeric peptide is transported into the brain at a much higher rate than the neuropeptide alone to thereby provide an effective means for introducing hydrophilic neuropeptides into the brain through the blood-brain barrier.

Claims

1. A chimeric peptide adapted for delivering a neuropharmaceutical agent into the brain by transcytosis through the blood-brain barrier, said chimeric peptide comprising:

a transportable peptide capable of crossing the blood-brain barrier by transcytosis, said peptide being selected from the group consisting of insulin, transferrin, IGF-I, IGF-II, basic albumin and prolactin; and

a neuropharmaceutical agent selected from the group consisting of somatostatin, thyrotropin releasing hormone, vasopressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glutamyl-L-histidyl-L-phenylalanyl-D-lysyl-L-phenylalanine, wherein said neuropharmaceutical agent is conjugated with said transportable peptide.

2. A chimeric peptide according to claim 1 wherein said transportable peptide and neuropharmaceutical agent are conjugated via a conjugation agent.

3. A chimeric peptide according to claim 2 wherein said conjugation agent is capable of conjugating the transportable peptide to said neuropharmaceutical agent by peptide thiolation or lysine coupling via glutaraldehyde.

4. A chimeric peptide according to claim 3 wherein said transportable peptide is insulin.

5. A chimeric peptide according to claim 4 wherein said neuropharmaceutical agent is somatostatin.

6. A chimeric peptide according to claim 1 having the formula ##STR3## wherein A is said neuropharmaceutical agent and B is said transportable peptide.

7. A chimeric peptide according to claim 6 wherein A is somatostatin and B is insulin.

8. A composition comprising a chimeric peptide according to claim 1 and a pharmaceutically acceptable carrier for said chimeric peptide.

9. A composition according to claim 8 wherein said pharmaceutically acceptable carrier is sterile saline.

10. A method for delivering a neuropharmaceutical agent into the brain of an animal by transcytosis through the blood-brain barrier comprising the step of introducing a chimeric peptide into the bloodstream of said animal in a sufficient amount to provide transport of said chimeric peptide across said blood-brain barrier, wherein said chimeric peptide comprises a transportable peptide capable of crossing the blood-brain barrier conjugated with a neuropharmaceutical agent.

11. A method according to claim 10 wherein said chimeric peptide is introduced intra into the subject'"'"'s bloodstream.

13. A method according to claim 10 wherein said transportable peptide is selected from the group consisting of insulin, transferrin, IGF-I, IGF-II, basic albumin and prolactin.

14. A method according to claim 10 wherein said neuropharmaceutical agent is a hydrophilic peptide.

15. A method according to claim 14 wherein said neuropharmaceutical agent is selected from the group consisting of somatostatin, thyrotropin releasing hormone, vasopressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glutamyl-L-histidyl-L-phenylalanyl-D-lysyl-L-phenylalanine.

16. A method according to claim 10 wherein said transportable peptide and neuropharmaceutical agent are conjugated via a conjugation agent.

17. A method according to claim 16 wherein said conjugation agent is capable of conjugating the transportable peptide to said neuropharmaceutical agent by peptide thiolation or lysine coupling via glutaraldehyde.

18. A method according to claim 17 wherein said transportable peptide is insulin.

19. A method according to claim 18 wherein said neuropharmaceutical agent is somatostatin.

12. In a method for introducing a neuropharmaceutical agent into the brain across the blood-brain barrier, wherein the improvement comprises increasing the rate at which said neuropharmaceutical agent crosses the blood-brain barrier by conjugating said neuropharmaceutical agent with a transportable peptide capable of crossing the blood-brain carrier by transcytosis.