Chimeric peptides for neuropeptide delivery through the blood-brain barrier

• US 4,902,505 A
• Filed: 04/25/1988
• Issued: 02/20/1990
• Est. Priority Date: 07/30/1986
• Status: Expired due to Fees

• Current Assignee: Alkermes A Corporation PA, Regents of the University of California (University of California)
• Original Assignee: Alkermes Pharma Ireland Limited (Alkermes plc), Regents of the University of California (University of California)
• Inventors: Pardridge, William M., Schimmel, Paul R.
• Primary Examiner(s): Hazel, Blondel
• Application Number:
  US07/185,702
• Time in Patent Office: 666 Days
• Field of Search: 424/85.7, 514/4, 514/2, 514/3, 530/302, 530/303, 530/395, 530/350, 530/351, 530/311, 530/315, 530/323, 530/402
• US Class Current: 424/85.7
• 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: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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

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 conjugated with said neuropharmaceutical agent, wherein said transportable peptide is histone.

2. A chimeric peptide according to claim 1 wherein said histone is isolated from a human source.

3. A chimeric peptide according to claim 1 wherein said histone is selected from a class I-V type of histone.

4. A chimeric peptide according to claim 2 wherein said histone is selected from a class I-V type of histone.

5. A chimeric peptide according to claim 1 wherein said neuropharmaceutical agent is a hydrophilic peptide.

6. A chimeric peptide according to claim 5 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-glytamyl-L-histidyl-L-phenylalanyl-D-lysyl-L-phenylalanine.

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

8. A chimeric peptide according to claim 1 wherein said conjugation agent is capable of conjugating the transportable peptide to said neuropharmaceutical agent by peptide thiolation or lysine coupling via glutaraldehyde.

9. A chimeric peptide according to claim 1 having the formula ##STR3## wherein A is a neuropharmaceutical agent and B is histone.

10. A chimeric peptide according to claim 9 wherein A is selected from the group consisting of somatostatin, thyrotropin releasing hormone, vasopressin, alpha interferon, endorphin, muramyl dipeptide and L-methionyl(sulfone)-L-glytamyl-L-histidyl-L-phenyl-alanyl-D-lysyl-L-phenylalanine.

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

12. A composition according to claim 11 wherein said pharmaceutically acceptable carrier is sterile saline.

13. 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 according to claim 1 into the bloodstream of said animal in a sufficient amount to provide transport of said chimeric peptide across said blood-brain barrier.

14. A method according to claim 13 wherein said chimeric peptide is introduced intranasally into the subject'"'"'s bloodstream.

15. In a method for introducing a hydrophilic neuropeptide into the brain across the blood-brain barrier, wherein the improvement comprises increasing the rate at which said neuropeptide crosses the blood-brain barrier by conjugating said neuropeptide with histone.

16. The improved method according to claim 15 wherein said histone is isolated from a human source.

17. The improved method according to claim 15 wherein said histone is selected from a class I-V type of histone.

18. The improved method according to claim 16 wherein said histone is selected from a class I-V type of histone.