Methods and compositions for treating pain

• US 9,233,159 B2
• Filed: 10/24/2012
• Issued: 01/12/2016
• Est. Priority Date: 10/24/2011
• Status: Active Grant

• Current Assignee: Mannkind Corporation, Torrey Pines Institute for Molecular Studies, Torrey Pines Institute Of Molecular Studies
• Original Assignee: Mannkind Corporation, Torrey Pines Institute for Molecular Studies
• Inventors: Leone-Bay, Andrea, Houghten, Richard A., Guarneri, Joseph J., Stowell, Grayson W.
• Primary Examiner(s): Ha, Julie
• Application Number:
  US14/354,092
• Publication Number:
  US 20140302151A1
• Time in Patent Office: 1,175 Days
• Field of Search: 514/10.7, 514/18.4, 424/489
• US Class Current: 1/1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/401 Proline; Derivatives thereof, e.g. captopril
• CPC Class Codes: A61K 31/405 Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
• CPC Class Codes: A61K 31/495 having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazinesA61K31/48 takes precedence ; with three nitrogen atoms A61K31/53
• CPC Class Codes: A61K 38/04 Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof enzyme inhibitors A61K38/005; gastrins A61K38/2207, somatostatins A61K38/31, melanotropins A61K38/34 ; protease inhibitors A61K38/55
• CPC Class Codes: A61K 38/07 Tetrapeptides
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 9/0075 for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
• CPC Class Codes: A61K 9/14 Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: C07K 5/10 Tetrapeptides
• CPC Class Codes: C07K 5/1016 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

Methods and compositions for treating pain are disclosed. The compositions are based on dry powders comprising microparticles of diketopiperazines and an analgesic active agent. The analgesic in the compositions comprises one or more peptide analgesics or derivatives thereof, which are administered to a subject using a pulmonary inhalation drug delivery system comprising a dry powder inhaler and the analgesic composition. The present compositions produce fewer side effects associated with current opioid therapy.

Claims

1. An inhalable, analgesic composition comprising microparticles of a diketopiperazine and a peptide comprising less than 20 amino acids;

wherein said composition is effective at relieving pain, wherein the peptide is an opioid receptor agonist.

2. The inhalable analgesic composition of claim 1, wherein the peptide comprises at least three amino acids independently selected from arginine, phenylalanine, leucine, isoleucine, norleucine, tyrosine, serine, proline, and tryptophan.

3. The inhalable analgesic composition of claim 2, wherein the peptide is an amino acid sequence of from three to eight amino acids in length.

4. The inhalable analgesic composition of claim 3, wherein the peptide is a four amino acid sequence and the composition is for pulmonary administration.

5. The inhalable analgesic composition of claim 3, wherein the peptide comprises:

(D)Phe-(D)Phe-(D)Ile-(D)Arg-NH₂ (SEQ ID NO;

     1) or (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂ (SEQ ID NO;

     2).

6. The inhalable analgesic composition of claim 1, wherein the peptide binds to a μ

opioid receptor, a δ

opioid receptor, or a κ

opioid receptor, or combinations of receptors thereof, on cells in the central or peripheral nervous systems.

7. The inhalable analgesic composition of claim 1, wherein the peptide is a κ

opioid receptor agonist.

8. The inhalable analgesic composition of claim 1, wherein the composition comprises a dry powder, and the peptide comprises at least 0.25% of the weight of the composition.

9. The inhalable analgesic composition of claim 1, wherein the composition comprises a dry powder for inhalation and comprises microparticles having a volumetric mean geometric diameter less than 8 μ

m in diameter.

10. The inhalable analgesic composition of claim 1, wherein the diketopiperazine is an N-substituted-3,6-aminoalkyl-2,5-diketopiperazine.

11. The inhalable analgesic composition of claim 10, wherein the diketopiperazine is 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine, or 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine disodium salt.

12. The inhalable analgesic composition of claim 1, wherein the diketopiperazine is 3,6-bis(N-X-4-aminobutyl)-2,5-diketopiperazine, wherein X is fumaryl, succinyl, glutaryl, maleyl, malonyl, oxalyl, or a pharmaceutically acceptable salt thereof.

13. The inhalable analgesic composition of claim 1, further comprising one or more pharmaceutical carrier or excipients selected from amino acids, sugars and surfactants.

14. The inhalable analgesic composition of claim 13, wherein the amino acids comprise at least one of leucine, isoleucine, glycine and methionine.

15. The inhalable analgesic composition of claim 13, wherein the sugars comprise at least one of mannitol, lactose, trehalose and raffinose.

16. A dry powder for pulmonary inhalation comprising the inhalable analgesic composition of claim 11.

17. A method for treating pain, comprising administering to a subject in need of treatment a therapeutically effective amount of an inhalable analgesic composition comprising microparticles of a diketopiperazine and a peptide comprising less than 20 amino acids using a dry powder drug delivery system, wherein the peptide is an opioid receptor agonist.

18. The method of claim 17, wherein the dry powder drug delivery system comprises a dry powder inhaler configured with a container to hold said inhalable analgesic composition in a containment configuration and in a dosing configuration.

19. The method of claim 17, wherein the inhalable analgesic composition comprises a dry powder comprising a peptide that binds to an opiate receptor.

20. The method of claim 19, wherein the diketopiperazine is 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine, or 3,6-bis(N-fumaryl-4-aminobutyl)-2,5-diketopiperazine dosodium salt.

21. The method of claim 19, wherein the peptide comprises:

(D)Phe-(D)Phe-(D)Ile-(D)Arg-NH₂ (SEQ ID NO;

     1) or (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂ (SEQ ID NO;

     2).

22. The method of claim 19, wherein the peptide binds to a μ

opioid receptor, a δ

opioid receptor, or a κ

opioid receptor, or combinations of receptors thereof, of cells in the central or peripheral nervous systems.

23. An inhalable analgesic composition comprising 3,6-bis(N-X-4-aminobutyl)-2,5-diketopiperazine wherein X is fumaryl or a pharmaceutically acceptable salt thereof, and a synthetic peptide having the amino acid sequence:

(D)Phe-(D)-Phe-(D)Ile-(D)Arg-NH₂ (SEQ ID NO;

     1) or (D)Phe-(D)Phe-(D)Nle-(D)Arg-NH₂ (SEQ ID NO;

     2).

24. The inhalable analgesic composition of claim 23, further comprising one or more amino acids selected from the group consisting of leucine, isoleucine, glycine and methionine.

25. The inhalable analgesic composition of claim 23, wherein the peptide binds to a κ

opioid receptor on cells in the central or peripheral nervous systems.