Methods and compositions for treating pain

• US 10,258,664 B2
• Filed: 02/22/2017
• Issued: 04/16/2019
• Est. Priority Date: 10/24/2011
• Status: Active Grant

• Current Assignee: Mannkind Corporation, Torrey Pines Institute for Molecular Studies
• Original Assignee: Mannkind Corporation
• Inventors: Leone-Bay, Andrea, Houghten, Richard A., Guarneri, Joseph J., Stowell, Grayson W.
• Primary Examiner(s): Ha, Julie
• Application Number:
  US15/439,813
• Publication Number:
  US 20170209525A1
• Time in Patent Office: 783 Days
• Field of Search: 514 183, 514 11, 514 214, 514 215, 514 216, 514 217, 514 218, 514 219, 530329, 530330
• 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. A method of reducing at least one of respiration depression, gastrointestinal distress, addiction, somnolescence, tolerance, nausea, and constipation in an opioid-dependent patient comprising reducing the opioid dosage amount while administering to the patient a composition comprising 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, and wherein the peptide is an opioid receptor agonist, and further wherein the peptide comprises at least one of;

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

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

     2), Trp-(D)Pro-Ser-Phe-NH₂ (SEQ ID NO;

     3), Trp-(D)Ser-Ser-Phe-NH₂ (SEQ ID NO;

     4);

Dmt-D-Arg-Phe-Lys-NH₂ (SEQ ID NO;

     5), Ac-His-(D)Phe-Arg-(D)Trp-Gly-NH₂ (SEQ ID NO;

     6), and Ac-Nle-Gln-His-(D)Phe-Arg-(D)Trp-Gly-NH₂ (SEQ ID NO;

7).

2. The method of claim 1, wherein the composition is for pulmonary administration.

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

4. The method of claim 3, wherein the composition comprises a dry powder for inhalation and comprises microparticles having a volumetric mean geometric diameter less than 8 .mu.m in diameter.

5. The method of claim 4, wherein the diketopiperazine is an N-substituted-3,6-aminoalkyl-2,5-diketopiperazine.

6. The method of claim 5, 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.

7. The method of claim 6, 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.

8. The method of claim 7, further comprising one or more pharmaceutical carrier or excipients selected from amino acids, sugars and surfactants.

9. The method of claim 8, wherein the sugars comprise at least one of mannitol, lactose, trehalose and raffinose.

10. The method of claim 9 wherein the peptide comprises SEQ ID NO:

1.

11. The method of claim 9 wherein the peptide comprises SEQ ID NO:

2.

12. The method of claim 9 wherein the peptide comprises SEQ ID NO:

3.