Method of drug formulation

• US 10,143,655 B2
• Filed: 08/10/2016
• Issued: 12/04/2018
• Est. Priority Date: 09/14/2005
• Status: Active Grant

• Current Assignee: Mannkind Corporation
• Original Assignee: Mannkind Corporation
• Inventors: Hokenson, Mark, Oberg, Keith A.
• Primary Examiner(s): Ha, Julie
• Application Number:
  US15/233,794
• Publication Number:
  US 20160346212A1
• Time in Patent Office: 846 Days
• Field of Search: 514 113, 514 118, 514 59, 514 97, 424491
• CPC Class Codes: A61K 38/13 Cyclosporins
• CPC Class Codes: A61K 38/22 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35
• CPC Class Codes: A61K 38/25 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/28 Insulins
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 9/0073 Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/1676 having a drug-free core with discrete complete coating layer containing drug adsorbates of liquid drug formulations on inert powders without simultaneous granulation step A61K9/141; with further drug-free outer coating A61K9/5078; drug conjugated to non-active particles A61K47/6921
• CPC Class Codes: A61K 9/5052 Proteins, e.g. albumin
• CPC Class Codes: A61K 9/5089 Processes
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/04 : Immunostimulants
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Abstract

Methods are provided for promoting the adsorption of an active agent to microparticles by modifying the structural properties of the active agent in order to facilitate favorable association to the microparticle.

Claims

1. A method for making a microparticle coated with an active agent, the method comprising:

i. combining (a) a microparticle comprising crystalline fumaryl diketopiperazine, (b) an active agent, and (c) a solvent for said active agent thereby forming a suspension of said microparticles with said active agent;

ii. adding an active agent modifier to said suspension wherein adding said active agent modifier causes adsorption of said active agent onto said microparticle.

2. The method of claim 1, wherein said active agent modifier is a salt, surfactant, ion, osmolyte, alcohol, chaotrope, kosmotrope, acid, base, or anti-solvent.

3. The method of claim 1 further comprising removing said solvent subsequent to said adsorption of the active agent.

4. The method of claim 2, wherein said anti-solvent is an aqueous solvent.

5. The method of claim 4 wherein said anti-solvent is an organic solvent.

6. The method of claim 2, wherein said anti-solvent is an organic solvent.

7. The method of claim 6 wherein said anti-solvent is water.

8. The method of claim 2, wherein said salt is sodium chloride.

9. The method of claim 2, wherein said osmolyte is hexylene-glycol, trehalose, glycine, polyethylene glycol, trimethylamine N-oxide, mannitol, or proline.

10. The method of claim 2, wherein said alcohol is methanol, ethanol, trifluoroethanol, or hexafluoroisopropanol.

11. The method of claim 2, wherein said chaotrope is NaSCN, (CH₃)₃N—

HCl, Na₂NO₃, NaClO₄, or CsCl.

12. The method of claim 2, wherein said kosmotrope is sodium citrate or sodium sulfate.

13. The method of claim 1, wherein at least 70% of said active agent becomes adsorbed to said microparticle.

14. The method of claim 1, wherein at least 80% of said active agent becomes adsorbed to said microparticle.

15. The method of claim 1, wherein at least 90% of said active agent becomes adsorbed to said microparticle.

16. The method of claim 1, wherein all of said active agent becomes adsorbed to said microparticle.

17. The method of claim 1, wherein said microparticle is coated with a monolayer of said active agent.

18. The method of claim 1, wherein adding said active agent modifier favorably modulates one or more energetic interactions with said microparticle.

19. The method of claim 18, wherein said one or more energetically favorable interactions between said active agent and said microparticle comprises a hydrophobic interaction.

20. The method of claim 18, wherein said one or more energetically favorable interactions between said active agent and said microparticle comprises a hydrogen bonding interaction.

21. The method of claim 18, wherein said one or more energetically favorable interactions between said active agent and said microparticle comprises an electrostatic interaction.

22. The method of claim 1, wherein adding said active agent modifier modifies the structure, flexibility, rigidity, solubility or stability of said active agent.

23. The method of claim 1, wherein said active agent is a peptide or a protein.

24. The method of claim 1, wherein said active agent is an insulin and an insulin analog.